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Biomedicines, Volume 9, Issue 5 (May 2021) – 140 articles

Cover Story (view full-size image): Anthracycline antibiotics—i.e., doxo and daunorubicin—deactivate respiratory chain complexes and disrupt calcium homeostasis, as well as the self-antioxidant defense system, leading to the overproduction of free radicals, plus mPTP formation, which promotes the proapoptotic factor release into cell cytosol and triggers the apoptosis cascade. In addition, they inhibit the glycolytic energy production pathway in tumor cells, thereby exhibiting cytotoxicity.View this paper
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27 pages, 1913 KiB  
Review
Peptide-Based Nanoparticles for Therapeutic Nucleic Acid Delivery
by Prisca Boisguérin, Karidia Konate, Emilie Josse, Eric Vivès and Sébastien Deshayes
Biomedicines 2021, 9(5), 583; https://doi.org/10.3390/biomedicines9050583 - 20 May 2021
Cited by 29 | Viewed by 5967
Abstract
Gene therapy offers the possibility to skip, repair, or silence faulty genes or to stimulate the immune system to fight against disease by delivering therapeutic nucleic acids (NAs) to a patient. Compared to other drugs or protein treatments, NA-based therapies have the advantage [...] Read more.
Gene therapy offers the possibility to skip, repair, or silence faulty genes or to stimulate the immune system to fight against disease by delivering therapeutic nucleic acids (NAs) to a patient. Compared to other drugs or protein treatments, NA-based therapies have the advantage of being a more universal approach to designing therapies because of the versatility of NA design. NAs (siRNA, pDNA, or mRNA) have great potential for therapeutic applications for an immense number of indications. However, the delivery of these exogenous NAs is still challenging and requires a specific delivery system. In this context, beside other non-viral vectors, cell-penetrating peptides (CPPs) gain more and more interest as delivery systems by forming a variety of nanocomplexes depending on the formulation conditions and the properties of the used CPPs/NAs. In this review, we attempt to cover the most important biophysical and biological aspects of non-viral peptide-based nanoparticles (PBNs) for therapeutic nucleic acid formulations as a delivery system. The most relevant peptides or peptide families forming PBNs in the presence of NAs described since 2015 will be presented. All these PBNs able to deliver NAs in vitro and in vivo have common features, which are characterized by defined formulation conditions in order to obtain PBNs from 60 nm to 150 nm with a homogeneous dispersity (PdI lower than 0.3) and a positive charge between +10 mV and +40 mV. Full article
(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)
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12 pages, 2673 KiB  
Article
Multi-Omic Meta-Analysis of Transcriptomes and the Bibliome Uncovers Novel Hypoxia-Inducible Genes
by Yoko Ono and Hidemasa Bono
Biomedicines 2021, 9(5), 582; https://doi.org/10.3390/biomedicines9050582 - 20 May 2021
Cited by 10 | Viewed by 7881
Abstract
Hypoxia is a condition in which cells, tissues, or organisms are deprived of sufficient oxygen supply. Aerobic organisms have a hypoxic response system, represented by hypoxia-inducible factor 1-α (HIF1A), to adapt to this condition. Due to publication bias, there has been little focus [...] Read more.
Hypoxia is a condition in which cells, tissues, or organisms are deprived of sufficient oxygen supply. Aerobic organisms have a hypoxic response system, represented by hypoxia-inducible factor 1-α (HIF1A), to adapt to this condition. Due to publication bias, there has been little focus on genes other than well-known signature hypoxia-inducible genes. Therefore, in this study, we performed a meta-analysis to identify novel hypoxia-inducible genes. We searched publicly available transcriptome databases to obtain hypoxia-related experimental data, retrieved the metadata, and manually curated it. We selected the genes that are differentially expressed by hypoxic stimulation, and evaluated their relevance in hypoxia by performing enrichment analyses. Next, we performed a bibliometric analysis using gene2pubmed data to examine genes that have not been well studied in relation to hypoxia. Gene2pubmed data provides information about the relationship between genes and publications. We calculated and evaluated the number of reports and similarity coefficients of each gene to HIF1A, which is a representative gene in hypoxia studies. In this data-driven study, we report that several genes that were not known to be associated with hypoxia, including the G protein-coupled receptor 146 gene, are upregulated by hypoxic stimulation. Full article
(This article belongs to the Special Issue Hypoxia-Inducible Factors: Regulation and Therapeutic Potential)
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16 pages, 6213 KiB  
Article
The Insulin Receptor: A Potential Target of Amarogentin Isolated from Gentiana rigescens Franch That Induces Neurogenesis in PC12 Cells
by Lihong Cheng, Hiroyuki Osada, Tianyan Xing, Minoru Yoshida, Lan Xiang and Jianhua Qi
Biomedicines 2021, 9(5), 581; https://doi.org/10.3390/biomedicines9050581 - 20 May 2021
Cited by 7 | Viewed by 2822
Abstract
Amarogentin (AMA) is a secoiridoid glycoside isolated from the traditional Chinese medicine, Gentiana rigescens Franch. AMA exhibits nerve growth factor (NGF)-mimicking and NGF-enhancing activities in PC12 cells and in primary cortical neuron cells. In this study, a possible mechanism was found showing the [...] Read more.
Amarogentin (AMA) is a secoiridoid glycoside isolated from the traditional Chinese medicine, Gentiana rigescens Franch. AMA exhibits nerve growth factor (NGF)-mimicking and NGF-enhancing activities in PC12 cells and in primary cortical neuron cells. In this study, a possible mechanism was found showing the remarkable induction of phosphorylation of the insulin receptor (INSR) and protein kinase B (AKT). The potential target of AMA was predicted by using a small-interfering RNA (siRNA) and the cellular thermal shift assay (CETSA). The AMA-induced neurite outgrowth was reduced by the siRNA against the INSR and the results of the CETSA suggested that the INSR showed a significant thermal stability-shifted effect upon AMA treatment. Other neurotrophic signaling pathways in PC12 cells were investigated using specific inhibitors, Western blotting and PC12(rasN17) and PC12(mtGAP) mutants. The inhibitors of the glucocorticoid receptor (GR), phospholipase C (PLC) and protein kinase C (PKC), Ras, Raf and mitogen-activated protein kinase (MEK) significantly reduced the neurite outgrowth induced by AMA in PC12 cells. Furthermore, the phosphorylation reactions of GR, PLC, PKC and an extracellular signal-regulated kinase (ERK) were significantly increased after inducing AMA and markedly decreased after treatment with the corresponding inhibitors. Collectively, these results suggested that AMA-induced neuritogenic activity in PC12 cells potentially depended on targeting the INSR and activating the downstream Ras/Raf/ERK and PI3K/AKT signaling pathways. In addition, the GR/PLC/PKC signaling pathway was found to be involved in the neurogenesis effect of AMA. Full article
(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)
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10 pages, 3007 KiB  
Article
Surface-Enhanced Raman Spectroscopy to Characterize Different Fractions of Extracellular Vesicles from Control and Prostate Cancer Patients
by Eric Boateng Osei, Liliia Paniushkina, Konrad Wilhelm, Jürgen Popp, Irina Nazarenko and Christoph Krafft
Biomedicines 2021, 9(5), 580; https://doi.org/10.3390/biomedicines9050580 - 20 May 2021
Cited by 7 | Viewed by 2599
Abstract
Extracellular vesicles (EVs) are membrane-enclosed structures ranging in size from about 60 to 800 nm that are released by the cells into the extracellular space; they have attracted interest as easily available biomarkers for cancer diagnostics. In this study, EVs from plasma of [...] Read more.
