International Journal of Molecular Sciences

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Open AccessArticle

Progressive Vascular Functional and Structural Damage in a Bronchopulmonary Dysplasia Model in Preterm Rabbits Exposed to Hyperoxia

by Julio Jiménez, Jute Richter, Taro Nagatomo, Thomas Salaets, Rozenn Quarck, Allard Wagennar, Hongmei Wang, Jeroen Vanoirbeek, Jan Deprest and Jaan Toelen

Int. J. Mol. Sci. 2016, 17(10), 1776; https://doi.org/10.3390/ijms17101776 - 24 Oct 2016

Cited by 29 | Viewed by 6752

Abstract

Bronchopulmonary dysplasia (BPD) is caused by preterm neonatal lung injury and results in oxygen dependency and pulmonary hypertension. Current clinical management fails to reduce the incidence of BPD, which calls for novel therapies. Fetal rabbits have a lung development that mimics humans and [...] Read more.

Bronchopulmonary dysplasia (BPD) is caused by preterm neonatal lung injury and results in oxygen dependency and pulmonary hypertension. Current clinical management fails to reduce the incidence of BPD, which calls for novel therapies. Fetal rabbits have a lung development that mimics humans and can be used as a translational model to test novel treatment options. In preterm rabbits, exposure to hyperoxia leads to parenchymal changes, yet vascular damage has not been studied in this model. In this study we document the early functional and structural changes of the lung vasculature in preterm rabbits that are induced by hyperoxia after birth. Pulmonary artery Doppler measurements, micro-CT barium angiograms and media thickness of peripheral pulmonary arteries were affected after seven days of hyperoxia when compared to controls. The parenchyma was also affected both at the functional and structural level. Lung function testing showed higher tissue resistance and elastance, with a decreased lung compliance and lung capacity. Histologically hyperoxia leads to fewer and larger alveoli with thicker walls, less developed distal airways and more inflammation than normoxia. In conclusion, we show that the rabbit model develops pulmonary hypertension and developmental lung arrest after preterm lung injury, which parallel the early changes in human BPD. Thus it enables the testing of pharmaceutical agents that target the cardiovascular compartment of the lung for further translation towards the clinic. Full article

(This article belongs to the Special Issue Vascular Biology and Therapeutics)

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Open AccessReview

Dissecting the Heterogeneity of Circulating Tumor Cells in Metastatic Breast Cancer: Going Far Beyond the Needle in the Haystack

by Michela Bulfoni, Matteo Turetta, Fabio Del Ben, Carla Di Loreto, Antonio Paolo Beltrami and Daniela Cesselli

Int. J. Mol. Sci. 2016, 17(10), 1775; https://doi.org/10.3390/ijms17101775 - 24 Oct 2016

Cited by 54 | Viewed by 9579

Abstract

Although the enumeration of circulating tumor cells (CTC) defined as expressing both epithelial cell adhesion molecule and cytokeratins (EpCAM⁺/CK⁺) can predict prognosis and response to therapy in metastatic breast, colon and prostate cancer, its clinical utility (i.e., the ability [...] Read more.

Although the enumeration of circulating tumor cells (CTC) defined as expressing both epithelial cell adhesion molecule and cytokeratins (EpCAM⁺/CK⁺) can predict prognosis and response to therapy in metastatic breast, colon and prostate cancer, its clinical utility (i.e., the ability to improve patient outcome by guiding therapy) has not yet been proven in clinical trials. Therefore, scientists are now focusing on the molecular characterization of CTC as a way to explore its possible use as a “surrogate” of tumor tissues to non-invasively assess the genomic landscape of the cancer and its evolution during treatment. Additionally, evidences confirm the existence of CTC in epithelial-to-mesenchymal transition (EMT) characterized by a variable loss of epithelial markers. Since the EMT process can originate cells with enhanced invasiveness, stemness and drug-resistance, the enumeration and characterization of this population, perhaps the one truly responsible of tumor recurrence and progression, could be more clinically useful. For these reasons, several devices able to capture CTC independently from the expression of epithelial markers have been developed. In this review, we will describe the types of heterogeneity so far identified and the key role played by the epithelial-to-mesenchymal transition in driving CTC heterogeneity. The clinical relevance of detecting CTC-heterogeneity will be discussed as well. Full article

(This article belongs to the Special Issue Circulating Tumor Cells)

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Open AccessArticle

Translationally Controlled Tumor Protein Stimulates Dopamine Release from PC12 Cells via Ca²⁺-Independent Phospholipase A₂ Pathways

by Jihui Seo, Jeehye Maeng and Hwa-Jung Kim

Int. J. Mol. Sci. 2016, 17(10), 1774; https://doi.org/10.3390/ijms17101774 - 24 Oct 2016

Cited by 7 | Viewed by 5393

Abstract

The translationally controlled tumor protein (TCTP), initially identified as a tumor- and growth-related protein, is also known as a histamine-releasing factor (HRF). TCTP is widely distributed in the neuronal systems, but its function is largely uncharacterized. Here, we report a novel function of [...] Read more.

The translationally controlled tumor protein (TCTP), initially identified as a tumor- and growth-related protein, is also known as a histamine-releasing factor (HRF). TCTP is widely distributed in the neuronal systems, but its function is largely uncharacterized. Here, we report a novel function of TCTP in the neurotransmitter release from a neurosecretory, pheochromocytoma (PC12) cells. Treatment with recombinant TCTP (rTCTP) enhanced both basal and depolarization (50 mM KCl)-evoked [³H]dopamine release in concentration- and time-dependent manners. Interestingly, even though rTCTP induced the increase in intracellular calcium levels ([Ca²⁺]_i), the rTCTP-driven effect on dopamine release was mediated by a Ca²⁺-independent pathway, as evidenced by the fact that Ca²⁺-modulating agents such as Ca²⁺ chelators and a voltage-gated L-type Ca²⁺-channel blocker did not produce any changes in rTCTP-evoked dopamine release. In a study to investigate the involvement of phospholipase A₂ (PLA₂) in rTCTP-induced dopamine release, the inhibitor for Ca²⁺-independent PLA₂ (iPLA₂) produced a significant inhibitory effect on rTCTP-induced dopamine release, whereas this release was not significantly inhibited by Ca²⁺-dependent cytosolic PLA₂ (cPLA₂) and secretory PLA₂ (sPLA₂) inhibitors. We found that rTCTP-induced dopamine release from neuronal PC12 cells was modulated by a Ca²⁺-independent mechanism that involved PLA₂ in the process, suggesting the regulatory role of TCTP in the neuronal functions. Full article

(This article belongs to the Section Biochemistry)

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Open AccessReview

miR-155: A Novel Target in Allergic Asthma

by Hong Zhou, Junyao Li, Peng Gao, Qi Wang and Jie Zhang

Int. J. Mol. Sci. 2016, 17(10), 1773; https://doi.org/10.3390/ijms17101773 - 24 Oct 2016

Cited by 72 | Viewed by 6926

Abstract

MicroRNAs (miRNAs), a class of small non-coding RNAs of 18–24 nucleotides in length, function to posttranscriptionally regulate protein expression. miR-155 was one of the first identified and, to date, the most studied miRNA, and has been linked to various cellular processes such as [...] Read more.

