International Journal of Molecular Sciences

17 pages, 1289 KiB

Open AccessArticle

Targeting Quorum Sensing: High-Throughput Screening to Identify Novel LsrK Inhibitors

by Viviana Gatta, Polina Ilina, Alison Porter, Stuart McElroy and Päivi Tammela

Int. J. Mol. Sci. 2019, 20(12), 3112; https://doi.org/10.3390/ijms20123112 - 25 Jun 2019

Cited by 13 | Viewed by 4346

Since quorum sensing (QS) is linked to the establishment of bacterial infection, its inactivation represents one of the newest strategies to fight bacterial pathogens. LsrK is a kinase playing a key role in the processing of autoinducer-2 (AI-2), a quorum-sensing mediator in gut [...] Read more.

Since quorum sensing (QS) is linked to the establishment of bacterial infection, its inactivation represents one of the newest strategies to fight bacterial pathogens. LsrK is a kinase playing a key role in the processing of autoinducer-2 (AI-2), a quorum-sensing mediator in gut enteric bacteria. Inhibition of LsrK might thus impair the quorum-sensing cascade and consequently reduce bacterial pathogenicity. Aiming for the development of a target-based assay for the discovery of LsrK inhibitors, we evaluated different assay set-ups based on ATP detection and optimized an automation-compatible method for the high-throughput screening of chemical libraries. The assay was then used to perform the screening of a 2000-compound library, which provided 12 active compounds with an IC₅₀ ≤ 10 µM confirming the effectiveness and sensitivity of our assay. Follow-up studies on the positive hits led to the identification of two compounds, harpagoside and rosolic acid, active in a cell-based AI-2 QS interference assay, which are at the moment the most promising candidates for the development of a new class of antivirulence agents based on LsrK inhibition. Full article

(This article belongs to the Section Molecular Microbiology)

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10 pages, 288 KiB

Open AccessReview

Effects of Estrogens on Platelets and Megakaryocytes

by Marion Dupuis, Sonia Severin, Emmanuelle Noirrit-Esclassan, Jean-François Arnal, Bernard Payrastre and Marie-Cécile Valéra

Int. J. Mol. Sci. 2019, 20(12), 3111; https://doi.org/10.3390/ijms20123111 - 25 Jun 2019

Cited by 31 | Viewed by 5072

Abstract

In women, oral menopausal hormonal therapy (MHT) is associated with adverse effects including an increased incidence of thromboembolic events, classically attributed to an increase in several liver-derived coagulation factors due to hepatic first pass. While platelets are central players in thrombus constitution, their [...] Read more.

In women, oral menopausal hormonal therapy (MHT) is associated with adverse effects including an increased incidence of thromboembolic events, classically attributed to an increase in several liver-derived coagulation factors due to hepatic first pass. While platelets are central players in thrombus constitution, their implication in women treated with estrogens remains incompletely characterized. Platelets and their medullar progenitors, megakaryocytes, express estrogen receptors (ER) that may explain, at least in part, a sensitivity to hormonal changes. The purpose of this review is to summarize our current knowledge of estrogen actions on platelets and megakaryocytes in mice following in vivo administration and in women using MHT. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Thrombotic Diseases)

14 pages, 9252 KiB

Open AccessArticle

High-Fish Oil and High-Lard Diets Differently Affect Testicular Antioxidant Defense and Mitochondrial Fusion/Fission Balance in Male Wistar Rats: Potential Protective Effect of ω3 Polyunsaturated Fatty Acids Targeting Mitochondria Dynamics

by Vincenzo Migliaccio, Raffaella Sica, Ilaria Di Gregorio, Rosalba Putti and Lillà Lionetti

Int. J. Mol. Sci. 2019, 20(12), 3110; https://doi.org/10.3390/ijms20123110 - 25 Jun 2019

Cited by 13 | Viewed by 4419

Abstract

High-fat diets rich in fish oil (HFO diet, mainly ω3-PUFAs), in contrast to high-fat diets rich in lard (HL diet, mainly saturated fatty acids) have been shown to induce improvement in mitochondrial function and fusion processes associated with a reduction in reactive oxygen [...] Read more.

High-fat diets rich in fish oil (HFO diet, mainly ω3-PUFAs), in contrast to high-fat diets rich in lard (HL diet, mainly saturated fatty acids) have been shown to induce improvement in mitochondrial function and fusion processes associated with a reduction in reactive oxygen species production in both liver and skeletal muscle. High-fat diets may also impair testicular function, and mitochondria represent important cellular organelles with a pivotal role in reproductive function. Mitochondria are dynamic organelles that frequently undergo fission/fusion processes. A shift toward mitochondrial fusion process has been associated with improvement of mitochondrial function, as well as with ω3-PUFAs protective effects. The present study aimed to analyze the effect of chronic overfeeding (six weeks) with HFO or HL diet on testicular tissue histology, oxidative stress, antioxidant defenses, and mitochondrial fusion (mitofusin 2) and fission (dynamic related protein 1) protein. Our results showed that HFO diet induced less testicular histology impairment, oxidative stress, and apoptosis compared to a HL diet. This finding was associated with an increase in antioxidant activities and a shift toward mitochondrial fusion processes induced by HFO diet compared to HL diet, suggesting that ω3-PUFAs may act as bioactive compound targeting mitochondria dynamics to prevent testicular impairment. Full article

(This article belongs to the Special Issue Targeted Protection of Bioactive Compounds to Mitochondria)

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15 pages, 934 KiB

Open AccessReview

Implications of Diet and The Gut Microbiome in Neuroinflammatory and Neurodegenerative Diseases

by Sarah Hirschberg, Barbara Gisevius, Alexander Duscha and Aiden Haghikia

Int. J. Mol. Sci. 2019, 20(12), 3109; https://doi.org/10.3390/ijms20123109 - 25 Jun 2019

Cited by 72 | Viewed by 10176

Abstract

Within the last century, human lifestyle and dietary behaviors have changed dramatically. These changes, especially concerning hygiene, have led to a marked decrease in some diseases, i.e., infectious diseases. However, other diseases that can be attributed to the so-called ‘Western’ lifestyle have increased, [...] Read more.

Within the last century, human lifestyle and dietary behaviors have changed dramatically. These changes, especially concerning hygiene, have led to a marked decrease in some diseases, i.e., infectious diseases. However, other diseases that can be attributed to the so-called ‘Western’ lifestyle have increased, i.e., metabolic and cardiovascular disorders. More recently, multifactorial disorders, such as autoimmune and neurodegenerative diseases, have been associated with changes in diet and the gut microbiome. In particular, short chain fatty acid (SCFA)-producing bacteria are of high interest. SCFAs are the main metabolites produced by bacteria and are often reduced in a dysbiotic state, causing an inflammatory environment. Based on advanced technologies, high-resolution investigations of the abundance and composition of the commensal microbiome are now possible. These techniques enable the assessment of the relationship between the gut microbiome, its metabolome and gut-associated immune and neuronal cells. While a growing number of studies have shown the indirect impact of gut metabolites, mediated by alterations of immune-mediated mechanisms, the direct influence of these compounds on cells of the central nervous system needs to be further elucidated. For instance, the SCFA propionic acid (PA) increases the amount of intestine-derived regulatory T cells, which furthermore can positively affect the central nervous system (CNS), e.g., by increasing remyelination. However, the question of if and how PA can directly interact with CNS-resident cells is a matter of debate. In this review, we discuss the impact of an altered microbiome composition in relation to various diseases and discuss how the commensal microbiome is shaped, starting from the beginning of human life. Full article

(This article belongs to the Special Issue Gut Microbiome Regulation of Immunity and Inflammation)

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43 pages, 11848 KiB

Open AccessReview

Approaches to CNS Drug Delivery with a Focus on Transporter-Mediated Transcytosis

by Rana Abdul Razzak, Gordon J. Florence and Frank J. Gunn-Moore

Int. J. Mol. Sci. 2019, 20(12), 3108; https://doi.org/10.3390/ijms20123108 - 25 Jun 2019

Cited by 67 | Viewed by 13570

Abstract

Drug delivery to the central nervous system (CNS) conferred by brain barriers is a major obstacle in the development of effective neurotherapeutics. In this review, a classification of current approaches of clinical or investigational importance for the delivery of therapeutics to the CNS [...] Read more.

