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Biomedicines, Volume 6, Issue 4 (December 2018)

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Cover Story (view full-size image) Recombinant viruses are a novel therapeutic tool that can be utilized in the treatment of various [...] Read more.
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Open AccessReview Constrained α-Helical Peptides as Inhibitors of Protein-Protein and Protein-DNA Interactions
Biomedicines 2018, 6(4), 118; https://doi.org/10.3390/biomedicines6040118
Received: 7 August 2018 / Revised: 13 September 2018 / Accepted: 14 September 2018 / Published: 18 December 2018
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Abstract
Intracellular regulatory pathways are replete with protein-protein and protein-DNA interactions, offering attractive targets for therapeutic interventions. So far, most drugs are targeted toward enzymes and extracellular receptors. Protein-protein and protein-DNA interactions have long been considered as “undruggable”. Protein-DNA interactions, in particular, present a [...] Read more.
Intracellular regulatory pathways are replete with protein-protein and protein-DNA interactions, offering attractive targets for therapeutic interventions. So far, most drugs are targeted toward enzymes and extracellular receptors. Protein-protein and protein-DNA interactions have long been considered as “undruggable”. Protein-DNA interactions, in particular, present a difficult challenge due to the repetitive nature of the B-DNA. Recent studies have provided several breakthroughs; however, a design methodology for these classes of inhibitors is still at its infancy. A dominant motif of these macromolecular interactions is an α-helix, raising possibilities that an appropriate conformationally-constrained α-helical peptide may specifically disrupt these interactions. Several methods for conformationally constraining peptides to the α-helical conformation have been developed, including stapling, covalent surrogates of hydrogen bonds and incorporation of unnatural amino acids that restrict the conformational space of the peptide. We will discuss these methods and several case studies where constrained α-helices have been used as building blocks for appropriate molecules. Unlike small molecules, the delivery of these short peptides to their targets is not straightforward as they may possess unfavorable cell penetration and ADME properties. Several methods have been developed in recent times to overcome some of these problems. We will discuss these issues and the prospects of this class of molecules as drugs. Full article
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
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Open AccessArticle Genetic Association and Altered Gene Expression of CYBB in Multiple Sclerosis Patients
Biomedicines 2018, 6(4), 117; https://doi.org/10.3390/biomedicines6040117
Received: 21 November 2018 / Revised: 13 December 2018 / Accepted: 15 December 2018 / Published: 18 December 2018
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Abstract
Multiple sclerosis (MS) is a chronic neurological disorder characterized by inflammation, demyelination, and axonal damage. Increased levels of reactive oxygen species (ROS), produced by macrophages and leading to oxidative stress, have been implicated as mediators of demyelination and axonal injury in both MS [...] Read more.
Multiple sclerosis (MS) is a chronic neurological disorder characterized by inflammation, demyelination, and axonal damage. Increased levels of reactive oxygen species (ROS), produced by macrophages and leading to oxidative stress, have been implicated as mediators of demyelination and axonal injury in both MS and experimental autoimmune encephalomyelitis, the murine model of the disease. On the other hand, reduced ROS levels can increase susceptibility to autoimmunity. In this work, we screened for association with MS 11 single nucleotide polymorphisms (SNPs) and two microsatellite markers in the five genes (NCF1, NCF2, NCF4, CYBA, and CYBB) of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) system, the enzymatic pathway producing ROS in the brain and neural tissues, in 347 Finnish patients with MS and 714 unaffected family members. This analysis showed suggestive association signals for NCF1 and CYBB (lowest p = 0.038 and p = 0.013, respectively). Functional relevance for disease predisposition was further supported for the CYBB gene, by microarray analysis in CD4+/− mononuclear cells of 21 individuals from five Finnish multiplex MS families, as well as by real-time RT-PCRs performed on RNA extracted from peripheral blood mononuclear cells of an Italian replication cohort of 21 MS cases and 21 controls. Our results showed a sex-specific differential expression of CYBB, suggesting that this gene, and more in general the NOX2 system, deserve to be further investigated for their possible role in MS. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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Open AccessReview Structural Features and Binding Modes of Thioether-Cyclized Peptide Ligands
Biomedicines 2018, 6(4), 116; https://doi.org/10.3390/biomedicines6040116
Received: 12 November 2018 / Revised: 10 December 2018 / Accepted: 11 December 2018 / Published: 13 December 2018
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Abstract
Macrocyclic peptides are an emerging class of bioactive compounds for therapeutic use. In part, this is because they are capable of high potency and excellent target affinity and selectivity. Over the last decade, several biochemical techniques have been developed for the identification of [...] Read more.
Macrocyclic peptides are an emerging class of bioactive compounds for therapeutic use. In part, this is because they are capable of high potency and excellent target affinity and selectivity. Over the last decade, several biochemical techniques have been developed for the identification of bioactive macrocyclic peptides, allowing for the rapid isolation of high affinity ligands to a target of interest. A common feature of these techniques is a general reliance on thioether formation to effect macrocyclization. Increasingly, the compounds identified using these approaches have been subjected to x-ray crystallographic analysis bound to their respective targets, providing detailed structural information about their conformation and mechanism of target binding. The present review provides an overview of the target bound thioether-closed macrocyclic peptide structures that have been obtained to date. Full article
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
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Open AccessReview Oral Dysbiosis in Pancreatic Cancer and Liver Cirrhosis: A Review of the Literature
Biomedicines 2018, 6(4), 115; https://doi.org/10.3390/biomedicines6040115
Received: 31 October 2018 / Revised: 3 December 2018 / Accepted: 7 December 2018 / Published: 11 December 2018
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Abstract
The human body is naturally colonized by a huge number of different commensal microbial species, in a relatively stable equilibrium. When this microbial community undergoes dysbiosis at any part of the body, it interacts with the innate immune system and results in a [...] Read more.