MicroRNAs (miRNAs), a class of small non-coding RNAs of 18–24 nucleotides in length, function to posttranscriptionally regulate protein expression. miR-155 was one of the first identified and, to date, the most studied miRNA, and has been linked to various cellular processes such as modulation of immune responses and oncogenesis. Previous studies have identified miR-155 as a crucial positive regulator of Th1 immune response in autoimmune diseases, but as a suppressor of Th2 immunity in allergic disorders. However, recent studies have found new evidence that miR-155 plays an indispensible role in allergic asthma. This review summarizes the recent findings with respect to miR-155 in immune responses and the underlying mechanisms responsible for miR-155-related allergic diseases, as well as the similarities between miR-155 and glucocorticoids in immunity. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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Open AccessArticle

Metabolic Response to XD14 Treatment in Human Breast Cancer Cell Line MCF-7

by Daqiang Pan, Michel Kather, Lucas Willmann, Manuel Schlimpert, Christoph Bauer, Simon Lagies, Karin Schmidtkunz, Steffen U. Eisenhardt, Manfred Jung, Stefan Günther and Bernd Kammerer

Int. J. Mol. Sci. 2016, 17(10), 1772; https://doi.org/10.3390/ijms17101772 - 24 Oct 2016

Cited by 9 | Viewed by 6977

Abstract

XD14 is a 4-acyl pyrrole derivative, which was discovered by a high-throughput virtual screening experiment. XD14 inhibits bromodomain and extra-terminal domain (BET) proteins (BRD2, BRD3, BRD4 and BRDT) and consequently suppresses cell proliferation. In this study, metabolic profiling reveals the molecular effects in [...] Read more.

XD14 is a 4-acyl pyrrole derivative, which was discovered by a high-throughput virtual screening experiment. XD14 inhibits bromodomain and extra-terminal domain (BET) proteins (BRD2, BRD3, BRD4 and BRDT) and consequently suppresses cell proliferation. In this study, metabolic profiling reveals the molecular effects in the human breast cancer cell line MCF-7 (Michigan Cancer Foundation-7) treated by XD14. A three-day time series experiment with two concentrations of XD14 was performed. Gas chromatography-mass spectrometry (GC-MS) was applied for untargeted profiling of treated and non-treated MCF-7 cells. The gained data sets were evaluated by several statistical methods: analysis of variance (ANOVA), clustering analysis, principle component analysis (PCA), and partial least squares discriminant analysis (PLS-DA). Cell proliferation was strongly inhibited by treatment with 50 µM XD14. Samples could be discriminated by time and XD14 concentration using PLS-DA. From the 117 identified metabolites, 67 were significantly altered after XD14 treatment. These metabolites include amino acids, fatty acids, Krebs cycle and glycolysis intermediates, as well as compounds of purine and pyrimidine metabolism. This massive intervention in energy metabolism and the lack of available nucleotides could explain the decreased proliferation rate of the cancer cells. Full article

(This article belongs to the Special Issue Metabolomic Technologies in Medicine)

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Open AccessReview

Melatonin as a Potential Agent in the Treatment of Sarcopenia

by Ana Coto-Montes, Jose A. Boga, Dun X. Tan and Russel J. Reiter

Int. J. Mol. Sci. 2016, 17(10), 1771; https://doi.org/10.3390/ijms17101771 - 24 Oct 2016

Cited by 53 | Viewed by 9271

Abstract

Considering the increased speed at which the world population is aging, sarcopenia could become an epidemic in this century. This condition currently has no means of prevention or treatment. Melatonin is a highly effective and ubiquitously acting antioxidant and free radical scavenger that [...] Read more.

Considering the increased speed at which the world population is aging, sarcopenia could become an epidemic in this century. This condition currently has no means of prevention or treatment. Melatonin is a highly effective and ubiquitously acting antioxidant and free radical scavenger that is normally produced in all organisms. This molecule has been implicated in a huge number of biological processes, from anticonvulsant properties in children to protective effects on the lung in chronic obstructive pulmonary disease. In this review, we summarize the data which suggest that melatonin may be beneficial in attenuating, reducing or preventing each of the symptoms that characterize sarcopenia. The findings are not limited to sarcopenia, but also apply to osteoporosis-related sarcopenia and to age-related neuromuscular junction dysfunction. Since melatonin has a high safety profile and is drastically reduced in advanced age, its potential utility in the treatment of sarcopenic patients and related dysfunctions should be considered. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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Open AccessArticle

Trans-Stilbenes in Commercial Grape Juices: Quantification Using HPLC Approaches

by Julia López-Hernández and Ana Rodríguez-Bernaldo de Quirós

Int. J. Mol. Sci. 2016, 17(10), 1769; https://doi.org/10.3390/ijms17101769 - 24 Oct 2016

Cited by 16 | Viewed by 5135

Abstract

Trans-stilbenes belong to the group of polyphenolic phytoalexins, and occur in many plant foods. These compounds have received great attention by researchers due to their well-known beneficial health effects. In the present study a chromatographic method that comprises the use of variable [...] Read more.

Trans-stilbenes belong to the group of polyphenolic phytoalexins, and occur in many plant foods. These compounds have received great attention by researchers due to their well-known beneficial health effects. In the present study a chromatographic method that comprises the use of variable wavelength (VWD) and fluorescence (FLD) detectors in series for the analysis of trans-stilbenes is presented. The relation of peak-area obtained with both detectors is proposed as an alternative and complementary approach for the rapid identification of these phenolic compounds. The proposed method was applied to determine trans-stilbenes in commercial fruit juices. Trans-piceid was the most common trans-stilbene found in the samples analyzed. The method was validated in terms of linearity, sensitivity and repeatability. Appropriate sensitivity and good linearity (r² > 0.9991) were achieved. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals and Functional Food Ingredients in Fruits and Vegetables 2016)

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The Efficacy of Non-Pharmacological Interventions on Brain-Derived Neurotrophic Factor in Schizophrenia: A Systematic Review and Meta-Analysis

by Kenji Sanada, Iñaki Zorrilla, Yusuke Iwata, Cristina Bermúdez-Ampudia, Ariel Graff-Guerrero, Mónica Martínez-Cengotitabengoa and Ana González-Pinto

Int. J. Mol. Sci. 2016, 17(10), 1766; https://doi.org/10.3390/ijms17101766 - 24 Oct 2016

Cited by 29 | Viewed by 7100

Abstract

Several studies have investigated the relationship between non-pharmacological interventions (NPIs) and peripheral brain-derived neurotrophic factor (BDNF) in schizophrenia patients. We conducted a systematic review and meta-analysis to review the efficacy of NPIs on peripheral serum and plasma BDNF in subjects with schizophrenia (including [...] Read more.

