15 pages, 2880 KiB  
Article
Eggmanone Effectively Overcomes Prostate Cancer Cell Chemoresistance
by Chen Xie 1, Pen-Jen Lin 2 and Jijun Hao 1,2,*
1 College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, USA
2 Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA
Biomedicines 2021, 9(5), 538; https://doi.org/10.3390/biomedicines9050538 - 12 May 2021
Cited by 2 | Viewed by 2765
Abstract
Prostate cancer chemoresistance is a major therapeutic problem, and the underlying mechanism is not well understood and effective therapies to overcome this problem are not available. Phosphodiesterase-4 (PDE4), a main intracellular enzyme for cAMP hydrolysis, has been previously shown to involve in the [...] Read more.
Prostate cancer chemoresistance is a major therapeutic problem, and the underlying mechanism is not well understood and effective therapies to overcome this problem are not available. Phosphodiesterase-4 (PDE4), a main intracellular enzyme for cAMP hydrolysis, has been previously shown to involve in the early chemo-sensitive prostate cancer cell proliferation and progression, but its role in the more-advanced chemo-resistant prostate cancer is completely unknown. Here we found that the expression of PDE4 subtype, PDE4D, is highly elevated in the chemo-resistant prostate cancer cells (DU145-TxR and PC3-TxR) in comparison to the chemo-sensitive prostate cancer cells (DU145 and PC3). Inhibition of PDE4D with a potent and selective PDED4 inhibitor, Eggmanone, effectively decreases the invasion and proliferation as well as induces cell death of the chemo-resistant prostate cancer cells (DU145-TxR and PC3-TxR). These results were confirmed by siRNA knockdown of PDE4D. We and colleagues previously reported that Eggmanone can effectively blocked sonic Hedgehog signaling via PDE4D inhibition, and here our study suggests that that Eggmanone downregulated proliferation of the chemo-resistant prostate cancer cells via sonic Hedgehog signaling. In addition, Eggmanone treatment dose-dependently increases docetaxel cytotoxicity to DU145-TxR and PC3-TxR. As cancer stem cells (CSCs) are known to be implicated in cancer chemoresistance, we further examined Eggmanone impacts on CSC-like properties in the chemo-resistant prostate cancer cells. Our study shows that Eggmanone effectively down-regulates the expression of CSCs’ marker genes Nanog and ABC sub-family G member 2 (ABCG2) and attenuates sphere formation in DU145-TxR and PC3-TxR cells. In summary, our work shows that Eggmanone effectively overcomes the chemoresistance of prostate cancer cells presumably through sonic Hedgehog signaling and targeting CSCs, suggesting that Eggmanone may serve as a novel agent for chemo-resistant prostate cancer. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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11 pages, 1767 KiB  
Article
The Relationship between the Strength Characteristics of Cerebral Aneurysm Walls with Their Status and Laser-Induced Fluorescence Data
by Elena Tsibulskaya 1, Anna Lipovka 2,*, Alexandr Chupakhin 2, Andrey Dubovoy 2,3, Daniil Parshin 2 and Nikolay Maslov 1
1 Khristianovich Institute of Theoretical and Applied Mechanics SB RAS, 630090 Novosibrsk, Russia
2 Lavrentyev Institute of Hydrodynamics SB RAS, 630090 Novosibirsk, Russia
3 Federal Neurosurgical Center, 630048 Novosibirsk, Russia
Biomedicines 2021, 9(5), 537; https://doi.org/10.3390/biomedicines9050537 - 12 May 2021
Cited by 2 | Viewed by 2328
Abstract
Background: Cerebral aneurysms (CA) are a widespread vascular disease affecting 50 per 1000 population. The study of the influence of histological, morphological and hemodynamic factors on the status of the aneurysm has been the subject of many works. However, an accurate and generally [...] Read more.
