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Biomedicines, Volume 10, Issue 2 (February 2022) – 318 articles

Cover Story (view full-size image): While patients with an early or locally advanced breast cancer can be cured, the metastatic disease remains a challenge and so far, palliative treatment is the only option. Metastasis formation is a critical step in breast cancer development. It involves activation of miscellaneous processes, including activation of angiogenesis, vasculogenesis, chemotaxis or coagulation. These are essential for subsequent events occurring during systemic cancer spread, including the escaping of tumor cells from the primary tumor, migration through the basement membrane, extracellular matrix and vascular walls into the circulation, and extravasation and homing to the target organs, finally resulting in growth of secondary tumors. Understanding the pathogenesis of breast cancer metastasis formation is crucial for development of new treatment strategies. View this paper
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12 pages, 5675 KiB  
Article
Ribose and Non-Ribose A2A Adenosine Receptor Agonists: Do They Share the Same Receptor Recognition Mechanism?
by Giovanni Bolcato, Matteo Pavan, Davide Bassani, Mattia Sturlese and Stefano Moro
Biomedicines 2022, 10(2), 515; https://doi.org/10.3390/biomedicines10020515 - 21 Feb 2022
Cited by 11 | Viewed by 2543
Abstract
Adenosine receptors have been a promising class of targets for the development of new therapies for several diseases. In recent years, a renewed interest in this field has risen, thanks to the implementation of a novel class of agonists that lack the ribose [...] Read more.
Adenosine receptors have been a promising class of targets for the development of new therapies for several diseases. In recent years, a renewed interest in this field has risen, thanks to the implementation of a novel class of agonists that lack the ribose moiety, once considered essential for the agonistic profile. Recently, an X-ray crystal structure of the A2A adenosine receptor has been solved, providing insights about the receptor activation from this novel class of agonists. Starting from this structural information, we have performed supervised molecular dynamics (SuMD) simulations to investigate the binding pathway of a non-nucleoside adenosine receptor agonist as well as one of three classic agonists. Furthermore, we analyzed the possible role of water molecules in receptor activation. Full article
(This article belongs to the Section Drug Discovery, Development and Delivery)
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25 pages, 2808 KiB  
Review
Parthenolide and Its Soluble Analogues: Multitasking Compounds with Antitumor Properties
by Daniela Carlisi, Marianna Lauricella, Antonella D’Anneo, Anna De Blasio, Adriana Celesia, Giovanni Pratelli, Antonietta Notaro, Giuseppe Calvaruso, Michela Giuliano and Sonia Emanuele
Biomedicines 2022, 10(2), 514; https://doi.org/10.3390/biomedicines10020514 - 21 Feb 2022
Cited by 18 | Viewed by 3458
Abstract
Due to its chemical properties and multiple molecular effects on different tumor cell types, the sesquiterpene lactone parthenolide (PN) can be considered an effective drug with significant potential in cancer therapy. PN has been shown to induce either classic apoptosis or alternative caspase-independent [...] Read more.
Due to its chemical properties and multiple molecular effects on different tumor cell types, the sesquiterpene lactone parthenolide (PN) can be considered an effective drug with significant potential in cancer therapy. PN has been shown to induce either classic apoptosis or alternative caspase-independent forms of cell death in many tumor models. The therapeutical potential of PN has been increased by chemical design and synthesis of more soluble analogues including dimethylaminoparthenolide (DMAPT). This review focuses on the molecular mechanisms of both PN and analogues action in tumor models, highlighting their effects on gene expression, signal transduction and execution of different types of cell death. Recent findings indicate that these compounds not only inhibit prosurvival transcriptional factors such as NF-κB and STATs but can also determine the activation of specific death pathways, increasing intracellular reactive oxygen species (ROS) production and modifications of Bcl-2 family members. An intriguing property of these compounds is its specific targeting of cancer stem cells. The unusual actions of PN and its analogues make these agents good candidates for molecular targeted cancer therapy. Full article
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31 pages, 4417 KiB  
Article
Single Application of Low-Dose, Hydroxyapatite-Bound BMP-2 or GDF-5 Induces Long-Term Bone Formation and Biomechanical Stabilization of a Bone Defect in a Senile Sheep Lumbar Osteopenia Model
by Ines Hasenbein, André Sachse, Peter Hortschansky, Klaus D. Schmuck, Victoria Horbert, Christoph Anders, Thomas Lehmann, René Huber, Alexander Maslaris, Frank Layher, Christina Braun, Andreas Roth, Frank Plöger and Raimund W. Kinne
Biomedicines 2022, 10(2), 513; https://doi.org/10.3390/biomedicines10020513 - 21 Feb 2022
Cited by 7 | Viewed by 2600
Abstract
Effects of hydroxyapatite (HA) particles with bone morphogenetic BMP-2 or GDF-5 were compared in sheep lumbar osteopenia; in vitro release in phosphate-buffered saline (PBS) or sheep serum was assessed by ELISA. Lumbar (L) vertebral bone defects (Ø 3.5 mm) were generated in aged, [...] Read more.
Effects of hydroxyapatite (HA) particles with bone morphogenetic BMP-2 or GDF-5 were compared in sheep lumbar osteopenia; in vitro release in phosphate-buffered saline (PBS) or sheep serum was assessed by ELISA. Lumbar (L) vertebral bone defects (Ø 3.5 mm) were generated in aged, osteopenic female sheep (n = 72; 9.00 ± 0.11 years; mean ± SEM). Treatment was: (a) HA particles (2.5 mg; L5); or (b) particles coated with BMP-2 (1 µg; 10 µg) or GDF-5 (5 µg; 50 µg; L4; all groups n = 6). Untouched vertebrae (L3) served as controls. Three and nine months post-therapy, bone formation was assessed by osteodensitometry, histomorphometry, and biomechanical testing. Cumulative 14-day BMP release was high in serum (76–100%), but max. 1.4% in PBS. In vivo induction of bone formation by HA particles with either growth factor was shown by: (i) significantly increased bone volume, trabecular and cortical thickness (overall increase HA + BMP vs. control close to the injection channel 71%, 110%, and 37%, respectively); (ii) partial significant effects for bone mineral density, bone formation, and compressive strength (increase 17%; 9 months; GDF-5). Treatment effects were not dose-dependent. Combined HA and BMPs (single low-dose) highly augment long-term bone formation and biomechanical stabilization in sheep lumbar osteopenia. Thus, carrier-bound BMP doses 20,000-fold to 1000-fold lower than previously applied appear suitable for spinal fusion/bone regeneration and improved treatment safety. Full article
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11 pages, 689 KiB  
Article
Comparative Study of the Aftereffect of CO2 Inhalation or Tiletamine–Zolazepam–Xylazine Anesthesia on Laboratory Outbred Rats and Mice
by Oksana N. Khokhlova, Natalya A. Borozdina, Elena S. Sadovnikova, Irina A. Pakhomova, Pavel A. Rudenko, Yuliya V. Korolkova, Sergey A. Kozlov and Igor A. Dyachenko
Biomedicines 2022, 10(2), 512; https://doi.org/10.3390/biomedicines10020512 - 21 Feb 2022
Cited by 5 | Viewed by 2074
Abstract
CO2 inhalation is currently the most common method of euthanasia for laboratory rats and mice, and it is often used for further terminal blood sampling for clinical biochemical assays. Lately, this method has been criticized due to animal welfare issues associated with [...] Read more.