Several studies have investigated the relationship between non-pharmacological interventions (NPIs) and peripheral brain-derived neurotrophic factor (BDNF) in schizophrenia patients. We conducted a systematic review and meta-analysis to review the efficacy of NPIs on peripheral serum and plasma BDNF in subjects with schizophrenia (including schizoaffective disorder). Meta-analyses were conducted to examine the effects of NPIs on blood BDNF levels by using the standardized mean differences (SMDs) between the intervention groups and controls. In total, six randomized controlled trials with 289 participants were included. Of them, five studies used exercise, physical training or diet products. One study used cognitive training. Overall, the BDNF levels in the NPI group increased significantly compared with the control groups (SMD = 0.95, 95% confidence interval (CI) = 0.07 to 1.83, p = 0.03). Subgroup analyses indicated beneficial effects of a non-exercise intervention on peripheral BDNF levels (SMD = 0.41, 95% CI = 0.08 to 0.74, p = 0.01). Meta-regression analyses showed that the completion rate influenced the variation in SMD (p = 0.01). Despite insufficient evidence to draw a conclusion, our results suggest that use of NPIs as adjunctive treatments, specifically non-exercise interventions, may affect positively serum or plasma BDNF in patients with schizophrenia. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)

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Open AccessArticle

CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation

by Cheng Ye, Duo Zhang, Lei Zhao, Yan Li, Xiaohan Yao, Hui Wang, Shengjie Zhang, Wei Liu, Hongchao Cao, Shuxian Yu, Yucheng Wang, Jingjing Jiang, Hui Wang, Xihua Li and Hao Ying

Int. J. Mol. Sci. 2016, 17(10), 1695; https://doi.org/10.3390/ijms17101695 - 24 Oct 2016

Cited by 23 | Viewed by 7534

Abstract

Skeletal muscle has a major role in locomotion and muscle disorders are associated with poor regenerative efficiency. Therefore, a deeper understanding of muscle regeneration is needed to provide a new insight for new therapies. CaMKK2 plays a role in the calcium/calmodulin-dependent kinase cascade; [...] Read more.

Skeletal muscle has a major role in locomotion and muscle disorders are associated with poor regenerative efficiency. Therefore, a deeper understanding of muscle regeneration is needed to provide a new insight for new therapies. CaMKK2 plays a role in the calcium/calmodulin-dependent kinase cascade; however, its role in skeletal muscle remains unknown. Here, we found that CaMKK2 expression levels were altered under physiological and pathological conditions including postnatal myogensis, freeze or cardiotoxin-induced muscle regeneration, and Duchenne muscular dystrophy. Overexpression of CaMKK2 suppressed C2C12 myoblast proliferation and differentiation, while inhibition of CaMKK2 had opposite effect. We also found that CaMKK2 is able to activate AMPK in C2C12 myocytes. Inhibition of AMPK could attenuate the effect of CaMKK2 overexpression, while AMPK agonist could abrogate the effect of CaMKK2 knockdown on C2C12 cell differentiation and proliferation. These results suggest that CaMKK2 functions as an AMPK kinase in muscle cells and AMPK mediates the effect of CaMKK2 on myoblast proliferation and differentiation. Our data also indicate that CaMKK2 might inhibit myoblast proliferation through AMPK-mediated cell cycle arrest by inducing cdc2-Tyr15 phosphorylation and repress differentiation through affecting PGC1α transcription. Lastly, we show that overexpressing CaMKK2 in the muscle of mice via electroporation impaired the muscle regeneration during freeze-induced injury, indicating that CaMKK2 could serve as a potential target to treat patients with muscle injury or myopathies. Together, our study reveals a new role for CaMKK2 as a negative regulator of myoblast differentiation and proliferation and sheds new light on the molecular regulation of muscle regeneration. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Morphine Protects Spinal Cord Astrocytes from Glutamate-Induced Apoptosis via Reducing Endoplasmic Reticulum Stress

by Chao Zhang, Chendan Wang, Jianbo Ren, Xiangjie Guo and Keming Yun

Int. J. Mol. Sci. 2016, 17(10), 1523; https://doi.org/10.3390/ijms17101523 - 24 Oct 2016

Cited by 21 | Viewed by 6327

Abstract

Glutamate is not only a neurotransmitter but also an important neurotoxin in central nervous system (CNS). Chronic elevation of glutamate induces both neuronal and glial cell apoptosis. However, its effect on astrocytes is complex and still remains unclear. In this study, we investigated [...] Read more.

Glutamate is not only a neurotransmitter but also an important neurotoxin in central nervous system (CNS). Chronic elevation of glutamate induces both neuronal and glial cell apoptosis. However, its effect on astrocytes is complex and still remains unclear. In this study, we investigated whether morphine, a common opioid ligand, could affect glutamate-induced apoptosis in astrocytes. Primary cultured astrocytes were incubated with glutamate in the presence/absence of morphine. It was found that morphine could reduce glutamate-induced apoptosis of astrocytes. Furthermore, glutamate activated Ca²⁺ release, thereby inducing endoplasmic reticulum (ER) stress in astrocytes, while morphine attenuated this deleterious effect. Using siRNA to reduce the expression of κ-opioid receptor, morphine could not effectively inhibit glutamate-stimulated Ca²⁺ release in astrocytes, the protective effect of morphine on glutamate-injured astrocytes was also suppressed. These results suggested that morphine could protect astrocytes from glutamate-induced apoptosis via reducing Ca²⁺ overload and ER stress pathways. In conclusion, this study indicated that excitotoxicity participated in the glutamate mediated apoptosis in astrocytes, while morphine attenuated this deleterious effect via regulating Ca²⁺ release and ER stress. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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Open AccessArticle

Annexin-1 Mediates Microglial Activation and Migration via the CK2 Pathway during Oxygen–Glucose Deprivation/Reperfusion

by Shuangxi Liu, Yan Gao, Xiaoli Yu, Baoming Zhao, Lu Liu, Yin Zhao, Zhenzhao Luo and Jing Shi

Int. J. Mol. Sci. 2016, 17(10), 1770; https://doi.org/10.3390/ijms17101770 - 22 Oct 2016

Cited by 138 | Viewed by 7458

Abstract

Annexin-1 (ANXA1) has shown neuroprotective effects and microglia play significant roles during central nervous system injury, yet the underlying mechanisms remain unclear. This study sought to determine whether ANXA1 regulates microglial response to oxygen–glucose deprivation/reperfusion (OGD/R) treatment and to clarify the downstream molecular [...] Read more.

Annexin-1 (ANXA1) has shown neuroprotective effects and microglia play significant roles during central nervous system injury, yet the underlying mechanisms remain unclear. This study sought to determine whether ANXA1 regulates microglial response to oxygen–glucose deprivation/reperfusion (OGD/R) treatment and to clarify the downstream molecular mechanism. In rat hippocampal slices, OGD/R treatment enhanced the ANXA1 expression in neuron, the formyl peptide receptor (FPRs) expression in microglia, and the microglial activation in the CA1 region (cornu ammonis 1). These effects were reversed by the FPRs antagonist Boc1. The cell membrane currents amplitude of BV-2 microglia (the microglial like cell-line) was increased when treated with Ac2-26, the N-terminal peptide of ANXA1. Ac2-26 treatment enhanced BV-2 microglial migration whereas Boc1 treatment inhibited the migration. In BV-2 microglia, both the expression of the CK2 target phosphorylated α-E-catenin and the binding of casein kinase II (CK2) with α-E-catenin were elevated by Ac2-26, these effects were counteracted by the CK2 inhibitor TBB and small interfering (si) RNA directed against transcripts of CK2 and FPRs. Moreover, both TBB and siRNA-mediated inhibition of CK2 blocked Ac2-26-mediated BV-2 microglia migration. Our findings indicate that ANXA1 promotes microglial activation and migration during OGD/R via FPRs, and CK2 target α-E-catenin phosphorylation is involved in this process. Full article

(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)

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Open AccessArticle

Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies

by Alessandra Ammazzalorso, Barbara De Filippis, Cristina Campestre, Antonio Laghezza, Alessandro Marrone, Rosa Amoroso, Paolo Tortorella and Mariangela Agamennone

Int. J. Mol. Sci. 2016, 17(10), 1768; https://doi.org/10.3390/ijms17101768 - 22 Oct 2016

Cited by 11 | Viewed by 5477

Abstract

Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of [...] Read more.

Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc-binding inhibitors (NZIs) have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data. Full article

(This article belongs to the Special Issue Enzyme-Inhibitor Interaction as Examples of Molecular Recognition)

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Open AccessArticle

Maternal Chromium Restriction Leads to Glucose Metabolism Imbalance in Mice Offspring through Insulin Signaling and Wnt Signaling Pathways

by Qian Zhang, Xiaofang Sun, Xinhua Xiao, Jia Zheng, Ming Li, Miao Yu, Fan Ping, Zhixin Wang, Cuijuan Qi, Tong Wang and Xiaojing Wang

Int. J. Mol. Sci. 2016, 17(10), 1767; https://doi.org/10.3390/ijms17101767 - 22 Oct 2016

Cited by 22 | Viewed by 8221

Abstract

An adverse intrauterine environment, induced by a chromium-restricted diet, is a potential cause of metabolic disease in adult life. Up to now, the relative mechanism has not been clear. C57BL female mice were time-mated and fed either a control diet (CD), or a [...] Read more.

An adverse intrauterine environment, induced by a chromium-restricted diet, is a potential cause of metabolic disease in adult life. Up to now, the relative mechanism has not been clear. C57BL female mice were time-mated and fed either a control diet (CD), or a chromium-restricted diet (CR) throughout pregnancy and the lactation period. After weaning, some offspring continued the diet diagram (CD-CD or CR-CR), while other offspring were transferred to another diet diagram (CD-CR or CR-CD). At 32 weeks of age, glucose metabolism parameters were measured, and the liver from CR-CD group and CD-CD group was analyzed using a gene array. Quantitative real-time polymerase chain reaction (qPCR) and Western blot were used to verify the result of the gene array. A maternal chromium-restricted diet resulted in obesity, hyperglycemia, hyperinsulinemia, increased area under the curve (AUC) of glucose in oral glucose tolerance testing and homeostasis model assessment of insulin resistance (HOMA-IR). There were 463 genes that differed significantly (>1.5-fold change, p < 0.05) between CR-CD offspring (264 up-regulated genes, 199 down-regulated genes) and control offspring. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) analysis revealed that the insulin signaling pathway and Wnt signaling pathway were in the center of the gene network. Our study provides the first evidence that maternal chromium deficiency influences glucose metabolism in pups through the regulation of insulin signaling and Wnt signaling pathways. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Association Analysis of Noncoding Variants in Neuroligins 3 and 4X Genes with Autism Spectrum Disorder in an Italian Cohort

by Martina Landini, Ivan Merelli, M. Elisabetta Raggi, Nadia Galluccio, Francesca Ciceri, Arianna Bonfanti, Serena Camposeo, Angelo Massagli, Laura Villa, Erika Salvi, Daniele Cusi, Massimo Molteni, Luciano Milanesi, Anna Marabotti and Alessandra Mezzelani

Int. J. Mol. Sci. 2016, 17(10), 1765; https://doi.org/10.3390/ijms17101765 - 22 Oct 2016

Cited by 19 | Viewed by 5575

Abstract

Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and 4X have been studied as good positional and functional candidate genes for autism spectrum disorder pathogenesis, although contradictory results have been reported. Here, we performed a case-control study to assess the [...] Read more.

Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and 4X have been studied as good positional and functional candidate genes for autism spectrum disorder pathogenesis, although contradictory results have been reported. Here, we performed a case-control study to assess the association between noncoding genetic variants in NLGN3 and NLGN4X genes and autism, in an Italian cohort of 202 autistic children analyzed by high-resolution melting. The results were first compared with data from 379 European healthy controls (1000 Genomes Project) and then with those from 1061 Italian controls genotyped by Illumina single nucleotide polymorphism (SNP) array 1M-duo. Statistical evaluations were performed using Plink v1.07, with the Omnibus multiple loci approach. According to both the European and the Italian control groups, a 6-marker haplotype on NLGN4X (rs6638575(G), rs3810688(T), rs3810687(G), rs3810686(C), rs5916269(G), rs1882260(T)) was associated with autism (odd ratio = 3.58, p-value = 2.58 × 10⁻⁶ for the European controls; odds ratio = 2.42, p-value = 6.33 × 10⁻³ for the Italian controls). Furthermore, several haplotype blocks at 5-, 4-, 3-, and 2-, including the first 5, 4, 3, and 2 SNPs, respectively, showed a similar association with autism. We provide evidence that noncoding polymorphisms on NLGN4X may be associated to autism, suggesting the key role of NLGN4X in autism pathophysiology and in its male prevalence. Full article

(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders 2017)

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Open AccessReview

What Is Breast in the Bone?

by Carrie S. Shemanko, Yingying Cong and Amanda Forsyth

Int. J. Mol. Sci. 2016, 17(10), 1764; https://doi.org/10.3390/ijms17101764 - 22 Oct 2016

Cited by 29 | Viewed by 8441

Abstract

The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is [...] Read more.

The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is secreted from the pituitary gland, as well as from normal and cancerous breast cells. Experimental and epidemiologic data suggest that prolactin is associated with mammary gland development, and also the increased risk of breast tumors and metastatic disease in postmenopausal women. Breast cancer spreads to the bone in approximately 70% of cases with advanced breast cancer. Despite treatment, new bone metastases will still occur in 30%–50% of patients. Only 20% of patients with bone metastases survive five years after the diagnosis of bone metastasis. The breast cancer cells in the bone microenvironment release soluble factors that engage osteoclasts and/or osteoblasts and result in bone breakdown. The breakdown of the bone matrix, in turn, enhances the proliferation of the cancer cells, creating a vicious cycle. Recently, it was shown that prolactin accelerated the breast cancer cell-mediated osteoclast differentiation and bone breakdown by the regulation of breast cancer-secreted proteins. Interestingly, prolactin has the potential to affect multiple proteins that are involved in both breast development and likely bone metastasis, as well. Prolactin has normal bone homeostatic roles and, combined with the natural “recycling” of proteins in different tissues that can be used for breast development and function, or in bone function, increases the impact of prolactin signaling in breast cancer bone metastases. Thus, this review will focus on the role of prolactin in breast development, bone homeostasis and in breast cancer to bone metastases, covering the molecular aspects of the vicious cycle. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)

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Open AccessArticle

Transcriptome Sequencing and De Novo Assembly of Golden Cuttlefish Sepia esculenta Hoyle

by Changlin Liu, Fazhen Zhao, Jingping Yan, Chunsheng Liu, Siwei Liu and Siqing Chen

Int. J. Mol. Sci. 2016, 17(10), 1749; https://doi.org/10.3390/ijms17101749 - 22 Oct 2016

Cited by 17 | Viewed by 5697

Abstract

Golden cuttlefish Sepia esculenta Hoyle is an economically important cephalopod species. However, artificial hatching is currently challenged by low survival rate of larvae due to abnormal embryonic development. Dissecting the genetic foundation and regulatory mechanisms in embryonic development requires genomic background knowledge. Therefore, [...] Read more.