Drug delivery to the central nervous system (CNS) conferred by brain barriers is a major obstacle in the development of effective neurotherapeutics. In this review, a classification of current approaches of clinical or investigational importance for the delivery of therapeutics to the CNS is presented. This classification includes the use of formulations administered systemically that can elicit transcytosis-mediated transport by interacting with transporters expressed by transvascular endothelial cells. Neurotherapeutics can also be delivered to the CNS by means of surgical intervention using specialized catheters or implantable reservoirs. Strategies for delivering drugs to the CNS have evolved tremendously during the last two decades, yet, some factors can affect the quality of data generated in preclinical investigation, which can hamper the extension of the applications of these strategies into clinically useful tools. Here, we disclose some of these factors and propose some solutions that may prove valuable at bridging the gap between preclinical findings and clinical trials. Full article

(This article belongs to the Special Issue Development of Novel Drugs for Alzheimer's Disease and Myasthenia Gravis)

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19 pages, 3346 KiB

Open AccessArticle

MMP-12, Secreted by Pro-Inflammatory Macrophages, Targets Endoglin in Human Macrophages and Endothelial Cells

by Mikel Aristorena, Eunate Gallardo-Vara, Matej Vicen, Mateo de Las Casas-Engel, Luisa Ojeda-Fernandez, Concepción Nieto, Francisco J. Blanco, Ana C. Valbuena-Diez, Luisa M. Botella, Petr Nachtigal, Angel L. Corbi, María Colmenares and Carmelo Bernabeu

Int. J. Mol. Sci. 2019, 20(12), 3107; https://doi.org/10.3390/ijms20123107 - 25 Jun 2019

Cited by 51 | Viewed by 6755

Abstract

Upon inflammation, monocyte-derived macrophages (MΦ) infiltrate blood vessels to regulate several processes involved in vascular pathophysiology. However, little is known about the mediators involved. Macrophage polarization is crucial for a fast and efficient initial response (GM-MΦ) and a good resolution (M-MΦ) of the [...] Read more.

Upon inflammation, monocyte-derived macrophages (MΦ) infiltrate blood vessels to regulate several processes involved in vascular pathophysiology. However, little is known about the mediators involved. Macrophage polarization is crucial for a fast and efficient initial response (GM-MΦ) and a good resolution (M-MΦ) of the inflammatory process. The functional activity of polarized MΦ is exerted mainly through their secretome, which can target other cell types, including endothelial cells. Endoglin (CD105) is a cell surface receptor expressed by endothelial cells and MΦ that is markedly upregulated in inflammation and critically involved in angiogenesis. In addition, a soluble form of endoglin with anti-angiogenic activity has been described in inflammation-associated pathologies. The aim of this work was to identify components of the MΦ secretome involved in the shedding of soluble endoglin. We find that the GM-MΦ secretome contains metalloprotease 12 (MMP-12), a GM-MΦ specific marker that may account for the anti-angiogenic activity of the GM-MΦ secretome. Cell surface endoglin is present in both GM-MΦ and M-MΦ, but soluble endoglin is only detected in GM-MΦ culture supernatants. Moreover, MMP-12 is responsible for the shedding of soluble endoglin in vitro and in vivo by targeting membrane-bound endoglin in both MΦ and endothelial cells. These data demonstrate a direct correlation between GM-MΦ polarization, MMP-12, and soluble endoglin expression and function. By targeting endothelial cells, MMP-12 may represent a novel mediator involved in vascular homeostasis. Full article

(This article belongs to the Special Issue Cell and Molecular Interactions in Blood Vessels)

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16 pages, 2080 KiB

Open AccessReview

Synthetic Flavonoids as Novel Modulators of Platelet Function and Thrombosis

by Thomas M. Vallance, Divyashree Ravishankar, Dina A. I. Albadawi, Helen M. I. Osborn and Sakthivel Vaiyapuri

Int. J. Mol. Sci. 2019, 20(12), 3106; https://doi.org/10.3390/ijms20123106 - 25 Jun 2019

Cited by 15 | Viewed by 4491

Abstract

Cardiovascular diseases represent a major cause of mortality and morbidity in the world, and specifically, thrombotic conditions such as heart attacks and strokes are caused by unwarranted activation of platelets and subsequent formation of blood clots (thrombi) within the blood vessels during pathological [...] Read more.

Cardiovascular diseases represent a major cause of mortality and morbidity in the world, and specifically, thrombotic conditions such as heart attacks and strokes are caused by unwarranted activation of platelets and subsequent formation of blood clots (thrombi) within the blood vessels during pathological circumstances. Therefore, platelets act as a primary therapeutic target to treat and prevent thrombotic conditions. Current treatments are limited due to intolerance, and they are associated with severe side effects such as bleeding complications. Hence, the development of novel therapeutic strategies for thrombotic diseases is an urgent priority. Flavonoids are naturally occurring plant-derived molecules that exert numerous beneficial effects in humans through modulating the functions of distinct cell types. However, naturally occurring flavonoids suffer from several issues such as poor solubility, lipophilicity, and bioavailability, which hinder their efficacy and potency. Despite these, flavonoids act as versatile templates for the design and synthesis of novel molecules for various therapeutic targets. Indeed, several synthetic flavonoids have recently been developed to improve their stability, bioavailability, and efficacy, including for the modulation of platelet function. Here, we provide insight into the actions of certain natural flavonoids along with the advantages of synthetic flavonoids in the modulation of platelet function, haemostasis, and thrombosis. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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22 pages, 405 KiB

Open AccessReview

Adipose-Derived Mesenchymal Stem Cells: A Promising Tool in the Treatment of Musculoskeletal Diseases

by Marta Torres-Torrillas, Monica Rubio, Elena Damia, Belen Cuervo, Ayla del Romero, Pau Peláez, Deborah Chicharro, Laura Miguel and Joaquin J. Sopena

Int. J. Mol. Sci. 2019, 20(12), 3105; https://doi.org/10.3390/ijms20123105 - 25 Jun 2019

Cited by 63 | Viewed by 6372

Abstract

Chronic musculoskeletal (MSK) pain is one of the most common medical complaints worldwide and musculoskeletal injuries have an enormous social and economical impact. Current pharmacological and surgical treatments aim to relief pain and restore function; however, unsatiscactory outcomes are commonly reported. In order [...] Read more.

