International Journal of Molecular Sciences

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Open AccessEditorial

International Journal of Molecular Science Best Paper Award 2014

by Stephen A. Bustin, Ian A. Nicholls and Michael Iba

Int. J. Mol. Sci. 2014, 15(1), 1683-1685; https://doi.org/10.3390/ijms15011683 - 22 Jan 2014

Cited by 6 | Viewed by 10739

International Journal of Molecular Science is instituting an annual award to recognize outstanding papers in the area of chemistry, molecular physics and molecular biology published in International Journal of Molecular Science. We are pleased to announce the third “International Journal of [...] Read more.

International Journal of Molecular Science is instituting an annual award to recognize outstanding papers in the area of chemistry, molecular physics and molecular biology published in International Journal of Molecular Science. We are pleased to announce the third “International Journal of Molecular Science Best Paper Award” for 2014 [1,2]. Nominations were made by the Section Editors-in-Chief of International Journal of Molecular Science from all papers published in 2010. [...] Full article

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Open AccessArticle

The hOGG1 Ser326Cys Gene Polymorphism and the Risk of Coronary Ectasia in the Chinese Population

by Po-Chao Hsu, Chiao-Ling Wang, Ho-Ming Su, Suh-Hang Juo, Tsung-Hsien Lin, Wen-Chol Voon, Shyi-Jang Shin, Wen-Ter Lai and Sheng-Hsiung Sheu

Int. J. Mol. Sci. 2014, 15(1), 1671-1682; https://doi.org/10.3390/ijms15011671 - 22 Jan 2014

Cited by 12 | Viewed by 6365

Abstract

Oxidative stress (OS) is related to vascular inflammation possibly, contributing to the development of coronary ectasia (CE). Base excision repair (BER) and nucleotide excision repair are the main DNA repair pathways that can help to remove 8-hydroxydeoxyguanine (8-OHdG), a marker of OS. Human [...] Read more.

Oxidative stress (OS) is related to vascular inflammation possibly, contributing to the development of coronary ectasia (CE). Base excision repair (BER) and nucleotide excision repair are the main DNA repair pathways that can help to remove 8-hydroxydeoxyguanine (8-OHdG), a marker of OS. Human 8-oxoguanine DNA glycosylase 1 (hOGG1) is a key enzyme of the BER pathway and catalyzes the removal of 8-OHdG. The aim of our study was to investigate the association between hOGG1 Ser326Cys gene polymorphism and CE in a Chinese population. Five-hundred forty-seven patients who underwent diagnostic coronary angiography in a tertiary medical center were recruited. The angiographic definition of CE is the diameter of the ectatic segment being more than 1.5 times larger compared with an adjacent healthy reference segment. The gene polymorphisms were analyzed by polymerase chain reaction. The urine 8OHdG concentration was measured using a commercial ELISA kit. The distribution of hOGG1 Ser326Cys genotypes was significantly different between CE and non-CE groups (p = 0.033). The odds ratio of CE development for the Ser to the Cys variant was 1.55 (95% confidence interval (CI), 1.04–2.31, p = 0.033). Both univariate and logistic regression analysis showed a significant association of hOGG1 Ser326Cys polymorphism in the dominant model with CE development (p = 0.009 and 0.011, respectively). Urine 8-OHdG levels were significantly higher in subjects carrying the hOGG1 Ser variant than in those with the Cys/Cys genotype (p < 0.03). In conclusion, our study suggests that the hOGG1 Ser326Cys gene variant might play a role in susceptibility to the development of CE. Full article

(This article belongs to the Special Issue Human Single Nucleotide Polymorphisms and Disease Diagnostics)

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Open AccessReview

Signaling Involved in Hair Follicle Morphogenesis and Development

by Pisal Rishikaysh, Kapil Dev, Daniel Diaz, Wasay Mohiuddin Shaikh Qureshi, Stanislav Filip and Jaroslav Mokry

Int. J. Mol. Sci. 2014, 15(1), 1647-1670; https://doi.org/10.3390/ijms15011647 - 22 Jan 2014

Cited by 271 | Viewed by 23847

Abstract

Hair follicle morphogenesis depends on Wnt, Shh, Notch, BMP and other signaling pathways interplay between epithelial and mesenchymal cells. The Wnt pathway plays an essential role during hair follicle induction, Shh is involved in morphogenesis and late stage differentiation, Notch signaling determines stem [...] Read more.

Hair follicle morphogenesis depends on Wnt, Shh, Notch, BMP and other signaling pathways interplay between epithelial and mesenchymal cells. The Wnt pathway plays an essential role during hair follicle induction, Shh is involved in morphogenesis and late stage differentiation, Notch signaling determines stem cell fate while BMP is involved in cellular differentiation. The Wnt pathway is considered to be the master regulator during hair follicle morphogenesis. Wnt signaling proceeds through EDA/EDAR/NF-κB signaling. NF-κB regulates the Wnt pathway and acts as a signal mediator by upregulating the expression of Shh ligand. Signal crosstalk between epithelial and mesenchymal cells takes place mainly through primary cilia. Primary cilia formation is initiated with epithelial laminin-511 interaction with dermal β-1 integrin, which also upregulates expression of downstream effectors of Shh pathway in dermal lineage. PDGF signal transduction essential for crosstalk is mediated through epithelial PDGF-A and PDGFRα expressed on the primary cilia. Dermal Shh and PDGF signaling up-regulates dermal noggin expression; noggin is a potent inhibitor of BMP signaling which helps in counteracting BMP mediated β-catenin inhibition. This interplay of signaling between the epithelial and dermal lineage helps in epithelial Shh signal amplification. The dermal Wnt pathway helps in upregulation of epithelial Notch expression. Dysregulation of these pathways leads to certain abnormalities and in some cases even tumor outgrowth. Full article

(This article belongs to the Special Issue Molecular Research of Epidermal Stem Cells)

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Open AccessArticle

Resveratrol Partially Prevents Rotenone-Induced Neurotoxicity in Dopaminergic SH-SY5Y Cells through Induction of Heme Oxygenase-1 Dependent Autophagy

by Tsu-Kung Lin, Shang-Der Chen, Yao-Chung Chuang, Hung-Yu Lin, Chi-Ren Huang, Jiin-Haur Chuang, Pei-Wen Wang, Sheng-Teng Huang, Mao-Meng Tiao, Jin-Bor Chen and Chia-Wei Liou

Int. J. Mol. Sci. 2014, 15(1), 1625-1646; https://doi.org/10.3390/ijms15011625 - 22 Jan 2014

Cited by 145 | Viewed by 13997

Abstract

Parkinson disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons. Mitochondrial dysfunction, oxidative stress or protein misfolding and aggregation may underlie this process. Autophagy is an intracellular catabolic mechanism responsible for protein degradation and recycling of damaged [...] Read more.