Background: Cerebral aneurysms (CA) are a widespread vascular disease affecting 50 per 1000 population. The study of the influence of histological, morphological and hemodynamic factors on the status of the aneurysm has been the subject of many works. However, an accurate and generally accepted relationship has not yet been identified. Methods: In our work, the results of mechanical and spectroscopic measurements are considered. Total investigated 14 patients and 36 their samples of CA tissue. Results: The excitation–emission matrix of each specimen was evaluated, after which the strength characteristics of the samples were investigated. Conclusions: It has been shown that there is a statistically significant difference in the size of the peaks of two components, which characterizes the status of the aneurysms. In addition, a linear regression model has been built that describes the correlation of the magnitude of the ultimate strain and stress with the magnitude of the peaks of one of the components. The results of this study will serve as a basis for the non-invasive determination of the strength characteristics of the cerebral tissue aneurysms and determination of their status. Full article
(This article belongs to the Special Issue Optical Nanoparticles for Biomedicine)
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15 pages, 1020 KiB  
Review
Outstanding Contributions of LAL Technology to Pharmaceutical and Medical Science: Review of Methods, Progress, Challenges, and Future Perspectives in Early Detection and Management of Bacterial Infections and Invasive Fungal Diseases
by Hiroshi Tamura 1,2,*, Johannes Reich 3 and Isao Nagaoka 2
1 LPS Consulting Office, Tokyo 160-0023, Japan
2 Department of Host Defense and Biochemical Research, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
3 Microcoat Biotechnologie GmbH, 82347 Bernried, Germany
Biomedicines 2021, 9(5), 536; https://doi.org/10.3390/biomedicines9050536 - 11 May 2021
Cited by 30 | Viewed by 7447
Abstract
The blue blood of the horseshoe crab is a natural, irreplaceable, and precious resource that is highly valued by the biomedical industry. The Limulus amebocyte lysate (LAL) obtained from horseshoe crab blood cells functions as a surprisingly sophisticated sensing system that allows for [...] Read more.
The blue blood of the horseshoe crab is a natural, irreplaceable, and precious resource that is highly valued by the biomedical industry. The Limulus amebocyte lysate (LAL) obtained from horseshoe crab blood cells functions as a surprisingly sophisticated sensing system that allows for the extremely sensitive detection of bacterial and fungal cell-wall components. Notably, LAL tests have markedly contributed to the quality control of pharmaceutical drugs and medical devices as successful alternatives to the rabbit pyrogen test. Furthermore, LAL-based endotoxin and (1→3)-β-D-glucan (β-glucan) assay techniques are expected to have optimal use as effective biomarkers, serving as adjuncts in the diagnosis of bacterial sepsis and fungal infections. The innovative β-glucan assay has substantially contributed to the early diagnosis and management of invasive fungal diseases; however, the clinical significance of the endotoxin assay remains unclear and is challenging to elucidate. Many obstacles need to be overcome to enhance the analytical sensitivity and clinical performance of the LAL assay in detecting circulating levels of endotoxin in human blood. Additionally, there are complex interactions between endotoxin molecules and blood components that are attributable to the unique physicochemical properties of lipopolysaccharide (LPS). In this regard, while exploring the potential of new LPS-sensing technologies, a novel platform for the ultrasensitive detection of blood endotoxin will enable a reappraisal of the LAL assay for the highly sensitive and reliable detection of endotoxemia. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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13 pages, 5594 KiB  
Article
Leukotriene B4 Receptors Are Necessary for the Stimulation of NLRP3 Inflammasome and IL-1β Synthesis in Neutrophil-Dominant Asthmatic Airway Inflammation
by Dong-Wook Kwak 1, Donghwan Park 1 and Jae-Hong Kim 2,*
1 Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea
2 Division of Life Sciences, College of Life Sciences, Korea University, Seoul 02841, Korea
Biomedicines 2021, 9(5), 535; https://doi.org/10.3390/biomedicines9050535 - 11 May 2021
Cited by 10 | Viewed by 3275
Abstract
The stimulation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and IL-1β synthesis are associated with chronic respiratory diseases such as neutrophil-dominant severe asthma. Leukotriene B4 (LTB4) is a principal chemoattractant molecule for neutrophil recruitment, and its [...] Read more.