Chronic musculoskeletal (MSK) pain is one of the most common medical complaints worldwide and musculoskeletal injuries have an enormous social and economical impact. Current pharmacological and surgical treatments aim to relief pain and restore function; however, unsatiscactory outcomes are commonly reported. In order to find an accurate treatment to such pathologies, over the last years, there has been a significantly increasing interest in cellular therapies, such as adipose-derived mesenchymal stem cells (AMSCs). These cells represent a relatively new strategy in regenerative medicine, with many potential applications, especially regarding MSK disorders, and preclinical and clinical studies have demonstrated their efficacy in muscle, tendon, bone and cartilage regeneration. Nevertheless, several worries about their safety and side effects at long-term remain unsolved. This article aims to review the current state of AMSCs therapy in the treatment of several MSK diseases and their clinical applications in veterinary and human medicine. Full article

(This article belongs to the Special Issue Adipose Stem Cells 2019)

10 pages, 1239 KiB

Open AccessCommunication

Lithium and Not Acetoacetate Influences the Growth of Cells Treated with Lithium Acetoacetate

by Silvia Vidali, Sepideh Aminzadeh-Gohari, Renaud Vatrinet, Luisa Iommarini, Anna Maria Porcelli, Barbara Kofler and René Günther Feichtinger

Int. J. Mol. Sci. 2019, 20(12), 3104; https://doi.org/10.3390/ijms20123104 - 25 Jun 2019

Cited by 10 | Viewed by 4526

Abstract

The ketogenic diet (KD), a high-fat/low-carbohydrate/adequate-protein diet, has been proposed as a treatment for a variety of diseases, including cancer. KD leads to generation of ketone bodies (KBs), predominantly acetoacetate (AcAc) and 3-hydroxy-butyrate, as a result of fatty acid oxidation. Several studies investigated [...] Read more.

The ketogenic diet (KD), a high-fat/low-carbohydrate/adequate-protein diet, has been proposed as a treatment for a variety of diseases, including cancer. KD leads to generation of ketone bodies (KBs), predominantly acetoacetate (AcAc) and 3-hydroxy-butyrate, as a result of fatty acid oxidation. Several studies investigated the antiproliferative effects of lithium acetoacetate (LiAcAc) and sodium 3-hydroxybutyrate on cancer cells in vitro. However, a critical point missed in some studies using LiAcAc is that Li ions have pleiotropic effects on cell growth and cell signaling. Thus, we tested whether Li ions per se contribute to the antiproliferative effects of LiAcAc in vitro. Cell proliferation was analyzed on neuroblastoma, renal cell carcinoma, and human embryonic kidney cell lines. Cells were treated for 5 days with 2.5, 5, and 10 mM LiAcAc and with equimolar concentrations of lithium chloride (LiCl) or sodium chloride (NaCl). LiAcAc affected the growth of all cell lines, either negatively or positively. However, the effects of LiAcAc were always similar to those of LiCl. In contrast, NaCl showed no effects, indicating that the Li ion impacts cell proliferation. As Li ions have significant effects on cell growth, it is important for future studies to include sources of Li ions as a control. Full article

(This article belongs to the Special Issue The Effects of Ketones on Metabolic Function)

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10 pages, 2268 KiB

Open AccessArticle

Neutrophil Gelatinase-Associated Lipocalin Is Not Associated with Tacrolimus-Induced Acute Kidney Injury in Liver Transplant Patients Who Received Mycophenolate Mofetil with Delayed Introduction of Tacrolimus

by Mio Fukuda, Kimitaka Suetsugu, Soichiro Tajima, Yurie Katsube, Hiroyuki Watanabe, Noboru Harada, Tomoharu Yoshizumi, Nobuaki Egashira, Masaki Mori and Satohiro Masuda

Int. J. Mol. Sci. 2019, 20(12), 3103; https://doi.org/10.3390/ijms20123103 - 25 Jun 2019

Cited by 3 | Viewed by 4930

Abstract

Tacrolimus is widely used as an immunosuppressant in liver transplantation, and tacrolimus-induced acute kidney injury (AKI) is a serious complication. The urinary neutrophil gelatinase-associated lipocalin (NGAL) level has been linked to tacrolimus-induced AKI in patients starting tacrolimus treatment the morning after liver transplantation. [...] Read more.

Tacrolimus is widely used as an immunosuppressant in liver transplantation, and tacrolimus-induced acute kidney injury (AKI) is a serious complication. The urinary neutrophil gelatinase-associated lipocalin (NGAL) level has been linked to tacrolimus-induced AKI in patients starting tacrolimus treatment the morning after liver transplantation. Here we tested this association using a different immunosuppression protocol: Mycophenolate mofetil administration beginning on Postoperative Day 1 and tacrolimus administration beginning on Postoperative Day 2 or 3. Urine samples were collected from 26 living donor liver transplant recipients before (Postoperative Day 1) and after (Postoperative Day 7 or 14) tacrolimus administration. NGAL levels were measured via enzyme-linked immunosorbent assays, as were those of three additional urinary biomarkers for kidney diseases: Monocyte chemotactic protein-1 (MCP-1), liver-type fatty acid-binding protein (L-FABP), and human epididymis secretory protein 4 (HE4). HE4 levels after tacrolimus administration were significantly higher in patients who developed AKI (n = 6) than in those who did not (n = 20), whereas NGAL, MCP-1, and L-FABP levels did not differ significantly before or after tacrolimus administration. These findings indicate that NGAL may not be a universal biomarker of AKI in tacrolimus-treated liver transplant recipients. To reduce the likelihood of tacrolimus-induced AKI, our immunosuppression protocol is recommended. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)

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16 pages, 9252 KiB

Open AccessArticle

Tandem 13-Lipoxygenase Genes in a Cluster Confers Yellow-Green Leaf in Cucumber

by Yin Ding, Wei Yang, Chenggang Su, Huihui Ma, Yu Pan, Xingguo Zhang and Jinhua Li

Int. J. Mol. Sci. 2019, 20(12), 3102; https://doi.org/10.3390/ijms20123102 - 25 Jun 2019

Cited by 22 | Viewed by 3757

Abstract

Some lipoxygenase (LOX) isoenzymes can co-oxidize carotenoids. Carotenoids are collectors of light energy for photosynthesis and can protect plants from reactive oxygen species and coloration. This study isolated the cucumber (Cucumis sativus L.) yellow-green leaf mutant (ygl1), which had yellow-green [...] Read more.