Parkinson disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons. Mitochondrial dysfunction, oxidative stress or protein misfolding and aggregation may underlie this process. Autophagy is an intracellular catabolic mechanism responsible for protein degradation and recycling of damaged proteins and cytoplasmic organelles. Autophagic dysfunction may hasten the progression of neuronal degeneration. In this study, resveratrol promoted autophagic flux and protected dopaminergic neurons against rotenone-induced apoptosis. In an in vivo PD model, rotenone induced loss of dopaminergic neurons, increased oxidation of mitochondrial proteins and promoted autophagic vesicle development in brain tissue. The natural phytoalexin resveratrol prevented rotenone-induced neuronal apoptosis in vitro, and this pro-survival effect was abolished by an autophagic inhibitor. Although both rotenone and resveratrol promoted LC3-II accumulation, autophagic flux was inhibited by rotenone and augmented by resveratrol. Further, rotenone reduced heme oxygenase-1 (HO-1) expression, whereas resveratrol increased HO-1 expression. Pharmacological inhibition of HO-1 abolished resveratrol-mediated autophagy and neuroprotection. Notably, the effects of a pharmacological inducer of HO-1 were similar to those of resveratrol, and protected against rotenone-induced cell death in an autophagy-dependent manner, validating the hypothesis of HO-1 dependent autophagy in preventing neuronal death in the in vitro PD model. Collectively, our findings suggest that resveratrol induces HO-1 expression and prevents dopaminergic cell death by regulating autophagic flux; thus protecting against rotenone-induced neuronal apoptosis. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2014)

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Open AccessArticle

Intravitreal Injection of Ranibizumab and CTGF shRNA Improves Retinal Gene Expression and Microvessel Ultrastructure in a Rodent Model of Diabetes

by Bojie Hu, Yan Zhang, Qing Zeng, Qian Han, Lijuan Zhang, Mian Liu and Xiaorong Li

Int. J. Mol. Sci. 2014, 15(1), 1606-1624; https://doi.org/10.3390/ijms15011606 - 22 Jan 2014

Cited by 53 | Viewed by 8579

Abstract

Therapeutic modalities targeting vascular endothelial growth factor (VEGF) have been used to treat neovascularization and macular edema. However, anti-VEGF treatment alone may cause up-regulation of connective tissue growth factor (CTGF) in the retina, increasing the risk of fibrosis and tractional retinal detachment. Therefore, [...] Read more.

Therapeutic modalities targeting vascular endothelial growth factor (VEGF) have been used to treat neovascularization and macular edema. However, anti-VEGF treatment alone may cause up-regulation of connective tissue growth factor (CTGF) in the retina, increasing the risk of fibrosis and tractional retinal detachment. Therefore, in this study, we employ a novel dual-target intervention that involves intravitreal injection of the VEGF inhibitor ranibizumab and a transfection reagent-treated non-viral vector carrying anti-CTGF short hairpin RNA (shRNA) driven by human RNA polymerase III promoter U6. The effects of the dual-target intervention on the expression of VEGF and CTGF and on microvessel ultrastructure were examined in retina of streptozocin-induced diabetic rats. CTGF was significantly up-regulated at week 8 after diabetic induction, whereas VEGF was not up-regulated until week 10. The high expression of both genes was maintained at week 12. Transmission electron microscopy also revealed progressive exacerbation of microvessel ultrastructure during the same period. In addition, ranibizumab significantly lowered VEGF but elevated CTGF mRNA, whereas CTGF shRNA significantly reduced the mRNA levels of both CTGF and VEGF in diabetic retinas. Importantly, dual-target intervention normalized the transcript levels of both target genes and ameliorated retinal microvessel ultrastructural damage better than either single-target intervention. These results suggest the advantages of dual-target over single-target interventions in diabetic retina and reveal a novel therapeutic modality for diabetic retinopathy. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Magnetic Nanoparticles as Intraocular Drug Delivery System to Target Retinal Pigmented Epithelium (RPE)

by Martina Giannaccini, Marianna Giannini, M. Pilar Calatayud, Gerardo F. Goya, Alfred Cuschieri, Luciana Dente and Vittoria Raffa

Int. J. Mol. Sci. 2014, 15(1), 1590-1605; https://doi.org/10.3390/ijms15011590 - 22 Jan 2014

Cited by 45 | Viewed by 9043

Abstract

One of the most challenging efforts in drug delivery is the targeting of the eye. The eye structure and barriers render this organ poorly permeable to drugs. Quite recently the entrance of nanoscience in ocular drug delivery has improved the penetration and half-life [...] Read more.

One of the most challenging efforts in drug delivery is the targeting of the eye. The eye structure and barriers render this organ poorly permeable to drugs. Quite recently the entrance of nanoscience in ocular drug delivery has improved the penetration and half-life of drugs, especially in the anterior eye chamber, while targeting the posterior chamber is still an open issue. The retina and the retinal pigment epithelium/choroid tissues, located in the posterior eye chamber, are responsible for the majority of blindness both in childhood and adulthood. In the present study, we used magnetic nanoparticles (MNPs) as a nanotool for ocular drug delivery that is capable of specific localization in the retinal pigmented epithelium (RPE) layer. We demonstrate that, following intraocular injection in Xenopus embryos, MNPs localize specifically in RPE where they are retained for several days. The specificity of the localization did not depend on particle size and surface properties of the MNPs used in this work. Moreover, through similar experiments in zebrafish, we demonstrated that the targeting of RPE by the nanoparticles is not specific for the Xenopus species. Full article

(This article belongs to the Special Issue Interaction between Nano-Structure Materials and Cells)

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Open AccessArticle

Genetic Variants of GPER/GPR30, a Novel Estrogen-Related G Protein Receptor, Are Associated with Human Seminoma

by Nicolas Chevalier, Rachel Paul-Bellon, Philippe Camparo, Jean-François Michiels, Daniel Chevallier and Patrick Fénichel

Int. J. Mol. Sci. 2014, 15(1), 1574-1589; https://doi.org/10.3390/ijms15011574 - 21 Jan 2014

Cited by 29 | Viewed by 8877

Abstract

Testicular germ cell tumors (TGCTs) are the most common solid cancers in young men, with an increasing incidence over several years. However, their pathogenesis remains a matter of debate. Some epidemiological data suggest the involvement of both environmental and genetic factors. We reported [...] Read more.

