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Biomedicines
Volume 8
Issue 6
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Biomedicines, Volume 8, Issue 6 (June 2020) – 42 articles

Cover Story (view full-size image): In cardiomyocyte-specific CYP2J2 transgenic (Tr) mice, cis-epoxyeicosatrienoic acids (EETs) increased in cardiac and erythrocyte membranes following acute myocardial infarction. This increase was associated with improved cardiac outcomes compared to wild-type mice subjected to similar conditions. The association between the cardiac and erythrocyte membrane total cis-EETs in Tr mice was both positive and significant, suggesting that erythrocyte membrane cis-EETs could be used to report cardiac EET levels. View this paper
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14 pages, 1079 KiB  
Review
Defining Parallels between the Salivary Glands and Pancreas to Better Understand Pancreatic Carcinogenesis
by Céline Tiffon
Biomedicines 2020, 8(6), 178; https://doi.org/10.3390/biomedicines8060178 - 26 Jun 2020
Cited by 12 | Viewed by 7422
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a dismal prognosis, largely due to its late presentation. Methods for early detection, the development of reliable screening tools, and the identification of sensitive and specific biomarkers have remained essential research priorities to [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a dismal prognosis, largely due to its late presentation. Methods for early detection, the development of reliable screening tools, and the identification of sensitive and specific biomarkers have remained essential research priorities to improve early patient management and outcomes. The pancreas and salivary glands share histological and functional similarities, and the salivary glands have demonstrated a role in oral and systemic health. This review focuses on the similarities and differences between the pancreas and salivary glands and how these can inform our understanding of PDAC genesis and early diagnosis. In particular, chemical exposure, which alters salivary gland gene transcription and morphogenesis, may not only directly impact salivary gland regulation but alter pancreatic function via the systemic secretion of growth hormones. Diabetes and obesity are associated with an increased risk of pancreatic cancer, and a link between chemical exposure and the development of diabetes, obesity, and consequently PDAC genesis is proposed. Possible mechanisms include altering salivary or pancreatic morphology and organ function, disrupting endocrine signaling, or altering pro-inflammatory homeostasis. Finally, saliva contains putative specific biomarkers that show promise as non-invasive diagnostic tools for PDAC. Full article
(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: From Pathophysiology to Novel Therapeutic Approaches)
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14 pages, 2215 KiB  
Article
Carnosine Activates Cellular Stress Response in Podocytes and Reduces Glycative and Lipoperoxidative Stress
by Maria Scuto, Angela Trovato Salinaro, Sergio Modafferi, Alessandra Polimeni, Tilman Pfeffer, Tim Weigand, Vittorio Calabrese, Claus Peter Schmitt and Verena Peters
Biomedicines 2020, 8(6), 177; https://doi.org/10.3390/biomedicines8060177 - 26 Jun 2020
Cited by 24 | Viewed by 3393
Abstract
Carnosine improves diabetic complications, including diabetic nephropathy, in in vivo models. To further understand the underlying mechanism of nephroprotection, we studied the effect of carnosine under glucose-induced stress on cellular stress response proteins in murine immortalized podocytes, essential for glomerular function. High-glucose stress [...] Read more.
Carnosine improves diabetic complications, including diabetic nephropathy, in in vivo models. To further understand the underlying mechanism of nephroprotection, we studied the effect of carnosine under glucose-induced stress on cellular stress response proteins in murine immortalized podocytes, essential for glomerular function. High-glucose stress initiated stress response by increasing intracellular heat shock protein 70 (Hsp70), sirtuin-1 (Sirt-1), thioredoxin (Trx), glutamate-cysteine ligase (gamma-glutamyl cysteine synthetase; γ-GCS) and heme oxygenase-1 (HO-1) in podocytes by 30–50% compared to untreated cells. Carnosine (1 mM) also induced a corresponding upregulation of these intracellular stress markers, which was even more prominent compared to glucose for Hsp70 (21%), γ-GCS and HO-1 (13% and 20%, respectively; all p < 0.001). Co-incubation of carnosine (1 mM) and glucose (25 mM) induced further upregulation of Hsp70 (84%), Sirt-1 (52%), Trx (35%), γ-GCS (90%) and HO-1 (73%) concentrations compared to untreated cells (all p < 0.001). The glucose-induced increase in 4-hydroxy-trans-2-nonenal (HNE) and protein carbonylation was reduced dose-dependently by carnosine by more than 50% (p < 0.001). Although podocytes tolerated high carnosine concentrations (10 mM), high carnosine levels only slightly increased Trx and γ-GCS (10% and 19%, respectively, compared to controls; p < 0.001), but not Hsp70, Sirt-1 and HO-1 proteins (p not significant), and did not modify the glucose-induced oxidative stress response. In podocytes, carnosine induced cellular stress tolerance and resilience pathways and was highly effective in reducing high-glucose-induced glycative and lipoperoxidative stress. Carnosine in moderate concentrations exerted a direct podocyte molecular protective action. Full article
(This article belongs to the Section Tumor Cell Biology)
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15 pages, 4826 KiB  
Article
Hyperthermia Disturbs and Delays Spontaneous Differentiation of Human Embryoid Bodies
by Ji Hyun Kwon, Hyun Kyu Kim, Tae Won Ha, Jeong Suk Im, Byung Hoo Song, Ki Sung Hong, Jae Sang Oh, Jaeseok Han and Man Ryul Lee
Biomedicines 2020, 8(6), 176; https://doi.org/10.3390/biomedicines8060176 - 26 Jun 2020
Cited by 2 | Viewed by 2929
Abstract
Various types of stress stimuli have been shown to threaten the normal development of embryos during embryogenesis. Prolonged heat exposure is the most common stressor that poses a threat to embryo development. Despite the extensive investigation of heat stress control mechanisms in the [...] Read more.
Various types of stress stimuli have been shown to threaten the normal development of embryos during embryogenesis. Prolonged heat exposure is the most common stressor that poses a threat to embryo development. Despite the extensive investigation of heat stress control mechanisms in the cytosol, the endoplasmic reticulum (ER) heat stress response remains unclear. In this study, we used human embryonic stem cells (hESCs) to examine the effect of heat stress on early embryonic development, specifically alterations in the ER stress response. In a hyperthermic (42 °C) culture, ER stress response genes involved in hESC differentiation were induced within 1 h of exposure, which resulted in disturbed and delayed differentiation. In addition, hyperthermia increased the expression levels of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) genes, which are associated with the protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway. Furthermore, we demonstrated that tauroursodeoxycholic acid, a chemical chaperone, mitigated the delayed differentiation under hyperthermia. Our study identified novel gene markers in response to hyperthermia-induced ER stress on hESCs, thereby providing further insight into the mechanisms that regulate human embryogenesis. Full article
(This article belongs to the Section Model Systems in Research and Development)
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15 pages, 1076 KiB  
Review
Risk Factors Contributing to the Occurrence and Recurrence of Hepatocellular Carcinoma in Hepatitis C Virus Patients Treated with Direct-Acting Antivirals
by Sara Kishta, Ashraf Tabll, Tea Omanovic Kolaric, Robert Smolic and Martina Smolic
Biomedicines 2020, 8(6), 175; https://doi.org/10.3390/biomedicines8060175 - 25 Jun 2020
Cited by 12 | Viewed by 4384
Abstract
Although hepatitis C virus (HCV) RNA may be eliminated from blood circulation by direct-acting antivirals (DAA) therapy as assessed by real-time polymerase chain reaction (PCR), HCV RNA can still be present in liver tissue, and this is known as occult HCV. There has [...] Read more.