CO2 inhalation is currently the most common method of euthanasia for laboratory rats and mice, and it is often used for further terminal blood sampling for clinical biochemical assays. Lately, this method has been criticized due to animal welfare issues associated with some processes that develop after CO2 inhalation. The stress reaction and the value of the clinical laboratory parameters significantly depend on the used anesthetics, method, and the site of blood sampling. Especially in small rodents, an acute terminal state followed by a cascade of metabolic reactions that can affect the studied biochemical profile may develop and cause unnecessary suffering of animals. The aim of this study was to compare the stability of biochemical parameters of outbred Sprague Dawley rats and CD-1 mice serum collected after CO2 inhalation or the intramuscular injection of tiletamine–zolazepam–xylazine (TZX). The serum content of total protein and albumin, cholesterol, triglycerides, aspartate aminotransferase (AST), alanine aminotr ansferase (ALT), alkaline phosphatase (ALP), total bilirubin, and creatinine was decreased by the injection of TZX in comparison with CO2 inhalation. In addition, the levels of calcium, phosphates, chlorides and potassium were lowered by TZX vs. CO2 administration, while the level of sodium increased. Finally, the level of the majority of serum clinical biochemical parameters in rats and mice tend to be overestimated after CO2 inhalation, which may lead to masking the possible effect of anti-inflammatory drugs in animal tests. Injection anesthesia for small rodents with TZX is a more feasible method for terminal blood sampling, which also reduces the suffering of animals. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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14 pages, 3273 KiB  
Article
Preventive Effects of a Human Hematopoietic Mesenchymal Stem Cell (hHMSC) Therapy in Ovalbumin-Induced Food Allergy
by Dong-Geon Lee, Yu-Jin Lee, Song-Hee Park, Hye-Ree Park, Hoon Kang and Jung-Eun Kim
Biomedicines 2022, 10(2), 511; https://doi.org/10.3390/biomedicines10020511 - 21 Feb 2022
Cited by 1 | Viewed by 2166
Abstract
No effective therapeutic strategies have been developed against food allergies. Immunomodulation during early infant period could prevent the development of food allergies. We investigated the preventive effects of human hematopoietic mesenchymal stem cells (hHMSCs) in mice with ovalbumin (OVA)-induced food allergy. BALB/c mice [...] Read more.
No effective therapeutic strategies have been developed against food allergies. Immunomodulation during early infant period could prevent the development of food allergies. We investigated the preventive effects of human hematopoietic mesenchymal stem cells (hHMSCs) in mice with ovalbumin (OVA)-induced food allergy. BALB/c mice with OVA-induced food allergy were divided into 3 groups, and each group was treated with hHMSCs or hHMSC culture medium (hHMSC-CM) or saline. Ear thickness, allergy score, rectal temperature, and diarrhea occurrence were checked. Total IgE, OVA-specific IgE, and mucosal mast cell protease-1 (mMCP-1) were measured by ELISA. Other allergic parameters were analyzed using histology specimens, RT-PCR, and flow cytometry. Treatment with hHMSCs or hHMSC-CM significantly suppressed the frequency of anaphylactic response and rectal temperature decline, reduced diarrhea, total IgE, OVA-specific IgE, and mMCP-1. While the treatment decreased the level of Th2 cytokines, it enhanced IL-10 and TGF-β1 mRNA. Exposure to hHMSC or hHMSC-CM did not generate regulatory T cells, but reduced mast cells. The immunomodulatory effect on the Th2 cytokines was greater in hHMSC-CM than in hHMSCs. hHMSC treatment may be a promising preventive intervention against food allergy. Further studies are needed to elucidate the key substances released from hHMSC to induce immune tolerance. Full article
(This article belongs to the Special Issue New Insights in Gene and Cell Therapy)
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16 pages, 802 KiB  
Review
Cigarette Smoking and Human Gut Microbiota in Healthy Adults: A Systematic Review
by Martina Antinozzi, Monica Giffi, Nicolò Sini, Francesca Gallè, Federica Valeriani, Corrado De Vito, Giorgio Liguori, Vincenzo Romano Spica and Maria Sofia Cattaruzza
Biomedicines 2022, 10(2), 510; https://doi.org/10.3390/biomedicines10020510 - 21 Feb 2022
Cited by 25 | Viewed by 3782
Abstract
The intestinal microbiota is a crucial regulator of human health and disease because of its interactions with the immune system. Tobacco smoke also influences the human ecosystem with implications for disease development. This systematic review aims to analyze the available evidence, until June [...] Read more.
The intestinal microbiota is a crucial regulator of human health and disease because of its interactions with the immune system. Tobacco smoke also influences the human ecosystem with implications for disease development. This systematic review aims to analyze the available evidence, until June 2021, on the relationship between traditional and/or electronic cigarette smoking and intestinal microbiota in healthy human adults. Of the 2645 articles published in PubMed, Scopus, and Web of Science, 13 were included in the review. Despite differences in design, quality, and participants’ characteristics, most of the studies reported a reduction in bacterial species diversity, and decreased variability indices in smokers’ fecal samples. At the phylum or genus level, the results are very mixed on bacterial abundance both in smokers and non-smokers with two exceptions. Prevotella spp. appears significantly increased in smokers and former smokers but not in electronic cigarette users, while Proteobacteria showed a progressive increase in Desulfovibrio with the number of pack-years of cigarette (p = 0.001) and an increase in Alphaproteobacteria (p = 0.04) in current versus never smokers. This attempt to systematically characterize the effects of tobacco smoking on the composition of gut microbiota gives new perspectives on future research in smoking cessation and on a new possible use of probiotics to contrast smoke-related dysbiosis. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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16 pages, 1627 KiB  
Article
Age and Intrinsic Fitness Affect the Female Rotator Cuff Tendon Tissue
by Manuela Thierbach, Estelle Heyne, Michael Schwarzer, Lauren G. Koch, Steven L. Britton and Britt Wildemann
Biomedicines 2022, 10(2), 509; https://doi.org/10.3390/biomedicines10020509 - 21 Feb 2022
Cited by 2 | Viewed by 1864
Abstract
The risk of the development of tendon disorders or ruptures increases with age, but it is unclear whether intrinsic fitness during lifetime might also affect tendon properties. To investigate this, a contrasting rat model of high-capacity runners (HCR with high intrinsic fitness) and [...] Read more.
The risk of the development of tendon disorders or ruptures increases with age, but it is unclear whether intrinsic fitness during lifetime might also affect tendon properties. To investigate this, a contrasting rat model of high-capacity runners (HCR with high intrinsic fitness) and low-capacity runners (LCR with low intrinsic fitness) was employed. Histological and molecular changes in rotator cuff (RC) tendons from 10 weeks old (young; HCR-10 and LCR-10) and 100 weeks old (old; HCR-100 and LCR-100) female rats were investigated. Age-dependent changes of RC tendons observed in HCR and LCR were increase of weight, decrease of tenocytes and RNA content, reduction of the wavy pattern of collagen and elastic fibers, repressed expression of Col1a1, Eln, Postn, Tnmd, Tgfb3 and Egr1 and reduction of the Col1:Col3 and Col1:Eln ratio. The LCR rats showed less physical activity, increased body weight, signs of metabolic disease and a reduced life expectancy. Their RC tendons revealed increased weight (more than age-dependent) and enlargement of the tenocyte nuclei (consistent with degenerative tendons). Low intrinsic fitness led to repressed expression of a further nine genes (Col3a1, Fbn1, Dcn, Tnc, Scx, Mkx, Bmp1, Tgfb1, Esr1) as well as the rise of the Col1:Col3 and Col1:Eln ratios (related to the lesser expression of Col3a1 and Eln). The intrinsic fitness influences the female RC tendons at least as much as age. Lower intrinsic fitness accelerates aging of RC tendons and leads to further impairment; this could result in decreased healing potential and elasticity and increased stiffness. Full article
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13 pages, 781 KiB  
Article
Familial Predisposition to Leiomyomata: Searching for Protective Genetic Factors
by Maria V. Kuznetsova, Nelly S. Sogoyan, Andrew J. Donnikov, Dmitry Y. Trofimov, Leila V. Adamyan, Natalia D. Mishina, Jekaterina Shubina, Dmitry V. Zelensky and Gennady T. Sukhikh
Biomedicines 2022, 10(2), 508; https://doi.org/10.3390/biomedicines10020508 - 21 Feb 2022
Cited by 4 | Viewed by 1694
Abstract
In order to determine genetic loci associated with decreasing risk of uterine leiomyomata (UL), a genome-wide association study (GWAS) was performed. We analyzed a group of patients with a family history of UL and a control group consisting of patients without uterine fibroids [...] Read more.