Testicular germ cell tumors (TGCTs) are the most common solid cancers in young men, with an increasing incidence over several years. However, their pathogenesis remains a matter of debate. Some epidemiological data suggest the involvement of both environmental and genetic factors. We reported two distinct effects of estrogens and/or xeno-estrogens on in vitro human seminoma-derived cells proliferation: (1) an antiproliferative effect via a classical estrogen receptor beta-dependent pathway, and (2) a promotive effect via a non-classical membrane G-protein-coupled receptor, GPR30/GPER, which is only overexpressed in seminomas, the most common TGCT. In order to explain this overexpression, we investigated the possible association of polymorphisms in the GPER gene by using allele-specific tetra-primer polymerase chain reaction performed on tissue samples from 150 paraffin-embedded TGCT specimens (131 seminomas, 19 non seminomas). Compared to control population, loss of homozygous ancestral genotype GG in two polymorphisms located in the promoter region of GPER (rs3808350 and rs3808351) was more frequent in seminomas but not in non-seminomas (respectively, OR = 1.960 (1.172–3.277) and 7.000 (2.747–17.840); p < 0.01). These polymorphisms may explain GPER overexpression and represent a genetic factor of susceptibility supporting the contribution of environmental GPER ligands in testicular carcinogenesis. Full article

(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)

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Open AccessArticle

Phosphorylation of Histone H2AX in the Mouse Brain from Development to Senescence

by Serena Barral, Riccardo Beltramo, Chiara Salio, Patrizia Aimar, Laura Lossi and Adalberto Merighi

Int. J. Mol. Sci. 2014, 15(1), 1554-1573; https://doi.org/10.3390/ijms15011554 - 21 Jan 2014

Cited by 33 | Viewed by 15328

Abstract

Phosphorylation of the histone H2AX (γH2AX form) is an early response to DNA damage and a marker of aging and disease in several cells and tissues outside the nervous system. Little is known about in vivo phosphorylation of H2AX in neurons, although it [...] Read more.

Phosphorylation of the histone H2AX (γH2AX form) is an early response to DNA damage and a marker of aging and disease in several cells and tissues outside the nervous system. Little is known about in vivo phosphorylation of H2AX in neurons, although it was suggested that γH2AX is an early marker of neuronal endangerment thus opening the possibility to target it as a neuroprotective strategy. After experimental labeling of DNA-synthesizing cells with 5-bromo-2-deoxyuridine (BrdU), we studied the brain occurrence of γH2AX in developing, postnatal, adult and senescent (2 years) mice by light and electron microscopic immunocytochemistry and Western blotting. Focal and/or diffuse γH2AX immunostaining appears in interkinetic nuclei, mitotic chromosomes, and apoptotic nuclei. Immunoreactivity is mainly associated with neurogenetic areas, i.e., the subventricular zone (SVZ) of telencephalon, the cerebellar cortex, and, albeit to a much lesser extent, the subgranular zone of the hippocampal dentate gyrus. In addition, γH2AX is highly expressed in the adult and senescent cerebral cortex, particularly the piriform cortex. Double labeling experiments demonstrate that γH2AX in neurogenetic brain areas is temporally and functionally related to proliferation and apoptosis of neuronal precursors, i.e., the type C transit amplifying cells (SVZ) and the granule cell precursors (cerebellum). Conversely, γH2AX-immunoreactive cortical neurons incorporating the S phase-label BrdU do not express the proliferation marker phosphorylated histone H3, indicating that these postmitotic cells undergo a significant DNA damage response. Our study paves the way for a better comprehension of the role of H2AX phosphorylation in the normal brain, and offers additional data to design novel strategies for the protection of neuronal precursors and mature neurons in central nervous system (CNS) degenerative diseases. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2014)

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Open AccessArticle

Egr-1 Upregulates Siva-1 Expression and Induces Cardiac Fibroblast Apoptosis

by Karin Zins, Jiri Pomyje, Erhard Hofer, Dietmar Abraham, Trevor Lucas and Seyedhossein Aharinejad

Int. J. Mol. Sci. 2014, 15(1), 1538-1553; https://doi.org/10.3390/ijms15011538 - 21 Jan 2014

Cited by 19 | Viewed by 7336

Abstract

The early growth response transcription factor Egr-1 controls cell specific responses to proliferation, differentiation and apoptosis. Expression of Egr-1 and downstream transcription is closely controlled and cell specific upregulation induced by processes such as hypoxia and ischemia has been previously linked to multiple [...] Read more.

The early growth response transcription factor Egr-1 controls cell specific responses to proliferation, differentiation and apoptosis. Expression of Egr-1 and downstream transcription is closely controlled and cell specific upregulation induced by processes such as hypoxia and ischemia has been previously linked to multiple aspects of cardiovascular injury. In this study, we showed constitutive expression of Egr-1 in cultured human ventricular cardiac fibroblasts, used adenoviral mediated gene transfer to study the effects of continuous Egr-1 overexpression and studied downstream transcription by Western blotting, immunohistochemistry and siRNA transfection. Apoptosis was assessed by fluorescence microscopy and flow cytometry in the presence of caspase inhibitors. Overexpression of Egr-1 directly induced apoptosis associated with caspase activation in human cardiac fibroblast cultures in vitro assessed by fluorescence microscopy and flow cytometry. Apoptotic induction was associated with a caspase activation associated loss of mitochondrial membrane potential and transient downstream transcriptional up-regulation of the pro-apoptotic gene product Siva-1. Suppression of Siva-1 induction by siRNA partially reversed Egr-1 mediated loss of cell viability. These findings suggest a previously unknown role for Egr-1 and transcriptional regulation of Siva-1 in the control of cardiac accessory cell death. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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Open AccessArticle

Role of Insulin-Transferrin-Selenium in Auricular Chondrocyte Proliferation and Engineered Cartilage Formation in Vitro

by Xia Liu, Jinchun Liu, Ning Kang, Li Yan, Qian Wang, Xin Fu, Yuanyuan Zhang, Ran Xiao and Yilin Cao

Int. J. Mol. Sci. 2014, 15(1), 1525-1537; https://doi.org/10.3390/ijms15011525 - 21 Jan 2014

Cited by 29 | Viewed by 7476

Abstract

The goal of this study is to determine the effects of Insulin-Transferrin-Selenium (ITS) on proliferation of auricular chondrocytes and formation of engineered cartilage in vitro. Pig auricular monolayer chondrocytes and chondrocyte pellets were cultured in media containing 1% ITS at different concentrations [...] Read more.

The goal of this study is to determine the effects of Insulin-Transferrin-Selenium (ITS) on proliferation of auricular chondrocytes and formation of engineered cartilage in vitro. Pig auricular monolayer chondrocytes and chondrocyte pellets were cultured in media containing 1% ITS at different concentrations of fetal bovine serum (FBS, 10%, 6%, 2%, 0%), or 10% FBS alone as a control for four weeks. Parameters including cell proliferation in monolayer, wet weight, collagen type I/II/X (Col I, II, X) and glycosaminoglycan (GAG) expression, GAG content of pellets and gene expression associated with cartilage formation/dedifferentiation (lost cartilage phenotype)/hypertrophy within the chondrocyte pellets were assessed. The results showed that chondrocytes proliferation rates increased when FBS concentrations increased (2%, 6%, 10% FBS) in ITS supplemented groups. In addition, 1% ITS plus 10% FBS significantly promoted cell proliferation than 10% FBS alone. No chondrocytes grew in ITS alone medium. 1% ITS plus 10% FBS enhanced cartilage formation in terms of size, wet weight, cartilage specific matrices, and homogeneity, compared to 10% FBS alone group. Furthermore, ITS prevented engineered cartilage from dedifferentiation (i.e., higher index of Col II/Col I mRNA expression and expression of aggrecan) and hypertrophy (i.e., lower mRNA expression of Col X and MMP13). In conclusion, our results indicated that ITS efficiently enhanced auricular chondrocytes proliferation, retained chondrogenic phenotypes, and promoted engineered cartilage formation when combined with FBS, which is potentially used as key supplementation in auricular chondrocytes and engineered cartilage culture. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Temperature-Responsive Poly(ε-caprolactone) Cell Culture Platform with Dynamically Tunable Nano-Roughness and Elasticity for Control of Myoblast Morphology

by Koichiro Uto, Mitsuhiro Ebara and Takao Aoyagi

Int. J. Mol. Sci. 2014, 15(1), 1511-1524; https://doi.org/10.3390/ijms15011511 - 21 Jan 2014

Cited by 43 | Viewed by 7905

Abstract

We developed a dynamic cell culture platform with dynamically tunable nano-roughness and elasticity. Temperature-responsive poly(ε-caprolactone) (PCL) films were successfully prepared by crosslinking linear and tetra-branched PCL macromonomers. By optimizing the mixing ratios, the crystal-amorphous transition temperature (T_m) of the crosslinked [...] Read more.