Some lipoxygenase (LOX) isoenzymes can co-oxidize carotenoids. Carotenoids are collectors of light energy for photosynthesis and can protect plants from reactive oxygen species and coloration. This study isolated the cucumber (Cucumis sativus L.) yellow-green leaf mutant (ygl1), which had yellow-green leaves with decreased chlorophyll synthesis, increased relative carotenoid content, and delayed chloroplast development. Genetic analysis demonstrated that the phenotype of ygl1 was caused by a recessive mutation in a nuclear gene. The bulked segregants were resequenced, and the candidate ygl1 locus identified was mapped to the 9.2 kb region of the chromosome 4. Sequence analysis revealed that ygl1 encodes the tandem 13-LOX genes in a cluster. Four missense mutations were found in four tandem 13-LOX genes (Csa4M286960, Csa4M287550, Csa4M288070, and Csa4M288080) in the ygl1 mutant, and the four 13-LOX genes showed high similarity with one another. The transient RNA interference and virus-induced gene silencing of these genes simultaneously resulted in yellow-green leaves with a reduced amount of chloroplasts and increased relative carotenoid content, which were observed in the ygl1 mutant. This evidence supported the non-synonymous SNPs (Single Nucleotide Polymorphism) in the four tandem 13-LOX genes as being the causative mutation for the yellow-green leaves. Furthermore, this study provides a new allele for breeding cucumbers with yellow-green leaves and serves as an additional resource for studying carotenoid biosynthesis. Full article

(This article belongs to the Section Molecular Plant Sciences)

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22 pages, 3485 KiB

Open AccessArticle

Genome-Wide Analysis of ROS Antioxidant Genes in Resurrection Species Suggest an Involvement of Distinct ROS Detoxification Systems during Desiccation

by Saurabh Gupta, Yanni Dong, Paul P. Dijkwel, Bernd Mueller-Roeber and Tsanko S. Gechev

Int. J. Mol. Sci. 2019, 20(12), 3101; https://doi.org/10.3390/ijms20123101 - 25 Jun 2019

Cited by 35 | Viewed by 5456

Abstract

Abiotic stress is one of the major threats to plant crop yield and productivity. When plants are exposed to stress, production of reactive oxygen species (ROS) increases, which could lead to extensive cellular damage and hence crop loss. During evolution, plants have acquired [...] Read more.

Abiotic stress is one of the major threats to plant crop yield and productivity. When plants are exposed to stress, production of reactive oxygen species (ROS) increases, which could lead to extensive cellular damage and hence crop loss. During evolution, plants have acquired antioxidant defense systems which can not only detoxify ROS but also adjust ROS levels required for proper cell signaling. Ascorbate peroxidase (APX), glutathione peroxidase (GPX), catalase (CAT) and superoxide dismutase (SOD) are crucial enzymes involved in ROS detoxification. In this study, 40 putative APX, 28 GPX, 16 CAT, and 41 SOD genes were identified from genomes of the resurrection species Boea hygrometrica, Selaginella lepidophylla, Xerophyta viscosa, and Oropetium thomaeum, and the mesophile Selaginella moellendorffii. Phylogenetic analyses classified the APX, GPX, and SOD proteins into five clades each, and CAT proteins into three clades. Using co-expression network analysis, various regulatory modules were discovered, mainly involving glutathione, that likely work together to maintain ROS homeostasis upon desiccation stress in resurrection species. These regulatory modules also support the existence of species-specific ROS detoxification systems. The results suggest molecular pathways that regulate ROS in resurrection species and the role of APX, GPX, CAT and SOD genes in resurrection species during stress. Full article

(This article belongs to the Special Issue Oxidative Stress and Redox Regulation in Plants)

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15 pages, 425 KiB

Open AccessReview

Identification of Novel Biomarkers of Homologous Recombination Defect in DNA Repair to Predict Sensitivity of Prostate Cancer Cells to PARP-Inhibitors

by Daniela Criscuolo, Francesco Morra, Riccardo Giannella, Aniello Cerrato and Angela Celetti

Int. J. Mol. Sci. 2019, 20(12), 3100; https://doi.org/10.3390/ijms20123100 - 25 Jun 2019

Cited by 30 | Viewed by 6005

Abstract

One of the most common malignancies in men is prostate cancer, for which androgen deprivation is the standard therapy. However, prostate cancer cells become insensitive to anti-androgen treatment and proceed to a castration-resistant state with limited therapeutic options. Therefore, besides the androgen deprivation [...] Read more.

One of the most common malignancies in men is prostate cancer, for which androgen deprivation is the standard therapy. However, prostate cancer cells become insensitive to anti-androgen treatment and proceed to a castration-resistant state with limited therapeutic options. Therefore, besides the androgen deprivation approach, novel biomarkers are urgently required for specific targeting in this deadly disease. Recently, germline or somatic mutations in the homologous recombination (HR) DNA repair genes have been identified in at least 20–25% of metastatic castration-resistant prostate cancers (mCRPC). Defects in genes involved in HR DNA repair can sensitize cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors, a class of drugs already approved by the Food and Drug Administration (FDA) for breast and ovarian cancer carrying germline mutations in BRCA1/2 genes. For advanced prostate cancer carrying Breast cancer1/2 (BRCA1/2) or ataxia telengiectasia mutated (ATM) mutations, preclinical studies and clinical trials support the use of PARP-inhibitors, which received breakthrough therapy designation by the FDA. Based on these assumptions, several trials including DNA damage response and repair (DDR) targeting have been launched and are ongoing for prostate cancer. Here, we review the state-of-the-art potential biomarkers that could be predictive of cancer cell synthetic lethality with PARP inhibitors. The identification of key molecules that are affected in prostate cancer could be assayed in future clinical studies to better stratify prostate cancer patients who might benefit from target therapy. Full article

(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer 2019)

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17 pages, 3181 KiB

Open AccessArticle

Exploring the Hospital Microbiome by High-Resolution 16S rRNA Profiling

by Pabulo H. Rampelotto, Aline F.R. Sereia, Luiz Felipe V. de Oliveira and Rogério Margis

Int. J. Mol. Sci. 2019, 20(12), 3099; https://doi.org/10.3390/ijms20123099 - 25 Jun 2019

Cited by 36 | Viewed by 5176

Abstract

The aim of this work was to analyze and compare the bacterial communities of 663 samples from a Brazilian hospital by using high-throughput sequencing of the 16S rRNA gene. To increase taxonomic profiling and specificity of 16S-based identification, a strict sequence quality filtering [...] Read more.

The aim of this work was to analyze and compare the bacterial communities of 663 samples from a Brazilian hospital by using high-throughput sequencing of the 16S rRNA gene. To increase taxonomic profiling and specificity of 16S-based identification, a strict sequence quality filtering process was applied for the accurate identification of clinically relevant bacterial taxa. Our results indicate that the hospital environment is predominantly inhabited by closely related species. A massive dominance of a few taxa in all taxonomic levels down to the genera was observed, where the ten most abundant genera in each facility represented 64.4% of all observed taxa, with a major predominance of Acinetobacter and Pseudomonas. The presence of several nosocomial pathogens was revealed. Co-occurrence analysis indicated that the present hospital microbial network had low connectedness, forming a clustered topology, but not structured among groups of nodes (i.e., modules). Furthermore, we were able to detect ecologically relevant relationships between specific microbial taxa, in particular, potential competition between pathogens and non-pathogens. Overall, these results provide new insight into different aspects of a hospital microbiome and indicate that 16S rRNA sequencing may serve as a robust one-step tool for microbiological identification and characterization of a wide range of clinically relevant bacterial taxa in hospital settings with a high resolution. Full article

(This article belongs to the Section Molecular Microbiology)

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21 pages, 3835 KiB

Open AccessArticle

A Free-Operant Reward-Tracking Paradigm to Study Neural Mechanisms and Neurochemical Modulation of Adaptive Behavior in Rats

by Vanya V. Stoilova, Sina A. Wette and Maik C. Stüttgen

Int. J. Mol. Sci. 2019, 20(12), 3098; https://doi.org/10.3390/ijms20123098 - 25 Jun 2019

Cited by 2 | Viewed by 4124

Abstract

The ability to respond flexibly to changing environmental circumstances is a hallmark of goal-directed behavior, and compromised flexibility is associated with a wide range of psychiatric conditions in humans, such as addiction and stress-related disorders. To identify neural circuits and transmitter systems implicated [...] Read more.