In order to determine genetic loci associated with decreasing risk of uterine leiomyomata (UL), a genome-wide association study (GWAS) was performed. We analyzed a group of patients with a family history of UL and a control group consisting of patients without uterine fibroids and a family predisposition to this pathology. Six significant single nucleotide polymorphisms were selected for PCR-genotyping of a large data set of patients with UL. All investigated loci (rs3020434, rs11742635, rs124577644, rs12637801, rs2861221, and rs17677069) demonstrated the lower frequency of minor alleles within a group of women with UL, especially in a subgroup consisting of patients with UL and a familial history of leiomyomata. We also found that the minor allele frequencies of these SNPs in our control group were higher than those across the Caucasian population in all. Based on the obtained data, an evaluation of the common risk of UL was performed. Further work will pave the way to create a specific SNP-panel and allow us to estimate a genotype-based leiomyoma incidence risk. Subsequent studies of genetic variability in a group of patients with a familial predisposition to UL will allow us to make the prediction of the development and course of the disease more individualized, as well as to give our patients personalized recommendations about individual reproductive strategies. Full article
(This article belongs to the Special Issue Feature Papers in Molecular and Translation Medicine)
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26 pages, 1585 KiB  
Review
Oxidative Stress, Inflammation and Connexin Hemichannels in Muscular Dystrophies
by Arlek González-Jamett, Walter Vásquez, Gabriela Cifuentes-Riveros, Rafaela Martínez-Pando, Juan C. Sáez and Ana M. Cárdenas
Biomedicines 2022, 10(2), 507; https://doi.org/10.3390/biomedicines10020507 - 21 Feb 2022
Cited by 5 | Viewed by 3345
Abstract
Muscular dystrophies (MDs) are a heterogeneous group of congenital neuromuscular disorders whose clinical signs include myalgia, skeletal muscle weakness, hypotonia, and atrophy that leads to progressive muscle disability and loss of ambulation. MDs can also affect cardiac and respiratory muscles, impairing life-expectancy. MDs [...] Read more.
Muscular dystrophies (MDs) are a heterogeneous group of congenital neuromuscular disorders whose clinical signs include myalgia, skeletal muscle weakness, hypotonia, and atrophy that leads to progressive muscle disability and loss of ambulation. MDs can also affect cardiac and respiratory muscles, impairing life-expectancy. MDs in clude Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy. These and other MDs are caused by mutations in genes that encode proteins responsible for the structure and function of skeletal muscles, such as components of the dystrophin-glycoprotein-complex that connect the sarcomeric-actin with the extracellular matrix, allowing contractile force transmission and providing stability during muscle contraction. Consequently, in dystrophic conditions in which such proteins are affected, muscle integrity is disrupted, leading to local inflammatory responses, oxidative stress, Ca2+-dyshomeostasis and muscle degeneration. In this scenario, dysregulation of connexin hemichannels seem to be an early disruptor of the homeostasis that further plays a relevant role in these processes. The interaction between all these elements constitutes a positive feedback loop that contributes to the worsening of the diseases. Thus, we discuss here the interplay between inflammation, oxidative stress and connexin hemichannels in the progression of MDs and their potential as therapeutic targets. Full article
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26 pages, 1181 KiB  
Review
Is Tissue Still the Issue? The Promise of Liquid Biopsy in Uveal Melanoma
by Daniël P. de Bruyn, Aaron B. Beasley, Robert M. Verdijk, Natasha M. van Poppelen, Dion Paridaens, Ronald O. B. de Keizer, Nicole C. Naus, Elin S. Gray, Annelies de Klein, Erwin Brosens and Emine Kiliç
Biomedicines 2022, 10(2), 506; https://doi.org/10.3390/biomedicines10020506 - 21 Feb 2022
Cited by 10 | Viewed by 3100
Abstract
Uveal melanoma (UM) is the second most frequent type of melanoma. Therapeutic options for UM favor minimally invasive techniques such as irradiation for vision preservation. As a consequence, no tumor material is obtained. Without available tissue, molecular analyses for gene expression, mutation or [...] Read more.
Uveal melanoma (UM) is the second most frequent type of melanoma. Therapeutic options for UM favor minimally invasive techniques such as irradiation for vision preservation. As a consequence, no tumor material is obtained. Without available tissue, molecular analyses for gene expression, mutation or copy number analysis cannot be performed. Thus, proper patient stratification is impossible and patients’ uncertainty about their prognosis rises. Minimally invasive techniques have been studied for prognostication in UM. Blood-based biomarker analysis has become more common in recent years; however, no clinically standardized protocol exists. This review summarizes insights in biomarker analysis, addressing new insights in circulating tumor cells, circulating tumor DNA, extracellular vesicles, proteomics, and metabolomics. Additionally, medical imaging can play a significant role in staging, surveillance, and prognostication of UM and is addressed in this review. We propose that combining multiple minimally invasive modalities using tumor biomarkers should be the way forward and warrant more attention in the coming years. Full article
(This article belongs to the Topic Cancer Biology and Therapy)
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18 pages, 11668 KiB  
Article
IGF-1 as a Potential Therapy for Spinocerebellar Ataxia Type 3
by Yong-Shiou Lin, Wen-Ling Cheng, Jui-Chih Chang, Ta-Tsung Lin, Yi-Chun Chao and Chin-San Liu
Biomedicines 2022, 10(2), 505; https://doi.org/10.3390/biomedicines10020505 - 21 Feb 2022
Cited by 8 | Viewed by 2818
Abstract
Although the effects of growth hormone (GH) therapy on spinocerebellar ataxia type 3 (SCA3) have been examined in transgenic SCA3 mice, it still poses a nonnegligible risk of cancer when used for a long term. This study investigated the efficacy of IGF-1, a [...] Read more.