Although hepatitis C virus (HCV) RNA may be eliminated from blood circulation by direct-acting antivirals (DAA) therapy as assessed by real-time polymerase chain reaction (PCR), HCV RNA can still be present in liver tissue, and this is known as occult HCV. There has been a lot of controversy surrounding the recurrence of hepatocellular carcinoma (HCC) after DAA treatment of hepatic cells infected with chronic HCV. One of the main risk factors that leads to de novo HCC is the chronicity of HCV in hepatic cells. There are many studies regarding the progression of HCV-infected hepatic cells to HCC. However, there is a lack of research on the different molecular mechanisms that lead to the progression of chronic HCV infection to HCC, as well as on the effect of HCV on the alteration of DNA ploidy, which eventually leads to a recurrence of HCC after DAA treatment. In this review article, we will address some risk factors that could lead to the development/recurrence of HCC after treatment of HCV with DAA therapy, such as the role of liver cirrhosis, the alteration of DNA ploidy, the reactivation of hepatitis B virus (HBV), the role of cytokines and the alteration of the immune system, concomitant non- alcoholic fatty liver disease (NAFLD), obesity, alcohol consumption and also occult HCV infection/co-infection. Clinicians should be cautious considering that full eradication of hepatocarcinogenesis cannot be successfully accomplished by anti-HCV treatment alone. Full article
(This article belongs to the Section Virology, Vaccines and Viral Vectors)
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14 pages, 1232 KiB  
Article
Evaluation of Ethnic Variations in Visceral, Subcutaneous, Intra-Pancreatic, and Intra-Hepatic Fat Depositions by Magnetic Resonance Imaging among New Zealanders
by John Zhiyong Yang, Dech Dokpuang, Reza Nemati, Kevin Haokun He, Andy Baige Zheng, Maxim S. Petrov and Jun Lu
Biomedicines 2020, 8(6), 174; https://doi.org/10.3390/biomedicines8060174 - 25 Jun 2020
Cited by 10 | Viewed by 4266
Abstract
Anthropometric indices, such as body mass index (BMI), waist circumference (WC), and waist to height ratio (WHtR), have limitations in accurately predicting the pathophysiology of diabetes mellitus, cardiovascular diseases, and metabolic syndrome due to ethnic differences in fat distribution. Recent studies showed that [...] Read more.
Anthropometric indices, such as body mass index (BMI), waist circumference (WC), and waist to height ratio (WHtR), have limitations in accurately predicting the pathophysiology of diabetes mellitus, cardiovascular diseases, and metabolic syndrome due to ethnic differences in fat distribution. Recent studies showed that the visceral adipose tissue (VAT) deposition and fat content of internal organs, most notably intra-hepatic and intra-pancreatic fat, has emerged as a more important parameter. In this study, we aimed to assess the coordination between the traditional anthropometric indices and the various fat depositions within different ethnicities in New Zealand. We recruited 104 participants with different ethnic backgrounds, including New Zealand Europeans, Māori (the indigenous people of New Zealand), Pacific Islanders (PI), and Asians. Their weight, height, and WC were measured, and subcutaneous, visceral, intra-hepatic, and intra-pancreatic fat depositions were obtained by magnetic resonance imaging (MRI). The result showed VAT, but not subcutaneous adipose tissue (SAT) depositions at all levels were significantly varied among the three groups. BMI was associated best with L23SAT in NZ Europeans (30%) and L45VAT in Māori/PI (24.3%). WC and WHtR were correlated well with L45SAT in the total population (18.8% and 12.2%, respectively). Intra-pancreatic fat deposition had a positive Pearson relationship with NZ European BMI and Māori/PI WC, but no regression correlation with anthropometric indices. Conventional anthropometric indices did not correspond to the same fat depositions across different ethnic groups. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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12 pages, 834 KiB  
Article
The Percentage of Free PSA and Urinary Markers Distinguish Prostate Cancer from Benign Hyperplasia and Contribute to a More Accurate Indication for Prostate Biopsy
by Zlata Huskova, Jana Knillova, Zdenek Kolar, Jana Vrbkova, Milan Kral and Jan Bouchal
Biomedicines 2020, 8(6), 173; https://doi.org/10.3390/biomedicines8060173 - 25 Jun 2020
Cited by 7 | Viewed by 3318
Abstract
The main advantage of urinary biomarkers is their noninvasive character and the ability to detect multifocal prostate cancer (CaP). We have previously implemented a quadruplex assay of urinary markers into clinical practice (PCA3, AMACR, TRPM8 and MSMB with KLK3 normalization). In this [...] Read more.
The main advantage of urinary biomarkers is their noninvasive character and the ability to detect multifocal prostate cancer (CaP). We have previously implemented a quadruplex assay of urinary markers into clinical practice (PCA3, AMACR, TRPM8 and MSMB with KLK3 normalization). In this study, we aimed to validate it in a larger cohort with serum PSA 2.5–10 ng/mL and test other selected transcripts and clinical parameters, including the percentage of free prostate-specific antigen (PSA) (% free PSA) and inflammation. In the main cohort of 299 men, we tested the quadruplex transcripts. In a subset of 146 men, we analyzed additional transcripts (CD45, EPCAM, EZH2, Ki67, PA2G4, PSGR, RHOA and TBP). After a prostate massage, the urine was collected, RNA isolated from a cell sediment and qRT-PCR performed. Ct values of KLK3 (i.e., PSA) were strongly correlated with Ct values of other genes which play a role in CaP (i.e., PCA3, AMACR, TRPM8, MSMB and PSGR). AMACR, PCA3, TRPM8 and EZH2 mRNA expression, as well as % free PSA, were significantly different for BPH and CaP. The best combined model (% free PSA plus PCA3 and AMACR) achieved an AUC of 0.728 in the main cohort. In the subset of patients, the best AUC 0.753 was achieved for the combination of PCA3, % free PSA, EPCAM and PSGR. PCA3 mRNA was increased in patients with inflammation, however, this did not affect the stratification of patients indicated for prostate biopsy. In conclusion, the percentage of free PSA and urinary markers contribute to a more accurate indication for prostate biopsy. Full article
(This article belongs to the Special Issue Liquid Biopsies in Cancer Diagnosis, Monitoring and Prognosis)
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10 pages, 1172 KiB  
Review
False Myths versus Medical Facts: Ten Common Misconceptions Related to Dry Eye Disease
by Giuseppe Giannaccare and Vincenzo Scorcia
Biomedicines 2020, 8(6), 172; https://doi.org/10.3390/biomedicines8060172 - 24 Jun 2020
Cited by 5 | Viewed by 3303
Abstract
Since the first definition of dry eye, rapid progress has been made in this field over the past decades that has guided profound changes in the definition, classification, diagnosis and management of the disease. Although dry eye is one of the most frequently [...] Read more.
Since the first definition of dry eye, rapid progress has been made in this field over the past decades that has guided profound changes in the definition, classification, diagnosis and management of the disease. Although dry eye is one of the most frequently encountered ocular conditions, various “old” misconceptions persist, in particular among comprehensive ophthalmologists not specialized in ocular surface diseases. These misconceptions hamper the correct diagnosis and the proper management of dry eye in the routine clinical practice. In the present review, we described the 10 most common misconceptions related to dry eye and provided an evidence-based guide for reconsidering them using the format “false myth versus medical fact”. These misconceptions concern the dry eye definition and classification (#1, #2, #3), disease physiopathology (#4), diagnosis (#5), symptoms (#6, #7) and treatment (#8, #9, #10). Nowadays, dry eye is still an under-recognized and evolving disease that poses significant clinical challenges to ophthalmologists. The two major reasons behind these challenges include the heterogeneity of the conditions that fall under the umbrella term of dry eye and the common discrepancy between signs and symptoms. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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21 pages, 6678 KiB  
Article
Impact of Local High Doses of Radiation by Neutron Activated Mn Dioxide Powder in Rat Lungs: Protracted Pathologic Damage Initiated by Internal Exposure
by Kazuko Shichijo, Toshihiro Takatsuji, Zhaslan Abishev, Darkhan Uzbekov, Nailya Chaizhunusova, Dariya Shabdarbaeva, Daisuke Niino, Minako Kurisu, Yoshio Takahashi, Valeriy Stepanenko, Almas Azhimkhanov and Masaharu Hoshi
Biomedicines 2020, 8(6), 171; https://doi.org/10.3390/biomedicines8060171 - 23 Jun 2020
Cited by 7 | Viewed by 3541
Abstract
Internal radiation exposure from neutron-induced radioisotopes environmentally activated following atomic bombing or nuclear accidents should be considered for a complete picture of pathologic effects on survivors. Inhaled hot particles expose neighboring tissues to locally ultra-high doses of β-rays and can cause pathologic damage. [...] Read more.