Extracellular vesicles (EVs) are membrane-enclosed structures ranging in size from about 60 to 800 nm that are released by the cells into the extracellular space; they have attracted interest as easily available biomarkers for cancer diagnostics. In this study, EVs from plasma of control and prostate cancer patients were fractionated by differential centrifugation at 5000× g, 12,000× g and 120,000× g. The remaining supernatants were purified by ultrafiltration to produce EV-depleted free-circulating (fc) fractions. Spontaneous Raman and surface-enhanced Raman spectroscopy (SERS) at 785 nm excitation using silver nanoparticles (AgNPs) were employed as label-free techniques to collect fingerprint spectra and identify the fractions that best discriminate between control and cancer patients. SERS spectra from 10 µL droplets showed an enhanced Raman signature of EV-enriched fractions that were much more intense for cancer patients than controls. The Raman spectra of dehydrated pellets of EV-enriched fractions without AgNPs were dominated by spectral contributions of proteins and showed variations in S-S stretch, tryptophan and protein secondary structure bands between control and cancer fractions. We conclude that the AgNPs-mediated SERS effect strongly enhances Raman bands in EV-enriched fractions, and the fractions, EV12 and EV120 provide the best separation of cancer and control patients by Raman and SERS spectra. Full article
(This article belongs to the Section Biomedical Materials and Nanomedicine)
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40 pages, 2433 KiB  
Review
Identifying Novel Actionable Targets in Colon Cancer
by Maria Grazia Cerrito and Emanuela Grassilli
Biomedicines 2021, 9(5), 579; https://doi.org/10.3390/biomedicines9050579 - 20 May 2021
Cited by 10 | Viewed by 6677
Abstract
Colorectal cancer is the fourth cause of death from cancer worldwide, mainly due to the high incidence of drug-resistance toward classic chemotherapeutic and newly targeted drugs. In the last decade or so, the development of novel high-throughput approaches, both genome-wide and chemical, allowed [...] Read more.
Colorectal cancer is the fourth cause of death from cancer worldwide, mainly due to the high incidence of drug-resistance toward classic chemotherapeutic and newly targeted drugs. In the last decade or so, the development of novel high-throughput approaches, both genome-wide and chemical, allowed the identification of novel actionable targets and the development of the relative specific inhibitors to be used either to re-sensitize drug-resistant tumors (in combination with chemotherapy) or to be synthetic lethal for tumors with specific oncogenic mutations. Finally, high-throughput screening using FDA-approved libraries of “known” drugs uncovered new therapeutic applications of drugs (used alone or in combination) that have been in the clinic for decades for treating non-cancerous diseases (re-positioning or re-purposing approach). Thus, several novel actionable targets have been identified and some of them are already being tested in clinical trials, indicating that high-throughput approaches, especially those involving drug re-positioning, may lead in a near future to significant improvement of the therapy for colon cancer patients, especially in the context of a personalized approach, i.e., in defined subgroups of patients whose tumors carry certain mutations. Full article
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17 pages, 2538 KiB  
Article
5-Aminolevulinic Acid as a Novel Therapeutic for Inflammatory Bowel Disease
by Vipul Yadav, Yang Mai, Laura E. McCoubrey, Yasufumi Wada, Motoyasu Tomioka, Satofumi Kawata, Shrikant Charde and Abdul W. Basit
Biomedicines 2021, 9(5), 578; https://doi.org/10.3390/biomedicines9050578 - 20 May 2021
Cited by 10 | Viewed by 3979
Abstract
5-Aminolevulinic acid (5-ALA) is a naturally occurring nonprotein amino acid licensed as an optical imaging agent for the treatment of gliomas. In recent years, 5-ALA has been shown to possess anti-inflammatory and immunoregulatory properties through upregulation of heme oxygenase-1 via enhancement of porphyrin, [...] Read more.
5-Aminolevulinic acid (5-ALA) is a naturally occurring nonprotein amino acid licensed as an optical imaging agent for the treatment of gliomas. In recent years, 5-ALA has been shown to possess anti-inflammatory and immunoregulatory properties through upregulation of heme oxygenase-1 via enhancement of porphyrin, indicating that it may be beneficial for the treatment of inflammatory conditions. This study systematically examines 5-ALA for use in inflammatory bowel disease (IBD). Firstly, the ex vivo colonic stability and permeability of 5-ALA was assessed using human and mouse fluid and tissue. Secondly, the in vivo efficacy of 5-ALA, in the presence of sodium ferrous citrate, was investigated via the oral and intracolonic route in an acute DSS colitis mouse model of IBD. Results showed that 5-ALA was stable in mouse and human colon fluid, as well as in colon tissue. 5-ALA showed more tissue restricted pharmacokinetics when exposed to human colonic tissue. In vivo dosing demonstrated significantly improved colonic inflammation, increased local heme oxygenase-1 levels, and decreased concentrations of proinflammatory cytokines TNF-α, IL-6, and IL-1β in both plasma and colonic tissue. These effects were superior to that measured concurrently with established anti-inflammatory treatments, ciclosporin and 5-aminosalicylic acid (mesalazine). As such, 5-ALA represents a promising addition to the IBD armamentarium, with potential for targeted colonic delivery. Full article
(This article belongs to the Section Drug Discovery and Development)
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4 pages, 156 KiB  
Editorial
The Genius of the Zebrafish Model: Insights on Development and Disease
by James A. Marrs and Swapnalee Sarmah
Biomedicines 2021, 9(5), 577; https://doi.org/10.3390/biomedicines9050577 - 20 May 2021
Cited by 3 | Viewed by 2100
Abstract
The zebrafish is an outstanding and inexpensive vertebrate model system for biomedical research [...] Full article
(This article belongs to the Special Issue Zebrafish Models for Development and Disease 2.0)
19 pages, 1941 KiB  
Review
Systemic Actions of SGLT2 Inhibition on Chronic mTOR Activation as a Shared Pathogenic Mechanism between Alzheimer’s Disease and Diabetes
by Gabriela Dumitrita Stanciu, Razvan Nicolae Rusu, Veronica Bild, Leontina Elena Filipiuc, Bogdan-Ionel Tamba and Daniela Carmen Ababei
Biomedicines 2021, 9(5), 576; https://doi.org/10.3390/biomedicines9050576 - 19 May 2021
Cited by 19 | Viewed by 3557
Abstract
Alzheimer’s disease (AD) affects tens of millions of people worldwide. Despite the advances in understanding the disease, there is an increased urgency for pharmacological approaches able of impacting its onset and progression. With a multifactorial nature, high incidence and prevalence in later years [...] Read more.