Although the effects of growth hormone (GH) therapy on spinocerebellar ataxia type 3 (SCA3) have been examined in transgenic SCA3 mice, it still poses a nonnegligible risk of cancer when used for a long term. This study investigated the efficacy of IGF-1, a downstream mediator of GH, in vivo for SCA3 treatment. IGF-1 (50 mg/kg) or saline, once a week, was intraperitoneally injected to SCA3 84Q transgenic mice harboring a human ATXN3 gene with a pathogenic expanded 84 cytosine–adenine–guanine (CAG) repeat motif at 9 months of age. Compared with the control mice harboring a 15 CAG repeat motif, the SCA3 84Q mice treated with IGF-1 for 9 months exhibited the improvement only in locomotor function and minimized degeneration of the cerebellar cortex as indicated by the survival of more Purkinje cells with a more favorable mitochondrial function along with a decrease in oxidative stress caused by DNA damage. These findings could be attributable to the inhibition of mitochondrial fission, resulting in mitochondrial fusion, and decreased immunofluorescence staining in aggresome formation and ataxin-3 mutant protein levels, possibly through the enhancement of autophagy. The findings of this study show the therapeutic potential effect of IGF-1 injection for SCA3 to prevent the exacerbation of disease progress. Full article
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17 pages, 742 KiB  
Review
Emerging Evidence and Treatment Perspectives from Randomized Clinical Trials in Systemic Sclerosis: Focus on Interstitial Lung Disease
by Caterina Oriana Aragona, Antonio Giovanni Versace, Carmelo Ioppolo, Daniela La Rosa, Rita Lauro, Maria Concetta Tringali, Simona Tomeo, Guido Ferlazzo, William Neal Roberts, Alessandra Bitto, Natasha Irrera and Gianluca Bagnato
Biomedicines 2022, 10(2), 504; https://doi.org/10.3390/biomedicines10020504 - 21 Feb 2022
Cited by 2 | Viewed by 3148
Abstract
Systemic sclerosis (SSc) is a complex rare autoimmune disease with heterogeneous clinical manifestations. Currently, interstitial lung disease (ILD) and cardiac involvement (including pulmonary arterial hypertension) are recognized as the leading causes of SSc-associated mortality. New molecular targets have been discovered and phase II [...] Read more.
Systemic sclerosis (SSc) is a complex rare autoimmune disease with heterogeneous clinical manifestations. Currently, interstitial lung disease (ILD) and cardiac involvement (including pulmonary arterial hypertension) are recognized as the leading causes of SSc-associated mortality. New molecular targets have been discovered and phase II and phase III clinical trials published in the last 5 years on SSc-ILD will be discussed in this review. Details on the study design; the drug tested and its dose; the inclusion and exclusion criteria of the study; the concomitant immunosuppression; the outcomes and the duration of the study were reviewed. The two most common drugs used for the treatment of SSc-ILD are cyclophosphamide and mycophenolate mofetil, both supported by randomized controlled trials. Additional drugs, such as nintedanib and tocilizumab, have been approved to slow pulmonary function decline in SSc-ILD. In this review, we discuss the therapeutic alternatives for SSc management, offering the option to customize the design of future studies to stratify SSc patients and provide a patient-specific treatment according to the new emerging pathogenic features of SSc-ILD. Full article
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15 pages, 3173 KiB  
Article
Cytoprotective Effect of Idebenone through Modulation of the Intrinsic Mitochondrial Pathway of Apoptosis in Human Retinal Pigment Epithelial Cells Exposed to Oxidative Stress Induced by Hydrogen Peroxide
by Maria Elisabetta Clementi, Michela Pizzoferrato, Giada Bianchetti, Anna Brancato, Beatrice Sampaolese, Giuseppe Maulucci and Giuseppe Tringali
Biomedicines 2022, 10(2), 503; https://doi.org/10.3390/biomedicines10020503 - 21 Feb 2022
Cited by 21 | Viewed by 3683
Abstract
Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is believed to restore mitochondrial ATP synthesis. As such, idebenone is investigated in numerous clinical trials for diseases of mitochondrial aetiology and it is authorized as a drug for the treatment of [...] Read more.
Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is believed to restore mitochondrial ATP synthesis. As such, idebenone is investigated in numerous clinical trials for diseases of mitochondrial aetiology and it is authorized as a drug for the treatment of Leber’s hereditary optic neuropathy. Mitochondria of retinal pigment epithelium (RPE) are particularly vulnerable to oxidative damage associated with cellular senescence. Therefore, the aim of this study was to explore idebenone’s cytoprotective effect and its underlying mechanism. We used a human-RPE cell line (ARPE-19) exposed to idebenone pre-treatment for 24 h followed by conditions inducing H2O2 oxidative damage for a further 24 h. We found that idebenone: (a) ameliorated H2O2-lowered cell viability in the RPE culture; (b) activated Nrf2 signaling pathway by promoting Nrf2 nuclear translocation; (c) increased Bcl-2 protein levels, leaving unmodified those of Bax, thereby reducing the Bax/Bcl-2 ratio; (d) maintained the mitochondrial membrane potential (ΔΨm) at physiological levels, preserving the functionality of mitochondrial respiratory complexes and counteracting the excessive production of ROS; and (e) reduced mitochondrial cytochrome C-mediated caspase-3 activity. Taken together, our findings show that idebenone protects RPE from oxidative damage by modulating the intrinsic mitochondrial pathway of apoptosis, suggesting its possible role in retinal epitheliopathies associated with mitochondrial dysfunction. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)
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16 pages, 1419 KiB  
Review
Drugs Modulating Renin-Angiotensin System in COVID-19 Treatment
by Jose L. Labandeira-Garcia, Carmen M. Labandeira, Rita Valenzuela, Maria A. Pedrosa, Aloia Quijano and Ana I. Rodriguez-Perez
Biomedicines 2022, 10(2), 502; https://doi.org/10.3390/biomedicines10020502 - 21 Feb 2022
Cited by 11 | Viewed by 4992
Abstract
A massive worldwide vaccination campaign constitutes the main tool against the COVID-19 pandemic. However, drug treatments are also necessary. Antivirals are the most frequently considered treatments. However, strategies targeting mechanisms involved in disease aggravation may also be effective. A major role of the [...] Read more.
A massive worldwide vaccination campaign constitutes the main tool against the COVID-19 pandemic. However, drug treatments are also necessary. Antivirals are the most frequently considered treatments. However, strategies targeting mechanisms involved in disease aggravation may also be effective. A major role of the tissue renin-angiotensin system (RAS) in the pathophysiology and severity of COVID-19 has been suggested. The main link between RAS and COVID-19 is angiotensin-converting enzyme 2 (ACE2), a central RAS component and the primary binding site for SARS-CoV-2 that facilitates the virus entry into host cells. An initial suggestion that the susceptibility to infection and disease severity may be enhanced by angiotensin type-1 receptor blockers (ARBs) and ACE inhibitors (ACEIs) because they increase ACE2 levels, led to the consideration of discontinuing treatments in thousands of patients. More recent experimental and clinical data indicate that ACEIs and, particularly, ARBs can be beneficial for COVID-19 outcome, both by reducing inflammatory responses and by triggering mechanisms (such as ADAM17 inhibition) counteracting viral entry. Strategies directly activating RAS anti-inflammatory components such as soluble ACE2, Angiotensin 1-7 analogues, and Mas or AT2 receptor agonists may also be beneficial. However, while ACEIs and ARBs are cheap and widely used, the second type of strategies are currently under study. Full article
(This article belongs to the Special Issue Non-antiviral Agents for Treatment of COVID-19)
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15 pages, 3595 KiB  
Article
Identification of Altered Evoked and Non-Evoked Responses in a Heterologous Mouse Model of Endometriosis-Associated Pain
by Miguel A. Tejada, Ana I. Santos-Llamas, Lesley Escriva, Juan J. Tarin, Antonio Cano, Maria J. Fernández-Ramírez, Paulina Nunez-Badinez, Bianca De Leo, Philippa T. K. Saunders, Victor Vidal, Florent Barthas, Katy Vincent, Patrick J. Sweeney, Rowland R. Sillito, James Douglas Armstrong, Jens Nagel and Raúl Gomez
Biomedicines 2022, 10(2), 501; https://doi.org/10.3390/biomedicines10020501 - 21 Feb 2022
Cited by 5 | Viewed by 2783
Abstract
The aim of this study was to develop and refine a heterologous mouse model of endometriosis-associated pain in which non-evoked responses, more relevant to the patient experience, were evaluated. Immunodeficient female mice (N = 24) were each implanted with four endometriotic human lesions [...] Read more.