The ability to respond flexibly to changing environmental circumstances is a hallmark of goal-directed behavior, and compromised flexibility is associated with a wide range of psychiatric conditions in humans, such as addiction and stress-related disorders. To identify neural circuits and transmitter systems implicated in the provision of cognitive flexibility, suitable animal paradigms are needed. Ideally, such models should be easy to implement, allow for rapid task acquisition, provide multiple behavioral readouts, and permit combination with physiological and pharmacological testing and manipulation. Here, we describe a paradigm meeting these requirements and employ it to investigate the neural substrates and neurochemical modulation of adaptive behavior. Water-restricted rats learned to emit operant responses for positive reinforcement (water reward) within minutes in a free-operant conditioning environment. Without further training, animals were able to track changes in the reward schedule. Given prior evidence that the medial prefrontal cortex (mPFC) and the dopaminergic system are required for flexible behavior, we aimed to assess both in more detail. Silencing of mPFC compromised flexible behavior when avoidance of punishment was required. Systemic injections of the D2-receptor agonist quinpirole and the D2-receptor antagonist eticlopride had complex, differential impacts on reward seeking and adaptive behavior. Full article

(This article belongs to the Special Issue Rhine-Main Neuroscience Network: rmn^2-Oberwesel 2018)

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20 pages, 3373 KiB

Open AccessArticle

Age-Associated mRNA and miRNA Expression Changes in the Blood-Brain Barrier

by Emily F. Goodall, Vicki Leach, Chunfang Wang, Johnathan Cooper-Knock, Paul R. Heath, David Baker, David R. Drew, M. Jill Saffrey, Julie E. Simpson, Ignacio A. Romero and Stephen B. Wharton

Int. J. Mol. Sci. 2019, 20(12), 3097; https://doi.org/10.3390/ijms20123097 - 25 Jun 2019

Cited by 18 | Viewed by 5795

Abstract

Functional and structural age-associated changes in the blood-brain barrier (BBB) may affect the neurovascular unit and contribute to the onset and progression of age-associated neurodegenerative pathologies, including Alzheimer’s disease. The current study interrogated the RNA profile of the BBB in an ageing human [...] Read more.

Functional and structural age-associated changes in the blood-brain barrier (BBB) may affect the neurovascular unit and contribute to the onset and progression of age-associated neurodegenerative pathologies, including Alzheimer’s disease. The current study interrogated the RNA profile of the BBB in an ageing human autopsy brain cohort and an ageing mouse model using combined laser capture microdissection and expression profiling. Only 12 overlapping genes were altered in the same direction in the BBB of both ageing human and mouse cohorts. These included genes with roles in regulating vascular tone, tight junction protein expression and cell adhesion, all processes prone to dysregulation with advancing age. Integrated mRNA and miRNA network and pathway enrichment analysis of the datasets identified 15 overlapping miRNAs that showed altered expression. In addition to targeting genes related to DNA binding and/or autophagy, many of the miRNAs identified play a role in age-relevant processes, including BBB dysfunction and regulating the neuroinflammatory response. Future studies have the potential to develop targeted therapeutic approaches against these candidates to prevent vascular dysfunction in the ageing brain. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction)

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20 pages, 1312 KiB

Open AccessArticle

Serum Proteome Alterations in Human Cystathionine β-Synthase Deficiency and Ischemic Stroke Subtypes

by Marta Sikora, Izabela Lewandowska, Małgorzata Kupc, Jolanta Kubalska, Ałła Graban, Łukasz Marczak, Radosław Kaźmierski and Hieronim Jakubowski

Int. J. Mol. Sci. 2019, 20(12), 3096; https://doi.org/10.3390/ijms20123096 - 25 Jun 2019

Cited by 10 | Viewed by 3792

Abstract

Ischemic stroke induces brain injury via thrombotic or embolic mechanisms involving large or small vessels. Cystathionine β-synthase deficiency (CBS), an inborn error of metabolism, is associated with vascular thromboembolism, the major cause of morbidity and mortality in affected patients. Because thromboembolism involves the [...] Read more.

Ischemic stroke induces brain injury via thrombotic or embolic mechanisms involving large or small vessels. Cystathionine β-synthase deficiency (CBS), an inborn error of metabolism, is associated with vascular thromboembolism, the major cause of morbidity and mortality in affected patients. Because thromboembolism involves the brain vasculature in these patients, we hypothesize that CBS deficiency and ischemic stroke have similar molecular phenotypes. We used label-free mass spectrometry for quantification of changes in serum proteomes in CBS-deficient patients (n = 10) and gender/age-matched unaffected controls (n = 14), as well as in patients with cardioembolic (n = 17), large-vessel (n = 26), or lacunar (n = 25) ischemic stroke subtype. In CBS-deficient patients, 40 differentially expressed serum proteins were identified, of which 18 were associated with elevated homocysteine (Hcy) and 22 were Hcy-independent. We also identified Hcy-independent differentially expressed serum proteins in ischemic stroke patients, some of which were unique to a specific subtype: 10 of 32 for cardioembolic vs. large-vessel, six of 33 for cardioembolic vs. lacunar, and six of 23 for large-vessel vs. lacunar. There were significant overlaps between proteins affected by CBS deficiency and ischemic stroke, particularly the cardioembolic subtype, similar to protein overlaps between ischemic stroke subtypes. Top molecular pathways affected by CBS deficiency and ischemic stroke subtypes included acute phase response signaling and coagulation system. Similar molecular networks centering on NFκB were affected by CBS deficiency and stroke subtypes. These findings suggest common mechanisms involved in the pathologies of CBS deficiency and ischemic stroke subtypes. Full article

(This article belongs to the Special Issue Amino Acid Metabolism and Regulation in Health and Disease)

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3 pages, 160 KiB

Open AccessEditorial

Special Issue on Basic and Translational Research in Colorectal Cancer

by Paola Ulivi, Emanuela Scarpi and Alessandro Passardi

Int. J. Mol. Sci. 2019, 20(12), 3095; https://doi.org/10.3390/ijms20123095 - 25 Jun 2019

Cited by 1 | Viewed by 3187

Abstract

The present editorial aims to summarize the 17 scientific papers that have contributed to this Special Issue focusing on different aspects of basic and translational research in colorectal cancer. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

17 pages, 754 KiB

Open AccessReview

Mitochondria as a Source and a Target for Uremic Toxins

by Vasily A. Popkov, Denis N. Silachev, Arthur O. Zalevsky, Dmitry B. Zorov and Egor Y. Plotnikov

Int. J. Mol. Sci. 2019, 20(12), 3094; https://doi.org/10.3390/ijms20123094 - 25 Jun 2019

Cited by 39 | Viewed by 5344

Abstract

Elucidation of molecular and cellular mechanisms of the uremic syndrome is a very challenging task. More than 130 substances are now considered to be “uremic toxins” and represent a very diverse group of molecules. The toxicity of these molecules affects many cellular processes, [...] Read more.