Alzheimer’s disease (AD) affects tens of millions of people worldwide. Despite the advances in understanding the disease, there is an increased urgency for pharmacological approaches able of impacting its onset and progression. With a multifactorial nature, high incidence and prevalence in later years of life, there is growing evidence highlighting a relationship between metabolic dysfunction related to diabetes and subject’s susceptibility to develop AD. The link seems so solid that sometimes AD and type 3 diabetes are used interchangeably. A candidate for a shared pathogenic mechanism linking these conditions is chronically-activated mechanistic target of rapamycin (mTOR). Chronic activation of unrestrained mTOR could be responsible for sustaining metabolic dysfunction that causes the breakdown of the blood-brain barrier, tau hyperphosphorylation and senile plaques formation in AD. It has been suggested that inhibition of sodium glucose cotransporter 2 (SGLT2) mediated by constant glucose loss, may restore mTOR cycle via nutrient-driven, preventing or even decreasing the AD progression. Currently, there is an unmet need for further research insight into molecular mechanisms that drive the onset and AD advancement as well as an increase in efforts to expand the testing of potential therapeutic strategies aimed to counteract disease progression in order to structure effective therapies. Full article
(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease)
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22 pages, 11949 KiB  
Article
Hypoxia Engineered Bone Marrow Mesenchymal Stem Cells Targeting System with Tumor Microenvironment Regulation for Enhanced Chemotherapy of Breast Cancer
by Jingzhi Zu, Liwei Tan, Li Yang, Qi Wang, Jing Qin, Jing Peng, Hezhong Jiang, Rui Tan and Jian Gu
Biomedicines 2021, 9(5), 575; https://doi.org/10.3390/biomedicines9050575 - 19 May 2021
Cited by 5 | Viewed by 2544
Abstract
Improving the tumor targeting of docetaxel (DTX) would not only be favored for the chemotherapeutic efficacy, but also reduce its side effects. However, the regulation of the tumor microenvironment could further inhibit the growth of tumors. In this study, we introduced a system [...] Read more.
Improving the tumor targeting of docetaxel (DTX) would not only be favored for the chemotherapeutic efficacy, but also reduce its side effects. However, the regulation of the tumor microenvironment could further inhibit the growth of tumors. In this study, we introduced a system consisting of hypoxia-engineered bone marrow mesenchymal stem cells (H-bMSCs) and DTX micelles (DTX-M) for breast cancer treatment. First, the stem cell chemotherapy complex system (DTX@H-bMSCs) with tumor-targeting ability was constructed according to the uptake of DTX-M by hypoxia-induced bMSCs (H-bMSCs). DTX micellization improved the uptake efficiency of DTX by H-bMSCs, which equipped DTX@H-bMSCs with satisfactory drug loading and stability. Furthermore, the migration of DTX@H-bMSCs revealed that it could effectively target the tumor site and facilitate the drug transport between cells. Moreover, in vitro and in vivo pharmacodynamics of DTX@H-bMSCs exhibited a superior antitumor effect, which could promote the apoptosis of 4T1 cells and upregulate the expression of inflammatory factors at the tumor site. In brief, DTX@H-bMSCs enhanced the chemotherapeutic effect in breast cancer treatment. Full article
(This article belongs to the Section Gene and Cell Therapy)
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20 pages, 4726 KiB  
Article
Deciphering the Molecular Mechanism of Water Interaction with Gelatin Methacryloyl Hydrogels: Role of Ionic Strength, pH, Drug Loading and Hydrogel Network Characteristics
by Margaux Vigata, Christoph Meinert, Nathalie Bock, Bronwin L. Dargaville and Dietmar W. Hutmacher
Biomedicines 2021, 9(5), 574; https://doi.org/10.3390/biomedicines9050574 - 19 May 2021
Cited by 24 | Viewed by 4593
Abstract
Water plays a primary role in the functionality of biomedical polymers such as hydrogels. The state of water, defined as bound, intermediate, or free, and its molecular organization within hydrogels is an important factor governing biocompatibility and hemocompatibility. Here, we present a systematic [...] Read more.
Water plays a primary role in the functionality of biomedical polymers such as hydrogels. The state of water, defined as bound, intermediate, or free, and its molecular organization within hydrogels is an important factor governing biocompatibility and hemocompatibility. Here, we present a systematic study of water states in gelatin methacryloyl (GelMA) hydrogels designed for drug delivery and tissue engineering applications. We demonstrate that increasing ionic strength of the swelling media correlated with the proportion of non-freezable bound water. We attribute this to the capability of ions to create ion–dipole bonds with both the polymer and water, thereby reinforcing the first layer of polymer hydration. Both pH and ionic strength impacted the mesh size, having potential implications for drug delivery applications. The mechanical properties of GelMA hydrogels were largely unaffected by variations in ionic strength or pH. Loading of cefazolin, a small polar antibiotic molecule, led to a dose-dependent increase of non-freezable bound water, attributed to the drug’s capacity to form hydrogen bonds with water, which helped recruit water molecules in the hydrogels’ first hydration layer. This work enables a deeper understanding of water states and molecular arrangement at the hydrogel–polymer interface and how environmental cues influence them. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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18 pages, 266 KiB  
Review
Treatment of Painful Diabetic Neuropathy—A Narrative Review of Pharmacological and Interventional Approaches
by Mayank Gupta, Nebojsa Nick Knezevic, Alaa Abd-Elsayed, Mahoua Ray, Kiran Patel and Bhavika Chowdhury
Biomedicines 2021, 9(5), 573; https://doi.org/10.3390/biomedicines9050573 - 19 May 2021
Cited by 27 | Viewed by 5679
Abstract
Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus that is associated with a significant decline in quality of life. Like other painful neuropathic conditions, PDN is difficult to manage clinically, and a variety of pharmacological and non-pharmacological options are available [...] Read more.
Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus that is associated with a significant decline in quality of life. Like other painful neuropathic conditions, PDN is difficult to manage clinically, and a variety of pharmacological and non-pharmacological options are available for this condition. Recommended pharmacotherapies include anticonvulsive agents, antidepressant drugs, and topical capsaicin; and tapentadol, which combines opioid agonism and norepinephrine reuptake inhibition, has also recently been approved for use. Additionally, several neuromodulation therapies have been successfully used for pain relief in PDN, including intrathecal therapy, transcutaneous electrical nerve stimulation (TENS), and spinal cord stimulation (SCS). Recently, 10 kHz SCS has been shown to provide clinically meaningful pain relief for patients refractory to conventional medical management, with a subset of patients demonstrating improvement in neurological function. This literature review is intended to discuss the dosage and prospective data associated with pain management therapies for PDN. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
14 pages, 2738 KiB  
Hypothesis
A Cell Membrane-Level Approach to Cicatricial Alopecia Management: Is Caveolin-1 a Viable Therapeutic Target in Frontal Fibrosing Alopecia?
by Ivan Jozic, Jérémy Chéret, Beatriz Abdo Abujamra, Mariya Miteva, Jennifer Gherardini and Ralf Paus
Biomedicines 2021, 9(5), 572; https://doi.org/10.3390/biomedicines9050572 - 19 May 2021
Cited by 6 | Viewed by 3463
Abstract
Irreversible destruction of the hair follicle (HF) in primary cicatricial alopecia and its most common variant, frontal fibrosing alopecia (FFA), results from apoptosis and pathological epithelial-mesenchymal transition (EMT) of epithelial HF stem cells (eHFSCs), in conjunction with the collapse of bulge immune privilege [...] Read more.