The human body is naturally colonized by a huge number of different commensal microbial species, in a relatively stable equilibrium. When this microbial community undergoes dysbiosis at any part of the body, it interacts with the innate immune system and results in a poor health status, locally or systemically. Research studies show that bacteria are capable of significantly influencing specific cells of the immune system, resulting in many diseases, including a neoplastic response. Amongst the multiple different types of diseases, pancreatic cancer and liver cirrhosis were significantly considered in this paper, as they are major fatal diseases. Recently, these two diseases were shown to be associated with increased or decreased numbers of certain oral bacterial species. These findings open the way for a broader perception and more specific investigative studies, to better understand the possible future treatment and prevention. This review aims to describe the correlation between oral dysbiosis and both pancreatic cancer and liver cirrhotic diseases, as well as demonstrating the possible diagnostic and treatment modalities, relying on the oral microbiota, itself, as prospective, simple, applicable non-invasive approaches to patients, by focusing on the state of the art. PubMed was electronically searched, using the following key words: “oral microbiota” and “pancreatic cancer” (PC), “liver cirrhosis”, “systemic involvement”, and “inflammatory mediators”. Oral dysbiosis is a common problem related to poor oral or systemic health conditions. Oral pathogens can disseminate to distant body organs via the local, oral blood circulation, or pass through the gastrointestinal tract and enter the systemic circulation. Once oral pathogens reach an organ, they modify the immune response and stimulate the release of the inflammatory mediators, this results in a disease. Recent studies have reported a correlation between oral dysbiosis and the increased risk of pancreatic and liver diseases and provided evidence of the presence of oral pathogens in diseased organs. The profound impact that microbial communities have on human health, provides a wide domain towards precisely investigating and clearly understanding the mechanism of many diseases, including cancer. Oral microbiota is an essential contributor to health status and imbalance in this community was correlated to oral and systemic diseases. The presence of elevated numbers of certain oral bacteria, particularly P. gingivalis, as well as elevated levels of blood serum antibodies, against this bacterial species, was associated with a higher risk of pancreatic cancer and liver cirrhosis incidence. Attempts are increasingly directed towards investigating the composition of oral microbiome as a simple diagnostic approach in multiple diseases, including pancreatic and liver pathosis. Moreover, treatment efforts are concerned in the recruitment of microbiota, for remedial purposes of the aforementioned and other different diseases. Further investigation is required to confirm and clarify the role of oral microbiota in enhancing pancreatic and liver diseases. Improving the treatment modalities requires an exertion of more effort, especially, concerning the microbiome engineering and oral microbiota transplantation. Full article
Open AccessReview The Role of Yes-Associated Protein (YAP) in Regulating Programmed Death-Ligand 1 (PD-L1) in Thoracic Cancer
Biomedicines 2018, 6(4), 114; https://doi.org/10.3390/biomedicines6040114
Received: 10 November 2018 / Revised: 29 November 2018 / Accepted: 4 December 2018 / Published: 7 December 2018
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Abstract
The programmed death-ligand 1(PD-L1)/PD-1 pathway is an immunological checkpoint in cancer cells. The binding of PD-L1 and PD-1 promotes T-cell tolerance and helps tumor cells escape from host immunity. Immunotherapy targeting the PD-L1/PD-1 axis has been developed as an anti-cancer therapy and used [...] Read more.
The programmed death-ligand 1(PD-L1)/PD-1 pathway is an immunological checkpoint in cancer cells. The binding of PD-L1 and PD-1 promotes T-cell tolerance and helps tumor cells escape from host immunity. Immunotherapy targeting the PD-L1/PD-1 axis has been developed as an anti-cancer therapy and used in treating advanced human non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Yes-associated protein (YAP) is a key mediator of the Hippo/YAP signaling pathway, and plays important roles in promoting cancer development, drug resistance and metastasis in human NSCLC and MPM. YAP has been suggested as a new therapeutic target in NSCLC and MPM. The role of YAP in regulating tumor immunity such as PD-L1 expression has just begun to be explored, and the correlation between YAP-induced tumorigenesis and host anti-tumor immune responses is not well known. Here, we review recent studies investigating the correlation between YAP and PD-L1 and demonstrating the mechanism by which YAP regulates PD-L1 expression in human NSCLC and MPM. Future work should focus on the interactions between Hippo/YAP signaling pathways and the immune checkpoint PD-L1/PD-1 pathway. The development of new synergistic drugs for immune checkpoint PD-L1/PD-1 blockade in NSCLC and MPM is warranted. Full article
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Open AccessArticle Differences in Anxiety Levels of Various Murine Models in Relation to the Gut Microbiota Composition
Biomedicines 2018, 6(4), 113; https://doi.org/10.3390/biomedicines6040113
Received: 13 October 2018 / Revised: 23 November 2018 / Accepted: 26 November 2018 / Published: 4 December 2018
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Abstract
Psychobiotics are probiotic strains that confer mental health benefits to the host through the modulation of the gut microbial population. Mounting evidence shows that the gut microbiota play an important role in communication within the gut–brain axis. However, the relationship between the host [...] Read more.