Internal radiation exposure from neutron-induced radioisotopes environmentally activated following atomic bombing or nuclear accidents should be considered for a complete picture of pathologic effects on survivors. Inhaled hot particles expose neighboring tissues to locally ultra-high doses of β-rays and can cause pathologic damage. 55MnO2 powder was activated by a nuclear reactor to make 56MnO2 which emits β-rays. Internal exposures were compared with external γ-rays. Male Wistar rats were administered activated powder by inhalation. Lung samples were observed by histological staining at six hours, three days, 14 days, two months, six months and eight months after the exposure. Synchrotron radiation—X-ray fluorescence—X-ray absorption near-edge structure (SR–XRF–XANES) was utilized for the chemical analysis of the activated 56Mn embedded in lung tissues. 56Mn beta energy spectrum around the particles was calculated to assess the local dose rate and accumulated dose. Hot particles located in the bronchiole and in damaged alveolar tissue were identified as accumulations of Mn and iron. Histological changes showed evidence of emphysema, hemorrhage and severe inflammation from six hours through eight months. Apoptosis was observed in the bronchiole epithelium. Our study shows early event damage from the locally ultra-high internal dose leads to pathogenesis. The trigger of emphysema and hemorrhage was likely early event damage to blood vessels integral to alveolar walls. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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15 pages, 2730 KiB  
Article
ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells
by Amineh Ghaderi, Amir Hossein Daneshmanesh, Ali Moshfegh, Parviz Kokhaei, Jan Vågberg, Johan Schultz, Thomas Olin, Sara Harrysson, Karin E Smedby, Elias Drakos, Georgios Z. Rassidakis, Anders Österborg, Håkan Mellstedt and Mohammad Hojjat-Farsangi
Biomedicines 2020, 8(6), 170; https://doi.org/10.3390/biomedicines8060170 - 23 Jun 2020
Cited by 27 | Viewed by 15153
Abstract
The receptor tyrosine kinase ROR1 is absent in most normal adult tissues, but overexpressed in several malignancies. In this study, we explored clinical and functional inhibitory aspects of ROR1 in diffuse large B-cell lymphoma (DLBCL). ROR1 expression in tumor cells was more often [...] Read more.
The receptor tyrosine kinase ROR1 is absent in most normal adult tissues, but overexpressed in several malignancies. In this study, we explored clinical and functional inhibitory aspects of ROR1 in diffuse large B-cell lymphoma (DLBCL). ROR1 expression in tumor cells was more often observed in primary refractory DLBCL, Richter’s syndrome and transformed follicular lymphoma than in relapsed and non-relapsed DLBCL patients (p < 0.001). A survival effect of ROR1 expression was preliminarily observed in relapsed/refractory patients independent of gender and stage but not of age, cell of origin and international prognostic index. A second generation small molecule ROR1 inhibitor (KAN0441571C) induced apoptosis of ROR1+ DLBCL cell lines, similar to venetoclax (BCL-2 inhibitor) but superior to ibrutinib (BTK inhibitor). The combination of KAN0441571C and venetoclax at EC50 concentrations induced almost complete killing of DLBCL cell lines. Apoptosis was accompanied by the downregulation of BCL-2 and MCL-1 and confirmed by the cleavage of PARP and caspases 3, 8, 9. PI3Kδ/AKT/mTOR (non-canonical Wnt pathway) as well as β-catenin and CK1δ (canonical pathway) were inactivated. In zebra fishes transplanted with a ROR1+ DLBCL cell line, KAN0441571C induced a significant tumor reduction. New drugs with mechanisms of action other than those available for DLBCL are warranted. ROR1 inhibitors might represent a novel promising approach. Full article
(This article belongs to the Section Cancer Biology and Oncology)
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22 pages, 1414 KiB  
Review
From Orai to E-Cadherin: Subversion of Calcium Trafficking in Cancer to Drive Proliferation, Anoikis-Resistance, and Metastasis
by Aarushi Sharma and Randolph C. Elble
Biomedicines 2020, 8(6), 169; https://doi.org/10.3390/biomedicines8060169 - 21 Jun 2020
Cited by 12 | Viewed by 5005
Abstract
The common currency of epithelial differentiation and homeostasis is calcium, stored primarily in the endoplasmic reticulum, rationed according to need, and replenished from the extracellular milieu via store-operated calcium entry (SOCE). This currency is disbursed by the IP3 receptor in response to diverse [...] Read more.
The common currency of epithelial differentiation and homeostasis is calcium, stored primarily in the endoplasmic reticulum, rationed according to need, and replenished from the extracellular milieu via store-operated calcium entry (SOCE). This currency is disbursed by the IP3 receptor in response to diverse extracellular signals. The rate of release is governed by regulators of proliferation, autophagy, survival, and programmed cell death, the strength of the signal leading to different outcomes. Intracellular calcium acts chiefly through intermediates such as calmodulin that regulates growth factor receptors such as epidermal growth factor receptor (EGFR), actin polymerization, and adherens junction assembly and maintenance. Here we review this machinery and its role in differentiation, then consider how cancer cells subvert it to license proliferation, resist anoikis, and enable metastasis, either by modulating the level of intracellular calcium or its downstream targets or effectors such as EGFR, E-cadherin, IQGAP1, TMEM16A, CLCA2, and TRPA1. Implications are considered for the roles of E-cadherin and growth factor receptors in circulating tumor cells and metastasis. The discovery of novel, cell type-specific modulators and effectors of calcium signaling offers new possibilities for cancer chemotherapy. Full article
(This article belongs to the Special Issue Calcium Signaling and Its Dysregulation in Cancer)
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13 pages, 2078 KiB  
Article
The Effect of Sleeve Gastrectomy on Oxidative Stress in Obesity
by Alessio Metere, Claire E. Graves, Donatella Pietraforte and Giovanni Casella
Biomedicines 2020, 8(6), 168; https://doi.org/10.3390/biomedicines8060168 - 19 Jun 2020
Cited by 12 | Viewed by 2476
Abstract
High concentrations of free radicals are present in the blood of obese patients. Free radicals are associated with endothelial dysfunction, diabetes, and neoplastic transformation, all conditions that are closely related to obesity. The purpose of our study was to determine whether bariatric surgery [...] Read more.
High concentrations of free radicals are present in the blood of obese patients. Free radicals are associated with endothelial dysfunction, diabetes, and neoplastic transformation, all conditions that are closely related to obesity. The purpose of our study was to determine whether bariatric surgery modifies the production of free radicals in obese patients. In total, 20 patients with morbid obesity, who were candidates for laparoscopic sleeve gastrectomy (SG), and 18 controls were enrolled in the study. Oxidative stress was studied in obese subjects before and after sleeve gastrectomy. The evaluation of oxidative stress was carried out on blood samples using electron paramagnetic resonance, a refined spectroscopic technique used to identify and quantify the major free radicals, such as •OH, O2•, ONOO-, and NO. Oxidative stress was higher in subjects with morbid obesity prior to surgery, compared to the controls (CP• 9.9 ± 0.3 µM vs. 5.8 ± 0.2 µM). After SG, values decreased to levels comparable to those of controls (CP• 5.4 ± 0.2 µM). Further analysis identified O2• as the main free radical responsible for the oxidative stress. Obesity is associated with an increased blood concentration of free radicals. The normalization of free radicals after sleeve gastrectomy highlights another important benefit of this bariatric surgery technique. Full article
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11 pages, 2901 KiB  
Article
MSH2 Overexpression Due to an Unclassified Variant in 3’-Untranslated Region in a Patient with Colon Cancer
by Raffaella Liccardo, Antonio Nolano, Matilde Lambiase, Carlo Della Ragione, Marina De Rosa, Paola Izzo and Francesca Duraturo
Biomedicines 2020, 8(6), 167; https://doi.org/10.3390/biomedicines8060167 - 19 Jun 2020
Cited by 7 | Viewed by 3073
Abstract
Background: The loss or low expression of DNA mismatch repair (MMR) genes can result in genomic instability and tumorigenesis. One such gene, MSH2, is mutated or rearranged in Lynch syndrome (LS), which is characterized by a high risk of tumor development, including colorectal [...] Read more.