Irreversible destruction of the hair follicle (HF) in primary cicatricial alopecia and its most common variant, frontal fibrosing alopecia (FFA), results from apoptosis and pathological epithelial-mesenchymal transition (EMT) of epithelial HF stem cells (eHFSCs), in conjunction with the collapse of bulge immune privilege (IP) and interferon-gamma-mediated chronic inflammation. The scaffolding protein caveolin-1 (Cav1) is a key component of specialized cell membrane microdomains (caveolae) that regulates multiple signaling events, and even though Cav1 is most prominently expressed in the bulge area of human scalp HFs, it has not been investigated in any cicatricial alopecia context. Interestingly, in mice, Cav1 is involved in the regulation of (1) key HF IP guardians (TGF-β and α-MSH signaling), (2) IP collapse inducers/markers (IFNγ, substance P and MICA), and (3) EMT. Therefore, we hypothesize that Cav1 may be an unrecognized, important player in the pathobiology of cicatricial alopecias, and particularly, in FFA, which is currently considered as the most common type of primary lymphocytic scarring alopecia in the world. We envision that localized therapeutic inhibition of Cav1 in management of FFA (by cholesterol depleting agents, i.e., cyclodextrins/statins), could inhibit and potentially reverse bulge IP collapse and pathological EMT. Moreover, manipulation of HF Cav1 expression/localization would not only be relevant for management of cicatricial alopecia, but FFA could also serve as a model disease for elucidating the role of Cav1 in other stem cell- and/or IP collapse-related pathologies. Full article
(This article belongs to the Special Issue Hair Pathology)
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16 pages, 3452 KiB  
Article
CX-4945 and siRNA-Mediated Knockdown of CK2 Improves Cisplatin Response in HPV(+) and HPV(−) HNSCC Cell Lines
by Janeen H. Trembley, Bin Li, Betsy T. Kren, Amy A. Gravely, Emiro Caicedo-Granados, Mark A. Klein and Khalil Ahmed
Biomedicines 2021, 9(5), 571; https://doi.org/10.3390/biomedicines9050571 - 18 May 2021
Cited by 7 | Viewed by 2919
Abstract
Head and neck squamous cell carcinoma (HNSCC) can be categorized into human papillomavirus (HPV) positive or negative disease. Elevated protein kinase CK2 level and activity have been historically observed in HNSCC cells. Previous studies on CK2 in HNSCC did not generally include consideration [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) can be categorized into human papillomavirus (HPV) positive or negative disease. Elevated protein kinase CK2 level and activity have been historically observed in HNSCC cells. Previous studies on CK2 in HNSCC did not generally include consideration of HPV(+) and HPV(−) status. Here, we investigated the response of HPV(+) and HPV(−) HNSCC cells to CK2 targeting using CX-4945 or siRNA downregulation combined with cisplatin treatment. HNSCC cell lines were examined for CK2 expression levels and activity and response to CX-4945, with and without cisplatin. CK2 levels and NFκB p65-related activity were high in HPV(+) HNSCC cells relative to HPV(−) HNSCC cells. Treatment with CX-4945 decreased viability and cisplatin IC50 in all cell lines. Targeting of CK2 increased tumor suppressor protein levels for p21 and PDCD4 in most instances. Further study is needed to understand the role of CK2 in HPV(+) and HPV(−) HNSCC and to determine how incorporation of the CK2-targeted inhibitor CX-4945 could improve cisplatin response in HNSCC. Full article
(This article belongs to the Special Issue CK2 Regulation of Cell Death and Targeting in Cancer Treatment)
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22 pages, 8307 KiB  
Review
Smart Hydrogels Meet Carbon Nanomaterials for New Frontiers in Medicine
by Simone Adorinni, Petr Rozhin and Silvia Marchesan
Biomedicines 2021, 9(5), 570; https://doi.org/10.3390/biomedicines9050570 - 18 May 2021
Cited by 35 | Viewed by 5279
Abstract
Carbon nanomaterials include diverse structures and morphologies, such as fullerenes, nano-onions, nanodots, nanodiamonds, nanohorns, nanotubes, and graphene-based materials. They have attracted great interest in medicine for their high innovative potential, owing to their unique electronic and mechanical properties. In this review, we describe [...] Read more.
Carbon nanomaterials include diverse structures and morphologies, such as fullerenes, nano-onions, nanodots, nanodiamonds, nanohorns, nanotubes, and graphene-based materials. They have attracted great interest in medicine for their high innovative potential, owing to their unique electronic and mechanical properties. In this review, we describe the most recent advancements in their inclusion in hydrogels to yield smart systems that can respond to a variety of stimuli. In particular, we focus on graphene and carbon nanotubes, for applications that span from sensing and wearable electronics to drug delivery and tissue engineering. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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20 pages, 3722 KiB  
Article
Influence of Serotonin 5-HT4 Receptors on Responses to Cardiac Stressors in Transgenic Mouse Models
by Ulrich Gergs, Timo Gerigk, Jonas Wittschier, Constanze T. Schmidbaur, Clara Röttger, Mareen Mahnkopf, Hanna Edler, Hartmut Wache and Joachim Neumann
Biomedicines 2021, 9(5), 569; https://doi.org/10.3390/biomedicines9050569 - 18 May 2021
Cited by 6 | Viewed by 2461
Abstract
The current study aimed to deepen our knowledge on the role of cardiac 5-HT4 receptors under pathophysiological conditions. To this end, we used transgenic (TG) mice that overexpressed human 5-HT4a receptors solely in cardiac myocytes (5-HT4-TG mice) and their [...] Read more.
The current study aimed to deepen our knowledge on the role of cardiac 5-HT4 receptors under pathophysiological conditions. To this end, we used transgenic (TG) mice that overexpressed human 5-HT4a receptors solely in cardiac myocytes (5-HT4-TG mice) and their wild-type (WT) littermates that do not have functional cardiac 5-HT4 receptors as controls. We found that an inflammation induced by lipopolysaccharide (LPS) was detrimental to cardiac function in both 5-HT4-TG and WT mice. In a hypoxia model, isolated left atrial preparations from the 5-HT4-TG mice went into contracture faster during hypoxia and recovered slower following hypoxia than the WT mice. Similarly, using isolated perfused hearts, 5-HT4-TG mice hearts were more susceptible to ischemia compared to WT hearts. To study the influence of 5-HT4 receptors on cardiac hypertrophy, 5-HT4-TG mice were crossbred with TG mice overexpressing the catalytic subunit of PP2A in cardiac myocytes (PP2A-TG mice, a model for genetically induced hypertrophy). The cardiac contractility, determined by echocardiography, of the resulting double transgenic mice was attenuated like in the mono-transgenic PP2A-TG and, therefore, largely determined by the overexpression of PP2A. In summary, depending on the kind of stress put upon the animal or isolated tissue, 5-HT4 receptor overexpression could be either neutral (genetically induced hypertrophy, sepsis) or possibly detrimental (hypoxia, ischemia) for mechanical function. We suggest that depending on the underlying pathology, the activation or blockade of 5-HT4 receptors might offer novel drug therapy options in patients. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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12 pages, 19553 KiB  
Article
Differential Modulation of Dorsal Horn Neurons by Various Spinal Cord Stimulation Strategies
by Kwan Yeop Lee, Dongchul Lee, Zachary B. Kagan, Dong Wang and Kerry Bradley
Biomedicines 2021, 9(5), 568; https://doi.org/10.3390/biomedicines9050568 - 18 May 2021
Cited by 13 | Viewed by 2871
Abstract
New strategies for spinal cord stimulation (SCS) for chronic pain have emerged in recent years, which may work better via different analgesic mechanisms than traditional low-frequency (e.g., 50 Hz) paresthesia-based SCS. To determine if 10 kHz and burst SCS waveforms might have a [...] Read more.