Psychobiotics are probiotic strains that confer mental health benefits to the host through the modulation of the gut microbial population. Mounting evidence shows that the gut microbiota play an important role in communication within the gut–brain axis. However, the relationship between the host genetics and the gut microbiota and their influence on anxiety are still not fully understood. Hence, in our research, we attempted to draw a connection between host genetics, microbiota composition, and anxiety by performing an elevated plus maze (EPM) test on four genetically different mice. Four different breeds of 5-week-old mice were used in this experiment: Balb/c, Orient C57BL/6N, Taconic C57BL/6N, and Taconic C57BL/6J. After 1 week of adaptation, their initial anxiety level was monitored using the EPM test via an EthoVision XT, a standardized software used for behavorial testing. Significant differences in the initial anxiety level and microbial composition were detected. Subsequently, the microbiota of each group was modulated by the administration of either a probiotic, fecal microbiota transplantation, or antibiotics. Changes were observed in host anxiety levels in correlation to the shift of the gut microbiota. Our results suggest that the microbiota, host genetics, and psychological symptoms are strongly related, yet the deeper mechanistic links need further exploration. Full article
(This article belongs to the Section Neurologic Diseases)
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Open AccessCommentary Multiple Sclerosis: A Global Concern with Multiple Challenges in an Era of Advanced Therapeutic Complex Molecules and Biological Medicines
Biomedicines 2018, 6(4), 112; https://doi.org/10.3390/biomedicines6040112
Received: 11 November 2018 / Revised: 27 November 2018 / Accepted: 28 November 2018 / Published: 30 November 2018
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Abstract
Multiple sclerosis (MS) has become a common neurological disorder involving populations previously considered to be infrequently affected. Genetic dissemination from high- to low-risk groups is a determining influence interacting with environmental and epigenetic factors, mostly unidentified. Disease modifying therapies (DMT) are effective in [...] Read more.
Multiple sclerosis (MS) has become a common neurological disorder involving populations previously considered to be infrequently affected. Genetic dissemination from high- to low-risk groups is a determining influence interacting with environmental and epigenetic factors, mostly unidentified. Disease modifying therapies (DMT) are effective in treating relapsing MS in variable degrees; one agent is approved for primary progressive disease, and several are in development. In the era of high-efficacy medications, complex molecules, and monoclonal antibodies (MAB), including anti-VLA4 (natalizumab), anti-CD52 (alemtuzumab), and anti-CD20 (ocrelizumab), obtaining NEDA (no evidence of disease activity) becomes an elusive accomplishment in areas of the world where access to MS therapies and care are generally limited. Countries’ income and access to public MS care appear to be a shared socioeconomic challenge. This disparity is also notable in the utilization of diagnostic tools to adhere to the proposed elements of the McDonald Criteria. The impact of follow-on medications (“generics”); injectable non-biological complex drugs (NBCD), oral sphingosine-1-phosphate receptor modulators, and biosimilars (interferon 1-a and 1-b), utilized in many areas of the world, is disconcerting considering these products generally lack data documenting their efficacy and safety. Potential strategies addressing these concerns are discussed from an international point of view. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
Open AccessReview Viral-Mediated mRNA Degradation for Pathogenesis
Biomedicines 2018, 6(4), 111; https://doi.org/10.3390/biomedicines6040111
Received: 1 November 2018 / Revised: 25 November 2018 / Accepted: 29 November 2018 / Published: 29 November 2018
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Abstract
Cellular RNA decay machinery plays a vital role in regulating gene expression by altering the stability of mRNAs in response to external stresses, including viral infection. In the primary infection, viruses often conquer the host cell’s antiviral immune response by controlling the inherently [...] Read more.
Cellular RNA decay machinery plays a vital role in regulating gene expression by altering the stability of mRNAs in response to external stresses, including viral infection. In the primary infection, viruses often conquer the host cell’s antiviral immune response by controlling the inherently cellular mRNA degradation machinery to facilitate viral gene expression and establish a successful infection. This review summarizes the current knowledge about the diverse strategies of viral-mediated regulatory RNA shutoff for pathogenesis, and particularly sheds a light on the mechanisms that viruses evolve to elude immune surveillance during infection. Full article
(This article belongs to the Special Issue Viruses in Cancer and Therapy)
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Open AccessReview Dissecting the Immune Landscape of Acute Myeloid Leukemia
Biomedicines 2018, 6(4), 110; https://doi.org/10.3390/biomedicines6040110
Received: 2 October 2018 / Revised: 19 November 2018 / Accepted: 21 November 2018 / Published: 25 November 2018
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Abstract
Acute myeloid leukemia (AML) is a molecularly heterogeneous hematological malignancy with variable response to treatment. Recurring cytogenetic abnormalities and molecular lesions identify AML patient subgroups with different survival probabilities; however, 50–70% of AML cases harbor either normal or risk-indeterminate karyotypes. The discovery of [...] Read more.