Golden cuttlefish Sepia esculenta Hoyle is an economically important cephalopod species. However, artificial hatching is currently challenged by low survival rate of larvae due to abnormal embryonic development. Dissecting the genetic foundation and regulatory mechanisms in embryonic development requires genomic background knowledge. Therefore, we carried out a transcriptome sequencing on Sepia embryos and larvae via mRNA-Seq. 32,597,241 raw reads were filtered and assembled into 98,615 unigenes (N50 length at 911 bp) which were annotated in NR database, GO and KEGG databases respectively. Digital gene expression analysis was carried out on cleavage stage embryos, healthy larvae and malformed larvae. Unigenes functioning in cell proliferation exhibited higher transcriptional levels at cleavage stage while those related to animal disease and organ development showed increased transcription in malformed larvae. Homologs of key genes in regulatory pathways related to early development of animals were identified in Sepia. Most of them exhibit higher transcriptional levels in cleavage stage than larvae, suggesting their potential roles in embryonic development of Sepia. The de novo assembly of Sepia transcriptome is fundamental genetic background for further exploration in Sepia research. Our demonstration on the transcriptional variations of genes in three developmental stages will provide new perspectives in understanding the molecular mechanisms in early embryonic development of cuttlefish. Full article

(This article belongs to the Special Issue Fish Molecular Biology)

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Open AccessReview

Why Are Omics Technologies Important to Understanding the Role of Nutrition in Inflammatory Bowel Diseases?

by Lynnette R. Ferguson and Matthew P. G. Barnett

Int. J. Mol. Sci. 2016, 17(10), 1763; https://doi.org/10.3390/ijms17101763 - 21 Oct 2016

Cited by 8 | Viewed by 6665

Abstract

For many years, there has been confusion about the role that nutrition plays in inflammatory bowel diseases (IBD). It is apparent that good dietary advice for one individual may prove inappropriate for another. As with many diseases, genome-wide association studies across large collaborative [...] Read more.

For many years, there has been confusion about the role that nutrition plays in inflammatory bowel diseases (IBD). It is apparent that good dietary advice for one individual may prove inappropriate for another. As with many diseases, genome-wide association studies across large collaborative groups have been important in revealing the role of genetics in IBD, with more than 200 genes associated with susceptibility to the disease. These associations provide clues to explain the differences in nutrient requirements among individuals. In addition to genes directly involved in the control of inflammation, a number of the associated genes play roles in modulating the gut microbiota. Cell line models enable the generation of hypotheses as to how various bioactive dietary components might be especially beneficial for certain genetic groups. Animal models are necessary to mimic aspects of the complex aetiology of IBD, and provide an important link between tissue culture studies and human trials. Once we are sufficiently confident of our hypotheses, we can then take modified diets to an IBD population that is stratified according to genotype. Studies in IBD patients fed a Mediterranean-style diet have been important in validating our hypotheses and as a proof-of-principle for the application of these sensitive omics technologies to aiding in the control of IBD symptoms. Full article

(This article belongs to the Special Issue Metabolomic Technologies in Medicine)

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Screening the Toxicity of Selected Personal Care Products Using Embryo Bioassays: 4-MBC, Propylparaben and Triclocarban

by Tiago Torres, Isabel Cunha, Rosário Martins and Miguel M. Santos

Int. J. Mol. Sci. 2016, 17(10), 1762; https://doi.org/10.3390/ijms17101762 - 21 Oct 2016

Cited by 53 | Viewed by 7285

Abstract

Recently, several emerging pollutants, including Personal Care Products (PCPs), have been detected in aquatic ecosystems, in the ng/L or µg/L range. Available toxicological data is limited, and, for certain PCPs, evidence indicates a potential risk for the environment. Hence, there is an urgent [...] Read more.

Recently, several emerging pollutants, including Personal Care Products (PCPs), have been detected in aquatic ecosystems, in the ng/L or µg/L range. Available toxicological data is limited, and, for certain PCPs, evidence indicates a potential risk for the environment. Hence, there is an urgent need to gather ecotoxicological data on PCPs as a proxy to improve risk assessment. Here, the toxicity of three different PCPs (4-Methylbenzylidene Camphor (4-MBC), propylparaben and triclocarban) was tested using embryo bioassays with Danio rerio (zebrafish) and Paracentrotus lividus (sea urchin). The No Observed Effect Concentration (NOEC) for triclocarban was 0.256 µg/L for sea urchin and 100 µg/L for zebrafish, whereas NOEC for 4-MBC was 0.32 µg/L for sea urchin and 50 µg/L for zebrafish. Both PCPs impacted embryo development at environmentally relevant concentrations. In comparison with triclocarban and 4-MBC, propylparaben was less toxic for both sea urchin (NOEC = 160 µg/L) and zebrafish (NOEC = 1000 µg/L). Overall, this study further demonstrates the sensitivity of embryo bioassays as a high-throughput approach for testing the toxicity of emerging pollutants. Full article

(This article belongs to the Special Issue Zebrafish: A Model for Toxicological Research)

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Open AccessArticle

Role of Intracellular Lipid Logistics in the Preferential Usage of Very Long Chain-Ceramides in Glucosylceramide

by Toshiyuki Yamaji, Aya Horie, Yuriko Tachida, Chisato Sakuma, Yusuke Suzuki, Yasunori Kushi and Kentaro Hanada

Int. J. Mol. Sci. 2016, 17(10), 1761; https://doi.org/10.3390/ijms17101761 - 21 Oct 2016

Cited by 20 | Viewed by 5532

Abstract

Ceramide is a common precursor of sphingomyelin (SM) and glycosphingolipids (GSLs) in mammalian cells. Ceramide synthase 2 (CERS2), one of the six ceramide synthase isoforms, is responsible for the synthesis of very long chain fatty acid (C20–26 fatty acids) (VLC)-containing ceramides (VLC-Cer). It [...] Read more.

Ceramide is a common precursor of sphingomyelin (SM) and glycosphingolipids (GSLs) in mammalian cells. Ceramide synthase 2 (CERS2), one of the six ceramide synthase isoforms, is responsible for the synthesis of very long chain fatty acid (C20–26 fatty acids) (VLC)-containing ceramides (VLC-Cer). It is known that the proportion of VLC species in GSLs is higher than that in SM. To address the mechanism of the VLC-preference of GSLs, we used genome editing to establish three HeLa cell mutants that expressed different amounts of CERS2 and compared the acyl chain lengths of SM and GSLs by metabolic labeling experiments. VLC-sphingolipid expression was increased along with that of CERS2, and the proportion of VLC species in glucosylceramide (GlcCer) was higher than that in SM for all expression levels of CERS2. This higher proportion was still maintained even when the proportion of C16-Cer to the total ceramides was increased by disrupting the ceramide transport protein (CERT)-dependent C16-Cer delivery pathway for SM synthesis. On the other hand, merging the Golgi apparatus and the endoplasmic reticulum (ER) by Brefeldin A decreased the proportion of VLC species in GlcCer probably due to higher accessibility of UDP-glucose ceramide glucosyltransferase (UGCG) to C16-rich ceramides. These results suggest the existence of a yet-to-be-identified mechanism rendering VLC-Cer more accessible than C16-Cer to UGCG, which is independent of CERT. Full article

(This article belongs to the Section Biochemistry)

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Towards Stratified Medicine in Plasma Cell Myeloma

by Philip Egan, Stephen Drain, Caroline Conway, Anthony J. Bjourson and H. Denis Alexander

Int. J. Mol. Sci. 2016, 17(10), 1760; https://doi.org/10.3390/ijms17101760 - 21 Oct 2016

Cited by 11 | Viewed by 6441

Abstract

Plasma cell myeloma is a clinically heterogeneous malignancy accounting for approximately one to 2% of newly diagnosed cases of cancer worldwide. Treatment options, in addition to long-established cytotoxic drugs, include autologous stem cell transplant, immune modulators, proteasome inhibitors and monoclonal antibodies, plus further [...] Read more.