The stimulation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and IL-1β synthesis are associated with chronic respiratory diseases such as neutrophil-dominant severe asthma. Leukotriene B4 (LTB4) is a principal chemoattractant molecule for neutrophil recruitment, and its receptors BLT1 and BLT2 have been suggested to contribute to neutrophil-dominant asthmatic airway inflammation. However, the relationship between BLT1/2 and NLRP3 in neutrophil-dominant asthmatic airway inflammation has not been previously studied. In the present study, we investigated whether BLT1/2 play any roles in stimulating the NLRP3 inflammasome and IL-1βsynthesis. The blockade of BLT1 or BLT2 clearly suppressed the stimulation of the NLRP3 inflammasome and IL-1β synthesis in house dust mite (HDM)/lipopolysaccharide (LPS)-induced neutrophilic airway inflammation. The enzymes 5-lipoxygenase and 12-lipoxygenase, which catalyze the synthesis of BLT1/2 ligands [LTB4, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), and 12-hydroxyheptadecatreinoic acid (12-HHT)], were also critically associated with the stimulation of NLRP3 and IL-1β synthesis. Together, our results suggest that the 5-/12-LOX-BLT1/2-linked cascade are necessary for the simulation of the NLRP3 inflammasome and IL-1β synthesis, thus contributing to HDM/LPS-induced neutrophil-dominant airway inflammation. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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16 pages, 1144 KiB  
Review
Treatment of Rare Mutations in Patients with Lung Cancer
by Tarek Taha 1,†, Rasha Khoury 2,†, Ronen Brenner 3, Haitam Nasrallah 1, Irena Shofaniyeh 4, Samih Yousef 5 and Abed Agbarya 2,5,*
1 Oncology Institute, Technion Faculty of Medicine, Rambam Health Care Campus, 8 HaAliyah HaShniyah Street, 3525408 Haifa, Israel
2 Bnai-Zion Medical Center, Oncology Institute, Technion Faculty of Medicine, 47 Golomb Avenue, 3339419 Haifa, Israel
3 The Edith Wolfson Medical Center, Oncology Institute, 62 Halohamim Street, 5822012 Holon, Israel
4 MyBiotics Institute, 2 Yitzhak Modai Street, 7608804 Rehovot, Israel
5 Oncology Community Unit, Clalit Health Service, 15 Marj Ibn Amar Street, 1603701 Nazareth, Israel
† These authors have contributed equally.
Biomedicines 2021, 9(5), 534; https://doi.org/10.3390/biomedicines9050534 - 11 May 2021
Cited by 11 | Viewed by 5890
Abstract
Lung cancer is a worldwide prevalent malignancy. This disease has a low survival rate due to diagnosis at a late stage challenged by the involvement of metastatic sites. Non-small-cell lung cancer (NSCLC) is presented in 85% of cases. The last decade has experienced [...] Read more.
Lung cancer is a worldwide prevalent malignancy. This disease has a low survival rate due to diagnosis at a late stage challenged by the involvement of metastatic sites. Non-small-cell lung cancer (NSCLC) is presented in 85% of cases. The last decade has experienced substantial advancements in scientific research, leading to a novel targeted therapeutic approach. The newly developed pharmaceutical agents are aimed towards specific mutations, detected in individual patients inflicted by lung cancer. These drugs have longer and improved response rates compared to traditional chemotherapy. Recent studies were able to identify rare mutations found in pulmonary tumors. Among the gene alterations detected were mesenchymal epithelial transition factor (MET), human epidermal growth factor 2 (HER2), B-type Raf kinase (BRAF), c-ROS proto-oncogene (ROS1), rearranged during transfection (RET) and neurotrophic tyrosine kinase (NTRK). Ongoing clinical trials are gaining insight onto possible first and second lines of medical treatment options intended to enable progression-free survival to lung cancer patients. Full article
(This article belongs to the Special Issue Lung Cancer: Tumor Progression and Target Therapy)
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16 pages, 1264 KiB  
Article
Endocan and Circulating Progenitor Cells in Women with Systemic Sclerosis: Association with Inflammation and Pulmonary Hypertension
by Alberto Lo Gullo 1,*, Giuseppe Mandraffino 2,*,†, Javier Rodríguez-Carrio 3,4,5, Michele Scuruchi 6, Davide Sinicropi 2, Maria Postorino 2, Carmela Morace 2, Clemente Giuffrida 1, Davide Sciortino 7, Romina Gallizzi 8,9, Saverio Loddo 10, Concetta Zito 11 and Giovanni Squadrito 2
1 Medicine and Urgency Unit, Piemonte Hospital, IRCCS Neurolesi Bonino Pulejo, 98121 Messina, Italy
2 Internal Medicine Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
3 Area of Immunology, Department of Functional Biology, Faculty of Medicine, University of Oviedo, 33006 Oviedo, Spain
4 Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), 33011 Oviedo, Spain
5 Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN Del ISCIII, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
6 Molecular Biology Lab, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
7 Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
8 Unit of Pediatrics, Department of Human Pathology in Adulthood and Childhood, University of Messina, 98125 Messina, Italy
9 Pediatric Unit, Department of Medical of Health Sciences, Magna Graecia University, 88100 Catanzaro, Italy
10 Laboratory Medicine, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
11 Cardiology Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
† Co-first authors (Equally contributed to the work).
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Biomedicines 2021, 9(5), 533; https://doi.org/10.3390/biomedicines9050533 - 11 May 2021
Cited by 18 | Viewed by 3479
Abstract
Background: Systemic sclerosis (SSc) is characterized by early vasculopathy and fibrosis in the skin, lungs, and other tissues. Vascular manifestations of SSc include Raynaud’s phenomenon, digital ulcers, and pulmonary artery hypertension (PAH). PAH is the second most common cause of mortality in SSc. [...] Read more.