Acute myeloid leukemia (AML) is a molecularly heterogeneous hematological malignancy with variable response to treatment. Recurring cytogenetic abnormalities and molecular lesions identify AML patient subgroups with different survival probabilities; however, 50–70% of AML cases harbor either normal or risk-indeterminate karyotypes. The discovery of better biomarkers of clinical success and failure is therefore necessary to inform tailored therapeutic decisions. Harnessing the immune system against cancer with programmed death-1 (PD-1)-directed immune checkpoint blockade (ICB) and other immunotherapy agents is an effective therapeutic option for several advanced malignancies. However, durable responses have been observed in only a minority of patients, highlighting the need to gain insights into the molecular features that predict response and to also develop more effective and rational combination therapies that address mechanisms of immune evasion and resistance. We will review the state of knowledge of the immune landscape of AML and identify the broad opportunity to further explore this incompletely characterized space. Multiplexed, spatially-resolved immunohistochemistry, flow cytometry/mass cytometry, proteomic and transcriptomic approaches are advancing our understanding of the complexity of AML-immune interactions and are expected to support the design and expedite the delivery of personalized immunotherapy clinical trials. Full article
(This article belongs to the Special Issue Dissecting the Immunological Landscape of Human Malignancies)
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Open AccessArticle HSP70 Inhibitor Suppresses IGF-I-Stimulated Migration of Osteoblasts through p44/p42 MAP Kinase
Biomedicines 2018, 6(4), 109; https://doi.org/10.3390/biomedicines6040109
Received: 28 August 2018 / Revised: 14 November 2018 / Accepted: 15 November 2018 / Published: 21 November 2018
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Abstract
Heat shock protein 70 (HSP70) is a ubiquitously expressed molecular chaperone in a variety of cells including osteoblasts. We previously showed that insulin-like growth factor-I (IGF-I) elicits migration of osteoblast-like MC3T3-E1 cells through the activation of phosphatidylinositol 3-kinase/Akt and p44/p42 mitogen-activated protein (MAP) [...] Read more.
Heat shock protein 70 (HSP70) is a ubiquitously expressed molecular chaperone in a variety of cells including osteoblasts. We previously showed that insulin-like growth factor-I (IGF-I) elicits migration of osteoblast-like MC3T3-E1 cells through the activation of phosphatidylinositol 3-kinase/Akt and p44/p42 mitogen-activated protein (MAP) kinase. In the present study, we investigated the effects of HSP70 inhibitors on the IGF-I-elicited migration of these cells and the mechanism involved. The IGF-I-stimulated osteoblast migration evaluated by a wound-healing assay and by a transwell cell migration was significantly reduced by VER-155008 and YM-08, which are both HSP70 inhibitors. VER-155008 markedly suppressed the IGF-I-induced phosphorylation of p44/p42 MAP kinase without affecting that of Akt. In conclusion, our results strongly suggest that the HSP70 inhibitor reduces the IGF-I-elicited migration of osteoblasts via the p44/p42 MAP kinase. Full article
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Open AccessArticle The Antidepressant-Like Effect of Lactate in an Animal Model of Menopausal Depression
Biomedicines 2018, 6(4), 108; https://doi.org/10.3390/biomedicines6040108
Received: 21 October 2018 / Revised: 12 November 2018 / Accepted: 19 November 2018 / Published: 21 November 2018
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Abstract
Background: This study aimed to investigate the antidepressant-like effect of lactate and elucidate its mechanisms in ovariectomized rats with repeated stress. Methods: Two experiments were conducted on female rats in which all groups, except normal, were ovariectomized and underwent immobilization for 14 days. [...] Read more.
Background: This study aimed to investigate the antidepressant-like effect of lactate and elucidate its mechanisms in ovariectomized rats with repeated stress. Methods: Two experiments were conducted on female rats in which all groups, except normal, were ovariectomized and underwent immobilization for 14 days. Lactate was administered orally (100, 250, and 500 mg/kg) for 14 consecutive days, and the rats’ cutaneous body temperature was measured during the same period. Depression-like behavior in rats was assessed by the tail suspension test (TST) and forced swimming test (FST). Furthermore, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were conducted to evaluate the changes that occurred in the neurotransmitter levels and activity. Results: The lactate 100 and 250 groups had reduced time spent immobile in TST and FST and decreased peripheral body temperature. In ELISA tests, the lactate 250 group expressed elevated levels of serotonin and dopamine in many brain areas. Tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and protein kinase C (PKC) immunoreactive cells showed increased density and cell counts in lactate administered groups. Conclusion: Results indicated that lactate has an antidepressant effect that is achieved by activation of PKC and upregulation of TH and TPH expression, which eventually leads to enhanced serotonin and dopamine levels in the menopausal rat’s brain. Full article
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Open AccessArticle In Vitro Anti-Inflammatory Properties of Selected Green Leafy Vegetables
Biomedicines 2018, 6(4), 107; https://doi.org/10.3390/biomedicines6040107
Received: 9 October 2018 / Revised: 12 November 2018 / Accepted: 13 November 2018 / Published: 19 November 2018
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Abstract
The study investigated the anti-inflammatory activity of the hydro methanolic extract of six leafy vegetables, namely Cassia auriculata, Passiflora edulis, Sesbania grandiflora, Olax zeylanica, Gymnema lactiferum, and Centella asiatica. The anti-inflammatory activity of methanolic extracts of leafy [...] Read more.