Elucidation of molecular and cellular mechanisms of the uremic syndrome is a very challenging task. More than 130 substances are now considered to be “uremic toxins” and represent a very diverse group of molecules. The toxicity of these molecules affects many cellular processes, and expectably, some of them are able to disrupt mitochondrial functioning. However, mitochondria can be the source of uremic toxins as well, as the mitochondrion can be the site of complete synthesis of the toxin, whereas in some scenarios only some enzymes of the pathway of toxin synthesis are localized here. In this review, we discuss the role of mitochondria as both the target and source of pathological processes and toxic compounds during uremia. Our analysis revealed about 30 toxins closely related to mitochondria. Moreover, since mitochondria are key regulators of cellular redox homeostasis, their functioning might directly affect the production of uremic toxins, especially those that are products of oxidation or peroxidation of cellular components, such as aldehydes, advanced glycation end-products, advanced lipoxidation end-products, and reactive carbonyl species. Additionally, as a number of metabolic products can be degraded in the mitochondria, mitochondrial dysfunction would therefore be expected to cause accumulation of such toxins in the organism. Alternatively, many uremic toxins (both made with the participation of mitochondria, and originated from other sources including exogenous) are damaging to mitochondrial components, especially respiratory complexes. As a result, a positive feedback loop emerges, leading to the amplification of the accumulation of uremic solutes. Therefore, uremia leads to the appearance of mitochondria-damaging compounds, and consecutive mitochondrial damage causes a further rise of uremic toxins, whose synthesis is associated with mitochondria. All this makes mitochondrion an important player in the pathogenesis of uremia and draws attention to the possibility of reducing the pathological consequences of uremia by protecting mitochondria and reducing their role in the production of uremic toxins. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease)

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14 pages, 3272 KiB

Open AccessArticle

Reduced Anti-Histone Antibodies and Increased Risk of Rheumatoid Arthritis Associated with a Single Nucleotide Polymorphism in PADI4 in North Americans

by Aisha M. Mergaert, Mandar Bawadekar, Thai Q. Nguyen, Laura Massarenti, Caitlyn L. Holmes, Ryan Rebernick, Steven J. Schrodi and Miriam A. Shelef

Int. J. Mol. Sci. 2019, 20(12), 3093; https://doi.org/10.3390/ijms20123093 - 25 Jun 2019

Cited by 14 | Viewed by 3995

Abstract

Autoantibodies against citrullinated proteins are a hallmark of rheumatoid arthritis, a destructive inflammatory arthritis. Peptidylarginine deiminase 4 (PAD4) has been hypothesized to contribute to rheumatoid arthritis by citrullinating histones to induce neutrophil extracellular traps (NETs), which display citrullinated proteins that are targeted by [...] Read more.

Autoantibodies against citrullinated proteins are a hallmark of rheumatoid arthritis, a destructive inflammatory arthritis. Peptidylarginine deiminase 4 (PAD4) has been hypothesized to contribute to rheumatoid arthritis by citrullinating histones to induce neutrophil extracellular traps (NETs), which display citrullinated proteins that are targeted by autoantibodies to drive inflammation and arthritis. Consistent with this theory, PAD4-deficient mice have reduced NETs, autoantibodies, and arthritis. However, PAD4′s role in human rheumatoid arthritis is less clear. Here, we determine if single nucleotide polymorphism rs2240335 in PADI4, whose G allele is associated with reduced PAD4 in neutrophils, correlates with NETs, anti-histone antibodies, and rheumatoid arthritis susceptibility in North Americans. Control and rheumatoid arthritis subjects, divided into anti-cyclic citrullinated peptide (CCP) antibody positive and negative groups, were genotyped at rs2240335. In homozygotes, in vitro NETosis was quantified in immunofluorescent images and circulating NET and anti-histone antibody levels by enzyme linked immunosorbent assay (ELISA). Results were compared by t-test and correlation of rheumatoid arthritis diagnosis with rs2240335 by Armitage trend test. NET levels did not significantly correlate with genotype. G allele homozygotes in the CCP⁻ rheumatoid arthritis group had reduced anti-native and anti-citrullinated histone antibodies. However, the G allele conferred increased risk for rheumatoid arthritis diagnosis, suggesting a complex role for PAD4 in human rheumatoid arthritis. Full article

(This article belongs to the Special Issue Peptidylarginine Deiminases and Protein Deimination in Health and Disease)

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16 pages, 560 KiB

Open AccessReview

Carbonic Anhydrase as a Biomarker of Global and Local Impacts: Insights from Calcifying Animals

by Yuri Dornelles Zebral, Juliana da Silva Fonseca, Joseane Aparecida Marques and Adalto Bianchini

Int. J. Mol. Sci. 2019, 20(12), 3092; https://doi.org/10.3390/ijms20123092 - 25 Jun 2019

Cited by 29 | Viewed by 5098

Abstract

The emission of greenhouse gases has grown in unprecedented levels since the beginning of the industrial era. As a result, global climate changes, such as heightened global temperature and ocean acidification, are expected to negatively impact populations. Similarly, industrial and urban unsustainable development [...] Read more.

The emission of greenhouse gases has grown in unprecedented levels since the beginning of the industrial era. As a result, global climate changes, such as heightened global temperature and ocean acidification, are expected to negatively impact populations. Similarly, industrial and urban unsustainable development are also expected to impose local impacts of their own, such as environmental pollution with organic and inorganic chemicals. As an answer, biomarkers can be used in environmental programs to assess these impacts. These tools are based in the quantification of biochemical and cellular responses of target species that are known to respond in a sensitive and specific way to such stresses. In this context, carbonic anhydrase has shown to be a promising biomarker candidate for the assessment of global and local impacts in biomonitoring programs, especially in marine zones, such as coral reefs, considering the pivotal role of this enzyme in the calcification process. Therefore, the aim of this review is to show the recent advances in the carbonic anhydrase research and the reasons why it can be considered as a promising biomarker to be used for calcifying organisms. Full article

(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research)

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22 pages, 3833 KiB

Open AccessArticle

Transcriptomic Analysis Reveals the High-Oleic Acid Feedback Regulating the Homologous Gene Expression of Stearoyl-ACP Desaturase 2 (SAD2) in Peanuts

by Hao Liu, Jianzhong Gu, Qing Lu, Haifen Li, Yanbin Hong, Xiaoping Chen, Li Ren, Li Deng and Xuanqiang Liang

Int. J. Mol. Sci. 2019, 20(12), 3091; https://doi.org/10.3390/ijms20123091 - 25 Jun 2019

Cited by 24 | Viewed by 5220

Abstract

Peanuts with high oleic acid content are usually considered to be beneficial for human health and edible oil storage. In breeding practice, peanut lines with high monounsaturated fatty acids are selected using fatty acid desaturase 2 (FAD2), which is responsible for [...] Read more.