We developed a dynamic cell culture platform with dynamically tunable nano-roughness and elasticity. Temperature-responsive poly(ε-caprolactone) (PCL) films were successfully prepared by crosslinking linear and tetra-branched PCL macromonomers. By optimizing the mixing ratios, the crystal-amorphous transition temperature (T_m) of the crosslinked film was adjusted to the biological relevant temperature (~33 °C). While the crosslinked films are relatively stiff (50 MPa) below the T_m, they suddenly become soft (1 MPa) above the T_m. Correspondingly, roughness of the surface was decreased from 63.4–12.4 nm. It is noted that the surface wettability was independent of temperature. To investigate the role of dynamic surface roughness and elasticity on cell adhesion, cells were seeded on PCL films at 32 °C. Interestingly, spread myoblasts on the film became rounded when temperature was suddenly increased to 37 °C, while significant changes in cell morphology were not observed for fibroblasts. These results indicate that cells can sense dynamic changes in the surrounding environment but the sensitivity depends on cell types. Full article

(This article belongs to the Special Issue Interaction between Nano-Structure Materials and Cells)

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Open AccessArticle

Genetic Deletion of Rheb1 in the Brain Reduces Food Intake and Causes Hypoglycemia with Altered Peripheral Metabolism

by Wanchun Yang, Wanxiang Jiang, Liping Luo, Jicheng Bu, Dejiang Pang, Jing Wei, Chongyangzi Du, Xiaoqiang Xia, Yiyuan Cui, Shuang Liu, Qing Mao and Mina Chen

Int. J. Mol. Sci. 2014, 15(1), 1499-1510; https://doi.org/10.3390/ijms15011499 - 21 Jan 2014

Cited by 7 | Viewed by 6353

Abstract

Excessive food/energy intake is linked to obesity and metabolic disorders, such as diabetes. The hypothalamus in the brain plays a critical role in the control of food intake and peripheral metabolism. The signaling pathways in hypothalamic neurons that regulate food intake and peripheral [...] Read more.

Excessive food/energy intake is linked to obesity and metabolic disorders, such as diabetes. The hypothalamus in the brain plays a critical role in the control of food intake and peripheral metabolism. The signaling pathways in hypothalamic neurons that regulate food intake and peripheral metabolism need to be better understood for developing pharmacological interventions to manage eating behavior and obesity. Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a master regulator of cellular metabolism in different cell types. Pharmacological manipulations of mTOR complex 1 (mTORC1) activity in hypothalamic neurons alter food intake and body weight. Our previous study identified Rheb1 (Ras homolog enriched in brain 1) as an essential activator of mTORC1 activity in the brain. Here we examine whether central Rheb1 regulates food intake and peripheral metabolism through mTORC1 signaling. We find that genetic deletion of Rheb1 in the brain causes a reduction in mTORC1 activity and impairs normal food intake. As a result, Rheb1 knockout mice exhibit hypoglycemia and increased lipid mobilization in adipose tissue and ketogenesis in the liver. Our work highlights the importance of central Rheb1 signaling in euglycemia and energy homeostasis in animals. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Dopamine D₄ Receptor Counteracts Morphine-Induced Changes in µ Opioid Receptor Signaling in the Striosomes of the Rat Caudate Putamen

by Diana Suárez-Boomgaard, Belén Gago, Alejandra Valderrama-Carvajal, Ruth Roales-Buján, Kathleen Van Craenenbroeck, Jolien Duchou, Dasiel O. Borroto-Escuela, José Medina-Luque, Adelaida De la Calle, Kjell Fuxe and Alicia Rivera

Int. J. Mol. Sci. 2014, 15(1), 1481-1498; https://doi.org/10.3390/ijms15011481 - 21 Jan 2014

Cited by 16 | Viewed by 8531

Abstract

The mu opioid receptor (MOR) is critical in mediating morphine analgesia. However, prolonged exposure to morphine induces adaptive changes in this receptor leading to the development of tolerance and addiction. In the present work we have studied whether the continuous administration of morphine [...] Read more.

The mu opioid receptor (MOR) is critical in mediating morphine analgesia. However, prolonged exposure to morphine induces adaptive changes in this receptor leading to the development of tolerance and addiction. In the present work we have studied whether the continuous administration of morphine induces changes in MOR protein levels, its pharmacological profile, and MOR-mediated G-protein activation in the striosomal compartment of the rat CPu, by using immunohistochemistry and receptor and DAMGO-stimulated [³⁵S]GTPγS autoradiography. MOR immunoreactivity, agonist binding density and its coupling to G proteins are up-regulated in the striosomes by continuous morphine treatment in the absence of changes in enkephalin and dynorphin mRNA levels. In addition, co-treatment of morphine with the dopamine D₄ receptor (D₄R) agonist PD168,077 fully counteracts these adaptive changes in MOR, in spite of the fact that continuous PD168,077 treatment increases the [³H]DAMGO B_max values to the same degree as seen after continuous morphine treatment. Thus, in spite of the fact that both receptors can be coupled to G_i/0 protein, the present results give support for the existence of antagonistic functional D₄R-MOR receptor-receptor interactions in the adaptive changes occurring in MOR of striosomes on continuous administration of morphine. Full article

(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)

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Open AccessArticle

Plant Dependence on Rhizobia for Nitrogen Influences Induced Plant Defenses and Herbivore Performance

by Jennifer M. Dean, Mark C. Mescher and Consuelo M. De Moraes

Int. J. Mol. Sci. 2014, 15(1), 1466-1480; https://doi.org/10.3390/ijms15011466 - 21 Jan 2014

Cited by 48 | Viewed by 8025

Abstract

Symbiotic rhizobia induce many changes in legumes that could affect aboveground interactions with herbivores. We explored how changing the intensity of Bradyrhizobium japonicum, as modulated by soil nitrogen (N) levels, influenced the interaction between soybean (Glycine max) and herbivores of [...] Read more.