Background: Systemic sclerosis (SSc) is characterized by early vasculopathy and fibrosis in the skin, lungs, and other tissues. Vascular manifestations of SSc include Raynaud’s phenomenon, digital ulcers, and pulmonary artery hypertension (PAH). PAH is the second most common cause of mortality in SSc. Circulating CD34+ cells associated with cardiovascular health status in several conditions, including chronic immune-inflammatory disease. CD34+ cell numbers have been found inconstantly reduced in SSc. Endocan, a proteoglycan expressed by endothelial cells, was recently suggested as a marker of vascular stress. We tested the relationships among CD34+ cells, endocan, inflammatory markers, vitamin D levels, and clinical parameters in SSc patients with PAH. METHODS: Standard echocardiography was performed. Vitamin D levels, CD34+ cells, inflammatory markers, endocan plasma levels were determined in 36 female SSc patients (24 diffuse/12 limited) and 36 matched controls (HC). RESULTS: We found no difference in CD34+ and vitamin D levels in SSc as compared to controls; ESR, CRP, fibrinogen, endocan, sPAP were higher in SSc with respect to controls. We found a correlation between endocan and: CD34+ cells (r: −0.540, p = 0.002), pulmonary arterial pressure (sPAP) (r: 0.565, p < 0.001), tricuspid annular plane excursion (TAPSE) (r: −0.311, p < 0.01), and E/A ratio (r: −0.487, p < 0.001), but not with ejection fraction (r: −0.057, p = 0.785) in SSc. CD34+ cells correlate with fibrinogen (r: −0.619, p < 0.001), sPAP (r: −0.404, p = 0.011), E/A (r: 0.470, p < 0.005 in SSc. CONCLUSION: CD34+ cell number was significantly correlated with endocan levels and with sPAP in SSc; endocan and CD34+ progenitor cells might be suggested as a potential marker of disease status. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)
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8 pages, 633 KiB  
Review
Adipose-Derived Mesenchymal Stem Cells (AD-MSCs) against Ultraviolet (UV) Radiation Effects and the Skin Photoaging
by Pietro Gentile 1,2,* and Simone Garcovich 3
1 Department of Surgical Science, Plastic and Reconstructive Surgery, Medical School, “Tor Vergata” University, 00133 Rome, Italy
2 Scientific Director of Academy of International Regenerative Medicine & Surgery Societies (AIRMESS), 1201 Geneva, Switzerland
3 Institute of Dermatology, F. Policlinico Gemelli IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Biomedicines 2021, 9(5), 532; https://doi.org/10.3390/biomedicines9050532 - 11 May 2021
Cited by 38 | Viewed by 6480
Abstract
The skin is a natural barrier against the ultraviolet (UV) radiation of sunlight. The long-term and/or repetitive exposure to the sunlight and related UV radiation may change the skin structure, decreasing collagen production, promoting premature skin aging, which is termed “photoaging”. The signs [...] Read more.
The skin is a natural barrier against the ultraviolet (UV) radiation of sunlight. The long-term and/or repetitive exposure to the sunlight and related UV radiation may change the skin structure, decreasing collagen production, promoting premature skin aging, which is termed “photoaging”. The signs of photoaging include wrinkle formation, mottled pigmentation, and/or cancerous changes. For many years, adipose-derived mesenchymal stem cells (AD-MSCs) and fat grafting (F-GRF) have been used to combat photoaging signs, wrinkles, loss of elasticity, and face soft tissue defects. Several studies have analyzed in vitro actions of AD-MSCs against photoaging’s effects, thanks to their migratory activity, paracrine actions, and related in vivo–ex vivo outcomes. In fact, AD-MSCs act against skin photoaging in vitro via activation of dermal fibroblast proliferation, antioxidant effect, and matrix metalloproteinases (MMPs) reduction. In vivo and ex vivo outcomes regard the local injection of AD-MSCs, F-GRF, and/or enriched-F-GRF with AD-MSCs directly in the wrinkles and the face’s soft tissue defects. This concise review summarizes the most recent in vitro, in vivo and ex vivo outcomes and developments on the effects of AD-MSCs and F-GRF against photoaging. Full article
(This article belongs to the Special Issue Adipose-Derived Mesenchymal Stem Cells, Cell-Based Therapies, and Biomaterials as New Regenerative Strategies)
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21 pages, 5256 KiB  
Article
Vancomycin-Loaded Collagen/Hydroxyapatite Layers Electrospun on 3D Printed Titanium Implants Prevent Bone Destruction Associated with S. epidermidis Infection and Enhance Osseointegration