The study investigated the anti-inflammatory activity of the hydro methanolic extract of six leafy vegetables, namely Cassia auriculata, Passiflora edulis, Sesbania grandiflora, Olax zeylanica, Gymnema lactiferum, and Centella asiatica. The anti-inflammatory activity of methanolic extracts of leafy vegetables was evaluated using four in vitro-based assays: hemolysis inhibition, proteinase inhibition, protein denaturation inhibition, and lipoxygenase inhibition. Results showed that the percent inhibition of hemolysis from these leaf extracts (25–100 µg/mL dry weight basis (DW)) was within the range from 5.4% to 14.9%, and the leaves of P. edulis and O. zeylanica showed a significantly higher (p < 0.05) inhibition levels. Percent inhibition of protein denaturation of these leafy types was within the range of 36.0–61.0%, and the leaf extract of C. auriculata has exhibited a significantly higher (p < 0.05) inhibition level. Proteinase inhibitory activity of these leaf extracts was within the range of 20.2–25.9%. The lipoxygenase inhibition was within the range of 3.7–36.0%, and the leaf extract of G. lactiferum showed an improved ability to inhibit lipoxygenase activity. In conclusion, results revealed that all the studied leaves possess anti-inflammatory properties at different levels, and this could be due to the differences in the composition and concentration of bioactive compounds. Full article
(This article belongs to the Special Issue Anti-inflammatory Activity of Plant Polyphenols)
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Open AccessReview Alcoholic Liver Disease: Alcohol Metabolism, Cascade of Molecular Mechanisms, Cellular Targets, and Clinical Aspects
Biomedicines 2018, 6(4), 106; https://doi.org/10.3390/biomedicines6040106
Received: 18 September 2018 / Revised: 13 October 2018 / Accepted: 20 October 2018 / Published: 12 November 2018
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Abstract
Alcoholic liver disease is the result of cascade events, which clinically first lead to alcoholic fatty liver, and then mostly via alcoholic steatohepatitis or alcoholic hepatitis potentially to cirrhosis and hepatocellular carcinoma. Pathogenetic events are linked to the metabolism of ethanol and acetaldehyde [...] Read more.
Alcoholic liver disease is the result of cascade events, which clinically first lead to alcoholic fatty liver, and then mostly via alcoholic steatohepatitis or alcoholic hepatitis potentially to cirrhosis and hepatocellular carcinoma. Pathogenetic events are linked to the metabolism of ethanol and acetaldehyde as its first oxidation product generated via hepatic alcohol dehydrogenase (ADH) and the microsomal ethanol-oxidizing system (MEOS), which depends on cytochrome P450 2E1 (CYP 2E1), and is inducible by chronic alcohol use. MEOS induction accelerates the metabolism of ethanol to acetaldehyde that facilitates organ injury including the liver, and it produces via CYP 2E1 many reactive oxygen species (ROS) such as ethoxy radical, hydroxyethyl radical, acetyl radical, singlet radical, superoxide radical, hydrogen peroxide, hydroxyl radical, alkoxyl radical, and peroxyl radical. These attack hepatocytes, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells, and their signaling mediators such as interleukins, interferons, and growth factors, help to initiate liver injury including fibrosis and cirrhosis in susceptible individuals with specific risk factors. Through CYP 2E1-dependent ROS, more evidence is emerging that alcohol generates lipid peroxides and modifies the intestinal microbiome, thereby stimulating actions of endotoxins produced by intestinal bacteria; lipid peroxides and endotoxins are potential causes that are involved in alcoholic liver injury. Alcohol modifies SIRT1 (Sirtuin-1; derived from Silent mating type Information Regulation) and SIRT2, and most importantly, the innate and adapted immune systems, which may explain the individual differences of injury susceptibility. Metabolic pathways are also influenced by circadian rhythms, specific conditions known from living organisms including plants. Open for discussion is a 5-hit working hypothesis, attempting to define key elements involved in injury progression. In essence, although abundant biochemical mechanisms are proposed for the initiation and perpetuation of liver injury, patients with an alcohol problem benefit from permanent alcohol abstinence alone. Full article
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Open AccessReview CRISPR/Cas9 for Cancer Therapy: Hopes and Challenges
Biomedicines 2018, 6(4), 105; https://doi.org/10.3390/biomedicines6040105
Received: 17 October 2018 / Revised: 2 November 2018 / Accepted: 5 November 2018 / Published: 12 November 2018
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Abstract
Cancer is the second leading cause of death globally and remains a major economic and social burden. Although our understanding of cancer at the molecular level continues to improve, more effort is needed to develop new therapeutic tools and approaches exploiting these advances. [...] Read more.
Cancer is the second leading cause of death globally and remains a major economic and social burden. Although our understanding of cancer at the molecular level continues to improve, more effort is needed to develop new therapeutic tools and approaches exploiting these advances. Because of its high efficiency and accuracy, the CRISPR-Cas9 genome editing technique has recently emerged as a potentially powerful tool in the arsenal of cancer therapy. Among its many applications, CRISPR-Cas9 has shown an unprecedented clinical potential to discover novel targets for cancer therapy and to dissect chemical-genetic interactions, providing insight into how tumours respond to drug treatment. Moreover, CRISPR-Cas9 can be employed to rapidly engineer immune cells and oncolytic viruses for cancer immunotherapeutic applications. Perhaps more importantly, the ability of CRISPR-Cas9 to accurately edit genes, not only in cell culture models and model organisms but also in humans, allows its use in therapeutic explorations. In this review, we discuss important considerations for the use of CRISPR/Cas9 in therapeutic settings and major challenges that will need to be addressed prior to its clinical translation for a complex and polygenic disease such as cancer. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
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Open AccessReview A New Role for Vitamin D: The Enhancement of Oncolytic Viral Therapy in Pancreatic Cancer
Biomedicines 2018, 6(4), 104; https://doi.org/10.3390/biomedicines6040104
Received: 21 September 2018 / Revised: 25 October 2018 / Accepted: 30 October 2018 / Published: 5 November 2018
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Abstract
Oncolytic viruses have emerged as a novel class of anti-cancer therapeutics with one virus already receiving United States Food and Drug Administration (FDA) approval (talimogene laherparepvec) and many others undergoing testing in clinical trials. These viruses have direct lytic effects on tumor cells [...] Read more.