New strategies for spinal cord stimulation (SCS) for chronic pain have emerged in recent years, which may work better via different analgesic mechanisms than traditional low-frequency (e.g., 50 Hz) paresthesia-based SCS. To determine if 10 kHz and burst SCS waveforms might have a similar mechanistic basis, we examined whether these SCS strategies at intensities ostensibly below sensory thresholds would modulate spinal dorsal horn (DH) neuronal function in a neuron type-dependent manner. By using an in vivo electrophysiological approach in rodents, we found that low-intensity 10 kHz SCS, but not burst SCS, selectively activates inhibitory interneurons in the spinal DH. This study suggests that low-intensity 10 kHz SCS may inhibit pain-sensory processing in the spinal DH by activating inhibitory interneurons without activating DC fibers, resulting in paresthesia-free pain relief, whereas burst SCS likely operates via other mechanisms. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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11 pages, 3613 KiB  
Article
Cellular Senescence in Human Aldosterone-Producing Adrenocortical Cells and Related Disorders
by Jacopo Pieroni, Yuto Yamazaki, Xin Gao, Yuta Tezuka, Hiroko Ogata, Kei Omata, Yoshikiyo Ono, Ryo Morimoto, Yasuhiro Nakamura, Fumitoshi Satoh and Hironobu Sasano
Biomedicines 2021, 9(5), 567; https://doi.org/10.3390/biomedicines9050567 - 18 May 2021
Cited by 5 | Viewed by 2286
Abstract
In situ cortisol excess was previously reported to promote cellular senescence, a cell response to stress, in cortisol-producing adenomas (CPA). The aim of this study was to explore senescence pathways in aldosterone-producing cells and related disorders, and the influence of aldosterone overproduction on [...] Read more.
In situ cortisol excess was previously reported to promote cellular senescence, a cell response to stress, in cortisol-producing adenomas (CPA). The aim of this study was to explore senescence pathways in aldosterone-producing cells and related disorders, and the influence of aldosterone overproduction on in situ senescence. We analyzed 30 surgical cases of aldosterone-producing adenoma (APA), 10 idiopathic hyperaldosteronism (IHA) and 19 normal adrenals (NA). CYP11B2 and senescence markers p16 and p21 were immunolocalized in all those cases above and results were correlated with histological/endocrinological findings. In the three cohorts examined, the zona glomerulosa (ZG) was significantly more senescent than other corticosteroid-producing cells. In addition, the ZG of adjacent non-pathological adrenal glands of APA and IHA had significantly higher p16 expression than adjacent non-pathological zona fasciculata (ZF), reticularis (ZR) and ZG of NA. In addition, laboratory findings of primary aldosteronism (PA) were significantly correlated with p21 status in KCNJ5-mutated tumors. Results of our present study firstly demonstrated that non-aldosterone-producing cells in the ZG were the most senescent compared to other cortical zones and aldosterone-producing cells in PA. Therefore, aldosterone production, whether physiological or pathological, could be maintained by suppression of cell senescence in human adrenal cortex. Full article
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22 pages, 1243 KiB  
Article
Predict Score: A New Biological and Clinical Tool to Help Predict Risk of Intensive Care Transfer for COVID-19 Patients
by Mickael Gette, Sara Fernandes, Marion Marlinge, Marine Duranjou, Wijayanto Adi, Maelle Dambo, Pierre Simeone, Pierre Michelet, Nicolas Bruder, Regis Guieu and Julien Fromonot
Biomedicines 2021, 9(5), 566; https://doi.org/10.3390/biomedicines9050566 - 18 May 2021
Cited by 1 | Viewed by 1859
Abstract
Background: The COVID-19 crisis has strained world health care systems. This study aimed to develop an innovative prediction score using clinical and biological parameters (PREDICT score) to anticipate the need of intensive care of COVID-19 patients already hospitalized in standard medical units. Methods: [...] Read more.
Background: The COVID-19 crisis has strained world health care systems. This study aimed to develop an innovative prediction score using clinical and biological parameters (PREDICT score) to anticipate the need of intensive care of COVID-19 patients already hospitalized in standard medical units. Methods: PREDICT score was based on a training cohort and a validation cohort retrospectively recruited in 2020 in the Marseille University Hospital. Multivariate analyses were performed, including clinical, and biological parameters, comparing a baseline group composed of COVID-19 patients exclusively treated in standard medical units to COVID-19 patients that needed intensive care during their hospitalization. Results: Independent variables included in the PREDICT score were: age, Body Mass Index, Respiratory Rate, oxygen saturation, C-reactive protein, neutrophil–lymphocyte ratio and lactate dehydrogenase. The PREDICT score was able to correctly identify more than 83% of patients that needed intensive care after at least 1 day of standard medical hospitalization. Conclusions: The PREDICT score is a powerful tool for anticipating the intensive care need for COVID-19 patients already hospitalized in a standard medical unit. It shows limitations for patients who immediately need intensive care, but it draws attention to patients who have an important risk of needing intensive care after at least one day of hospitalization. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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13 pages, 2352 KiB  
Article
Radiosynthesis and Evaluation of Talazoparib and Its Derivatives as PARP-1-Targeting Agents
by Dong Zhou, Huaping Chen, Cedric Mpoy, Sadia Afrin, Buck E. Rogers, Joel R. Garbow, John A. Katzenellenbogen and Jinbin Xu
Biomedicines 2021, 9(5), 565; https://doi.org/10.3390/biomedicines9050565 - 18 May 2021
Cited by 18 | Viewed by 3035
Abstract
Poly (ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme in the DNA repair process and the target of several FDA-approved inhibitors. Several of these inhibitors have been radiolabeled for non-invasive imaging of PARP-1 expression or targeted radiotherapy of PARP-1 expressing tumors. In particular, derivatives [...] Read more.
Poly (ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme in the DNA repair process and the target of several FDA-approved inhibitors. Several of these inhibitors have been radiolabeled for non-invasive imaging of PARP-1 expression or targeted radiotherapy of PARP-1 expressing tumors. In particular, derivatives of olaparib and rucaparib, which have reduced trapping potency by PARP-1 compared to talazoparib, have been radiolabeled for these purposes. Here, we report the first radiosynthesis of [18F]talazoparib and its in vitro and in vivo evaluation. Talazoparib (3a″) and its bromo- or iodo-derivatives were synthesized as racemic mixtures (3a, 3b and 3c), and these compounds exhibit high affinity to PARP-1 (Ki for talazoparib (3a″): 0.65 ± 0.07 nM; 3a: 2.37 ± 0.56 nM; 3b: 1.92 ± 0.41 nM; 3c: 1.73 ± 0.43 nM; known PARP-1 inhibitor Olaparib: 1.87 ± 0.10 nM; non-PARP-1 compound Raclopride: >20,000 nM) in a competitive binding assay using a tritium-labeled PARP-1 radioligand [3H]WC-DZ for screening. [18F]Talazoparib (3a″) was radiosynthesized via a multiple-step procedure with good radiochemical and chiral purities (98%) and high molar activity (28 GBq/μmol). The preliminary biodistribution studies in the murine PC-3 tumor model showed that [18F]talazoparib had a good level of tumor uptake that persisted for over 8 h (3.78 ± 0.55 %ID/gram at 4 h and 4.52 ± 0.32 %ID/gram at 8 h). These studies show the potential for the bromo- and iodo- derivatives for PARP-1 targeted radiotherapy studies using therapeutic radionuclides. Full article
(This article belongs to the Section Drug Discovery and Development)
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11 pages, 762 KiB  
Review
The War after War: Volumetric Muscle Loss Incidence, Implication, Current Therapies and Emerging Reconstructive Strategies, a Comprehensive Review
by Stefano Testa, Ersilia Fornetti, Claudia Fuoco, Carles Sanchez-Riera, Francesco Rizzo, Mario Ciccotti, Stefano Cannata, Tommaso Sciarra and Cesare Gargioli
Biomedicines 2021, 9(5), 564; https://doi.org/10.3390/biomedicines9050564 - 18 May 2021
Cited by 12 | Viewed by 3542
Abstract
Volumetric muscle loss (VML) is the massive wasting of skeletal muscle tissue due to traumatic events or surgical ablation. This pathological condition exceeds the physiological healing process carried out by the muscle itself, which owns remarkable capacity to restore damages but only when [...] Read more.