Background: The loss or low expression of DNA mismatch repair (MMR) genes can result in genomic instability and tumorigenesis. One such gene, MSH2, is mutated or rearranged in Lynch syndrome (LS), which is characterized by a high risk of tumor development, including colorectal cancer. However, many variants identified in this gene are often defined as variants of uncertain significance (VUS). In this study, we selected a variant in the 3′ untranslated region (UTR) of MSH2 (c*226A > G), identified in three affected members of a LS family and already reported in the literature as a VUS. Methods: The effect of this variant on the activity of the MMR complex was examined using a set of functional assays to evaluate MSH2 expression. Results: We found MSH2 was overexpressed compared to healthy controls, as determined by RTqPCR and Western blot analyses of total RNA and proteins, respectively, extracted from peripheral blood samples. These results were confirmed by luciferase reporter gene assays. Conclusions: We therefore speculated that, in addition to canonical inactivation via a gene mutation, MMR activity may also be modulated by changes in MMR gene expression. Full article
(This article belongs to the Special Issue Colorectal Cancer: From Pathophysiology to Novel Therapeutic Approaches)
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16 pages, 1488 KiB  
Review
Mitochondrial Dysfunction and DNA Damage in the Context of Pathogenesis of Atherosclerosis
by Taisiia Shemiakova, Ekaterina Ivanova, Andrey V. Grechko, Elena V. Gerasimova, Igor A. Sobenin and Alexander N. Orekhov
Biomedicines 2020, 8(6), 166; https://doi.org/10.3390/biomedicines8060166 - 18 Jun 2020
Cited by 48 | Viewed by 6242
Abstract
Atherosclerosis is a multifactorial disease of the cardiovascular system associated with aging, inflammation, and oxidative stress. An important role in the development of atherosclerosis play elevated plasma lipoproteins. A number of external factors (smoking, diabetes, infections) can also contribute to the development of [...] Read more.
Atherosclerosis is a multifactorial disease of the cardiovascular system associated with aging, inflammation, and oxidative stress. An important role in the development of atherosclerosis play elevated plasma lipoproteins. A number of external factors (smoking, diabetes, infections) can also contribute to the development of the disease. For a long time, atherosclerosis remains asymptomatic, therefore, the search for early markers of the disease is critical for the timely management and better outcomes for patients. Mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage appear to connect different aspects of atherosclerosis pathogenesis. To date, multiple lines of research have demonstrated the strong association of mitochondrial dysfunction with the development of various human diseases. Therapies aimed at restoring the mitochondrial function are being actively developed, and are expected to broaden the therapeutic possibilities for several chronic human diseases. The development of such therapies depends on our understanding of the functional roles of different mtDNA variants associated with one or another disorder, and the molecular mechanisms linking mitochondrial dysfunction with a given pathological feature. These questions are, however, challenging and require future intensive research. This review summarizes the recent studies and describes the central processes of the development of atherosclerosis, and shows their relationship with mitochondrial dysfunction. One of the promising therapeutic approaches for future atherosclerosis treatments is the use of mitochondria-targeted antioxidants. Future studies should focus on characterizing the mechanisms of mitochondrial involvement in cardiovascular pathologies to better direct the search for novel therapies. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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17 pages, 1322 KiB  
Article
Varespladib Inhibits the Phospholipase A2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes
by Chunfang Xie, Laura-Oana Albulescu, Kristina B. M. Still, Julien Slagboom, Yumei Zhao, Zhengjin Jiang, Govert W. Somsen, Freek J. Vonk, Nicholas R. Casewell and Jeroen Kool
Biomedicines 2020, 8(6), 165; https://doi.org/10.3390/biomedicines8060165 - 17 Jun 2020
Cited by 26 | Viewed by 4439
Abstract
Phospholipase A2 (PLA2) enzymes are important toxins found in many snake venoms, and they can exhibit a variety of toxic activities including causing hemolysis and/or anticoagulation. In this study, the inhibiting effects of the small molecule PLA2 inhibitor varespladib [...] Read more.
Phospholipase A2 (PLA2) enzymes are important toxins found in many snake venoms, and they can exhibit a variety of toxic activities including causing hemolysis and/or anticoagulation. In this study, the inhibiting effects of the small molecule PLA2 inhibitor varespladib on snake venom PLA2s was investigated by nanofractionation analytics, which combined chromatography, mass spectrometry (MS), and bioassays. The venoms of the medically important snake species Bothrops asper, Calloselasma rhodostoma, Deinagkistrodon acutus, Daboia russelii, Echis carinatus, Echis ocellatus, and Oxyuranus scutellatus were separated by liquid chromatography (LC) followed by nanofractionation and interrogation of the fractions by a coagulation assay and a PLA2 assay. Next, we assessed the ability of varespladib to inhibit the activity of enzymatic PLA2s and the coagulopathic toxicities induced by fractionated snake venom toxins, and identified these bioactive venom toxins and those inhibited by varespladib by using parallel recorded LC-MS data and proteomics analysis. We demonstrated here that varespladib was not only capable of inhibiting the PLA2 activities of hemotoxic snake venoms, but can also effectively neutralize the coagulopathic toxicities (most profoundly anticoagulation) induced by venom toxins. While varespladib effectively inhibited PLA2 toxins responsible for anticoagulant effects, we also found some evidence that this inhibitory molecule can partially abrogate procoagulant venom effects caused by different toxin families. These findings further emphasize the potential clinical utility of varespladib in mitigating the toxic effects of certain snakebites. Full article
(This article belongs to the Special Issue Animal Venoms–Curse or Cure?)
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11 pages, 1655 KiB  
Article
β-Caryophyllene Reduces the Inflammatory Phenotype of Periodontal Cells by Targeting CB2 Receptors
by Giacomo Picciolo, Giovanni Pallio, Domenica Altavilla, Mario Vaccaro, Giacomo Oteri, Natasha Irrera and Francesco Squadrito
Biomedicines 2020, 8(6), 164; https://doi.org/10.3390/biomedicines8060164 - 17 Jun 2020
Cited by 42 | Viewed by 4037
Abstract
Human gingival fibroblasts (GF) and human oral mucosa epithelial cells (EC) with an inflammatory phenotype represent a valuable experimental paradigm to explore the curative activity of agents to be used in oral mucositis. The role of cannabinoid receptor 2 (CB2) has not yet [...] Read more.
Human gingival fibroblasts (GF) and human oral mucosa epithelial cells (EC) with an inflammatory phenotype represent a valuable experimental paradigm to explore the curative activity of agents to be used in oral mucositis. The role of cannabinoid receptor 2 (CB2) has not yet been investigated in oral mucositis. The aim of this study was to evaluate the therapeutic potential of β-Caryophyllene (BCP), a CB2 agonist, in an in vitro model of oral mucositis. GF and EC were stimulated with LPS (2 µg/mL) alone or in combination with BCP; a group of LPS challenged GF and EC were treated with BCP and AM630, a CB2 antagonist. LPS increased the inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-17A whereas it decreased the anti-inflammatory cytokine IL-13. The upstream signals were identified in an augmented expression of NF-κB and STAT-3 and in reduced mRNA levels of PPARγ and PGC-1α. BCP blunted the LPS-induced inflammatory phenotype and this effect was reverted by the CB2 antagonist AM630. These results suggest that CB2 receptors are an interesting target to develop innovative strategies for oral mucositis and point out that BCP exerts a marked curative effect in a preclinical model of oral mucositis which deserves to be confirmed in a clinical setting. Full article
(This article belongs to the Special Issue Natural Medicine in Therapy)
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9 pages, 495 KiB  
Article
Air Contamination in Different Departments of a Tertiary Hospital. Assessment of Microbial Load and of Antimicrobial Susceptibility
by Athanasios Tselebonis, Evangelia Nena, Maria Panopoulou, Christos Kontogiorgis, Eugenia Bezirtzoglou and Theodoros Constantinidis
Biomedicines 2020, 8(6), 163; https://doi.org/10.3390/biomedicines8060163 - 17 Jun 2020
Cited by 11 | Viewed by 2631
Abstract
Air contamination in the hospital setting can be a reason for the spread of nosocomial infection among susceptible patients. The aim of this study was to identify bacterial species, and their load and drug resistance, in the air of a tertiary hospital. Air [...] Read more.