Peanuts with high oleic acid content are usually considered to be beneficial for human health and edible oil storage. In breeding practice, peanut lines with high monounsaturated fatty acids are selected using fatty acid desaturase 2 (FAD2), which is responsible for the conversion of oleic acid (C18:1) to linoleic acid (C18:2). Here, comparative transcriptomics were used to analyze the global gene expression profile of high- and normal-oleic peanut cultivars at six time points during seed development. First, the mutant type of FAD2 was determined in the high-oleic peanut (H176). The result suggested that early translation termination occurred simultaneously in the coding sequence of FAD2-A and FAD2-B, and the cultivar H176 is capable of utilizing a potential germplasm resource for future high-oleic peanut breeding. Furthermore, transcriptomic analysis identified 74 differentially expressed genes (DEGs) involved in lipid metabolism in high-oleic peanut seed, of which five DEGs encoded the fatty acid desaturase. Aradu.XM2MR belonged to the homologous gene of stearoyl-ACP (acyl carrier protein) desaturase 2 (SAD2) that converted the C18:0 into C18:1. Further subcellular localization studies indicated that FAD2 was located at the endoplasmic reticulum (ER), and Aradu.XM2MR was targeted to the plastid in Arabidopsis protoplast cells. To examine the dynamic mechanism of this finding, we focused on the peroxidase (POD)-mediated fatty acid (FA) degradation pathway. The fad2 mutant significantly increased the POD activity and H₂O₂ concentration at the early stage of seed development, implying that redox signaling likely acted as a messenger to connect the signaling transduction between the high-oleic content and Aradu.XM2MR transcription level. Taken together, transcriptome analysis revealed the feedback mechanism of SAD2 (Aradu.XM2MR) associated with FAD2 mutation during the seed developmental stage, which could provide a potential peanut breeding strategy based on identified candidate genes to improve the content of oleic acid. Full article

(This article belongs to the Special Issue Plant Lipids: From Physiology to Biotechnological Applications)

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20 pages, 6670 KiB

Open AccessArticle

Diabetic Pregnancy and Maternal High-Fat Diet Impair Mitochondrial Dynamism in the Developing Fetal Rat Heart by Sex-Specific Mechanisms

by Tricia D. Larsen, Kyle H. Sabey, Alexis J. Knutson, Tyler C. T. Gandy, Eli J. Louwagie, Lothar Lauterboeck, Kennedy S. Mdaki and Michelle L. Baack

Int. J. Mol. Sci. 2019, 20(12), 3090; https://doi.org/10.3390/ijms20123090 - 25 Jun 2019

Cited by 33 | Viewed by 4935

Abstract

Infants born to diabetic or obese mothers are at greater risk of heart disease at birth and throughout life, but prevention is hindered because underlying mechanisms remain poorly understood. Using a rat model, we showed that prenatal exposure to maternal diabetes and a [...] Read more.

Infants born to diabetic or obese mothers are at greater risk of heart disease at birth and throughout life, but prevention is hindered because underlying mechanisms remain poorly understood. Using a rat model, we showed that prenatal exposure to maternal diabetes and a high-fat diet caused diastolic and systolic dysfunction, myocardial lipid accumulation, decreased respiratory capacity, and oxidative stress in newborn offspring hearts. This study aimed to determine whether mitochondrial dynamism played a role. Using confocal live-cell imaging, we examined mitochondrial dynamics in neonatal rat cardiomyocytes (NRCM) from four prenatally exposed groups: controls, diabetes, high-fat diet, and combination exposed. Cardiac expression of dynamism-related genes and proteins were compared, and gender-specific differences were evaluated. Findings show that normal NRCM have highly dynamic mitochondria with a well-balanced number of fusion and fission events. Prenatal exposure to diabetes or a high-fat diet impaired dynamism resulting in shorter, wider mitochondria. Mechanisms of impaired dynamism were gender-specific and protein regulated. Females had higher expression of fusion proteins which may confer a cardioprotective effect. Prenatally exposed male hearts had post-translational modifications known to impair dynamism and influence mitophagy-mediated cell death. This study identifies mitochondrial fusion and fission proteins as targetable, pathogenic regulators of heart health in offspring exposed to excess circulating maternal fuels. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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2 pages, 1126 KiB

Open AccessCorrection

Correction: Bonior, J., et al. Capsaicin-Sensitive Sensory Nerves Are Necessary for the Protective Effect of Ghrelin in Cerulein-Induced Acute Pancreatitis in Rats. Int. J. Mol. Sci. 2017, 18, 1402

by Joanna Bonior, Zygmunt Warzecha, Piotr Ceranowicz, Ryszard Gajdosz, Piotr Pierzchalski, Michalina Kot, Anna Leja-Szpak, Katarzyna Nawrot-Porąbka, Paweł Link-Lenczowski, Michał Pędziwiatr, Rafał Olszanecki, Krzysztof Bartuś, Rafał Trąbka, Beata Kuśnierz-Cabala, Artur Dembiński and Jolanta Jaworek

Int. J. Mol. Sci. 2019, 20(12), 3089; https://doi.org/10.3390/ijms20123089 - 25 Jun 2019

Cited by 1 | Viewed by 2254

Abstract

We would like to submit the correction to our published paper [...] Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 4360 KiB

Open AccessArticle

Transplantation of Adipose Stromal Cell Sheet Producing Hepatocyte Growth Factor Induces Pleiotropic Effect in Ischemic Skeletal Muscle

by Maria A. Boldyreva, Evgeny K. Shevchenko, Yuliya D. Molokotina, Pavel I. Makarevich, Irina B. Beloglazova, Ekaterina S. Zubkova, Konstantin V. Dergilev, Zoya I. Tsokolaeva, Dmitry Penkov, Mu-Nung Hsu, Yu-Chen Hu and Yelena V. Parfyonova

Int. J. Mol. Sci. 2019, 20(12), 3088; https://doi.org/10.3390/ijms20123088 - 24 Jun 2019

Cited by 19 | Viewed by 5099

Abstract

Cell therapy remains a promising approach for the treatment of cardiovascular diseases. In this regard, the contemporary trend is the development of methods to overcome low cell viability and enhance their regenerative potential. In the present study, we evaluated the therapeutic potential of [...] Read more.

Cell therapy remains a promising approach for the treatment of cardiovascular diseases. In this regard, the contemporary trend is the development of methods to overcome low cell viability and enhance their regenerative potential. In the present study, we evaluated the therapeutic potential of gene-modified adipose-derived stromal cells (ADSC) that overexpress hepatocyte growth factor (HGF) in a mice hind limb ischemia model. Angiogenic and neuroprotective effects were assessed following ADSC transplantation in suspension or in the form of cell sheet. We found superior blood flow restoration, tissue vascularization and innervation, and fibrosis reduction after transplantation of HGF-producing ADSC sheet compared to other groups. We suggest that the observed effects are determined by pleiotropic effects of HGF, along with the multifactorial paracrine action of ADSC which remain viable and functionally active within the engineered cell construct. Thus, we demonstrated the high therapeutic potential of the utilized approach for skeletal muscle recovery after ischemic damage associated with complex tissue degenerative effects. Full article

(This article belongs to the Special Issue Hepatocyte Growth Factor (HGF), II)

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14 pages, 2805 KiB

Open AccessArticle

Transcriptional Regulation of gga-miR-451 by AhR:Arnt in Mycoplasma gallisepticum (HS Strain) Infection

by Yabo Zhao, Yali Fu, Yingfei Sun, Mengyun Zou and Xiuli Peng

Int. J. Mol. Sci. 2019, 20(12), 3087; https://doi.org/10.3390/ijms20123087 - 24 Jun 2019

Cited by 11 | Viewed by 2821

Abstract

MicroRNAs (miRNAs) have been determined to be important regulators for pathogenic microorganism infection. However, it is largely unclear how miRNAs are triggered during pathogen infection. We previously reported that the up-regulation of gga-miR-451 negatively regulates the Mycoplasma gallisepticum (MG)-induced production of inflammatory cytokines [...] Read more.