by Tomáš Suchý 1,2,3,*, Lucie Vištejnová 3,4, Monika Šupová 1, Pavel Klein 3, Martin Bartoš 3,5,6, Yaroslav Kolinko 3,4, Tereza Blassová 3,4, Zbyněk Tonar 3,4, Marek Pokorný 7, Zbyněk Sucharda 1, Margit Žaloudková 1, František Denk 1,2, Rastislav Ballay 8, Štefan Juhás 9, Jana Juhásová 9, Eva Klapková 10, Lukáš Horný 2,3, Radek Sedláček 2,3, Tomáš Grus 11, Zdeněk Čejka, Jr. 12, Zdeněk Čejka 12, Kateřina Chudějová 3 and Jaroslav Hrabák 3add Show full author list remove Hide full author list
1 Department of Composites and Carbon Materials, Institute of Rock Structure and Mechanics, Czech Academy of Sciences, 18209 Prague 8, Czech Republic
2 Faculty of Mechanical Engineering, Czech Technical University in Prague, 16000 Prague 6, Czech Republic
3 Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 30100 Pilsen, Czech Republic
4 Department of Histology and Embryology, Faculty of Medicine in Pilsen, Charles University, 301 00 Pilsen, Czech Republic
5 Institute of Dental Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12000 Prague 2, Czech Republic
6 Institute of Anatomy, First Faculty of Medicine, Charles University, 12000 Prague 2, Czech Republic
7 R&D Department, Contipro Inc., 56102 Dolni Dobrouc, Czech Republic
8 1st Department of Orthopedics, First Faculty of Medicine, Charles University in Prague and Motol University Hospital, 150 06 Prague 5, Czech Republic
9 PIGMOD Centre, Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, 27721 Libechov, Czech Republic
10 Department of Medical Chemistry and Clinical Biochemistry, Charles University, 2nd Medical School and University Hospital Motol, 15006 Prague 5, Czech Republic
11 2nd Department of Cardiovascular Surgery, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12000 Prague 2, Czech Republic
12 ProSpon Ltd., 27201 Kladno, Czech Republic
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Biomedicines 2021, 9(5), 531; https://doi.org/10.3390/biomedicines9050531 - 10 May 2021
Cited by 25 | Viewed by 4764
Abstract
The aim of the study was to develop an orthopedic implant coating in the form of vancomycin-loaded collagen/hydroxyapatite layers (COLHA+V) that combine the ability to prevent bone infection with the ability to promote enhanced osseointegration. The ability to prevent bone infection was investigated [...] Read more.
The aim of the study was to develop an orthopedic implant coating in the form of vancomycin-loaded collagen/hydroxyapatite layers (COLHA+V) that combine the ability to prevent bone infection with the ability to promote enhanced osseointegration. The ability to prevent bone infection was investigated employing a rat model that simulated the clinically relevant implant-related introduction of bacterial contamination to the bone during a surgical procedure using a clinical isolate of Staphylococcus epidermidis. The ability to enhance osseointegration was investigated employing a model of a minipig with terminated growth. Six weeks following implantation, the infected rat femurs treated with the implants without vancomycin (COLHA+S. epidermidis) exhibited the obvious destruction of cortical bone as evinced via a cortical bone porosity of up to 20% greater than that of the infected rat femurs treated with the implants containing vancomycin (COLHA+V+S. epidermidis) (3%) and the non-infected rat femurs (COLHA+V) (2%). The alteration of the bone structure of the infected COLHA+S. epidermidis group was further demonstrated by a 3% decrease in the average Ca/P molar ratio of the bone mineral. Finally, the determination of the concentration of vancomycin released into the blood stream indicated a negligible systemic load. Six months following implantation in the pigs, the quantified ratio of new bone indicated an improvement in osseointegration, with a two-fold bone ingrowth on the COLHA (47%) and COLHA+V (52%) compared to the control implants without a COLHA layer (27%). Therefore, it can be concluded that COLHA+V layers are able to significantly prevent the destruction of bone structure related to bacterial infection with a minimal systemic load and, simultaneously, enhance the rate of osseointegration. Full article
(This article belongs to the Special Issue Scientific Advances in Fracture Healing and Bone Regeneration: Current Strategies for Enhancing Bone Repair)
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26 pages, 1654 KiB  
Review
Non-Immunotherapy Application of LNP-mRNA: Maximizing Efficacy and Safety
by Irena Vlatkovic
BioNTech SE, 55131 Mainz, Germany
Biomedicines 2021, 9(5), 530; https://doi.org/10.3390/biomedicines9050530 - 10 May 2021
Cited by 80 | Viewed by 22490
Abstract
Lipid nanoparticle (LNP) formulated messenger RNA-based (LNP-mRNA) vaccines came into the spotlight as the first vaccines against SARS-CoV-2 virus to be applied worldwide. Long-known benefits of mRNA-based technologies consisting of relatively simple and fast engineering of mRNA encoding for antigens and proteins of [...] Read more.