Air contamination in the hospital setting can be a reason for the spread of nosocomial infection among susceptible patients. The aim of this study was to identify bacterial species, and their load and drug resistance, in the air of a tertiary hospital. Air samples were collected on a monthly basis for 12 consecutive months in four different departments of the hospital (Intensive Care Unit (ICU), Internal Medicine Ward (IMW), Surgical Ward (SW), and Neonatal Unit (NU)). In total, 101 samples were collected, out of which 158 Gram-positive (GP) and 44 Gram-negative (GN) strains were isolated. The majority of GP isolates were Staphylococcus spp. (n = 100). The highest total microbial load was reported in the IMW (p = 0.005), while the highest Staphylococcus load was observed in the ICU (p = 0.018). GP bacterial load was higher in autumn, while GN load was higher in spring. Regarding drug resistance, four multi-drug-resistant (MDR) strains and one extensively drug-resistant (XDR) strain were isolated in the ICU, two MDR strains and one XDR strain in the SW, one MDR strain in the IMW and one MDR strain in the NU samples. Air in hospital settings is contaminated with various microbes; some of them are MDR, consisting a potential cause of hospital-acquired infection. Full article
(This article belongs to the Special Issue Microbial Ecology in Health and Disease)
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11 pages, 1218 KiB  
Article
17β-Estradiol Promotes Proinflammatory and Procoagulatory Phenotype of Innate Immune Cells in the Presence of Antiphospholipid Antibodies
by Gayane Manukyan, Anush Martirosyan, Ludek Slavik, Jana Ulehlova, Martin Dihel, Tomas Papajik and Eva Kriegova
Biomedicines 2020, 8(6), 162; https://doi.org/10.3390/biomedicines8060162 - 15 Jun 2020
Cited by 5 | Viewed by 3314
Abstract
Antiphospholipid syndrome (APS) is the most common cause of acquired thrombophilia and recurrent spontaneous miscarriages associated with extended persistence of antiphospholipid antibodies (aPL). How circulating aPL and high-17β-estradiol (E2) environment contribute to the pregnancy complications in APS is poorly defined. Therefore, we aimed [...] Read more.
Antiphospholipid syndrome (APS) is the most common cause of acquired thrombophilia and recurrent spontaneous miscarriages associated with extended persistence of antiphospholipid antibodies (aPL). How circulating aPL and high-17β-estradiol (E2) environment contribute to the pregnancy complications in APS is poorly defined. Therefore, we aimed to analyse whether E2 could be responsible for the immune cell hyperactivation in aPL- positive (lupus anticoagulant, anti-cardiolipin, anti-β2-glycoprotein) in women. For this, peripheral blood mononuclear cells (PBMCs) from 14 aPL- positive and 13 aPL- negative women were cultured in the presence or absence of E2, LPS or E2+LPS and cell immunophenotype and cytokine release were analysed. In the aPL+ group, E2 presence markedly increased the percentage of NK cells positive for CD69 (p < 0.05), monocytes positive for tissue factor (TF, CD142) (p < 0.05), and B cells expressing PD-L1 (p < 0.05), as well as the elevated production of IL-1β comparing to aPL- women (p < 0.01). Regardless of aPL positivity, E2 augmented the procoagulatory response elicited by LPS in monocytes. Our findings show the ability of E2 to promote proinflammatory and procoagulatory phenotype of innate immune cells in individuals with aPL positivity. Our data highlights the significant impact of female hormones on the activation of immune cells in the presence of aPL. Full article
(This article belongs to the Special Issue Antiphospholipid Syndrome: From Pathophysiology to Novel Therapeutic Approaches)
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14 pages, 1918 KiB  
Article
Distribution of Helicobacter pylori and Periodontopathic Bacterial Species in the Oral Cavity
by Tamami Kadota, Masakazu Hamada, Ryota Nomura, Yuko Ogaya, Rena Okawa, Narikazu Uzawa and Kazuhiko Nakano
Biomedicines 2020, 8(6), 161; https://doi.org/10.3390/biomedicines8060161 - 15 Jun 2020
Cited by 22 | Viewed by 3488
Abstract
The oral cavity may serve as a reservoir of Helicobacter pylori. However, the factors required for H. pylori colonization are unknown. Here, we analyzed the relationship between the presence of H. pylori in the oral cavity and that of major periodontopathic bacterial [...] Read more.
The oral cavity may serve as a reservoir of Helicobacter pylori. However, the factors required for H. pylori colonization are unknown. Here, we analyzed the relationship between the presence of H. pylori in the oral cavity and that of major periodontopathic bacterial species. Nested PCR was performed to detect H. pylori and these bacterial species in specimens of saliva, dental plaque, and dental pulp of 39 subjects. H. pylori was detected in seven dental plaque samples (17.9%), two saliva specimens (5.1%), and one dental pulp (2.6%) specimen. The periodontal pockets around the teeth, from which dental plaque specimens were collected, were significantly deeper in H. pylori-positive than H. pylori-negative subjects (p < 0.05). Furthermore, Porphyromonas gingivalis, a major periodontopathic pathogen, was detected at a significantly higher frequency in H. pylori-positive than in H. pylori-negative dental plaque specimens (p < 0.05). The distribution of genes encoding fimbriae (fimA), involved in the periodontal pathogenicity of P. gingivalis, differed between H. pylori-positive and H. pylori-negative subjects. We conclude that H. pylori can be present in the oral cavity along with specific periodontopathic bacterial species, although its interaction with these bacteria is not clear. Full article
(This article belongs to the Special Issue Models for Oral Biology Research)
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17 pages, 1004 KiB  
Article
New Pyrimidinone-Fused 1,4-Naphthoquinone Derivatives Inhibit the Growth of Drug Resistant Oral Bacteria
by Kyungmin Kim, Daseul Kim, Hyunjin Lee, Tae Hoon Lee, Ki-Young Kim and Hakwon Kim
Biomedicines 2020, 8(6), 160; https://doi.org/10.3390/biomedicines8060160 - 15 Jun 2020
Cited by 7 | Viewed by 2999
Abstract
Background: Dental caries is considered to be a preventable disease, and various antimicrobial agents have been developed for the prevention of dental disease. However, many bacteria show resistance to existing agents. Methods/Principal Findings: In this study, four known 1,4-naphthoquinones and newly synthesized 10 [...] Read more.