Symbiotic rhizobia induce many changes in legumes that could affect aboveground interactions with herbivores. We explored how changing the intensity of Bradyrhizobium japonicum, as modulated by soil nitrogen (N) levels, influenced the interaction between soybean (Glycine max) and herbivores of different feeding guilds. When we employed a range of fertilizer applications to manipulate soil N, plants primarily dependent on rhizobia for N exhibited increased root nodulation and higher levels of foliar ureides than plants given N fertilizer; yet all treatments maintained similar total N levels. Soybean podworm (Helicoverpa zea) larvae grew best on plants with the highest levels of rhizobia but, somewhat surprisingly, preferred to feed on high-N-fertilized plants when given a choice. Induction of the defense signaling compound jasmonic acid (JA) by H. zea feeding damage was highest in plants primarily dependent on rhizobia. Differences in rhizobial dependency on soybean did not appear to affect interactions with the phloem-feeding soybean aphid (Aphis glycines). Overall, our results suggest that rhizobia association can affect plant nutritional quality and the induction of defense signaling pathways and that these effects may influence herbivore feeding preferences and performance—though such effects may vary considerably for different classes of herbivores. Full article

(This article belongs to the Special Issue Symbiotic Nitrogen Fixation in Legume Nodules: Metabolism and Regulatory Mechanisms)

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Open AccessReview

Secondary Plant Products Causing Photosensitization in Grazing Herbivores: Their Structure, Activity and Regulation

by Jane C. Quinn, Allan Kessell and Leslie A. Weston

Int. J. Mol. Sci. 2014, 15(1), 1441-1465; https://doi.org/10.3390/ijms15011441 - 21 Jan 2014

Cited by 58 | Viewed by 12652

Abstract

Photosensitivity in animals is defined as a severe dermatitis that results from a heightened reactivity of skin cells and associated dermal tissues upon their exposure to sunlight, following ingestion or contact with UV reactive secondary plant products. Photosensitivity occurs in animal cells as [...] Read more.

Photosensitivity in animals is defined as a severe dermatitis that results from a heightened reactivity of skin cells and associated dermal tissues upon their exposure to sunlight, following ingestion or contact with UV reactive secondary plant products. Photosensitivity occurs in animal cells as a reaction that is mediated by a light absorbing molecule, specifically in this case a plant-produced metabolite that is heterocyclic or polyphenolic. In sensitive animals, this reaction is most severe in non-pigmented skin which has the least protection from UV or visible light exposure. Photosensitization in a biological system such as the epidermis is an oxidative or other chemical change in a molecule in response to light-induced excitation of endogenous or exogenously-delivered molecules within the tissue. Photo-oxidation can also occur in the plant itself, resulting in the generation of reactive oxygen species, free radical damage and eventual DNA degradation. Similar cellular changes occur in affected herbivores and are associated with an accumulation of photodynamic molecules in the affected dermal tissues or circulatory system of the herbivore. Recent advances in our ability to identify and detect secondary products at trace levels in the plant and surrounding environment, or in organisms that ingest plants, have provided additional evidence for the role of secondary metabolites in photosensitization of grazing herbivores. This review outlines the role of unique secondary products produced by higher plants in the animal photosensitization process, describes their chemistry and localization in the plant as well as impacts of the environment upon their production, discusses their direct and indirect effects on associated animal systems and presents several examples of well-characterized plant photosensitization in animal systems. Full article

(This article belongs to the Section Molecular Toxicology)

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Open AccessCommunication

Low Prostate Concentration of Lycopene Is Associated with Development of Prostate Cancer in Patients with High-Grade Prostatic Intraepithelial Neoplasia

by Simone Mariani, Luana Lionetto, Michele Cavallari, Andrea Tubaro, Debora Rasio, Cosimo De Nunzio, Gena M. Hong, Marina Borro and Maurizio Simmaco

Int. J. Mol. Sci. 2014, 15(1), 1433-1440; https://doi.org/10.3390/ijms15011433 - 21 Jan 2014

Cited by 40 | Viewed by 7317

Abstract

Prostate cancer (PC) is a frequent male malignancy and represents the second most diagnosed cancer in men. Since pre-cancerous lesions, i.e., the high-grade prostatic intraepithelial neoplasia (HGPIN), can be detected years before progression to PC, early diagnosis and chemoprevention are targeted strategies [...] Read more.

Prostate cancer (PC) is a frequent male malignancy and represents the second most diagnosed cancer in men. Since pre-cancerous lesions, i.e., the high-grade prostatic intraepithelial neoplasia (HGPIN), can be detected years before progression to PC, early diagnosis and chemoprevention are targeted strategies to reduce PC rates. Animal studies have shown that lycopene, a carotenoid contained in tomatoes, is a promising candidate for the chemoprevention of PC. However, its efficacy in humans remains controversial. The present study aimed to investigate the relevance of plasma and prostate concentration of lycopene after a lycopene-enriched diet in patients diagnosed with HGPIN. Thirty-two patients diagnosed with HGPIN were administered a lycopene-enriched diet (20–25 mg/day of lycopene; through 30 g/day of triple concentrated tomato paste) for 6 months. A 6-month follow-up prostate biopsy assessed progression to PC. Patients were classified into three groups according to the histopathological features of the 6-month follow-up biopsy results: prostatitis; HGPIN and PC. PSA and plasma lycopene levels were measured before and after the dietary lycopene supplementation. Prostatic lycopene concentration was only assessed after the supplementation diet. Only prostatic lycopene concentration showed significant differences between the three groups (p = 0.03). Prostatic lycopene concentration below a 1 ng/mg threshold was associated with PC at 6-month follow-up biopsy (p = 0.003). We observed no overall benefits from a 6-month lycopene supplementation, as the rate of HGPIN progression to PC in our population (9/32, 28%) was similar to rates reported in the literature. Baseline PSA levels also showed no significant changes after a lycopene-enriched diet. Our findings point to prostatic lycopene concentration as a promising biomarker of PC. Further prospective longitudinal studies are needed to assess the prognostic role of prostatic lycopene in PC. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Circulating MicroRNAs as Biomarkers of Acute Stroke

by Sugunavathi Sepramaniam, Jun-Rong Tan, Kay-Sin Tan, Deidre Ann DeSilva, Subramaniam Tavintharan, Fung-Peng Woon, Chee-Woon Wang, Fung-Lin Yong, Dwi-Setyowati Karolina, Prameet Kaur, Fu-Jia Liu, Kai-Ying Lim, Arunmozhiarasi Armugam and Kandiah Jeyaseelan

Int. J. Mol. Sci. 2014, 15(1), 1418-1432; https://doi.org/10.3390/ijms15011418 - 20 Jan 2014

Cited by 152 | Viewed by 10556

Abstract

MicroRNAs have been identified as key regulators of gene expression and thus their potential in disease diagnostics, prognosis and therapy is being actively pursued. Deregulation of microRNAs in cerebral pathogenesis has been reported to a limited extent in both animal models and human. [...] Read more.