The aim of this study was to develop and refine a heterologous mouse model of endometriosis-associated pain in which non-evoked responses, more relevant to the patient experience, were evaluated. Immunodeficient female mice (N = 24) were each implanted with four endometriotic human lesions (N = 12) or control tissue fat (N = 12) on the abdominal wall using tissue glue. Evoked pain responses were measured biweekly using von Frey filaments. Non-evoked responses were recorded weekly for 8 weeks using a home cage analysis (HCA). Endpoints were distance traveled, social proximity, time spent in the center vs. outer areas of the cage, drinking, and climbing. Significant differences between groups for von Frey response, climbing, and drinking were detected on days 14, 21, and 35 post implanting surgery, respectively, and sustained for the duration of the experiment. In conclusion, a heterologous mouse model of endometriosis-associated evoked a non-evoked pain was developed to improve the relevance of preclinical models to patient experience as a platform for drug testing. Full article
(This article belongs to the Special Issue Advanced Research in Endometriosis 2.0)
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15 pages, 711 KiB  
Review
Gastrointestinal Microbiome and Neurologic Injury
by Eric J. Panther, William Dodd, Alec Clark and Brandon Lucke-Wold
Biomedicines 2022, 10(2), 500; https://doi.org/10.3390/biomedicines10020500 - 21 Feb 2022
Cited by 25 | Viewed by 4228
Abstract
Communication between the enteric nervous system (ENS) of the gastrointestinal (GI) tract and the central nervous system (CNS) is vital for maintaining systemic homeostasis. Intrinsic and extrinsic neurological inputs of the gut regulate blood flow, peristalsis, hormone release, and immunological function. The health [...] Read more.
Communication between the enteric nervous system (ENS) of the gastrointestinal (GI) tract and the central nervous system (CNS) is vital for maintaining systemic homeostasis. Intrinsic and extrinsic neurological inputs of the gut regulate blood flow, peristalsis, hormone release, and immunological function. The health of the gut microbiome plays a vital role in regulating the overall function and well-being of the individual. Microbes release short-chain fatty acids (SCFAs) that regulate G-protein-coupled receptors to mediate hormone release, neurotransmitter release (i.e., serotonin, dopamine, noradrenaline, γ-aminobutyric acid (GABA), acetylcholine, and histamine), and regulate inflammation and mood. Further gaseous factors (i.e., nitric oxide) are important in regulating inflammation and have a response in injury. Neurologic injuries such as ischemic stroke, spinal cord injury, traumatic brain injury, and hemorrhagic cerebrovascular lesions can all lead to gut dysbiosis. Additionally, unfavorable alterations in the composition of the microbiota may be associated with increased risk for these neurologic injuries due to increased proinflammatory molecules and clotting factors. Interventions such as probiotics, fecal microbiota transplantation, and oral SCFAs have been shown to stabilize and improve the composition of the microbiome. However, the effect this has on neurologic injury prevention and recovery has not been studied extensively. The purpose of this review is to elaborate on the complex relationship between the nervous system and the microbiome and to report how neurologic injury modulates the status of the microbiome. Finally, we will propose various interventions that may be beneficial in the recovery from neurologic injury. Full article
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9 pages, 538 KiB  
Editorial
Chronic Obstructive Pulmonary Disease: The Present and Future
by Aditya Krishnan and Alice M. Turner
Biomedicines 2022, 10(2), 499; https://doi.org/10.3390/biomedicines10020499 - 20 Feb 2022
Cited by 5 | Viewed by 2289
Abstract
Chronic obstructive pulmonary disease (COPD) is a highly prevalent condition associated with smoking and is predicted to become a leading cause of death in the current decade [...] Full article
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22 pages, 1961 KiB  
Review
Orchestrated Cytokines Mediated by Biologics in Psoriasis and Its Mechanisms of Action
by Aina Akmal Mohd Noor, Maryam Azlan and Norhanani Mohd Redzwan
Biomedicines 2022, 10(2), 498; https://doi.org/10.3390/biomedicines10020498 - 20 Feb 2022
Cited by 15 | Viewed by 10174
Abstract
Psoriasis is an autoimmune disease mediated by disturbed T cells and other immune cells, and is defined by deep-red, well-demarcated skin lesions. Due to its varied etiologies and indefinite standard pathogenesis, it is challenging to consider the right treatment exclusively for each psoriasis [...] Read more.
Psoriasis is an autoimmune disease mediated by disturbed T cells and other immune cells, and is defined by deep-red, well-demarcated skin lesions. Due to its varied etiologies and indefinite standard pathogenesis, it is challenging to consider the right treatment exclusively for each psoriasis patient; thus, researchers yearn to seek even more precise treatments other than topical treatment and systemic therapy. Using biologics to target specific immune components, such as upregulated cytokines secreted by activated immune cells, is the most advanced therapy for psoriasis to date. By inhibiting the appropriate pro-inflammatory cytokines, cellular signaling can be altered and, thus, can inhibit further downstream inflammatory pathways. Herein, the roles of cytokines with their mechanisms of action in progressing psoriasis and how the usage of biologics alleviates cellular inflammation are discussed. In addition, other potential pro-inflammatory cytokines, with their mechanism of action, are presented herein. The authors hope that this gathered information may benefit future research in expanding the discovery of targeted psoriasis therapy. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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14 pages, 447 KiB  
Review
Concept of the Number Needed to Treat for the Analysis of Pain Relief Outcomes in Patients Treated with Spinal Cord Stimulation
by Ashley Bailey-Classen, Amar Parikh, Nima Adimi, Deborah Edgar, Alice Yan, Anand Rotte and David Caraway
Biomedicines 2022, 10(2), 497; https://doi.org/10.3390/biomedicines10020497 - 20 Feb 2022
Cited by 3 | Viewed by 2060
Abstract
In the rapidly evolving field of spinal cord stimulation (SCS), measures of treatment effects are needed to help understand the benefits of new therapies. The present article elaborates the number needed to treat (NNT) concept and applies it to the SCS field. We [...] Read more.
In the rapidly evolving field of spinal cord stimulation (SCS), measures of treatment effects are needed to help understand the benefits of new therapies. The present article elaborates the number needed to treat (NNT) concept and applies it to the SCS field. We reviewed the basic theory of the NNT, its calculation method, and its application to historical controlled trials of SCS. We searched the literature for controlled studies with ≥20 implanted SCS patients with chronic axial back and/or leg pain followed for ≥3 months and a reported responder rate defined as ≥50% pain relief. Relevant data necessary to estimate the NNT were extracted from the included articles. In total, 12 of 1616 records were eligible for inclusion. The records reported 10 clinical studies, including 7 randomized controlled trials, 2 randomized crossover trials, and 1 controlled cohort study. The studies investigated traditional SCS and more recently developed SCS modalities, including 10 kHz SCS. In conclusion, the NNT estimate may help SCS stakeholders better understand the effect size difference between compared treatments; however, interpretation of any NNT should take into account its full context. In addition, comparisons across trials of different therapies should be avoided since they are prone to interpretation biases. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms 2.0)
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14 pages, 1665 KiB  
Article
The lncRNAs/miR-30e/CHI3L1 Axis Is Dysregulated in Systemic Sclerosis
by Valentin Dichev, Nikolay Mehterov, Maria Kazakova, Rositsa Karalilova, Anastas Batalov and Victoria Sarafian
Biomedicines 2022, 10(2), 496; https://doi.org/10.3390/biomedicines10020496 - 19 Feb 2022
Cited by 8 | Viewed by 2121
Abstract
Systemic sclerosis (SSc) is an autoimmune disease with completely undefined etiology and treatment difficulties. The expression of both protein coding and non-coding RNAs is dysregulated during disease development. We aimed to examine a possible regulatory axis implemented in the control of chitinase-3 like [...] Read more.