Volumetric muscle loss (VML) is the massive wasting of skeletal muscle tissue due to traumatic events or surgical ablation. This pathological condition exceeds the physiological healing process carried out by the muscle itself, which owns remarkable capacity to restore damages but only when limited in dimensions. Upon VML occurring, the affected area is severely compromised, heavily influencing the affected a person’s quality of life. Overall, this condition is often associated with chronic disability, which makes the return to duty of highly specialized professional figures (e.g., military personnel or athletes) almost impossible. The actual treatment for VML is based on surgical conservative treatment followed by physical exercise; nevertheless, the results, in terms of either lost mass and/or functionality recovery, are still poor. On the other hand, the efforts of the scientific community are focusing on reconstructive therapy aiming at muscular tissue void volume replenishment by exploiting biomimetic matrix or artificial tissue implantation. Reconstructing strategies represent a valid option to build new muscular tissue not only to recover damaged muscles, but also to better socket prosthesis in terms of anchorage surfaces and reinnervation substrates for reconstructed mass. Full article
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24 pages, 2613 KiB  
Review
Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies
by Magali Seguret, Eva Vermersch, Charlène Jouve and Jean-Sébastien Hulot
Biomedicines 2021, 9(5), 563; https://doi.org/10.3390/biomedicines9050563 - 18 May 2021
Cited by 11 | Viewed by 4085
Abstract
Cardiac tissue engineering aims at creating contractile structures that can optimally reproduce the features of human cardiac tissue. These constructs are becoming valuable tools to model some of the cardiac functions, to set preclinical platforms for drug testing, or to alternatively be used [...] Read more.
Cardiac tissue engineering aims at creating contractile structures that can optimally reproduce the features of human cardiac tissue. These constructs are becoming valuable tools to model some of the cardiac functions, to set preclinical platforms for drug testing, or to alternatively be used as therapies for cardiac repair approaches. Most of the recent developments in cardiac tissue engineering have been made possible by important advances regarding the efficient generation of cardiac cells from pluripotent stem cells and the use of novel biomaterials and microfabrication methods. Different combinations of cells, biomaterials, scaffolds, and geometries are however possible, which results in different types of structures with gradual complexities and abilities to mimic the native cardiac tissue. Here, we intend to cover key aspects of tissue engineering applied to cardiology and the consequent development of cardiac organoids. This review presents various facets of the construction of human cardiac 3D constructs, from the choice of the components to their patterning, the final geometry of generated tissues, and the subsequent readouts and applications to model and treat cardiac diseases. Full article
(This article belongs to the Special Issue Tissue Engineering in Cardiology)
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20 pages, 2762 KiB  
Article
Synthesis, Characterization, and In Vitro Insulin-Mimetic Activity Evaluation of Valine Schiff Base Coordination Compounds of Oxidovanadium(V)
by Mihaela Turtoi, Maria Anghelache, Andrei A. Patrascu, Catalin Maxim, Ileana Manduteanu, Manuela Calin and Delia-Laura Popescu
Biomedicines 2021, 9(5), 562; https://doi.org/10.3390/biomedicines9050562 - 17 May 2021
Cited by 14 | Viewed by 2698
Abstract
Type 2 diabetes became an alarming global health issue since the existing drugs do not prevent its progression. Herein, we aimed to synthesize and characterize a family of oxidovanadium(V) complexes with Schiff base ligands derived from L-/D-valine (val) and salicylaldehyde (sal) or o [...] Read more.
Type 2 diabetes became an alarming global health issue since the existing drugs do not prevent its progression. Herein, we aimed to synthesize and characterize a family of oxidovanadium(V) complexes with Schiff base ligands derived from L-/D-valine (val) and salicylaldehyde (sal) or o-vanillin (van) as insulin-mimetic agents and to assess their potential anti-diabetic properties. Two new oxidovanadium(V) complexes, [{VVO(R-salval)(H2O)}(μ2-O){VVO(R-salval)}] and [{VVO(R-vanval)(CH3OH)}22-O)], and their S-enantiomers were synthesized and characterized. The compounds exhibit optical activity as shown by crystallographic and spectroscopic data. The stability, the capacity to bind bovine serum albumin (BSA), the cytotoxicity against human hepatoma cell line, as well as the potential anti-diabetic activity of the four compounds are investigated. The synthesized compounds are stable for up to three hours in physiological conditions and exhibit a high capacity of binding to BSA. Furthermore, the synthesized compounds display cytocompatibility at biologically relevant concentrations, exert anti-diabetic potential and insulin-mimetic activities by inhibiting the α-amylase and protein tyrosine phosphatase activity, and a long-term increase of insulin receptor phosphorylation compared to the insulin hormone. Thus, the in vitro anti-diabetic potential and insulin-mimetic properties of the newly synthesized oxidovanadium(V) compounds, correlated with their cytocompatibility, make them promising candidates for further investigation as anti-diabetic drugs. Full article
(This article belongs to the Special Issue Feature Papers in Drug Discovery and Development)
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19 pages, 3151 KiB  
Article
Radiotherapy in Follicular Lymphoma Staged by 18F-FDG-PET/CT: A German Monocenter Study
by Imke E. Karsten, Gabriele Reinartz, Michaela Pixberg, Kai Kröger, Michael Oertel, Birte Friedrichs, Georg Lenz and Hans Theodor Eich
Biomedicines 2021, 9(5), 561; https://doi.org/10.3390/biomedicines9050561 - 17 May 2021
Cited by 4 | Viewed by 3502
Abstract
This retrospective study examined the role of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) in stage-related therapy of follicular lymphomas (FL). Twelve patients each in stages I and II, 13 in stage III and 11 in stage IV were treated in the [...] Read more.