Oncolytic viruses have emerged as a novel class of anti-cancer therapeutics with one virus already receiving United States Food and Drug Administration (FDA) approval (talimogene laherparepvec) and many others undergoing testing in clinical trials. These viruses have direct lytic effects on tumor cells as well as immunomodulatory functions to increase inflammatory cell infiltrates in the tumor microenvironment. Despite all of the advances in cancer care, pancreatic cancer remains a highly lethal malignancy. One of the main barriers to successful systemic treatment of the disease is the fibrotic tumor stroma, as the unique extracellular matrix creates an environment that promotes tumor growth and is resistant to chemotherapy and other anti-cancer agents. The pleiotropic effects of Vitamin D have been widely studied, but recent research has now demonstrated it to be an effective agent in modulating pancreatic cancer stroma to facilitate the enhanced delivery of cytotoxic chemotherapy and immunogenicity in response to treatment. This review will explore the combination of Vitamin D with oncolytic viruses and how this novel application of Vitamin D’s ability to modulate pancreatic tumor stroma may result in a potential mechanism for increasing the efficacy of oncolytic virotherapy in pancreatic cancer. Full article
(This article belongs to the Special Issue Viruses in Cancer and Therapy)
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Open AccessReview Cellular Plasticity of Mammary Epithelial Cells Underlies Heterogeneity of Breast Cancer
Biomedicines 2018, 6(4), 103; https://doi.org/10.3390/biomedicines6040103
Received: 1 October 2018 / Revised: 25 October 2018 / Accepted: 30 October 2018 / Published: 1 November 2018
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Abstract
The hierarchical relationships between stem cells, lineage-committed progenitors, and differentiated cells remain unclear in several tissues, due to a high degree of cell plasticity, allowing cells to switch between different cell states. The mouse mammary gland, similarly to other tissues such as the [...] Read more.
The hierarchical relationships between stem cells, lineage-committed progenitors, and differentiated cells remain unclear in several tissues, due to a high degree of cell plasticity, allowing cells to switch between different cell states. The mouse mammary gland, similarly to other tissues such as the prostate, the sweat gland, and the respiratory tract airways, consists of an epithelium exclusively maintained by unipotent progenitors throughout adulthood. Such unipotent progenitors, however, retain a remarkable cellular plasticity, as they can revert to multipotency during epithelial regeneration as well as upon oncogene activation. Here, we revise the current knowledge on mammary cell hierarchies in light of the most recent lineage tracing studies performed in the mammary gland and highlight how stem cell differentiation or reversion to multipotency are at the base of tumor development and progression. In addition, we will discuss the current knowledge about the interplay between tumor cells of origin and defined genetic mutations, leading to different tumor types, and its implications in choosing specific therapeutic protocols for breast cancer patients. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
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Open AccessReview The Role of Gene Therapy in Premature Ovarian Insufficiency Management
Biomedicines 2018, 6(4), 102; https://doi.org/10.3390/biomedicines6040102
Received: 9 September 2018 / Revised: 23 October 2018 / Accepted: 26 October 2018 / Published: 1 November 2018
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Abstract
Premature ovarian insufficiency (POI) is a highly prevalent disorder, characterized by the development of menopause before the age of 40. Most cases are idiopathic; however, in some women the cause of this condition (e.g.; anticancer treatment, genetic disorders, and enzymatic defects) could be [...] Read more.
Premature ovarian insufficiency (POI) is a highly prevalent disorder, characterized by the development of menopause before the age of 40. Most cases are idiopathic; however, in some women the cause of this condition (e.g.; anticancer treatment, genetic disorders, and enzymatic defects) could be identified. Although hormone-replacement therapy, the principal therapeutic approach for POI, helps alleviate the related symptoms, this does not effectively solve the issue of fertility. Assisted reproductive techniques also lack efficacy in these women. Thus, an effective approach to manage patients with POI is highly warranted. Several mechanisms associated with POI have been identified, including the lack of function of the follicle-stimulating hormone (FSH) receptor, alterations in apoptosis control, mutations in Sal-like 4 genes, and thymulin or basonuclin-1 deficiency. The above mentioned may be good targets for gene therapy in order to correct defects leading to POI. The goal of this review is to summarize current experiences on POI studies that employed gene therapy, and to discuss possible future directions in this field. Full article
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Open AccessReview Notch and Wnt Dysregulation and Its Relevance for Breast Cancer and Tumor Initiation
Biomedicines 2018, 6(4), 101; https://doi.org/10.3390/biomedicines6040101
Received: 10 October 2018 / Revised: 24 October 2018 / Accepted: 26 October 2018 / Published: 1 November 2018
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Abstract
Breast cancer is the second leading cause of cancer deaths among women in the world. Treatment has been improved and, in combination with early detection, this has resulted in reduced mortality rates. Further improvement in therapy development is however warranted. This will be [...] Read more.