Systemic sclerosis (SSc) is an autoimmune disease with completely undefined etiology and treatment difficulties. The expression of both protein coding and non-coding RNAs is dysregulated during disease development. We aimed to examine a possible regulatory axis implemented in the control of chitinase-3 like protein 1 (CHI3L1) or YKL-40, an inflammation-associated glycoprotein, shown to be elevated in SSc. A panel of seven miRNAs and three lncRNAs potentially involved in the control of CHI3L1 were selected on the basis of in silico analysis. TagMan assay was used to evaluate the expression levels of miRNAs and RT-qPCR for lncRNAs in white blood cells (WBCs) and plasma from SSc patients and healthy controls. Among the eight screened miRNAs, miR-30e-5p (p = 0.04) and miR-30a-5p (p = 0.01) were significantly downregulated in WBCs and plasma of SSc patients, respectively. On the contrary, the expression of the metastasis associated lung adenocarcinoma transcript 1 (MALAT1) (p = 0.044) and the Nuclear enriched abundant transcript 1 (NEAT1) (p = 0.008) in WBCs was upregulated compared to the controls. Increased levels of MALAT1 and NEAT1 could be associated with the downregulation of miR-30e-5p and miR-30a-5p expression in WBCs and plasma. We present novel data on the involvement of a possible regulatory axis lncRNAs/miR-30e/CHI3L1 in SSc and hypothesize that MALAT1 and NEAT1 could act as miR-30e-5p and miR-30a-5p decoys. This may be a reason for the increased serum levels of CHI3L1 in SSc patients. Full article
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18 pages, 1660 KiB  
Article
FCGR2A-HH Gene Variants Encoding the Fc Gamma Receptor for the C-Reactive Protein Are Associated with Enhanced Monocyte CD32 Expression and Cardiovascular Events’ Recurrence after Primary Acute Coronary Syndrome
by Pascale Paul, Christophe Picard, Luc Lyonnet, Noémie Resseguier, Lucas Hubert, Laurent Arnaud, Julie Di Cristofaro, Marc Laine, Franck Paganelli, Françoise Dignat-George, Corinne Frère, Florence Sabatier, Regis Guieu and Laurent Bonello
Biomedicines 2022, 10(2), 495; https://doi.org/10.3390/biomedicines10020495 - 19 Feb 2022
Cited by 3 | Viewed by 1892
Abstract
Fcγ receptors (FcγRs) interact with the C-reactive protein (CRP) and mediate activation of inflammation-related pathogenic mechanisms affecting cardiovascular health. Our study evaluated whether FcγRIIA and FcγRIIIA profiles are associated with the recurrence of adverse cardiovascular events during the first year after a primary [...] Read more.
Fcγ receptors (FcγRs) interact with the C-reactive protein (CRP) and mediate activation of inflammation-related pathogenic mechanisms affecting cardiovascular health. Our study evaluated whether FcγRIIA and FcγRIIIA profiles are associated with the recurrence of adverse cardiovascular events during the first year after a primary acute coronary syndrome (ACS). The primary endpoint was the recurrence of cardiovascular events (RCE), identified as a composite outcome comprising acute heart failure (AHF) and major adverse cardiovascular events (MACE). We obtained blood samples of 145 ACS patients to measure hsCRP circulating levels, to identify FcγRIIA-131RH rs1801274 and FcγRIIIA-158FV rs396991 polymorphisms, to analyze circulating monocytes and NK cell subsets expressing CD16 and CD32, and to detect serum-mediated FCGR2A-HH activation by luciferase reporter assays. The hsCRP, CD32-expression, and Fc-R mediated activation levels were similar in all patients regardless of their MACE risk. In contrast, the hsCRP levels and the proportion of CD14+ circulating monocytes expressing the CD32 receptor for CRP were significantly higher in the patients who developed AHF. The FCGR2A rs1801274 HH genotype was significantly more common in patients who developed RCE and MACE than in RCE-free patients and associated with an enhanced percentage of circulating CD32+CD14+ monocytes. The FCGR2A-HH genotype was identified as an independent predictor of subsequent RCE (OR, 2.7; p = 0.048; CI, 1.01–7.44) by multivariate analysis. These findings bring preliminary evidence that host FCGR2A genetic variants can influence monocyte CD32 receptor expression and may contribute to the fine-tuning of CD32-driven chronic activating signals that affect the risk of developing RCEs following primary ACS events. Full article
(This article belongs to the Section Cell Biology and Pathology)
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12 pages, 1535 KiB  
Article
Obesity Reshapes the Microbial Population Structure along the Gut-Liver-Lung Axis in Mice
by Apostolos Galaris, Dionysios Fanidis, Elli-Anna Stylianaki, Vaggelis Harokopos, Alexandra-Styliani Kalantzi, Panagiotis Moulos, Antigone S. Dimas, Pantelis Hatzis and Vassilis Aidinis
Biomedicines 2022, 10(2), 494; https://doi.org/10.3390/biomedicines10020494 - 19 Feb 2022
Cited by 3 | Viewed by 2231
Abstract
The microbiome is emerging as a major player in tissue homeostasis in health and disease. Gut microbiome dysbiosis correlates with several autoimmune and metabolic diseases, while high-fat diets and ensuing obesity are known to affect the complexity and diversity of the microbiome, thus [...] Read more.
The microbiome is emerging as a major player in tissue homeostasis in health and disease. Gut microbiome dysbiosis correlates with several autoimmune and metabolic diseases, while high-fat diets and ensuing obesity are known to affect the complexity and diversity of the microbiome, thus modulating pathophysiology. Moreover, the existence of a gut-liver microbial axis has been proposed, which may extend to the lung. In this context, we systematically compared the microbiomes of the gut, liver, and lung of mice fed a high-fat diet to those of littermates fed a matched control diet. We carried out deep sequencing of seven hypervariable regions of the 16S rRNA microbial gene to examine microbial diversity in the tissues of interest. Comparison of the local microbiomes indicated that lung tissue has the least diverse microbiome under healthy conditions, while microbial diversity in the healthy liver clustered closer to the gut. Obesity increased microbial complexity in all three tissues, with lung microbial diversity being the most modified. Obesity promoted the expansion of Firmicutes along the gut-liver-lung axis, highlighting staphylococcus as a possible pathologic link between obesity and systemic pathophysiology, especially in the lungs. Full article
(This article belongs to the Special Issue Microbial Ecology in Health and Disease 2.0)
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18 pages, 7442 KiB  
Article
Synthesis and Characterization of Fatty Acid Grafted Chitosan Polymeric Micelles for Improved Gene Delivery of VGF to the Brain through Intranasal Route
by Richard Nii Lante Lamptey, Avinash Gothwal, Riddhi Trivedi, Sanjay Arora and Jagdish Singh
Biomedicines 2022, 10(2), 493; https://doi.org/10.3390/biomedicines10020493 - 19 Feb 2022
Cited by 15 | Viewed by 2682
Abstract
Multifunctional fatty acid grafted polymeric micelles are an effective and promising approach for drug and gene delivery to the brain. An alternative approach to bypass the blood–brain barrier is administration through intranasal route. Multifunctional fatty acid grafted polymeric micelles were prepared and characterized [...] Read more.