This retrospective study examined the role of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) in stage-related therapy of follicular lymphomas (FL). Twelve patients each in stages I and II, 13 in stage III and 11 in stage IV were treated in the Department of Radiation Oncology, University Hospital of Muenster, Germany from 2004 to 2016. Radiotherapy (RT), as well as additional chemoimmunotherapy were analyzed with a median follow-up of 87.6 months. Ultrasound (US), CT and 18F-FDG-PET/CT were used to determine progression-free survival (PFS), overall survival (OS) and lymphoma-specific survival (LSS) over 5- and 10- years. 23 of 24 patients with stage I/II (95.8%) had complete remissions (CR) and 17 of 24 patients with stages III/IV FL showed CR (70.8%). 5- and 10-year PFS in stages I/II was 90.0%/78.1% vs. 44.3%/28.5% in stages III/IV. 5- and 10-year OS rates in stages I/II was 100%/93.3% vs. 53.7%/48.4% in stages III/IV. 5- and 10-year LSS of stages I/II was 100%/93.8% vs. 69.2%/62.3% in stages III/IV. FL of stages I/II, staged by 18F-FDG-PET/CT, revealed better survival rates and lower risk of recurrence compared to studies without PET/CT-staging. Especially, patients with PET/CT proven stage I disease showed significantly better survival and lower relapses rates after RT. Full article
(This article belongs to the Special Issue New Insights in Radiotherapy)
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16 pages, 1263 KiB  
Review
Impact of Fatty Acid-Binding Proteins in α-Synuclein-Induced Mitochondrial Injury in Synucleinopathy
by An Cheng, Wenbin Jia, Ichiro Kawahata and Kohji Fukunaga
Biomedicines 2021, 9(5), 560; https://doi.org/10.3390/biomedicines9050560 - 17 May 2021
Cited by 9 | Viewed by 5884
Abstract
Synucleinopathies are diverse diseases with motor and cognitive dysfunction due to progressive neuronal loss or demyelination, due to oligodendrocyte loss in the brain. While the etiology of neurodegenerative disorders (NDDs) is likely multifactorial, mitochondrial injury is one of the most vital factors in [...] Read more.
Synucleinopathies are diverse diseases with motor and cognitive dysfunction due to progressive neuronal loss or demyelination, due to oligodendrocyte loss in the brain. While the etiology of neurodegenerative disorders (NDDs) is likely multifactorial, mitochondrial injury is one of the most vital factors in neuronal loss and oligodendrocyte dysfunction, especially in Parkinson’s disease, dementia with Lewy body, multiple system atrophy, and Krabbe disease. In recent years, the abnormal accumulation of highly neurotoxic α-synuclein in the mitochondrial membrane, which leads to mitochondrial dysfunction, was well studied. Furthermore, fatty acid-binding proteins (FABPs), which are members of a superfamily and are essential in fatty acid trafficking, were reported to trigger α-synuclein oligomerization in neurons and glial cells and to target the mitochondrial outer membrane, thereby causing mitochondrial loss. Here, we provide an updated overview of recent findings on FABP and α-synuclein interactions and mitochondrial injury in NDDs. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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19 pages, 4843 KiB  
Article
Simvastatin Enhances the Chondrogenesis But Not the Osteogenesis of Adipose-Derived Stem Cells in a Hyaluronan Microenvironment
by Shun-Cheng Wu, Chih-Hsiang Chang, Ling-Hua Chang, Che-Wei Wu, Jhen-Wei Chen, Chung-Hwan Chen, Yi-Shan Lin, Je-Ken Chang and Mei-Ling Ho
Biomedicines 2021, 9(5), 559; https://doi.org/10.3390/biomedicines9050559 - 17 May 2021
Cited by 7 | Viewed by 2709
Abstract
Directing adipose-derived stem cells (ADSCs) toward chondrogenesis is critical for ADSC-based articular cartilage regeneration. Simvastatin (SIM) was reported to promote both chondrogenic and osteogenic differentiation of ADSCs by upregulating bone morphogenetic protein-2 (BMP-2). We previously found that ADSC chondrogenesis is initiated and promoted [...] Read more.
Directing adipose-derived stem cells (ADSCs) toward chondrogenesis is critical for ADSC-based articular cartilage regeneration. Simvastatin (SIM) was reported to promote both chondrogenic and osteogenic differentiation of ADSCs by upregulating bone morphogenetic protein-2 (BMP-2). We previously found that ADSC chondrogenesis is initiated and promoted in a hyaluronan (HA) microenvironment (HAM). Here, we further hypothesized that SIM augments HAM-induced chondrogenesis but not osteogenesis of ADSCs. ADSCs were treated with SIM in a HAM (SIM plus HAM) by HA-coated wells or HA-enriched fibrin (HA/Fibrin) hydrogel, and chondrogenic differentiation of ADSCs was evaluated. SIM plus HAM increased chondrogenesis more than HAM or SIM alone, including cell aggregation, chondrogenic gene expression (collagen type II and aggrecan) and cartilaginous tissue formation (collagen type II and sulfated glycosaminoglycan). In contrast, SIM-induced osteogenesis in ADSCs was reduced in SIM plus HAM, including mRNA expression of osteogenic genes, osteocalcin and alkaline phosphatase (ALP), ALP activity and mineralization. SIM plus HAM also showed the most effective increases in the mRNA expression of BMP-2 and transcription factors of SOX-9 and RUNX-2 in ADSCs, while these effects were reversed by CD44 blockade. HAM suppressed the levels of JNK, p-JNK, P38 and p-P38 in ADSCs, and SIM plus HAM also decreased SIM-induced phosphorylated JNK and p38 levels. In addition, SIM enhanced articular cartilage regeneration, as demonstrated by implantation of an ADSCs/HA/Fibrin construct in an ex vivo porcine articular chondral defect model. The results from this study indicate that SIM may be an enhancer of HAM-initiated MSC-based chondrogenesis and avoid osteogenesis. Full article
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16 pages, 2940 KiB  
Article
Influence of Microbial Metabolites on the Nonspecific Permeability of Mitochondrial Membranes under Conditions of Acidosis and Loading with Calcium and Iron Ions
by Nadezhda Fedotcheva, Andrei Olenin and Natalia Beloborodova
Biomedicines 2021, 9(5), 558; https://doi.org/10.3390/biomedicines9050558 - 17 May 2021
Cited by 12 | Viewed by 2041
Abstract
Mitochondrial dysfunction is currently considered one of the main causes of multiple organ failure in chronic inflammation and sepsis. The participation of microbial metabolites in disorders of bioenergetic processes in mitochondria has been revealed, but their influence on the mitochondrial membrane permeability has [...] Read more.
Mitochondrial dysfunction is currently considered one of the main causes of multiple organ failure in chronic inflammation and sepsis. The participation of microbial metabolites in disorders of bioenergetic processes in mitochondria has been revealed, but their influence on the mitochondrial membrane permeability has not yet been studied. We tested the influence of various groups of microbial metabolites, including indolic and phenolic acids, trimethylamine-N-oxide (TMAO) and acetyl phosphate (AcP), on the nonspecific permeability of mitochondrial membranes under conditions of acidosis, imbalance of calcium ions and excess free iron, which are inherent in sepsis. Changes in the parameters of the calcium-induced opening of the mitochondrial permeability transition pore (MPTP) and iron-activated swelling of rat liver mitochondria were evaluated. The most active metabolites were indole-3-carboxylic acid (ICA) and benzoic acid (BA), which activated MPTP opening and swelling under all conditions. AcP showed the opposite effect on the induction of MPTP opening, increasing the threshold concentration of calcium by 1.5 times, while TMAO activated swelling only under acidification. All the redox-dependent effects of metabolites were suppressed by the lipid radical scavenger butyl-hydroxytoluene (BHT), which indicates the participation of these microbial metabolites in the activation of membrane lipid peroxidation. Thus, microbial metabolites can directly affect the nonspecific permeability of mitochondrial membranes, if conditions of acidosis, an imbalance of calcium ions and an excess of free iron are created in the pathological state. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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16 pages, 621 KiB  
Review
Immunosurveillance of Cancer and Viral Infections with Regard to Alterations of Human NK Cells Originating from Lifestyle and Aging
by Xuewen Deng, Hiroshi Terunuma and Mie Nieda
Biomedicines 2021, 9(5), 557; https://doi.org/10.3390/biomedicines9050557 - 17 May 2021
Cited by 6 | Viewed by 4046
Abstract
Natural killer (NK) cells are cytotoxic immune cells with an innate capacity for eliminating cancer cells and virus- infected cells. NK cells are critical effector cells in the immunosurveillance of cancer and viral infections. Patients with low NK cell activity or NK cell [...] Read more.