Breast cancer is the second leading cause of cancer deaths among women in the world. Treatment has been improved and, in combination with early detection, this has resulted in reduced mortality rates. Further improvement in therapy development is however warranted. This will be particularly important for certain sub-classes of breast cancer, such as triple-negative breast cancer, where currently no specific therapies are available. An important therapy development focus emerges from the notion that dysregulation of two major signaling pathways, Notch and Wnt signaling, are major drivers for breast cancer development. In this review, we discuss recent insights into the Notch and Wnt signaling pathways and into how they act synergistically both in normal development and cancer. We also discuss how dysregulation of the two pathways contributes to breast cancer and strategies to develop novel breast cancer therapies starting from a Notch and Wnt dysregulation perspective. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
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Open AccessReview Gastric Stem Cell and Cellular Origin of Cancer
Biomedicines 2018, 6(4), 100; https://doi.org/10.3390/biomedicines6040100
Received: 30 September 2018 / Revised: 28 October 2018 / Accepted: 28 October 2018 / Published: 31 October 2018
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Abstract
Several stem cell markers within the gastrointestinal epithelium have been identified in mice. One of the best characterized is Lgr5 (leucine-rich repeat-containing G-protein coupled receptor 5) and evidence suggests that Lgr5+ cells in the gut are the origin of gastrointestinal cancers. Reserve [...] Read more.
Several stem cell markers within the gastrointestinal epithelium have been identified in mice. One of the best characterized is Lgr5 (leucine-rich repeat-containing G-protein coupled receptor 5) and evidence suggests that Lgr5+ cells in the gut are the origin of gastrointestinal cancers. Reserve or facultative stem or progenitor cells with the ability to convert to Lgr5+ cells following injury have also been identified. Unlike the intestine, where Lgr5+ cells at the crypt base act as active stem cells, the stomach may contain unique stem cell populations, since gastric Lgr5+ cells seem to behave as a reserve rather than active stem cells, both in the corpus and in the antral glands. Gastrointestinal stem cells are supported by a specific microenvironment, the stem cell niche, which also promotes tumorigenesis. This review focuses on stem cell markers in the gut and their supporting niche factors. It also discusses the molecular mechanisms that regulate stem cell function and tumorigenesis. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
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Open AccessArticle Pyrrole-Mediated Peptide Cyclization Identified through Genetically Reprogrammed Peptide Synthesis
Biomedicines 2018, 6(4), 99; https://doi.org/10.3390/biomedicines6040099
Received: 28 September 2018 / Revised: 23 October 2018 / Accepted: 24 October 2018 / Published: 30 October 2018
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Abstract
Flexible in vitro translation (FIT) was used as a screening method to uncover a new methodology for peptide constraining based on the attack of a nucleophilic side-chain functionality onto an oxidized furylalanine side chain. A set of template peptides, each containing furylalanine as [...] Read more.
Flexible in vitro translation (FIT) was used as a screening method to uncover a new methodology for peptide constraining based on the attack of a nucleophilic side-chain functionality onto an oxidized furylalanine side chain. A set of template peptides, each containing furylalanine as furan-modified amino acid and a nucleophilic residue (Cys, His, Lys, Arg, Ser, or Tyr), was produced through FIT. The translation mixtures were treated with N-bromosuccinimide (NBS) to achieve selective furan oxidation and subsequent MALDI analysis demonstrated Lys and Ser as promising residues for cyclisation. Solid-phase peptide synthesis (SPPS) was used to synthesize suitable amounts of material for further in-depth analysis and characterisation. It was found that in the case of the peptide containing lysine next to a furylalanine residue, a one-pot oxidation and reduction reaction leads to the generation of a cyclic peptide featuring a pyrrole moiety as cyclisation motif, resulting from the attack of the lysine side chain onto the oxidized furylalanine side chain. Structural evidence was provided via NMR and the generality of the methodology was explored. We hereby expand the scope of our previously developed furan-based peptide labeling and crosslinking strategy. Full article
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
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Open AccessArticle Azasulfurylpeptide Modulation of CD36-Mediated Inflammation Without Effect on Neovascularization
Biomedicines 2018, 6(4), 98; https://doi.org/10.3390/biomedicines6040098
Received: 28 August 2018 / Revised: 26 September 2018 / Accepted: 5 October 2018 / Published: 22 October 2018
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Abstract
Modulation of the cluster of differentiation-36 receptor (CD36) has proven promising for dampening pro-inflammatory macrophage signaling. For example, azapeptides (e.g., 1 and 2) bind CD36 selectively with high affinity, mitigate Toll-like receptor (TLR) agonist-induced overproduction of nitric oxide (NO), and reduce pro-inflammatory [...] Read more.