Plasma cell myeloma is a clinically heterogeneous malignancy accounting for approximately one to 2% of newly diagnosed cases of cancer worldwide. Treatment options, in addition to long-established cytotoxic drugs, include autologous stem cell transplant, immune modulators, proteasome inhibitors and monoclonal antibodies, plus further targeted therapies currently in clinical trials. Whilst treatment decisions are mostly based on a patient’s age, fitness, including the presence of co-morbidities, and tumour burden, significant scope exists for better risk stratification, sub-classification of disease, and predictors of response to specific therapies. Clinical staging, recurring acquired cytogenetic aberrations, and serum biomarkers such as β-2 microglobulin, and free light chains are in widespread use but often fail to predict the disease progression or inform treatment decision making. Recent scientific advances have provided considerable insight into the biology of myeloma. For example, gene expression profiling is already making a contribution to enhanced understanding of the biology of the disease whilst Next Generation Sequencing has revealed great genomic complexity and heterogeneity. Pathways involved in the oncogenesis, proliferation of the tumour and its resistance to apoptosis are being unravelled. Furthermore, knowledge of the tumour cell surface and its interactions with bystander cells and the bone marrow stroma enhance this understanding and provide novel targets for cell and antibody-based therapies. This review will discuss the development in understanding of the biology of the tumour cell and its environment in the bone marrow, the implementation of new therapeutic options contributing to significantly improved outcomes, and the progression towards more personalised medicine in this disorder. Full article

(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)

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Open AccessArticle

Genetic Heterogeneity of HER2 Amplification and Telomere Shortening in Papillary Thyroid Carcinoma

by Paola Caria, Silvia Cantara, Daniela Virginia Frau, Furio Pacini, Roberta Vanni and Tinuccia Dettori

Int. J. Mol. Sci. 2016, 17(10), 1759; https://doi.org/10.3390/ijms17101759 - 21 Oct 2016

Cited by 7 | Viewed by 5123

Abstract

Extensive research is dedicated to understanding if sporadic and familial papillary thyroid carcinoma are distinct biological entities. We have previously demonstrated that familial papillary thyroid cancer (fPTC) cells exhibit short relative telomere length (RTL) in both blood and tissues and that these features [...] Read more.

Extensive research is dedicated to understanding if sporadic and familial papillary thyroid carcinoma are distinct biological entities. We have previously demonstrated that familial papillary thyroid cancer (fPTC) cells exhibit short relative telomere length (RTL) in both blood and tissues and that these features may be associated with chromosome instability. Here, we investigated the frequency of HER2 (Human Epidermal Growth Factor Receptor 2) amplification, and other recently reported genetic alterations in sporadic PTC (sPTC) and fPTC, and assessed correlations with RTL and BRAF mutational status. We analyzed HER2 gene amplification and the integrity of ALK, ETV6, RET, and BRAF genes by fluorescence in situ hybridization in isolated nuclei and paraffin-embedded formalin-fixed sections of 13 fPTC and 18 sPTC patients. We analyzed BRAF^V600E mutation and RTL by qRT-PCR. Significant HER2 amplification (p = 0.0076), which was restricted to scattered groups of cells, was found in fPTC samples. HER2 amplification in fPTCs was invariably associated with BRAF^V600E mutation. RTL was shorter in fPTCs than sPTCs (p < 0.001). No rearrangements of other tested genes were observed. These findings suggest that the association of HER2 amplification with BRAF^V600E mutation and telomere shortening may represent a marker of tumor aggressiveness, and, in refractory thyroid cancer, may warrant exploration as a site for targeted therapy. Full article

(This article belongs to the Special Issue Current Knowledge in Thyroid Cancer—From Bench to Bedside)

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Open AccessArticle

Stage-Wise Identification and Analysis of miRNA from Root-Knot Nematode Meloidogyne incognita

by Parthiban Subramanian, In-Chan Choi, Vimalraj Mani, Junhyung Park, Sathiyamoorthy Subramaniyam, Kang-Hyun Choi, Joon-Soo Sim, Chang-Muk Lee, Ja Choon Koo and Bum-Soo Hahn

Int. J. Mol. Sci. 2016, 17(10), 1758; https://doi.org/10.3390/ijms17101758 - 21 Oct 2016

Cited by 13 | Viewed by 5798

Abstract

In this study, we investigated global changes in miRNAs of Meloidogyne incognita throughout its life cycle. Small RNA sequencing resulted in approximately 62, 38, 38, 35, and 39 Mb reads in the egg, J2, J3, J4, and female stages, respectively. Overall, we identified [...] Read more.

In this study, we investigated global changes in miRNAs of Meloidogyne incognita throughout its life cycle. Small RNA sequencing resulted in approximately 62, 38, 38, 35, and 39 Mb reads in the egg, J2, J3, J4, and female stages, respectively. Overall, we identified 2724 known and 383 novel miRNAs (read count > 10) from all stages, of which 169 known and 13 novel miRNA were common to all the five stages. Among the stage-specific miRNAs, miR-286 was highly expressed in eggs, miR-2401 in J2, miR-8 and miR-187 in J3, miR-6736 in J4, and miR-17 in the female stages. These miRNAs are reported to be involved in embryo and neural development, muscular function, and control of apoptosis. Cluster analysis indicated the presence of 91 miRNA clusters, of which 36 clusters were novel and identified in this study. Comparison of miRNA families with other nematodes showed 17 families to be commonly absent in animal parasitic nematodes and M. incognita. Validation of 43 predicted common and stage-specific miRNA by quantitative PCR (qPCR) indicated their expression in the nematode. Stage-wise exploration of M. incognita miRNAs has not been carried out before and this work presents information on common and stage-specific miRNAs of the root-knot nematode. Full article

(This article belongs to the Section Biochemistry)

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Differential Amino Acid, Carbohydrate and Lipid Metabolism Perpetuations Involved in a Subtype of Rheumatoid Arthritis with Chinese Medicine Cold Pattern

by Hongtao Guo, Xuyan Niu, Yan Gu, Cheng Lu, Cheng Xiao, Kevin Yue, Ge Zhang, Xiaohua Pan, Miao Jiang, Yong Tan, Hongwei Kong, Zhenli Liu, Guowang Xu and Aiping Lu

Int. J. Mol. Sci. 2016, 17(10), 1757; https://doi.org/10.3390/ijms17101757 - 21 Oct 2016

Cited by 18 | Viewed by 6323

Abstract

Pattern classification is a key approach in Traditional Chinese Medicine (TCM), and it is used to classify the patients for intervention selection accordingly. TCM cold and heat patterns, two main patterns of rheumatoid arthritis (RA) had been explored with systems biology approaches. Different [...] Read more.