Multifunctional fatty acid grafted polymeric micelles are an effective and promising approach for drug and gene delivery to the brain. An alternative approach to bypass the blood–brain barrier is administration through intranasal route. Multifunctional fatty acid grafted polymeric micelles were prepared and characterized for pVGF delivery to the brain. In vitro pVGF expression was analyzed in bEnd.3 cells, primary astrocytes, and neurons. Comparative in-vivo pVGF expression was analyzed to evaluate the effective route of administration between intranasal and intravenous. Biocompatible, multifunctional polymeric micelles were prepared, having an average size of 200 nm, and cationic zeta potential. Modified polymers were found to be hemo- and cyto-compatible. When transfected with the different modified chitosan formulations, significantly (p < 0.05) higher VGF expression was observed in primary astrocytes and neurons using the mannose, Tat peptide, and oleic acid grafted chitosan polymer. Compared to intravenous administration, intranasal administration of pVGF in polyplex formulation led to significantly (p < 0.05) higher pVGF expression. Developed multifunctional polymeric micelles were an effective pVGF delivery platform to the brain. Mannose and Tat ligand tagging improved the pVGF delivery to the brain. Full article
(This article belongs to the Special Issue Lipid-Based Nanocarriers)
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10 pages, 1387 KiB  
Article
LL-37 and Double-Stranded RNA Synergistically Upregulate Bronchial Epithelial TLR3 Involving Enhanced Import of Double-Stranded RNA and Downstream TLR3 Signaling
by Sara Bodahl, Samuel Cerps, Lena Uller and Bengt-Olof Nilsson
Biomedicines 2022, 10(2), 492; https://doi.org/10.3390/biomedicines10020492 - 19 Feb 2022
Cited by 1 | Viewed by 2236
Abstract
The human host defense peptide LL-37 influences double-stranded RNA signaling, but this process is not well understood. Here, we investigate synergistic actions of LL-37 and synthetic double-stranded RNA (poly I:C) on toll-like receptor 3 (TLR3) expression and signaling, and examine underlying mechanisms. In [...] Read more.
The human host defense peptide LL-37 influences double-stranded RNA signaling, but this process is not well understood. Here, we investigate synergistic actions of LL-37 and synthetic double-stranded RNA (poly I:C) on toll-like receptor 3 (TLR3) expression and signaling, and examine underlying mechanisms. In bronchial epithelial BEAS-2B cells, LL-37 potentiated poly I:C-induced TLR3 mRNA and protein expression demonstrated by qPCR and Western blot, respectively. Interestingly, these effects were associated with increased uptake of rhodamine-tagged poly I:C visualized by immunocytochemistry. The LL-37/poly I:C-induced upregulation of TLR3 mRNA expression was prevented by the endosomal acidification inhibitor chloroquine, indicating involvement of downstream TLR3 signaling. The glucocorticoid dexamethasone reduced LL-37/poly I:C-induced TLR3 expression on both mRNA and protein levels, and this effect was associated with increased IκBα protein expression, suggesting that dexamethasone acts via attenuation of NF-κB activity. We conclude that LL-37 potentiates poly I:C-induced upregulation of TLR3 through a mechanism that may involve enhanced import of poly I:C and that LL-37/poly I:C-induced TLR3 expression is associated with downstream TLR3 signaling and sensitive to inhibition of NF-κB activity. Full article
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21 pages, 8506 KiB  
Article
PTML Modeling for Pancreatic Cancer Research: In Silico Design of Simultaneous Multi-Protein and Multi-Cell Inhibitors
by Valeria V. Kleandrova and Alejandro Speck-Planche
Biomedicines 2022, 10(2), 491; https://doi.org/10.3390/biomedicines10020491 - 18 Feb 2022
Cited by 12 | Viewed by 2559
Abstract
Pancreatic cancer (PANC) is a dangerous type of cancer that is a major cause of mortality worldwide and exhibits a remarkably poor prognosis. To date, discovering anti-PANC agents remains a very complex and expensive process. Computational approaches can accelerate the search for anti-PANC [...] Read more.
Pancreatic cancer (PANC) is a dangerous type of cancer that is a major cause of mortality worldwide and exhibits a remarkably poor prognosis. To date, discovering anti-PANC agents remains a very complex and expensive process. Computational approaches can accelerate the search for anti-PANC agents. We report for the first time two models that combined perturbation theory with machine learning via a multilayer perceptron network (PTML-MLP) to perform the virtual design and prediction of molecules that can simultaneously inhibit multiple PANC cell lines and PANC-related proteins, such as caspase-1, tumor necrosis factor-alpha (TNF-alpha), and the insulin-like growth factor 1 receptor (IGF1R). Both PTML-MLP models exhibited accuracies higher than 78%. Using the interpretation from one of the PTML-MLP models as a guideline, we extracted different molecular fragments desirable for the inhibition of the PANC cell lines and the aforementioned PANC-related proteins and then assembled some of those fragments to form three new molecules. The two PTML-MLP models predicted the designed molecules as potentially versatile anti-PANC agents through inhibition of the three PANC-related proteins and multiple PANC cell lines. Conclusions: This work opens new horizons for the application of the PTML modeling methodology to anticancer research. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
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22 pages, 1127 KiB  
Review
The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics
by Sanjana Saravanan, Caitlin J. Lewis, Bhavna Dixit, Matthew S. O’Connor, Alexandra Stolzing and Amutha Boominathan
Biomedicines 2022, 10(2), 490; https://doi.org/10.3390/biomedicines10020490 - 18 Feb 2022
Cited by 4 | Viewed by 4446
Abstract
Mitochondria are intracellular organelles that utilize nutrients to generate energy in the form of ATP by oxidative phosphorylation. Mitochondrial DNA (mtDNA) in humans is a 16,569 base pair double-stranded circular DNA that encodes for 13 vital proteins of the electron transport chain. Our [...] Read more.
Mitochondria are intracellular organelles that utilize nutrients to generate energy in the form of ATP by oxidative phosphorylation. Mitochondrial DNA (mtDNA) in humans is a 16,569 base pair double-stranded circular DNA that encodes for 13 vital proteins of the electron transport chain. Our understanding of the mitochondrial genome’s transcription, translation, and maintenance is still emerging, and human pathologies caused by mtDNA dysfunction are widely observed. Additionally, a correlation between declining mitochondrial DNA quality and copy number with organelle dysfunction in aging is well-documented in the literature. Despite tremendous advancements in nuclear gene-editing technologies and their value in translational avenues, our ability to edit mitochondrial DNA is still limited. In this review, we discuss the current therapeutic landscape in addressing the various pathologies that result from mtDNA mutations. We further evaluate existing gene therapy efforts, particularly allotopic expression and its potential to become an indispensable tool for restoring mitochondrial health in disease and aging. Full article
(This article belongs to the Special Issue Mitochondrial Genetics and Pathologies)
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21 pages, 5501 KiB  
Article
The Inflammatory Pattern of Chronic Limb-Threatening Ischemia in Muscles: The TNF-α Hypothesis
by Diego Caicedo, Clara V. Alvarez, Sihara Perez-Romero and Jesús Devesa
Biomedicines 2022, 10(2), 489; https://doi.org/10.3390/biomedicines10020489 - 18 Feb 2022
Cited by 4 | Viewed by 1957
Abstract
Background: Vascular inflammation plays a crucial role in peripheral arterial disease (PAD), although the role of the mediators involved has not yet been properly defined. The aim of this work is to investigate gene expression and plasma biomarkers in chronic limb-threating ischemia [...] Read more.