Modulation of the cluster of differentiation-36 receptor (CD36) has proven promising for dampening pro-inflammatory macrophage signaling. For example, azapeptides (e.g., 1 and 2) bind CD36 selectively with high affinity, mitigate Toll-like receptor (TLR) agonist-induced overproduction of nitric oxide (NO), and reduce pro-inflammatory cytokine and chemokine production in macrophages. Moreover, semicarbazides 1 and 2 inhibit microvascular sprouting mediated through CD36 in the choroid explant. Seeking a selective CD36 modulator that mediated inflammation without influencing neovascularization, a set of azasulfurylpeptides (e.g., 3ae) were synthesized in which the semicarbazide was replaced by an N-aminosulfamide residue using a novel solid-phase approach. Notably, azasulfurylpeptide 3c diminished selectively CD36-mediated TLR-2-triggered inflammatory response without affecting neovascularization. Subtle chemical modification at the peptide backbone from a carbonyl to a sulfuryl residue has had a selective effect on biological activity providing a valuable probe for studying CD36 chemical biology. Full article
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
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Open AccessArticle Engineering of an Anti-Inflammatory Peptide Based on the Disulfide-Rich Linaclotide Scaffold
Biomedicines 2018, 6(4), 97; https://doi.org/10.3390/biomedicines6040097
Received: 1 July 2018 / Revised: 11 September 2018 / Accepted: 21 September 2018 / Published: 6 October 2018
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Abstract
Inflammatory bowel diseases are a set of complex and debilitating diseases, for which there is no satisfactory treatment. Peptides as small as three amino acids have been shown to have anti-inflammatory activity in mouse models of colitis, but they are likely to be [...] Read more.
Inflammatory bowel diseases are a set of complex and debilitating diseases, for which there is no satisfactory treatment. Peptides as small as three amino acids have been shown to have anti-inflammatory activity in mouse models of colitis, but they are likely to be unstable, limiting their development as drug leads. Here, we have grafted a tripeptide from the annexin A1 protein into linaclotide, a 14-amino-acid peptide with three disulfide bonds, which is currently in clinical use for patients with chronic constipation or irritable bowel syndrome. This engineered disulfide-rich peptide maintained the overall fold of the original synthetic guanylate cyclase C agonist peptide, and reduced inflammation in a mouse model of acute colitis. This is the first study to show that this disulfide-rich peptide can be used as a scaffold to confer a new bioactivity. Full article
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
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Open AccessArticle Genistein Loaded Nanofibers Protect Spinal Cord Tissue Following Experimental Injury in Rats
Biomedicines 2018, 6(4), 96; https://doi.org/10.3390/biomedicines6040096
Received: 18 September 2018 / Revised: 28 September 2018 / Accepted: 1 October 2018 / Published: 4 October 2018
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Abstract
Innovative drug-delivery systems offer a unique approach to effectively provide therapeutic drug dose over the needed time to achieve better tissue protection and enhanced recovery. The hypothesis of the current study was to test the antioxidant and anti-inflammatory effects of genistein and nanofibers [...] Read more.
Innovative drug-delivery systems offer a unique approach to effectively provide therapeutic drug dose over the needed time to achieve better tissue protection and enhanced recovery. The hypothesis of the current study was to test the antioxidant and anti-inflammatory effects of genistein and nanofibers on the spinal cord tissue following experimental spinal cord injury (SCI). Rats were treated post SCI with genistein that is loaded on chitosan/polyvinyl alcohol (CS/PVA) nanofibers as an implantable drug-delivery system. SCI caused marked oxidative damage and inflammation, as is evident by the reduction in the super oxide dismutase (SOD) activity and the level of interleukin-10 (IL-10) in injured spinal cord tissue, as well as the significant increase in the levels of nitric oxide (NO), malondialdehyde (MDA), and tumor necrosis factor-alpha (TNF-α). Treatment of rats post SCI with genistein and CS/PVA nanofibers improved most of the above-mentioned biochemical parameters and shifted them toward the control group values. Genistein induced an increase in the activity of SOD and the level of IL-10, while causing a decrease in NO, MDA, and TNF-α in injured spinal cord tissue. Genistein and CS/PVA nanofibers provide a novel combination for treating inflammatory nervous tissue conditions, especially when combined as an implantable drug-delivery system. Full article
(This article belongs to the Section Neurologic Diseases)
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Open AccessEditorial Editorial of the Special Issue: Antisense Therapies
Biomedicines 2018, 6(4), 95; https://doi.org/10.3390/biomedicines6040095
Received: 5 September 2018 / Revised: 11 September 2018 / Accepted: 20 September 2018 / Published: 27 September 2018
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(This article belongs to the Special Issue Antisense Therapy)
Open AccessReview Recombinant Viruses for Cancer Therapy
Biomedicines 2018, 6(4), 94; https://doi.org/10.3390/biomedicines6040094
Received: 14 August 2018 / Revised: 17 September 2018 / Accepted: 20 September 2018 / Published: 25 September 2018
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Abstract
Recombinant viruses are novel therapeutic agents that can be utilized for treatment of various diseases, including cancers. Recombinant viruses can be engineered to express foreign transgenes and have a broad tropism allowing gene expression in a wide range of host cells. They can [...] Read more.
Recombinant viruses are novel therapeutic agents that can be utilized for treatment of various diseases, including cancers. Recombinant viruses can be engineered to express foreign transgenes and have a broad tropism allowing gene expression in a wide range of host cells. They can be selected or designed for specific therapeutic goals; for example, recombinant viruses could be used to stimulate host immune response against tumor-specific antigens and therefore overcome the ability of the tumor to evade the host’s immune surveillance. Alternatively, recombinant viruses could express immunomodulatory genes which stimulate an anti-cancer immune response. Oncolytic viruses can replicate specifically in tumor cells and induce toxic effects leading to cell lysis and apoptosis. However, each of these approaches face certain difficulties that must be resolved to achieve maximum therapeutic efficacy. In this review we discuss actively developing approaches for cancer therapy based on recombinant viruses, problems that need to be overcome, and possible prospects for further development of recombinant virus based therapy. Full article
(This article belongs to the Special Issue Viruses in Cancer and Therapy)
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