Pattern classification is a key approach in Traditional Chinese Medicine (TCM), and it is used to classify the patients for intervention selection accordingly. TCM cold and heat patterns, two main patterns of rheumatoid arthritis (RA) had been explored with systems biology approaches. Different regulations of apoptosis were found to be involved in cold and heat classification in our previous works. For this study, the metabolic profiling of plasma was explored in RA patients with typical TCM cold or heat patterns by integrating liquid chromatography/mass spectrometry (LC/MS) and gas chromatography/mass spectrometry (GC/MS) platforms in conjunction with the Ingenuity Pathway Analysis (IPA) software. Three main processes of metabolism, including amino acid, carbohydrate and lipid were focused on for function analysis. The results showed that 29 and 19 differential metabolites were found in cold and heat patterns respectively, compared with healthy controls. The perturbation of amino acid metabolism (increased essential amino acids), carbohydrate metabolism (galactose metabolism) and lipid metabolism, were found to be involved in both cold and heat pattern RA. In particular, more metabolic perturbations in protein and collagen breakdown, decreased glycolytic activity and aerobic oxidation, and increased energy utilization associated with RA cold pattern patients. These findings may be useful for obtaining a better understanding of RA pathogenesis and for achieving a better efficacy in RA clinical practice. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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A Comprehensive MicroRNA Expression Profile of Liver and Lung Metastases of Colorectal Cancer with Their Corresponding Host Tissue and Its Prognostic Impact on Survival

by Mathieu Pecqueux, Isabell Liebetrau, Wiebke Werft, Hendrik Dienemann, Thomas Muley, Joachim Pfannschmidt, Benjamin Müssle, Nuh Rahbari, Sebastian Schölch, Markus W. Büchler, Jürgen Weitz, Christoph Reissfelder and Christoph Kahlert

Int. J. Mol. Sci. 2016, 17(10), 1755; https://doi.org/10.3390/ijms17101755 - 21 Oct 2016

Cited by 18 | Viewed by 6597

Abstract

MicroRNAs are small non-coding RNAs with a length of 18–25 nucleotides. They can regulate tumor invasion and metastasis by changing the expression and translation of their target mRNAs. Their expression is substantially altered in colorectal cancer cells as well as in the adjacent [...] Read more.

MicroRNAs are small non-coding RNAs with a length of 18–25 nucleotides. They can regulate tumor invasion and metastasis by changing the expression and translation of their target mRNAs. Their expression is substantially altered in colorectal cancer cells as well as in the adjacent tumor-associated stroma. Both of these compartments have a mutual influence on tumor progression. In the development of metastases, cancer cells initially interact with the host tissue. Therefore, compartment-specific expression signatures of these three locations—tumor, associated stroma, and host tissue—can provide new insights into the complex tumor biology of colorectal cancer. Frozen tissue samples of colorectal liver (n = 25) and lung metastases (n = 24) were laser microdissected to separate tumor cells and the adjacent tumor-associated stroma cells. Additionally, normal lung and liver tissue was collected from the same patients. We performed a microarray analysis in four randomly selected liver metastases and four randomly selected lung metastases, analyzing a total of 939 human miRNAs. miRNAs with a significant change >2-fold between the tumor, tumor stroma, and host tissue were analyzed in all samples using RT-qPCR (11 miRNAs) and correlated with the clinical data. We found a differential expression of several miRNAs between the tumor, the tumor-associated stroma, and the host tissue compartment. When comparing liver and lung metastases, miR-194 showed a 1.5-fold; miR-125, miR-127, and miR-192 showed a 2.5-fold; miR-19 and miR-215 a 3-fold; miR-145, miR-199-3, and miR-429 a 5-fold; miR-21 a 7-fold; and, finally, miR-199-5 a 12.5-fold downregulation in liver metastases compared to lung metastases. Furthermore miR-19, miR-125, miR-127, miR-192, miR-194, miR-199-5, and miR-215 showed a significant upregulation in the normal liver tissue compared to the normal lung tissue. Univariate analysis identified an association of poor survival with the expression of miR-125 (p = 0.05), miR-127 (p = 0.001), miR-145 (p = 0.005), miR-192 (p = 0.015), miR-194 (0.003), miR-199-5 (p = 0.008), miR-215 (p < 0.001), and miR-429 (p = 0.03) in the host liver tissue of the liver metastases. Colorectal liver and lung metastases have a unique miRNA expression profile. miRNA expression in the host tissue of colorectal liver metastases seems to be able to influence tumor progression and survival. These findings can be used in the development of tailored therapies. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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Natural Occurring Silks and Their Analogues as Materials for Nerve Conduits

by Christine Radtke

Int. J. Mol. Sci. 2016, 17(10), 1754; https://doi.org/10.3390/ijms17101754 - 20 Oct 2016

Cited by 24 | Viewed by 6517

Abstract

Spider silk and its synthetic derivatives have a light weight in combination with good strength and elasticity. Their high cytocompatibility and low immunogenicity make them well suited for biomaterial products such as nerve conduits. Silk proteins slowly degrade enzymatically in vivo, thus allowing [...] Read more.

Spider silk and its synthetic derivatives have a light weight in combination with good strength and elasticity. Their high cytocompatibility and low immunogenicity make them well suited for biomaterial products such as nerve conduits. Silk proteins slowly degrade enzymatically in vivo, thus allowing for an initial therapeutic effect such as in nerve scaffolding to facilitate endogenous repair processes, and then are removed. Silks are biopolymers naturally produced by many species of arthropods including spiders, caterpillars and mites. The silk fibers are secreted by the labial gland of the larvae of some orders of Holometabola (insects with pupa) or the spinnerets of spiders. The majority of studies using silks for biomedical applications use materials from silkworms or spiders, mostly of the genus Nephila clavipes. Silk is one of the most promising biomaterials with effects not only in nerve regeneration, but in a number of regenerative applications. The development of silks for human biomedical applications is of high scientific and clinical interest. Biomaterials in use for biomedical applications have to meet a number of requirements such as biocompatibility and elicitation of no more than a minor inflammatory response, biodegradability in a reasonable time and specific structural properties. Here we present the current status in the field of silk-based conduit development for nerve repair and discuss current advances with regard to potential clinical transfer of an implantable nerve conduit for enhancement of nerve regeneration. Full article

(This article belongs to the Special Issue Silk-Based Materials: From Production to Characterization)

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Critical Analysis of the Melanogenic Pathway in Insects and Higher Animals

by Manickam Sugumaran and Hanine Barek

Int. J. Mol. Sci. 2016, 17(10), 1753; https://doi.org/10.3390/ijms17101753 - 20 Oct 2016

Cited by 156 | Viewed by 16319

Abstract

Animals synthesize melanin pigments for the coloration of their skin and use it for their protection from harmful solar radiation. Insects use melanins even more ingeniously than mammals and employ them for exoskeletal pigmentation, cuticular hardening, wound healing and innate immune responses. In [...] Read more.

Animals synthesize melanin pigments for the coloration of their skin and use it for their protection from harmful solar radiation. Insects use melanins even more ingeniously than mammals and employ them for exoskeletal pigmentation, cuticular hardening, wound healing and innate immune responses. In this review, we discuss the biochemistry of melanogenesis process occurring in higher animals and insects. A special attention is given to number of aspects that are not previously brought to light: (1) the molecular mechanism of dopachrome conversion that leads to the production of two different dihydroxyindoles; (2) the role of catecholamine derivatives other than dopa in melanin production in animals; (3) the critical parts played by various biosynthetic enzymes associated with insect melanogenesis; and (4) the presence of a number of important gaps in both melanogenic and sclerotinogenic pathways. Additionally, importance of the melanogenic process in insect physiology especially in the sclerotization of their exoskeleton, wound healing reactions and innate immune responses is highlighted. The comparative biochemistry of melanization with sclerotization is also discussed. Full article

(This article belongs to the Special Issue Biochemistry and Mechanisms of Melanogenesis)

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MicroRNA-Mediated Down-Regulation of Apoptosis Signal-Regulating Kinase 1 (ASK1) Attenuates the Apoptosis of Human Mesenchymal Stem Cells (MSCs) Transplanted into Infarcted Heart

by Chang Youn Lee, Sunhye Shin, Jiyun Lee, Hyang-Hee Seo, Kyu Hee Lim, Hyemin Kim, Jung-Won Choi, Sang Woo Kim, Seahyung Lee, Soyeon Lim and Ki-Chul Hwang

Int. J. Mol. Sci. 2016, 17(10), 1752; https://doi.org/10.3390/ijms17101752 - 20 Oct 2016

Cited by 21 | Viewed by 5740

Abstract

Stem cell therapy using adult stem cells, such as mesenchymal stem cells (MSCs) has produced some promising results in treating the damaged heart. However, the low survival rate of MSCs after transplantation is still one of the crucial factors that limit the therapeutic [...] Read more.