Background: Vascular inflammation plays a crucial role in peripheral arterial disease (PAD), although the role of the mediators involved has not yet been properly defined. The aim of this work is to investigate gene expression and plasma biomarkers in chronic limb-threating ischemia (CLTI). Methods: Using patients from the GHAS trial, both blood and ischemic muscle samples were obtained to analyze plasma markers and mRNA expression, respectively. Statistical analysis was performed by using univariate (Spearman, t-Student, and X2) and multivariate (multiple logistic regression) tests. Results: A total of 35 patients were available at baseline (29 for mRNA expression). Baseline characteristics (mean): Age: 71.4 ± 12.4 years (79.4% male); TNF-α: 10.7 ± 4.9 pg/mL; hsCRP:1.6 ± 2.2 mg/dL; and neutrophil-to-lymphocyte ratio (NLR): 3.5 ± 2.8. Plasma TNF-α was found elevated (≥8.1) in 68.6% of patients, while high hsCRP (≥0.5) was found in 60.5%. Diabetic patients with a high level of inflammation showed significantly higher levels of NOX4 expression at baseline (p = 0.0346). Plasma TNF-α had a negative correlation with NOS3 (eNOS) expression (−0.5, p = 0.015) and plasma hsCRP with VEGFA (−0.63, p = 0.005). The expression of NOX4 was parallel to that of plasma TNF-α (0.305, p = 0.037), especially in DM. Cumulative mortality at 12 months was related to NLR ≥ 3 (p = 0.019) and TNF-α ≥ 8.1 (p = 0.048). The best cutoff point for NLR to predict mortality was 3.4. Conclusions: NOX4 and TNF-α are crucial for the development and complications of lower limb ischemia, especially in DM. hsCRP could have a negative influence on angiogenesis too. NLR and TNF-α represent suitable markers of mortality in CLTI. These results are novel because they connect muscle gene expression and plasma information in patients with advanced PAD, deepening the search for new and accurate targets for this condition. Full article
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7 pages, 678 KiB  
Communication
A Comparison of Pharyngeal Swabs and Tracheal Secretions for the Diagnosing of COVID-19
by Maibritt Meldgaard Arildsen, Sif Bay Glenting, Anette Marianne Fedder, Bettina Jørgensen, Svend Ellermann-Eriksen, Marianne Kragh Thomsen, Christina Catherine Dahm and Michael Pedersen
Biomedicines 2022, 10(2), 488; https://doi.org/10.3390/biomedicines10020488 - 18 Feb 2022
Cited by 1 | Viewed by 1890
Abstract
The aim of this study was to compare the test results from patients who, within a short timescale, have been tested for COVID-19 using both a pharyngeal swab and tracheal secretion. Data were collected from the database of AUH, from patients hospitalized between [...] Read more.
The aim of this study was to compare the test results from patients who, within a short timescale, have been tested for COVID-19 using both a pharyngeal swab and tracheal secretion. Data were collected from the database of AUH, from patients hospitalized between 1 March 2020 and 1 March 2021 who, due to symptoms of COVID-19, were tested by a pharyngeal swab and by tracheal secretion. We found great agreement between oropharyngeal swab and tracheal secretion RT-PCR testing for the diagnosis of COVID-19, with 98.5% of double tests being concordant and only 1.5% being discordant. This finding may advocate a single-test strategy being either an oropharyngeal swab RT-PCR testing or tracheal secretion, although this study revealed 15.9% false negative oropharyngeal swabs. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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22 pages, 42052 KiB  
Article
Testicular Macrophages Produce Progesterone De Novo Promoted by cAMP and Inhibited by M1 Polarization Inducers
by Sawako Yamauchi, Kousuke Yamamoto and Kazushige Ogawa
Biomedicines 2022, 10(2), 487; https://doi.org/10.3390/biomedicines10020487 - 18 Feb 2022
Cited by 6 | Viewed by 2196
Abstract
Tissue-resident macrophages (Mø) originating from fetal precursors are maintained via self-renewal under tissue-/organ-specific microenvironments. Herein, we developed a propagation method of testicular tissue-resident Mø in mixed primary culture with interstitial cells composed of Leydig cells from the mouse testis. We examined Mø/monocyte marker [...] Read more.
Tissue-resident macrophages (Mø) originating from fetal precursors are maintained via self-renewal under tissue-/organ-specific microenvironments. Herein, we developed a propagation method of testicular tissue-resident Mø in mixed primary culture with interstitial cells composed of Leydig cells from the mouse testis. We examined Mø/monocyte marker expression in propagated testicular Mø using flow cytometry; gene expression involved in testosterone production as well as spermatogenesis in testicular Mø and interstitial cells propagated by mixed culture via RT-PCR; and progesterone (P4) de novo production in propagated testicular Mø treated with cyclic adenosine monophosphate, isoproterenol, and M1 polarization inducers using ELISA. Mø marker expression patterns in the propagated Mø were identical to those in testicular interstitial Mø with a CD206-positive/major histocompatibility complex (MHC) II-negative M2 phenotype. We identified the genes involved in P4 production, transcription factors essential for steroidogenesis, and androgen receptors, and showed that P4 production de novo was upregulated by cyclic adenosine monophosphate and β2-adrenergic stimulation and was downregulated by M1 polarization stimulation in Mø. We also demonstrated the formation of gap junctions between Leydig cells and interstitial Mø. This is the first study to demonstrate de novo P4 production in tissue-resident Mø. Based on previous studies revealing inhibition of testosterone production by P4, we propose that local feedback machinery between Leydig cells and adjacent interstitial Mø regulates testosterone production. The results presented in this study can facilitate future studies on immune-endocrine interactions in gonads that are related to infertility and hormonal disorders. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 3.0)
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31 pages, 49644 KiB  
Review
Functionalized Liposome and Albumin-Based Systems as Carriers for Poorly Water-Soluble Anticancer Drugs: An Updated Review
by Sofia Teixeira, Maria Alice Carvalho and Elisabete M. S. Castanheira
Biomedicines 2022, 10(2), 486; https://doi.org/10.3390/biomedicines10020486 - 18 Feb 2022
Cited by 16 | Viewed by 3335
Abstract
Cancer is one of the leading causes of death worldwide. In the available treatments, chemotherapy is one of the most used, but has several associated problems, namely the high toxicity to normal cells and the resistance acquired by cancer cells to the therapeutic [...] Read more.
Cancer is one of the leading causes of death worldwide. In the available treatments, chemotherapy is one of the most used, but has several associated problems, namely the high toxicity to normal cells and the resistance acquired by cancer cells to the therapeutic agents. The scientific community has been battling against this disease, developing new strategies and new potential chemotherapeutic agents. However, new drugs often exhibit poor solubility in water, which led researchers to develop functionalized nanosystems to carry and, specifically deliver, the drugs to cancer cells, targeting overexpressed receptors, proteins, and organelles. Thus, this review is focused on the recent developments of functionalized nanosystems used to carry poorly water-soluble drugs, with special emphasis on liposomes and albumin-based nanosystems, two major classes of organic nanocarriers with formulations already approved by the U.S. Food and Drug Administration (FDA) for cancer therapeutics. Full article
(This article belongs to the Special Issue Advances in Nanomaterials for Drug Delivery)
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