MicroRNAs (miRNAs) have been determined to be important regulators for pathogenic microorganism infection. However, it is largely unclear how miRNAs are triggered during pathogen infection. We previously reported that the up-regulation of gga-miR-451 negatively regulates the Mycoplasma gallisepticum (MG)-induced production of inflammatory cytokines via targeting tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein zeta (YWHAZ). The aim of this study was to investigate the mechanism regulating gga-miR-451 in MG infection in chickens. Analysis of gga-miR-451 precursor, pri-miR-451, and pre-miR-451 indicated that the regulation occurred transcriptionally. We also identified the transcriptional regulatory region of gga-miR-451 that contained consensus-binding motif for aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (Arnt) complex, which is known as the transcription factor that regulates gene expression. Luciferase reporter assays combined with chromatin immunoprecipitation (ChIP) demonstrated that AhR:Arnt bound directly to the promoter elements of gga-miR-451, which were responsible for gga-miR-451 transcription in the context of MG infection. Furthermore, upregulation of AhR:Arnt significantly induced gga-miR-451 and inhibited YWHAZ expression, suggesting that AhR:Arnt may play an anti-inflammatory role in MG infection. This discovery suggests that induced gga-miR-451 expression is modulated by AhR:Arnt in response to MG infection. Full article

(This article belongs to the Special Issue Transcriptional Regulation: Molecules, Involved Mechanisms and Misregulation 2019)

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2 pages, 1068 KiB

Open AccessCorrection

Correction: Warzecha, Z., et al. Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats. Int. J. Mol. Sci. 2017, 18, 882

by Zygmunt Warzecha, Paweł Sendur, Piotr Ceranowicz, Jakub Cieszkowski, Marcin Dembiński, Ryszard Sendur, Joanna Bonior, Jolanta Jaworek, Tadeusz Ambroży, Rafał Olszanecki, Beata Kuśnierz-Cabala, Kaczmarzyk Tomasz, Romana Tomaszewska and Artur Dembiński

Int. J. Mol. Sci. 2019, 20(12), 3086; https://doi.org/10.3390/ijms20123086 - 24 Jun 2019

Cited by 1 | Viewed by 2109

Abstract

We would like to submit this correction to our published paper [...] Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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11 pages, 2358 KiB

Open AccessArticle

Anti-Oxidant Activity and Dust-Proof Effect of Chitosan with Different Molecular Weights

by Yong Hyun Lee, So Yeon Park, Jae Eun Park, Byung Ok Jung, Jung Eun Park, Jae Kweon Park and You Jin Hwang

Int. J. Mol. Sci. 2019, 20(12), 3085; https://doi.org/10.3390/ijms20123085 - 24 Jun 2019

Cited by 9 | Viewed by 2848

Abstract

High molecular weight chitosan (HMWC) was degraded to prepare chitosan with different molecular weight based on the fenton reaction, which can produce aggressive OH-radicals produced from hydrogen peroxide in the presence of catalytic metal ions. The relative molecular weight, anti-oxidant activity, and fine [...] Read more.

High molecular weight chitosan (HMWC) was degraded to prepare chitosan with different molecular weight based on the fenton reaction, which can produce aggressive OH-radicals produced from hydrogen peroxide in the presence of catalytic metal ions. The relative molecular weight, anti-oxidant activity, and fine dust removal effect of chitosan hydrolysates were elucidated to define their molecular weight and their potent biological activity. Our results demonstrate that chitosan hydrolysates derived from the hydrolysis of HMWC may possess significant free-radical scavenging activity as good anti-oxidants against the radical scavenging activity of DPPH and ABTS, respectively. Furthermore, chitosan hydrolysates can effectively eliminate fine dust, which may contain some particulate matter (PM) and unknown species of microorganisms from the air, suggesting that our data provide important information for producing air filters, dust-proof masks and skin cleaner for the purpose of human healthcare and well-being. Full article

(This article belongs to the Special Issue Chitosan Functionalizations, Formulations and Composites)

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14 pages, 4405 KiB

Open AccessArticle

Improvement of the Firocoxib Dissolution Performance Using Electrospun Fibers Obtained from Different Polymer/Surfactant Associations

by Lauretta Maggi, Valeria Friuli, Enrica Chiesa, Silvia Pisani, Mirena Sakaj, Paolo Celestini and Giovanna Bruni

Int. J. Mol. Sci. 2019, 20(12), 3084; https://doi.org/10.3390/ijms20123084 - 24 Jun 2019

Cited by 12 | Viewed by 2846

Abstract

An electrospinning process was optimized to produce fibers of micrometric size with different combinations of polymeric and surfactant materials to promote the dissolution rate of an insoluble drug: firocoxib. Scanning Electron Microscopy (SEM) showed that only some combinations of the proposed carrier systems [...] Read more.

An electrospinning process was optimized to produce fibers of micrometric size with different combinations of polymeric and surfactant materials to promote the dissolution rate of an insoluble drug: firocoxib. Scanning Electron Microscopy (SEM) showed that only some combinations of the proposed carrier systems allowed the production of suitable fibers and further fine optimization of the technique is also needed to load the drug. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) suggest that the drug is in an amorphous state in the final product. Drug amorphization, the fine dispersion of the active in the carriers, and the large surface area exposed to water interaction obtained through the electrospinning process can explain the remarkable improvement in the dissolution performance of firocoxib from the final product developed. Full article

(This article belongs to the Special Issue Drug Delivery and Scaffolding in the Era of 3D-Printing and Microfluidic Techniques: Challenges and Opportunities)

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11 pages, 1490 KiB

Open AccessArticle

Proteolytic Rafts for Improving Intraparenchymal Migration of Minimally Invasively Administered Hydrogel-Embedded Stem Cells

by Marcin Piejko, Anna Jablonska, Piotr Walczak and Miroslaw Janowski

Int. J. Mol. Sci. 2019, 20(12), 3083; https://doi.org/10.3390/ijms20123083 - 24 Jun 2019

Cited by 3 | Viewed by 2730

Abstract

The physiological spaces (lateral ventricles, intrathecal space) or pathological cavities (stroke lesion, syringomyelia) may serve as an attractive gateway for minimally invasive deployment of stem cells. Embedding stem cells in injectable scaffolds is essential when transplanting into the body cavities as they secure [...] Read more.

The physiological spaces (lateral ventricles, intrathecal space) or pathological cavities (stroke lesion, syringomyelia) may serve as an attractive gateway for minimally invasive deployment of stem cells. Embedding stem cells in injectable scaffolds is essential when transplanting into the body cavities as they secure favorable microenvironment and keep cells localized, thereby preventing sedimentation. However, the limited migration of transplanted cells from scaffold to the host tissue is still a major obstacle, which prevents this approach from wider implementation for the rapidly growing field of regenerative medicine. Hyaluronan, a naturally occurring polymer, is frequently used as a basis of injectable scaffolds. We hypothesized that supplementation of hyaluronan with activated proteolytic enzymes could be a viable approach for dissolving the connective tissue barrier on the interface between the scaffold and the host, such as pia mater or scar tissue, thus demarcating lesion cavity. In a proof-of-concept study, we have found that collagenase and trypsin immobilized in hyaluronan-based hydrogel retain 60% and 28% of their proteolytic activity compared to their non-immobilized forms, respectively. We have also shown that immobilized enzymes do not have a negative effect on the viability of stem cells (glial progenitors and mesenchymal stem cells) in vitro. In conclusion, proteolytic rafts composed of hyaluronan-based hydrogels and immobilized enzymes may be an attractive strategy to facilitate migration of stem cells from injectable scaffolds into the parenchyma of surrounding tissue. Full article

(This article belongs to the Special Issue Stem Cell-Based Therapy)

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