Lipid nanoparticle (LNP) formulated messenger RNA-based (LNP-mRNA) vaccines came into the spotlight as the first vaccines against SARS-CoV-2 virus to be applied worldwide. Long-known benefits of mRNA-based technologies consisting of relatively simple and fast engineering of mRNA encoding for antigens and proteins of interest, no genomic integration, and fast and efficient manufacturing process compared with other biologics have been verified, thus establishing a basis for a broad range of applications. The intrinsic immunogenicity of LNP formulated in vitro transcribed (IVT) mRNA is beneficial to the LNP-mRNA vaccines. However, avoiding immune activation is critical for therapeutic applications of LNP-mRNA for protein replacement where targeted mRNA expression and repetitive administration of high doses for a lifetime are required. This review summarizes our current understanding of immune activation induced by mRNA, IVT byproducts, and LNP. It gives a comprehensive overview of the present status of preclinical and clinical studies in which LNP-mRNA is used for protein replacement and treatment of rare diseases with an emphasis on safety. Moreover, the review outlines innovations and strategies to advance pharmacology and safety of LNP-mRNA for non-immunotherapy applications. Full article
(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)
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19 pages, 3398 KiB  
Article
Fatty Acid-Binding Proteins Aggravate Cerebral Ischemia-Reperfusion Injury in Mice
by Qingyun Guo 1, Ichiro Kawahata 1, Tomohide Degawa 1, Yuri Ikeda-Matsuo 2, Meiling Sun 1, Feng Han 3 and Kohji Fukunaga 1,*
1 Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-Ku, Sendai 980-8578, Japan
2 Laboratory of Pharmacology, Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanagawa-Machi, Kanazawa 920-1181, Japan
3 School of Pharmacy, Nanjing Medical School, Nanjing 211166, China
Biomedicines 2021, 9(5), 529; https://doi.org/10.3390/biomedicines9050529 - 10 May 2021
Cited by 20 | Viewed by 4404
Abstract
Fatty acid-binding proteins (FABPs) regulate the intracellular dynamics of fatty acids, mediate lipid metabolism and participate in signaling processes. However, the therapeutic efficacy of targeting FABPs as novel therapeutic targets for cerebral ischemia is not well established. Previously, we synthesized a novel FABP [...] Read more.
Fatty acid-binding proteins (FABPs) regulate the intracellular dynamics of fatty acids, mediate lipid metabolism and participate in signaling processes. However, the therapeutic efficacy of targeting FABPs as novel therapeutic targets for cerebral ischemia is not well established. Previously, we synthesized a novel FABP inhibitor, i.e., FABP ligand 6 [4-(2-(5-(2-chlorophenyl)-1-(4-isopropylphenyl)-1H-pyrazol-3-yl)-4-fluorophenoxy)butanoic acid] (referred to here as MF6). In this study, we analyzed the ability of MF6 to ameliorate transient middle cerebral artery occlusion (tMCAO) and reperfusion-induced injury in mice. A single MF6 administration (3.0 mg/kg, per os) at 0.5 h post-reperfusion effectively reduced brain infarct volumes and neurological deficits. The protein-expression levels of FABP3, FABP5 and FABP7 in the brain gradually increased after tMCAO. Importantly, MF6 significantly suppressed infarct volumes and the elevation of FABP-expression levels at 12 h post-reperfusion. MF6 also inhibited the promotor activity of FABP5 in human neuroblastoma cells (SH-SY5Y). These data suggest that FABPs elevated infarct volumes after ischemic stroke and that inhibiting FABPs ameliorated the ischemic injury. Moreover, MF6 suppressed the inflammation-associated prostaglandin E2 levels through microsomal prostaglandin E synthase-1 expression in the ischemic hemispheres. Taken together, the results imply that the FABP inhibitor MF6 can potentially serve as a neuroprotective therapeutic for ischemic stroke. Full article
(This article belongs to the Special Issue Brain Injury and Neurodegeneration: Molecular, Functional, and Translational Approach)
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11 pages, 1952 KiB  
Article
NRG1 Genetic Variant Influences the Efficacy of Androgen-Deprivation Therapy in Men with Prostate Cancer
by Shu-Pin Huang 1,2,3,4,†, Yei-Tsung Chen 5,†, Lih-Chyang Chen 6, Cheng-Hsueh Lee 1,2, Chao-Yuan Huang 7, Chia-Cheng Yu 8,9,10, Victor C. Lin 11,12, Te-Ling Lu 13 and Bo-Ying Bao 13,14,15,*
1 Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
2 Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
3 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
4 Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
5 Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
6 Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan
7 Department of Urology, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 100, Taiwan
8 Department of Surgery, Division of Urology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
9 Department of Urology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan
10 Department of Pharmacy, College of Pharmacy and Health Care, Tajen University, Pingtung 907, Taiwan
11 Department of Urology, E-Da Hospital, Kaohsiung 824, Taiwan
12 School of Medicine for International Students, I-Shou University, Kaohsiung 840, Taiwan
13 Department of Pharmacy, China Medical University, Taichung 404, Taiwan
14 Sex Hormone Research Center, China Medical University Hospital, Taichung 404, Taiwan
15 Department of Nursing, Asia University, Taichung 413, Taiwan
† These authors contributed equally to this work.