Background: Dental caries is considered to be a preventable disease, and various antimicrobial agents have been developed for the prevention of dental disease. However, many bacteria show resistance to existing agents. Methods/Principal Findings: In this study, four known 1,4-naphthoquinones and newly synthesized 10 pyrimidinone-fused 1,4-naphthoquinones, i.e. KHQ 701, 702, 711, 712, 713, 714, 715, 716, 717 and 718, were evaluated for antimicrobial activity against Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mutans, Streptococcus sobrinus, Porphyromonas gingivalis, Actinomyces viscosus and Fusobacterium nucleatum. Pyrimidinone-fused 1,4-naphthoquinones were synthesized in good yields through a series of chemical reactions from a commercially available 1,4-dihydroxynaphthoic acid. MIC values of KHQ 711, 712, 713, 714, 715, 716, 717 and 718 were 6.25–50 μg/mL against E. faecalis (CCARM 5511), 6.25–25 μg/mL against E. faecium (KACC11954) and S. aureus (CCARM 3506), 1.56–25 μg/mL against S. epidermidis (KACC 13234), 3.125–100 μg/mL against S. mutans (KACC16833), 1.56–100 μg/mL against S. sobrinus (KCTC5809) and P. gingivalis (KCTC 5352), 3.125–50 μg/mL against A. viscosus (KCTC 9146) and 3.125–12.5 μg/mL against F. nucleatum (KCTC 2640) with a broth microdilution assay. A disk diffusion assay with KHQ derivatives also exhibited strong susceptibility with inhibition zones of 0.96 to 1.2 cm in size against P. gingivalis. Among the 10 compounds evaluated, KHQ 711, 712, 713, 715, 716 and 717 demonstrated strong antimicrobial activities against the 9 types of pathogenic oral bacteria. A pyrimidin-4-one moiety comprising a phenyl group at the C2 position and a benzyl group at the N3 position appears to be essential for physiological activity. Conclusion/Significance: Pyrimidinone-fused 1,4-naphthoquinones synthesized from simple starting compounds and four known 1,4-naphthoquinones were synthesized and showed strong antibacterial activity to the 9 common oral bacteria. These results suggest that these derivatives should be prospective for the treatment of dental diseases caused by oral bacteria, including drug-resistant strains. Full article
(This article belongs to the Special Issue Models for Oral Biology Research)
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13 pages, 2193 KiB  
Article
Leucine Potentiates Glucose-mediated 18F-FDG Uptake in Brown Adipose Tissue via β-Adrenergic Activation
by Brenda Huska, Sarah Niccoli, Christopher P. Phenix and Simon J. Lees
Biomedicines 2020, 8(6), 159; https://doi.org/10.3390/biomedicines8060159 - 13 Jun 2020
Cited by 2 | Viewed by 2810
Abstract
Significant depots of brown adipose tissue (BAT) have been identified in many adult humans through positron emission tomography (PET), with the amount of BAT being inversely correlated with obesity. As dietary activation of BAT has implications for whole body glucose metabolism, leucine was [...] Read more.
Significant depots of brown adipose tissue (BAT) have been identified in many adult humans through positron emission tomography (PET), with the amount of BAT being inversely correlated with obesity. As dietary activation of BAT has implications for whole body glucose metabolism, leucine was used in the present study to determine its ability to promote BAT activation resulting in increased glucose uptake. In order to assess this, 2-deoxy-2-(fluorine-18)fluoro-d-glucose (18F-FDG) uptake was measured in C57BL/6 mice using microPET after treatment with leucine, glucose, or both in interscapular BAT (IBAT). Pretreatment with propranolol (PRP) was used to determine the role of β-adrenergic activation in glucose and leucine-mediated 18F-FDG uptake. Analysis of maximum standardized uptake values (SUVMAX) determined that glucose administration increased 18F-FDG uptake in IBAT by 25.3%. While leucine did not promote 18F-FDG uptake alone, it did potentiate glucose-mediated 18F-FDG uptake, increasing 18F-FDG uptake in IBAT by 22.5%, compared to glucose alone. Pretreatment with PRP prevented the increase in IBAT 18F-FDG uptake following the combination of glucose and leucine administration. These data suggest that leucine is effective in promoting BAT 18F-FDG uptake through β-adrenergic activation in combination with glucose. Full article
(This article belongs to the Section Tumor Cell Biology)
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13 pages, 3259 KiB  
Article
Image Analysis of 3D Conjunctival Melanoma Cell Cultures Following Electrochemotherapy
by Miltiadis Fiorentzis, Periklis Katopodis, Helen Kalirai, Berthold Seitz, Arne Viestenz and Sarah E. Coupland
Biomedicines 2020, 8(6), 158; https://doi.org/10.3390/biomedicines8060158 - 13 Jun 2020
Cited by 5 | Viewed by 3779
Abstract
Three-dimensional (3D) cell cultures represent small avascular tumors in vitro and simulate some of the biological characteristics of solid tumors, enhancing the evaluation of anticancer drug efficacy. Automated image analysis can be used for the assessment of tumor growth and documentation of changes [...] Read more.
Three-dimensional (3D) cell cultures represent small avascular tumors in vitro and simulate some of the biological characteristics of solid tumors, enhancing the evaluation of anticancer drug efficacy. Automated image analysis can be used for the assessment of tumor growth and documentation of changes in the size parameters of 3D tumor spheroids following anticancer treatments such as electrochemotherapy. The objective of this article is to assess the effect of various electroporation (EP) conditions (500–750 Volts/cm, 8–20 pulses, 100 µs pulse duration, 5 Hz repetition rate) combined with different bleomycin concentrations (1–2.5 ug/mL) on normal epithelial (HCjE-Gi) and conjunctival melanoma (CRMM1, CRMM2) 3D-cell cultures, through an automated image analysis and a comparison with standard histological assays. A reduction in tumor mass with loss of cell definition was observed after ECT (750 Volts/cm with eight pulses and 500 Volts/cm with 20 pulses) with bleomycin (1 μg/mL and 2.5 μg/mL) in the histological and immunohistochemical analyses of 3D CRMM1 and CRMM2 spheroids, whereas an increase in volume and a decrease in sphericity was documented in the automated image analysis and 3D visualization of both melanoma cell lines. For all other treatment conditions and for the HCjE-Gi cell line, no significant changes to their morphological features were observed. Image analysis with integrated software tools provides an accessible and comprehensive platform for the preliminary selection of homogenous spheroids and for the monitoring of drug efficacy, implementing the traditional screening methods. Full article
(This article belongs to the Special Issue 3D Cell and Tissue Culture)
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9 pages, 901 KiB  
Article
Dose-Independent Therapeutic Benefit of Bone Marrow Stem Cell Transplantation after MI in Mice
by Nicole Zarniko, Anna Skorska, Gustav Steinhoff, Robert David and Ralf Gaebel
Biomedicines 2020, 8(6), 157; https://doi.org/10.3390/biomedicines8060157 - 11 Jun 2020
Cited by 6 | Viewed by 2836
Abstract
Several cell populations derived from bone marrow (BM) have been shown to possess cardiac regenerative potential. Among these are freshly isolated CD133+ hematopoietic as well as culture-expanded mesenchymal stem cells. Alternatively, by purifying CD271+ cells from BM, mesenchymal progenitors can be [...] Read more.
Several cell populations derived from bone marrow (BM) have been shown to possess cardiac regenerative potential. Among these are freshly isolated CD133+ hematopoietic as well as culture-expanded mesenchymal stem cells. Alternatively, by purifying CD271+ cells from BM, mesenchymal progenitors can be enriched without an ex vivo cultivation. With regard to the limited available number of freshly isolated BM-derived stem cells, the effect of the dosage on the therapeutic efficiency is of particular interest. Therefore, in the present pre-clinical study, we investigated human BM-derived CD133+ and CD271+ stem cells for their cardiac regenerative potential three weeks post-myocardial infarction (MI) in a dose-dependent manner. The improvement of the hemodynamic function as well as cardiac remodeling showed no therapeutic difference after the transplantation of both 100,000 and 500,000 stem cells. Therefore, beneficial stem cell transplantation post-MI is widely independent of the cell dose and detrimental stem cell amplification in vitro can likely be avoided. Full article
(This article belongs to the Section Gene and Cell Therapy)
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10 pages, 927 KiB  
Review
Arsenic Trioxide, Itraconazole, All-Trans Retinoic Acid and Nicotinamide: A Proof of Concept for Combined Treatments with Hedgehog Inhibitors in Advanced Basal Cell Carcinoma
by Terenzio Cosio, Monia Di Prete and Elena Campione
Biomedicines 2020, 8(6), 156; https://doi.org/10.3390/biomedicines8060156 - 11 Jun 2020
Cited by 18 | Viewed by 4197
Abstract
The treatment of advanced basal cell carcinoma has seen a progressive evolution in recent years following the introduction of Hedgehog pathway inhibitors. However, given the burden of mutations in the tumor microenvironment and lack of knowledge for the follow-up of advanced basal cell [...] Read more.