Stem cell therapy using adult stem cells, such as mesenchymal stem cells (MSCs) has produced some promising results in treating the damaged heart. However, the low survival rate of MSCs after transplantation is still one of the crucial factors that limit the therapeutic effect of stem cells. In the damaged heart, oxidative stress due to reactive oxygen species (ROS) production can cause the death of transplanted MSCs. Apoptosis signal-regulating kinase 1 (ASK1) has been implicated in the development of oxidative stress-related pathologic conditions. Thus, we hypothesized that down-regulation of ASK1 in human MSCs (hMSCs) might attenuate the post-transplantation death of MSCs. To test this hypothesis, we screened microRNAs (miRNAs) based on a miRNA-target prediction database and empirical data and investigated the anti-apoptotic effect of selected miRNAs on human adipose-derived stem cells (hASCs) and on rat myocardial infarction (MI) models. Our data indicated that miRNA-301a most significantly suppressed ASK1 expression in hASCs. Apoptosis-related genes were significantly down-regulated in miRNA-301a-enriched hASCs exposed to hypoxic conditions. Taken together, these data show that miRNA-mediated down-regulation of ASK1 protects MSCs during post-transplantation, leading to an increase in the efficacy of MSC-based cell therapy. Full article

(This article belongs to the Special Issue Advances in Cell Transplantation)

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Analogs of Natural 3-Deoxyanthocyanins: O-Glucosides of the 4′,7-Dihydroxyflavylium Ion and the Deep Influence of Glycosidation on Color

by Nuno Basílio, Sheiraz Al Bittar, Nathalie Mora, Olivier Dangles and Fernando Pina

Int. J. Mol. Sci. 2016, 17(10), 1751; https://doi.org/10.3390/ijms17101751 - 20 Oct 2016

Cited by 7 | Viewed by 4963

Abstract

3-Deoxyanthocyanidins and their O-β-d-glucosides are natural pigments abundant in black sorghum. O-glycosidation can perturb the acid-base properties of the chromophore and lower its electron density with a large impact on the distribution of colored and colorless forms in aqueous [...] Read more.

3-Deoxyanthocyanidins and their O-β-d-glucosides are natural pigments abundant in black sorghum. O-glycosidation can perturb the acid-base properties of the chromophore and lower its electron density with a large impact on the distribution of colored and colorless forms in aqueous solution. In this work, the influence of O-glycosidation on color is systematically studied from a series of 3-deoxyanthocyanin analogs. The pH- and light-dependent reversible reactions of 7-β-d-glucopyranosyloxy-4′-hydroxyflavylium (P3) and 4′-β-d-glucopyranosyloxy-7-hydroxyflavylium (P5) were completely characterized in mildly acidic solution and compared with the parent aglycone 4′,7-dihydroxyflavylium ion and the O-methylethers of P3 and P5. Except P5, the chalcone forms of the pigments exhibit a high cis-trans isomerization barrier that allows a pseudo-equilibrium involving all species except the trans-chalcone. At equilibrium, only the flavylium cation and trans-chalcone are observed. With all pigments, the colored flavylium ion can be generated by irradiation of the trans-chalcone (photochromism). Glycosidation of C7–OH accelerates hydration and strongly slows down cis-trans isomerization with the pH dependence of the apparent isomerization rate constant shifting from a bell-shaped curve to a sigmoid. The color of P5 is much more stable than that of its regioisomer P3 in near-neutral conditions. Full article

(This article belongs to the Special Issue Anthocyanins)

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Open AccessReview

Phytocystatins: Defense Proteins against Phytophagous Insects and Acari

by Manuel Martinez, Maria Estrella Santamaria, Mercedes Diaz-Mendoza, Ana Arnaiz, Laura Carrillo, Felix Ortego and Isabel Diaz

Int. J. Mol. Sci. 2016, 17(10), 1747; https://doi.org/10.3390/ijms17101747 - 20 Oct 2016

Cited by 56 | Viewed by 8064

Abstract

This review deals with phytocystatins, focussing on their potential role as defence proteins against phytophagous arthropods. Information about the evolutionary, molecular and biochemical features and inhibitory properties of phytocystatins are presented. Cystatin ability to inhibit heterologous cysteine protease activities is commented on as [...] Read more.

This review deals with phytocystatins, focussing on their potential role as defence proteins against phytophagous arthropods. Information about the evolutionary, molecular and biochemical features and inhibitory properties of phytocystatins are presented. Cystatin ability to inhibit heterologous cysteine protease activities is commented on as well as some approaches of tailoring cystatin specificity to enhance their defence function towards pests. A general landscape on the digestive proteases of phytophagous insects and acari and the remarkable plasticity of their digestive physiology after feeding on cystatins are highlighted. Biotechnological approaches to produce recombinant cystatins to be added to artificial diets or to be sprayed as insecticide–acaricide compounds and the of use cystatins as transgenes are discussed. Multiple examples and applications are included to end with some conclusions and future perspectives. Full article

(This article belongs to the Special Issue Plant-Insect Interactions)

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Tocopherols and Tocotrienols in Common and Emerging Dietary Sources: Occurrence, Applications, and Health Benefits

by Fereidoon Shahidi and Adriano Costa De Camargo

Int. J. Mol. Sci. 2016, 17(10), 1745; https://doi.org/10.3390/ijms17101745 - 20 Oct 2016

Cited by 291 | Viewed by 19996

Abstract

Edible oils are the major natural dietary sources of tocopherols and tocotrienols, collectively known as tocols. Plant foods with low lipid content usually have negligible quantities of tocols. However, seeds and other plant food processing by-products may serve as alternative sources of edible [...] Read more.

Edible oils are the major natural dietary sources of tocopherols and tocotrienols, collectively known as tocols. Plant foods with low lipid content usually have negligible quantities of tocols. However, seeds and other plant food processing by-products may serve as alternative sources of edible oils with considerable contents of tocopherols and tocotrienols. Tocopherols are among the most important lipid-soluble antioxidants in food as well as in human and animal tissues. Tocopherols are found in lipid-rich regions of cells (e.g., mitochondrial membranes), fat depots, and lipoproteins such as low-density lipoprotein cholesterol. Their health benefits may also be explained by regulation of gene expression, signal transduction, and modulation of cell functions. Potential health benefits of tocols include prevention of certain types of cancer, heart disease, and other chronic ailments. Although deficiencies of tocopherol are uncommon, a continuous intake from common and novel dietary sources of tocopherols and tocotrienols is advantageous. Thus, this contribution will focus on the relevant literature on common and emerging edible oils as a source of tocols. Potential application and health effects as well as the impact of new cultivars as sources of edible oils and their processing discards are presented. Future trends and drawbacks are also briefly covered. Full article

(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)

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