MicroRNAs have been identified as key regulators of gene expression and thus their potential in disease diagnostics, prognosis and therapy is being actively pursued. Deregulation of microRNAs in cerebral pathogenesis has been reported to a limited extent in both animal models and human. Due to the complexity of the pathology, identifying stroke specific microRNAs has been a challenge. This study shows that microRNA profiles reflect not only the temporal progression of stroke but also the specific etiologies. A panel of 32 microRNAs, which could differentiate stroke etiologies during acute phase was identified and verified using a customized TaqMan Low Density Array (TLDA). Furthermore we also found 5 microRNAs, miR-125b-2*, -27a*, -422a, -488 and -627 to be consistently altered in acute stroke irrespective of age or severity or confounding metabolic complications. Differential expression of these 5 microRNAs was also observed in rat stroke models. Hence, their specificity to the stroke pathology emphasizes the possibility of developing these microRNAs into accurate and useful tools for diagnosis of stroke. Full article

(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)

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Open AccessArticle

Phenoxybenzamine Is Neuroprotective in a Rat Model of Severe Traumatic Brain Injury

by Thomas F. Rau, Aakriti Kothiwal, Annela Rova, Joseph F. Rhoderick and David J. Poulsen

Int. J. Mol. Sci. 2014, 15(1), 1402-1417; https://doi.org/10.3390/ijms15011402 - 20 Jan 2014

Cited by 13 | Viewed by 7260

Abstract

Phenoxybenzamine (PBZ) is an FDA approved α-1 adrenergic receptor antagonist that is currently used to treat symptoms of pheochromocytoma. However, it has not been studied as a neuroprotective agent for traumatic brain injury (TBI). While screening neuroprotective candidates, we found that phenoxybenzamine reduced [...] Read more.

Phenoxybenzamine (PBZ) is an FDA approved α-1 adrenergic receptor antagonist that is currently used to treat symptoms of pheochromocytoma. However, it has not been studied as a neuroprotective agent for traumatic brain injury (TBI). While screening neuroprotective candidates, we found that phenoxybenzamine reduced neuronal death in rat hippocampal slice cultures following exposure to oxygen glucose deprivation (OGD). Using this system, we found that phenoxybenzamine reduced neuronal death over a broad dose range (0.1 µM–1 mM) and provided efficacy when delivered up to 16 h post-OGD. We further tested phenoxybenzamine in the rat lateral fluid percussion model of TBI. When administered 8 h after TBI, phenoxybenzamine improved neurological severity scoring and foot fault assessments. At 25 days post injury, phenoxybenzamine treated TBI animals also showed a significant improvement in both learning and memory compared to saline treated controls. We further examined gene expression changes within the cortex following TBI. At 32 h post-TBI phenoxybenzamine treated animals had significantly lower expression of pro-inflammatory signaling proteins CCL2, IL1β, and MyD88, suggesting that phenoxybenzamine may exert a neuroprotective effect by reducing neuroinflammation after TBI. These data suggest that phenonxybenzamine may have application in the treatment of TBI. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2014)

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Open AccessArticle

Extracellular Disposal of Tumor-Suppressor miRs-145 and -34a via Microvesicles and 5-FU Resistance of Human Colon Cancer Cells

by Yukihiro Akao, Fiona Khoo, Minami Kumazaki, Haruka Shinohara, Kohei Miki and Nami Yamada

Int. J. Mol. Sci. 2014, 15(1), 1392-1401; https://doi.org/10.3390/ijms15011392 - 20 Jan 2014

Cited by 70 | Viewed by 7979

Abstract

The dysregulation of microRNA (miRNA) expression causes various kinds of diseases. Especially, alterations in miRNA expression levels are frequently observed in human tumor cells and are associated with cancer pathogenesis. Earlier we established Fluorouracil (5-FU)-resistant human colon cancer DLD-1 cells (DLD-1/5FU) from parental [...] Read more.

The dysregulation of microRNA (miRNA) expression causes various kinds of diseases. Especially, alterations in miRNA expression levels are frequently observed in human tumor cells and are associated with cancer pathogenesis. Earlier we established Fluorouracil (5-FU)-resistant human colon cancer DLD-1 cells (DLD-1/5FU) from parental 5-FU- sensitive DLD-1 cells. In the present study, we examined the expression of miRNA in each cell line and in its extracellular microvesicles (MVs) before and after treatment with 5-FU. The nascent RNAs of anti-oncogenic miR-34a and -145 labeled with EU in both cells were proved to be transferred into MVs in both cell lines. The levels of miR-34a and -145 in the cells and in their MVs were not largely different in the two cell lines, and a substantial amount of both miRNAs was secreted by both cell lines even in the steady-state condition. The exposure of both cell lines to 5-FU significantly increased the intracellular levels of miR-145 and miR-34a in the 5-FU-sensitive DLD-1 cells, whereas the level of neither miR was elevated in the DLD-1/5FU cells. Interestingly, the amount of miR-145 detected in the small MVs shed into the medium of the parental cells was reduced after the treatment with 5-FU. On the other hand, the intracellular expression of miR-34a in the DLD-1/5FU cells was down-regulated compared with that in the parental DLD-1 cells even in the steady-state condition. As to the miR-34a secreted into MVs, the increase in the level in DLD-1/5FU cells was greater than that in the parental DLD-1 cells after the treatment with 5-FU. Thus, the intra- and extracellular miR-145 and -34a were closely associated with 5-FU resistance, and the resistance was in part due to the enhanced secretion of miR-145 and -34a via MVs, resulting in low intracellular levels of both miRNAs. Full article

(This article belongs to the Section Biochemistry)

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Open AccessReview

Beyond the Role of Dietary Protein and Amino Acids in the Prevention of Diet-Induced Obesity

by Klaus J. Petzke, Anne Freudenberg and Susanne Klaus

Int. J. Mol. Sci. 2014, 15(1), 1374-1391; https://doi.org/10.3390/ijms15011374 - 20 Jan 2014

Cited by 27 | Viewed by 9912

Abstract

High-protein diets have been shown to prevent the development of diet-induced obesity and can improve associated metabolic disorders in mice. Dietary leucine supplementation can partially mimic this effect. However, the molecular mechanisms triggering these preventive effects remain to be satisfactorily explained. Here we [...] Read more.

High-protein diets have been shown to prevent the development of diet-induced obesity and can improve associated metabolic disorders in mice. Dietary leucine supplementation can partially mimic this effect. However, the molecular mechanisms triggering these preventive effects remain to be satisfactorily explained. Here we review studies showing a connection between high protein or total amino nitrogen intake and obligatory water intake. High amino nitrogen intake may possibly lower lipid storage, and prevent insulin resistance. Suggestions are made for further systematical studies to explore the relationship between water consumption, satiety, and energy expenditure. Moreover, these examinations should better distinguish between leucine-specific and unspecific effects. Research in this field can provide important information to justify dietary recommendations and strategies in promoting long-term weight loss and may help to reduce health problems associated with the comorbidities of obesity. Full article

(This article belongs to the Special Issue Nutritional Control of Metabolism)

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Open AccessReview

In Silico Discovery of Aminoacyl-tRNA Synthetase Inhibitors

by Yaxue Zhao, Qingqing Meng, Linquan Bai and Huchen Zhou

Int. J. Mol. Sci. 2014, 15(1), 1358-1373; https://doi.org/10.3390/ijms15011358 - 20 Jan 2014

Cited by 14 | Viewed by 8779

Abstract

Aminoacyl-tRNA synthetases (aaRSs) are enzymes that catalyze the transfer of amino acids to their cognate tRNA. They play a pivotal role in protein synthesis and are essential for cell growth and survival. The aaRSs are one of the leading targets for development of [...] Read more.