The treatment of advanced basal cell carcinoma has seen a progressive evolution in recent years following the introduction of Hedgehog pathway inhibitors. However, given the burden of mutations in the tumor microenvironment and lack of knowledge for the follow-up of advanced basal cell carcinoma, we are proposing a possible synergistic therapeutic application. Our aim is to underline the use of arsenic trioxide, itraconazole, all-trans-retinoic acid and nicotinamide as possible adjuvant therapies either in advanced not responding basal cell carcinoma or during follow-up based on Hedgehog pathway. We have analyzed the rational use of these drugs as a pivotal point to block neoplasm progression, modulate epigenetic modification and prevent recurrences. Full article
(This article belongs to the Section Tumor Cell Biology)
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14 pages, 1653 KiB  
Article
Characterization of Synthetic Tf2 as a NaV1.3 Selective Pharmacological Probe
by Mathilde R. Israel, Thomas S. Dash, Stefanie N. Bothe, Samuel D. Robinson, Jennifer R. Deuis, David J. Craik, Angelika Lampert, Irina Vetter and Thomas Durek
Biomedicines 2020, 8(6), 155; https://doi.org/10.3390/biomedicines8060155 - 11 Jun 2020
Cited by 9 | Viewed by 4150
Abstract
NaV1.3 is a subtype of the voltage-gated sodium channel family. It has been implicated in the pathogenesis of neuropathic pain, although the contribution of this channel to neuronal excitability is not well understood. Tf2, a β-scorpion toxin previously identified from the [...] Read more.
NaV1.3 is a subtype of the voltage-gated sodium channel family. It has been implicated in the pathogenesis of neuropathic pain, although the contribution of this channel to neuronal excitability is not well understood. Tf2, a β-scorpion toxin previously identified from the venom of Tityus fasciolatus, has been reported to selectively activate NaV1.3. Here, we describe the activity of synthetic Tf2 and assess its suitability as a pharmacological probe for NaV1.3. As described for the native toxin, synthetic Tf2 (1 µM) caused early channel opening, decreased the peak current, and shifted the voltage dependence of NaV1.3 activation in the hyperpolarizing direction by −11.3 mV, with no activity at NaV1.1, NaV1.2, and NaV1.4-NaV1.8. Additional activity was found at NaV1.9, tested using the hNav1.9_C4 chimera, where Tf2 (1 µM) shifted the voltage dependence of activation by −6.3 mV. In an attempt to convert Tf2 into an NaV1.3 inhibitor, we synthetized the analogue Tf2[S14R], a mutation previously described to remove the excitatory activity of related β-scorpion toxins. Indeed, Tf2[S14R](10 µM) had reduced excitatory activity at NaV1.3, although it still caused a small −5.8 mV shift in the voltage dependence of activation. Intraplantar injection of Tf2 (1 µM) in mice caused spontaneous flinching and swelling, which was not reduced by the NaV1.1/1.3 inhibitor ICA-121431 nor in NaV1.9-/- mice, suggesting off-target activity. In addition, despite a loss of excitatory activity, intraplantar injection of Tf2[S14R](10 µM) still caused swelling, providing strong evidence that Tf2 has additional off-target activity at one or more non-neuronal targets. Therefore, due to activity at NaV1.9 and other yet to be identified target(s), the use of Tf2 as a selective pharmacological probe may be limited. Full article
(This article belongs to the Special Issue Animal Venoms–Curse or Cure?)
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45 pages, 3809 KiB  
Review
Free Fatty Acid Receptors 2 and 3 as Microbial Metabolite Sensors to Shape Host Health: Pharmacophysiological View
by Sidharth P. Mishra, Prashantha Karunakar, Subhash Taraphder and Hariom Yadav
Biomedicines 2020, 8(6), 154; https://doi.org/10.3390/biomedicines8060154 - 8 Jun 2020
Cited by 67 | Viewed by 7815
Abstract
The role of the gut microbiome in human health is becoming apparent. The major functional impact of the gut microbiome is transmitted through the microbial metabolites that are produced in the gut and interact with host cells either in the local gut environment [...] Read more.
The role of the gut microbiome in human health is becoming apparent. The major functional impact of the gut microbiome is transmitted through the microbial metabolites that are produced in the gut and interact with host cells either in the local gut environment or are absorbed into circulation to impact distant cells/organs. Short-chain fatty acids (SCFAs) are the major microbial metabolites that are produced in the gut through the fermentation of non-digestible fibers. SCFAs are known to function through various mechanisms, however, their signaling through free fatty acid receptors 2 and 3 (FFAR2/3; type of G-coupled protein receptors) is a new therapeutic approach. FFAR2/3 are widely expressed in diverse cell types in human and mice, and function as sensors of SCFAs to change several physiological and cellular functions. FFAR2/3 modulate neurological signaling, energy metabolism, intestinal cellular homeostasis, immune response, and hormone synthesis. FFAR2/3 function through Gi and/or Gq signaling, that is mediated through specific structural features of SCFAs-FFAR2/3 bindings and modulating specific signaling pathway. In this review, we discuss the wide-spread expression and structural homologies between human and mice FFAR2/3, and their role in different human health conditions. This information can unlock opportunities to weigh the potential of FFAR2/3 as a drug target to prevent human diseases. Full article
(This article belongs to the Special Issue Diabetes Complications: From Pathophysiology to Novel Therapeutic Approaches)
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15 pages, 3742 KiB  
Review
Possible Correlation between Cholinergic System Alterations and Neuro/Inflammation in Multiple Sclerosis
by Valentina Gatta, Guadalupe Mengod, Marcella Reale and Ada Maria Tata
Biomedicines 2020, 8(6), 153; https://doi.org/10.3390/biomedicines8060153 - 8 Jun 2020
Cited by 31 | Viewed by 6659
Abstract
Multiple sclerosis (MS) is an autoimmune and demyelinating disease of the central nervous system. Although the etiology of MS is still unknown, both genetic and environmental factors contribute to the pathogenesis of the disease. Acetylcholine participates in the modulation of central and peripheral [...] Read more.
Multiple sclerosis (MS) is an autoimmune and demyelinating disease of the central nervous system. Although the etiology of MS is still unknown, both genetic and environmental factors contribute to the pathogenesis of the disease. Acetylcholine participates in the modulation of central and peripheral inflammation. The cells of the immune system, as well as microglia, astrocytes and oligodendrocytes express cholinergic markers and receptors of muscarinic and nicotinic type. The role played by acetylcholine in MS has been recently investigated. In the present review, we summarize the evidence indicating the cholinergic dysfunction in serum and cerebrospinal fluid of relapsing–remitting (RR)-MS patients and in the brains of the MS animal model experimental autoimmune encephalomyelitis (EAE). The correlation between the increased activity of the cholinergic hydrolyzing enzymes acetylcholinesterase and butyrylcholinesterase, the reduced levels of acetylcholine and the increase of pro-inflammatory cytokines production were recently described in immune cells of MS patients. Moreover, the genetic polymorphisms for both hydrolyzing enzymes and the possible correlation with the altered levels of their enzymatic activity have been also reported. Finally, the changes in cholinergic markers expression in the central nervous system of EAE mice in peak and chronic phases suggest the involvement of the acetylcholine also in neuro-inflammatory processes. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment II)
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14 pages, 2048 KiB  
Article
A Human DUB Protein Array for Clarification of Linkage Specificity of Polyubiquitin Chain and Application to Evaluation of Its Inhibitors
by Hirotaka Takahashi, Satoshi Yamanaka, Shohei Kuwada, Kana Higaki, Kohki Kido, Yusuke Sato, Shuya Fukai, Fuminori Tokunaga and Tatsuya Sawasaki
Biomedicines 2020, 8(6), 152; https://doi.org/10.3390/biomedicines8060152 - 4 Jun 2020
Cited by 15 | Viewed by 4961
Abstract
Protein ubiquitinations play pivotal roles in many cellular processes, including homeostasis, responses to various stimulations, and progression of diseases. Deubiquitinating enzymes (DUBs) remove ubiquitin molecules from ubiquitinated proteins and cleave the polyubiquitin chain, thus negatively regulating numerous ubiquitin-dependent processes. Dysfunctions of many DUBs [...] Read more.