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Biomedicines 2021, 9(5), 528; https://doi.org/10.3390/biomedicines9050528 - 10 May 2021
Cited by 2 | Viewed by 2547
Abstract
Neuregulins (NRGs) activate receptor tyrosine kinases of the ErbB family, and play essential roles in the proliferation, survival, and differentiation of normal and malignant tissue cells. We hypothesized that genetic variants of NRG signalling pathway genes may influence treatment outcomes in prostate cancer. [...] Read more.
Neuregulins (NRGs) activate receptor tyrosine kinases of the ErbB family, and play essential roles in the proliferation, survival, and differentiation of normal and malignant tissue cells. We hypothesized that genetic variants of NRG signalling pathway genes may influence treatment outcomes in prostate cancer. To test this hypothesis, we performed a comprehensive analysis to evaluate the associations of 459 single-nucleotide polymorphisms in 19 NRG pathway genes with cancer-specific survival (CSS), overall survival (OS), and progression-free survival (PFS) in 630 patients with prostate cancer receiving androgen-deprivation therapy (ADT). After multivariate Cox regression and multiple testing correction, we found that NRG1 rs144160282 C > T is significantly associated with worsening CSS, OS, and PFS during ADT. Further analysis showed that low expression of NRG1 is closely related to prostate cancer, as indicated by a high Gleason score, an advanced stage, and a shorter PFS rate. Meta-analysis of 16 gene expression datasets of 1,081 prostate cancer samples and 294 adjacent normal samples indicate lower NRG1 expression in the former compared with the latter (p < 0.001). These results suggest that NRG1 rs144160282 might be a prognostic predictor of the efficacy of ADT. Further studies are required to confirm the significance of NRG1 as a biomarker and therapeutic target for prostate cancer. Full article
(This article belongs to the Special Issue Novel Strategy for Treating Castration-Resistant Prostate Cancer)
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17 pages, 14367 KiB  
Review
Injectable Hydrogels for Chronic Skin Wound Management: A Concise Review
by Mazlan Zawani and Mh Busra Fauzi *
Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, The National University of Malaysia, Kuala Lumpur 56000, Malaysia
Biomedicines 2021, 9(5), 527; https://doi.org/10.3390/biomedicines9050527 - 10 May 2021
Cited by 49 | Viewed by 7184
Abstract
Diabetic foot ulcers (DFU) are a predominant impediment among diabetic patients, increasing morbidity and wound care costs. There are various strategies including using biomaterials have been explored for the management of DFU. This paper will review the injectable hydrogel application as the most [...] Read more.