Natural killer (NK) cells are cytotoxic immune cells with an innate capacity for eliminating cancer cells and virus- infected cells. NK cells are critical effector cells in the immunosurveillance of cancer and viral infections. Patients with low NK cell activity or NK cell deficiencies are predisposed to increased risks of cancer and severe viral infections. However, functional alterations of human NK cells are associated with lifestyles and aging. Personal lifestyles, such as cigarette smoking, alcohol consumption, stress, obesity, and aging are correlated with NK cell dysfunction, whereas adequate sleep, moderate exercise, forest bathing, and listening to music are associated with functional healthy NK cells. Therefore, adherence to a healthy lifestyle is essential and will be favorable for immunosurveillance of cancer and viral infections with healthy NK cells. Full article
(This article belongs to the Special Issue Recent Therapeutic Advances in Natural Killer Cells)
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16 pages, 295 KiB  
Article
Predicting COVID-19—Comorbidity Pathway Crosstalk-Based Targets and Drugs: Towards Personalized COVID-19 Management
by Debmalya Barh, Alaa A. Aljabali, Murtaza M. Tambuwala, Sandeep Tiwari, Ángel Serrano-Aroca, Khalid J. Alzahrani, Bruno Silva Andrade, Vasco Azevedo, Nirmal Kumar Ganguly and Kenneth Lundstrom
Biomedicines 2021, 9(5), 556; https://doi.org/10.3390/biomedicines9050556 - 17 May 2021
Cited by 21 | Viewed by 3949
Abstract
It is well established that pre-existing comorbid conditions such as hypertension, diabetes, obesity, cardiovascular diseases (CVDs), chronic kidney diseases (CKDs), cancers, and chronic obstructive pulmonary disease (COPD) are associated with increased severity and fatality of COVID-19. The increased death from COVID-19 is due [...] Read more.
It is well established that pre-existing comorbid conditions such as hypertension, diabetes, obesity, cardiovascular diseases (CVDs), chronic kidney diseases (CKDs), cancers, and chronic obstructive pulmonary disease (COPD) are associated with increased severity and fatality of COVID-19. The increased death from COVID-19 is due to the unavailability of a gold standard therapeutic and, more importantly, the lack of understanding of how the comorbid conditions and COVID-19 interact at the molecular level, so that personalized management strategies can be adopted. Here, using multi-omics data sets and bioinformatics strategy, we identified the pathway crosstalk between COVID-19 and diabetes, hypertension, CVDs, CKDs, and cancers. Further, shared pathways and hub gene-based targets for COVID-19 and its associated specific and combination of comorbid conditions are also predicted towards developing personalized management strategies. The approved drugs for most of these identified targets are also provided towards drug repurposing. Literature supports the involvement of our identified shared pathways in pathogenesis of COVID-19 and development of the specific comorbid condition of interest. Similarly, shared pathways- and hub gene-based targets are also found to have potential implementations in managing COVID-19 patients. However, the identified targets and drugs need further careful evaluation for their repurposing towards personalized treatment of COVID-19 cases having pre-existing specific comorbid conditions we have considered in this analysis. The method applied here may also be helpful in identifying common pathway components and targets in other disease-disease interactions too. Full article
(This article belongs to the Section Molecular and Translational Medicine)
12 pages, 5051 KiB  
Article
Generation of Stilbene Glycoside with Promising Cell Rejuvenation Activity through Biotransformation by the Entomopathogenic Fungus Beauveria bassiana
by Sang Keun Ha, Min Cheol Kang, Seulah Lee, Om Darlami, Dongyun Shin, Inwook Choi, Ki Hyun Kim and Sun Yeou Kim
Biomedicines 2021, 9(5), 555; https://doi.org/10.3390/biomedicines9050555 - 17 May 2021
Cited by 3 | Viewed by 2478
Abstract
A stilbene glycoside (resvebassianol A) (1) with a unique sugar unit, 4-O-methyl-D-glucopyranose, was identified through biotransformation of resveratrol (RSV) by the entomopathogenic fungus Beauveria bassiana to obtain a superior RSV metabolite with enhanced safety. Its structure, including its absolute [...] Read more.
A stilbene glycoside (resvebassianol A) (1) with a unique sugar unit, 4-O-methyl-D-glucopyranose, was identified through biotransformation of resveratrol (RSV) by the entomopathogenic fungus Beauveria bassiana to obtain a superior RSV metabolite with enhanced safety. Its structure, including its absolute configurations, was determined using spectroscopic data, HRESIMS, and chemical reactions. Microarray analysis showed that the expression levels of filaggrin, HAS2-AS1, and CERS3 were higher, while those of IL23A, IL1A, and CXCL8 were lower in the resvebassianol A-treated group than in the RSV-treated group, as confirmed by qRT-PCR. Compound 1 exhibited the same regenerative and anti-inflammatory effects as RSV with no cytotoxicity in skin keratinocytes and TNF-α/IFN-γ-stimulated HIEC-6 cells, suggesting that compound 1 is a safe and stable methylglycosylated RSV. Our findings suggest that our biotransformation method can be an efficient biosynthetic platform for producing a broad range of natural glycosides with enhanced safety. Full article
(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)
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14 pages, 724 KiB  
Review
Subpopulations of High-Density Lipoprotein: Friends or Foes in Cardiovascular Disease Risk in Chronic Kidney Disease?
by Susana Coimbra, Flávio Reis, Maria João Valente, Susana Rocha, Cristina Catarino, Petronila Rocha-Pereira, Maria Sameiro-Faria, Elsa Bronze-da-Rocha, Luís Belo and Alice Santos-Silva
Biomedicines 2021, 9(5), 554; https://doi.org/10.3390/biomedicines9050554 - 16 May 2021
Cited by 2 | Viewed by 3187
Abstract
Dyslipidemia is a major traditional risk factor for cardiovascular disease (CVD) in chronic kidney disease (CKD) patients, although the altered lipid profile does not explain the number and severity of CVD events. High-density lipoprotein (HDL) is a heterogeneous (size, composition, and functionality) population [...] Read more.
Dyslipidemia is a major traditional risk factor for cardiovascular disease (CVD) in chronic kidney disease (CKD) patients, although the altered lipid profile does not explain the number and severity of CVD events. High-density lipoprotein (HDL) is a heterogeneous (size, composition, and functionality) population of particles with different atherogenic or atheroprotective properties. HDL-cholesterol concentrations per se may not entirely reflect a beneficial or a risk profile for CVD. Large HDL in CKD patients may have a unique proteome and lipid composition, impairing their cholesterol efflux capacity. This lack of HDL functionality may contribute to the paradoxical coexistence of increased large HDL and enhanced risk for CVD events. Moreover, CKD is associated with inflammation, oxidative stress, diabetes, and/or hypertension that are able to interfere with the anti-inflammatory, antioxidative, and antithrombotic properties of HDL subpopulations. How these changes interfere with HDL functions in CKD is still poorly understood. Further studies are warranted to fully clarify if different HDL subpopulations present different functionalities and/or atheroprotective effects. To achieve this goal, the standardization of techniques would be valuable. Full article
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