Protein ubiquitinations play pivotal roles in many cellular processes, including homeostasis, responses to various stimulations, and progression of diseases. Deubiquitinating enzymes (DUBs) remove ubiquitin molecules from ubiquitinated proteins and cleave the polyubiquitin chain, thus negatively regulating numerous ubiquitin-dependent processes. Dysfunctions of many DUBs reportedly cause various diseases; therefore, DUBs are considered as important drug targets, although the biochemical characteristics and cellular functions of many DUBs are still unclear. Here, we established a human DUB protein array to detect the activity and linkage specificity of almost all human DUBs. Using a wheat cell-free protein synthesis system, 88 full-length recombinant human DUB proteins were prepared and termed the DUB array. In vitro DUB assays were performed with all of these recombinant DUBs, using eight linkage types of diubiquitins as substrates. As a result, 80 DUBs in the array showed DUB activities, and their linkage specificities were determined. These 80 DUBs included many biochemically uncharacterized DUBs in the past. In addition, taking advantage of these active DUB proteins, we applied the DUB array to evaluate the selectivities of DUB inhibitors. We successfully developed a high-throughput and semi-quantitative DUB assay based on AlphaScreen technology, and a model study using two commercially available DUB inhibitors revealed individual selectivities to 29 DUBs, as previously reported. In conclusion, the DUB array established here is a powerful tool for biochemical analyses and drug discovery for human DUBs. Full article
(This article belongs to the Section Tumor Cell Biology)
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29 pages, 1440 KiB  
Review
Considering the Experimental Use of Temozolomide in Glioblastoma Research
by Verena J. Herbener, Timo Burster, Alicia Goreth, Maximilian Pruss, Hélène von Bandemer, Tim Baisch, Rahel Fitzel, Markus D. Siegelin, Georg Karpel-Massler, Klaus-Michael Debatin, Mike-Andrew Westhoff and Hannah Strobel
Biomedicines 2020, 8(6), 151; https://doi.org/10.3390/biomedicines8060151 - 4 Jun 2020
Cited by 30 | Viewed by 8812
Abstract
Temozolomide (TMZ) currently remains the only chemotherapeutic component in the approved treatment scheme for Glioblastoma (GB), the most common primary brain tumour with a dismal patient’s survival prognosis of only ~15 months. While frequently described as an alkylating agent that causes DNA damage [...] Read more.
Temozolomide (TMZ) currently remains the only chemotherapeutic component in the approved treatment scheme for Glioblastoma (GB), the most common primary brain tumour with a dismal patient’s survival prognosis of only ~15 months. While frequently described as an alkylating agent that causes DNA damage and thus—ultimately—cell death, a recent debate has been initiated to re-evaluate the therapeutic role of TMZ in GB. Here, we discuss the experimental use of TMZ and highlight how it differs from its clinical role. Four areas could be identified in which the experimental data is particularly limited in its translational potential: 1. transferring clinical dosing and scheduling to an experimental system and vice versa; 2. the different use of (non-inert) solvent in clinic and laboratory; 3. the limitations of established GB cell lines which only poorly mimic GB tumours; and 4. the limitations of animal models lacking an immune response. Discussing these limitations in a broader biomedical context, we offer suggestions as to how to improve transferability of data. Finally, we highlight an underexplored function of TMZ in modulating the immune system, as an example of where the aforementioned limitations impede the progression of our knowledge. Full article
(This article belongs to the Special Issue Principal Challenges in the Adjuvant Treatment of Glioblastoma)
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16 pages, 1445 KiB  
Review
Animal-Assisted and Pet-Robot Interventions for Ameliorating Behavioral and Psychological Symptoms of Dementia: A Systematic Review and Meta-Analysis
by Sangki Park, Ahream Bak, Sujin Kim, Yunkwon Nam, Hyeon soo Kim, Doo-Han Yoo and Minho Moon
Biomedicines 2020, 8(6), 150; https://doi.org/10.3390/biomedicines8060150 - 2 Jun 2020
Cited by 31 | Viewed by 10924
Abstract
Patients with dementia suffer from psychological symptoms such as depression, agitation, and aggression. One purpose of dementia intervention is to manage patients’ inappropriate behaviors and psychological symptoms while taking into consideration their quality of life (QOL). Animal-assisted intervention (AAI) and pet-robot intervention (PRI) [...] Read more.
Patients with dementia suffer from psychological symptoms such as depression, agitation, and aggression. One purpose of dementia intervention is to manage patients’ inappropriate behaviors and psychological symptoms while taking into consideration their quality of life (QOL). Animal-assisted intervention (AAI) and pet-robot intervention (PRI) are effective intervention strategies for older people with cognitive impairment and dementia. In addition, AAI and PRI have been shown to have positive effects on behavioral and psychological symptoms of dementia (BPSD). However, studies into the association between AAI/PRI and BPSD have elicited inconsistent results. Thus, we performed a meta-analysis to investigate this association. We analyzed nine randomized controlled trials on AAI and PRI for dementia patients published between January 2000 and August 2019 and evaluated the impact of AAI/PRI on agitation, depression, and QOL. We found that AAI and PRI significantly reduce depression in patients with dementia. Subsequent studies should investigate the impact of AAI and PRI on the physical ability and cognitive function of dementia patients and conduct a follow-up to investigate their effects on the rate of progression and reduction of symptoms of dementia. Our research will help with neuropsychological and environmental intervention to delay or improve the development and progression of BPSD. Full article
(This article belongs to the Special Issue Crosstalk between Depression, Anxiety, and Dementia: Comorbidity in Behavioral Neurology and Neuropsychiatry)
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16 pages, 4036 KiB  
Article
CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis
by Robin C. Su, Emily A. Warner, Joshua D. Breidenbach, Apurva Lad, Thomas M. Blomquist, Andrew L. Kleinhenz, Nikolai Modyanov, Deepak Malhotra, David J. Kennedy and Steven T. Haller
Biomedicines 2020, 8(6), 149; https://doi.org/10.3390/biomedicines8060149 - 2 Jun 2020
Cited by 10 | Viewed by 3346
Abstract
Inflammatory Bowel Disease (IBD) is one of the most common gastrointestinal (GI) disorders around the world, and includes diagnoses such as Crohn’s disease and ulcerative colitis. The etiology of IBD is influenced by genetic and environmental factors. One environmental perturbagen that is not [...] Read more.
Inflammatory Bowel Disease (IBD) is one of the most common gastrointestinal (GI) disorders around the world, and includes diagnoses such as Crohn’s disease and ulcerative colitis. The etiology of IBD is influenced by genetic and environmental factors. One environmental perturbagen that is not well studied within the intestines is microcystin-leucine arginine (MC-LR), which is a toxin produced by cyanobacteria in freshwater environments around the world. We recently reported that MC-LR has limited effects within the intestines of healthy mice, yet interestingly has significant toxicity within the intestines of mice with pre-existing colitis induced by dextran sulfate sodium (DSS). MC-LR was found to prolong DSS-induced weight loss, prolong DSS-induced bloody stools, exacerbate DSS-induced colonic shortening, exacerbate DSS-induced colonic ulceration, and exacerbate DSS-induced inflammatory cytokine upregulation. In addition, we previously reported a significant increase in expression of the pro-inflammatory receptor CD40 in the colons of these mice, along with downstream products of CD40 activation, including plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1). In the current study, we demonstrate that knocking out CD40 attenuates the effects of MC-LR in mice with pre-existing colitis by decreasing the severity of weight loss, allowing a full recovery in bloody stools, preventing the exacerbation of colonic shortening, preventing the exacerbation of colonic ulceration, and preventing the upregulation of the pro-inflammatory and pro-fibrotic cytokines IL-1β, MCP-1, and PAI-1. We also demonstrate the promising efficacy of a CD40 receptor blocking peptide to ameliorate the effects of MC-LR exposure in a proof-of-concept study. Our findings suggest for the first time that MC-LR acts through a CD40-dependent mechanism to exacerbate colitis. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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