Aminoacyl-tRNA synthetases (aaRSs) are enzymes that catalyze the transfer of amino acids to their cognate tRNA. They play a pivotal role in protein synthesis and are essential for cell growth and survival. The aaRSs are one of the leading targets for development of antibiotic agents. In this review, we mainly focused on aaRS inhibitor discovery and development using in silico methods including virtual screening and structure-based drug design. These computational methods are relatively fast and cheap, and are proving to be of great benefit for the rational development of more potent aaRS inhibitors and other pharmaceutical agents that may usher in a much needed generation of new antibiotics. Full article

(This article belongs to the Collection Computational, Structural and Spectroscopic Studies of Enzyme Mechanisms, Inhibition and Dynamics)

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Open AccessArticle

Development of Molecularly Imprinted Polymer in Porous Film Format for Binding of Phenol and Alkylphenols from Water

by Andriy O. Gryshchenko and Christina S. Bottaro

Int. J. Mol. Sci. 2014, 15(1), 1338-1357; https://doi.org/10.3390/ijms15011338 - 20 Jan 2014

Cited by 34 | Viewed by 7663

Abstract

Molecularly imprinted polymers (MIPs) were fabricated on glass slides with a “sandwich” technique giving ~20 µm thick films. Methanol/water as a solvent, and polyethyleneglycol and polyvinylacetate as solvent modifiers, were used to give a porous morphology, which was studied with scanning electron microscopy [...] Read more.

Molecularly imprinted polymers (MIPs) were fabricated on glass slides with a “sandwich” technique giving ~20 µm thick films. Methanol/water as a solvent, and polyethyleneglycol and polyvinylacetate as solvent modifiers, were used to give a porous morphology, which was studied with scanning electron microscopy and gravimetric analysis. Various MIPs were synthesized through non-covalent imprinting with phenol as the template; itaconic acid, 4-vinylpyridine, and styrene as monomers; ethylene glycol dimethacrylate, triethylene glycol dimethacrylate, and pentaerythritol triacrylate (PETA) as cross-linkers. Binding and imprinting properties of the MIPs were evaluated based on phenol adsorption isotherms. Since phenol has only one weakly acidic hydroxyl group and lacks unique structural characteristics necessary for binding specificity, the preparation of selective MIPs was challenging. The recognition of phenol via hydrogen bonding is suppressed in water, while hydrophobic interactions, though promoted, are not specific enough for highly-selective phenol recognition. Nevertheless, the styrene-PETA MIP gave modest imprinting effects, which were higher at lower concentrations (Imprinting Factor (IF) = 1.16 at 0.5 mg·L⁻¹). The isotherm was of a Freundlich type over 0.1–40 mg·L⁻¹ and there was broad cross-reactivity towards other structurally similar phenols. This shows that phenol MIPs or simple adsorbents can be developed based on styrene for hydrophobic binding, and PETA to form a tighter, hydrophilic network. Full article

(This article belongs to the Section Molecular Recognition)

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Open AccessReview

Molecular Basis of Cardiac Myxomas

by Pooja Singhal, Adriana Luk, Vivek Rao and Jagdish Butany

Int. J. Mol. Sci. 2014, 15(1), 1315-1337; https://doi.org/10.3390/ijms15011315 - 20 Jan 2014

Cited by 36 | Viewed by 8668

Abstract

Cardiac tumors are rare, and of these, primary cardiac tumors are even rarer. Metastatic cardiac tumors are about 100 times more common than the primary tumors. About 90% of primary cardiac tumors are benign, and of these the most common are cardiac myxomas. [...] Read more.

Cardiac tumors are rare, and of these, primary cardiac tumors are even rarer. Metastatic cardiac tumors are about 100 times more common than the primary tumors. About 90% of primary cardiac tumors are benign, and of these the most common are cardiac myxomas. Approximately 12% of primary cardiac tumors are completely asymptomatic while others present with one or more signs and symptoms of the classical triad of hemodynamic changes due to intracardiac obstruction, embolism and nonspecific constitutional symptoms. Echocardiography is highly sensitive and specific in detecting cardiac tumors. Other helpful investigations are chest X-rays, magnetic resonance imaging and computerized tomography scan. Surgical excision is the treatment of choice for primary cardiac tumors and is usually associated with a good prognosis. This review article will focus on the general features of benign cardiac tumors with an emphasis on cardiac myxomas and their molecular basis. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Purification of an Inducible DNase from a Thermophilic Fungus

by Kyle S. Landry, Andrea Vu and Robert E. Levin

Int. J. Mol. Sci. 2014, 15(1), 1300-1314; https://doi.org/10.3390/ijms15011300 - 20 Jan 2014

Cited by 4 | Viewed by 6768

Abstract

The ability to induce an extracellular DNase from a novel thermophilic fungus was studied and the DNAse purified using both traditional and innovative purification techniques. The isolate produced sterile hyphae under all attempted growing conditions, with an average diameter of 2 µm and [...] Read more.

The ability to induce an extracellular DNase from a novel thermophilic fungus was studied and the DNAse purified using both traditional and innovative purification techniques. The isolate produced sterile hyphae under all attempted growing conditions, with an average diameter of 2 µm and was found to have an optimal temperature of 45 °C and a maximum of 65 °C. Sequencing of the internal transcribed region resulted in a 91% match with Chaetomium sp., suggesting a new species, but further clarification on this point is needed. The optimal temperature for DNase production was found to be 55 °C and was induced by the presence of DNA and/or deoxyribose. Static growth of the organism resulted in significantly higher DNase production than agitated growth. The DNase was purified 145-fold using a novel affinity membrane purification system with 25% of the initial enzyme activity remaining. Electrophoresis of the purified enzyme resulted in a single protein band, indicating DNase homogeneity. Full article

(This article belongs to the Special Issue Thermophilic DNases, RNases and Proteases)

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Open AccessArticle

Rapid and Efficient Functionalized Ionic Liquid-Catalyzed Aldol Condensation Reactions Associated with Microwave Irradiation

by Chang Wang, Jing Liu, Wenguang Leng and Yanan Gao

Int. J. Mol. Sci. 2014, 15(1), 1284-1299; https://doi.org/10.3390/ijms15011284 - 17 Jan 2014

Cited by 30 | Viewed by 10109

Abstract

Five quaternary ammonium ionic liquid (IL) and two tetrabutylphosphonium ILs were prepared and characterized. An environmentally benign and convenient functionalized ionic liquid catalytic system was thus explored in the aldol condensation reactions of aromatic aldehydes with acetone. The aldol reactions proceeded more efficiently [...] Read more.