Diabetic foot ulcers (DFU) are a predominant impediment among diabetic patients, increasing morbidity and wound care costs. There are various strategies including using biomaterials have been explored for the management of DFU. This paper will review the injectable hydrogel application as the most studied polymer-based hydrogel based on published journals and articles. The main key factors that will be discussed in chronic wounds focusing on diabetic ulcers include the socioeconomic burden of chronic wounds, biomaterials implicated by the government for DFU management, commercial hydrogel product, mechanism of injectable hydrogel, the current study of novel injectable hydrogel and the future perspectives of injectable hydrogel for the management of DFU. Full article
(This article belongs to the Special Issue Bio-Inspired Porous Materials and Biomaterials)
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26 pages, 1836 KiB  
Review
Alternative Splicing of Human Telomerase Reverse Transcriptase (hTERT) and Its Implications in Physiological and Pathological Processes
by Anna A. Plyasova and Dmitry D. Zhdanov *
Institute of Biomedical Chemistry, Pogodinskaya st 10/8, 119121 Moscow, Russia
Biomedicines 2021, 9(5), 526; https://doi.org/10.3390/biomedicines9050526 - 9 May 2021
Cited by 17 | Viewed by 5399
Abstract
Alternative splicing (AS) of human telomerase catalytic subunit (hTERT, human telomerase reverse transcriptase) pre-mRNA strongly regulates telomerase activity. Several proteins can regulate AS in a cell type-specific manner and determine the functions of cells. In addition to being involved in telomerase activity regulation, [...] Read more.
Alternative splicing (AS) of human telomerase catalytic subunit (hTERT, human telomerase reverse transcriptase) pre-mRNA strongly regulates telomerase activity. Several proteins can regulate AS in a cell type-specific manner and determine the functions of cells. In addition to being involved in telomerase activity regulation, AS provides cells with different splice variants that may have alternative biological activities. The modulation of telomerase activity through the induction of hTERT AS is involved in the development of different cancer types and embryos, and the differentiation of stem cells. Regulatory T cells may suppress the proliferation of target human and murine T and B lymphocytes and NK cells in a contact-independent manner involving activation of TERT AS. This review focuses on the mechanism of regulation of hTERT pre-mRNA AS and the involvement of splice variants in physiological and pathological processes. Full article
(This article belongs to the Special Issue Telomerase: Role in Health and Aging)
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13 pages, 2751 KiB  
Article
Mutations in the B.1.1.7 SARS-CoV-2 Spike Protein Reduce Receptor-Binding Affinity and Induce a Flexible Link to the Fusion Peptide
by Eileen Socher 1,2,*, Marcus Conrad 3, Lukas Heger 4, Friedrich Paulsen 1,5, Heinrich Sticht 3,6, Friederike Zunke 7 and Philipp Arnold 1,*
1 Institute of Anatomy, Functional and Clinical Anatomy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
2 Institute for Clinical and Molecular Virology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, 91054 Erlangen, Germany
3 Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
4 Laboratory of Dendritic Cell Biology, Department of Dermatology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, 91052 Erlangen, Germany
5 Department of Operative Surgery and Topographic Anatomy, Sechenov University, 119992 Moscow, Russia
6 Erlangen National High Performance Computing Center (NHR@FAU), Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91058 Erlangen, Germany
7 Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, 91054 Erlangen, Germany
Biomedicines 2021, 9(5), 525; https://doi.org/10.3390/biomedicines9050525 - 8 May 2021
Cited by 28 | Viewed by 5747
Abstract
The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. Amino acid exchanges within the SARS-CoV-2 spike protein variant of B.1.1.7 affect inter-monomeric contact sites within the trimer (A570D and [...] Read more.
The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. Amino acid exchanges within the SARS-CoV-2 spike protein variant of B.1.1.7 affect inter-monomeric contact sites within the trimer (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the spike protein. However, the molecular consequences of mutations within B.1.1.7 on spike protein dynamics and stability or ACE2 binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein trimer. Furthermore, we found increased flexibility in direct spatial proximity of the fusion peptide due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7. This study also implies a reduced binding affinity for B.1.1.7 with ACE2, as the N501Y mutation restructures the RBD–ACE2 interface, significantly decreasing the linear interaction energy between the RBD and ACE2. Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD–ACE2 interface. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7. Full article
(This article belongs to the Special Issue Conformational Dynamics of Viral Proteins)
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38 pages, 1358 KiB  
Review
Neuroinflammation in Alzheimer’s Disease
by Isaac G. Onyango 1,*, Gretsen V. Jauregui 1, Mária Čarná 1, James P. Bennett, Jr. 2 and Gorazd B. Stokin 1,3,4,*
1 Centre for Translational Medicine International Clinical Research Centre, St. Anne’s University Hospital, CZ-65691 Brno, Czech Republic
2 Neurodegeneration Therapeutics, 3050A Berkmar Drive, Charlottesville, VA 22901, USA
3 Translational Aging and Neuroscience Program, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
4 Division of Neurology, University Medical Centre, Zaloška cesta 2, 1000 Ljubljana, Slovenia
Biomedicines 2021, 9(5), 524; https://doi.org/10.3390/biomedicines9050524 - 7 May 2021
Cited by 218 | Viewed by 22079
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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