Five quaternary ammonium ionic liquid (IL) and two tetrabutylphosphonium ILs were prepared and characterized. An environmentally benign and convenient functionalized ionic liquid catalytic system was thus explored in the aldol condensation reactions of aromatic aldehydes with acetone. The aldol reactions proceeded more efficiently through microwave-assisted heating than through conventional thermal heating. The yield of products obtained under microwave heating for 30 min was approximately 90%, and the ILs can be recovered and reused at least five times without apparent loss of activity. In addition, this catalytic system can be successfully extended to the Henry reactions. Full article

(This article belongs to the Special Issue Ionic Liquids 2014 & Selected Papers from ILMAT 2013)

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Open AccessArticle

Re-Evaluation of Binding Properties of Recombinant Lymphocyte Receptors NKR-P1A and CD69 to Chemically Synthesized Glycans and Peptides

by Daniel Rozbeský, Jana Krejzová, Karel Křenek, Jan Prchal, Richard Hrabal, Milan Košek, Lenka Weignerová, Michele Fiore, Pascal Dumy, Olivier Renaudet and Vladimír Křen

Int. J. Mol. Sci. 2014, 15(1), 1271-1283; https://doi.org/10.3390/ijms15011271 - 17 Jan 2014

Cited by 7 | Viewed by 7207

Abstract

The binding of monosaccharides and short peptides to lymphocyte receptors (human CD69 and rat NKR-P1A) was first reported in 1994 and then in a number of subsequent publications. Based on this observation, numerous potentially high-affinity saccharide ligands have been synthesized over the last [...] Read more.

The binding of monosaccharides and short peptides to lymphocyte receptors (human CD69 and rat NKR-P1A) was first reported in 1994 and then in a number of subsequent publications. Based on this observation, numerous potentially high-affinity saccharide ligands have been synthesized over the last two decades in order to utilize their potential in antitumor therapy. Due to significant inconsistencies in their reported binding properties, we decided to re-examine the interaction between multiple ligands and CD69 or NKR-P1A. Using NMR titration and isothermal titration calorimetry we were unable to detect the binding of the tested ligands such as N-acetyl-d-hexosamines and oligopeptides to both receptors, which contradicts the previous observations published in more than twenty papers over the last fifteen years. Full article

(This article belongs to the Section Molecular Recognition)

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Open AccessArticle

The Bioconcentration and Degradation of Nonylphenol and Nonylphenol Polyethoxylates by Chlorella vulgaris

by Hong-Wen Sun, Hong-Wei Hu, Lei Wang, Ying Yang and Guo-Lan Huang

Int. J. Mol. Sci. 2014, 15(1), 1255-1270; https://doi.org/10.3390/ijms15011255 - 17 Jan 2014

Cited by 16 | Viewed by 6591

Abstract

Nonylphenol polyethoxylates (NPnEOs), a major class of nonionic surfactants, can easily enter into aquatic environments through various pathways due to their wide applications, which leads to the extensive existence of their relative stable metabolites, namely nonylphenol (NP) and mono- to tri-ethoxylates. This study [...] Read more.

Nonylphenol polyethoxylates (NPnEOs), a major class of nonionic surfactants, can easily enter into aquatic environments through various pathways due to their wide applications, which leads to the extensive existence of their relative stable metabolites, namely nonylphenol (NP) and mono- to tri-ethoxylates. This study investigated the bioconcentration and degradation of NP and NPnEO oligomers (n = 1–12) by a green algae, Chlorella vulgaris. Experimental results showed that C. vulgaris can remove NP from water phase efficiently, and bioconcentration and degradation accounted for approximately half of its loss, respectively, with a 48 h BCF (bioconcentration factor) of 2.42 × 10³. Moreover, C. vulgaris could concentrate and degrade NPnEOs, distribution profiles of the series homologues of the NPnEOs in algae and water phase were quite different from the initial homologue profile. The 48 h BCF of the NPnEO homologues increased with the length of the EO chain. Degradation extent of total NPnEOs by C. vulgaris was 95.7%, and only 1.1% remained in water phase, and the other 3.2% remained in the algal cells. The algae removed the NPnEOs mainly through degradation. Due to rapid degradation, concentrations of the long chain NPnEO homologous in both water (n ≥ 2) and the algal phase (n ≥ 5) was quite low at the end of a 48 h experiment. Full article

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Synthesis and Antimicrobial Evaluation of Some Novel Thiazole, Pyridone, Pyrazole, Chromene, Hydrazone Derivatives Bearing a Biologically Active Sulfonamide Moiety

by Elham S. Darwish, Azza M. Abdel Fattah, Fawzy A. Attaby and Oqba N. Al-Shayea

Int. J. Mol. Sci. 2014, 15(1), 1237-1254; https://doi.org/10.3390/ijms15011237 - 17 Jan 2014

Cited by 55 | Viewed by 9164

Abstract

This study aimed for the synthesis of new heterocyclic compounds incorporating sulfamoyl moiety suitable for use as antimicrobial agents via a versatile, readily accessible N-[4-(aminosulfonyl)phenyl]-2-cyanoacetamide (3). The 2-pyridone derivatives were obtained via reaction of cyanoacetamide with acetylacetone or arylidenes malononitrile. [...] Read more.

This study aimed for the synthesis of new heterocyclic compounds incorporating sulfamoyl moiety suitable for use as antimicrobial agents via a versatile, readily accessible N-[4-(aminosulfonyl)phenyl]-2-cyanoacetamide (3). The 2-pyridone derivatives were obtained via reaction of cyanoacetamide with acetylacetone or arylidenes malononitrile. Cycloaddition reaction of cyanoacetamide with salicyaldehyde furnished chromene derivatives. Diazotization of 3 with the desired diazonium chloride gave the hydrazone derivatives 13a–e. Also, the reactivity of the hydrazone towards hydrazine hydrate to give Pyrazole derivatives was studied. In addition, treatment of 3 with elemental sulfur and phenyl isothiocyanate or malononitrile furnished thiazole and thiophene derivatives respectively. Reaction of 3 with phenyl isothiocyanate and KOH in DMF afforded the intermediate salt 17 which reacted in situ with 3-(2-bromoacetyl)-2H-chromen-2-one and methyl iodide afforded the thiazole and ketene N,S-acetal derivatives respectively. Finally, reaction of 3 with carbon disulfide and 1,3-dibromopropane afforded the N-[4-(aminosulfonyl) phenyl]-2-cyano-2-(1,3-dithian-2-ylidene)acetamide product 22. All newly synthesized compounds were elucidated by considering the data of both elemental and spectral analysis. The compounds were evaluated for both their in vitro antibacterial and antifungal activities and showed promising results. Full article

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Open AccessReview

Neuroprotective Strategies for Traumatic Brain Injury: Improving Clinical Translation

by Shruti V. Kabadi and Alan I. Faden

Int. J. Mol. Sci. 2014, 15(1), 1216-1236; https://doi.org/10.3390/ijms15011216 - 17 Jan 2014

Cited by 141 | Viewed by 11518

Abstract

Traumatic brain injury (TBI) induces secondary biochemical changes that contribute to delayed neuroinflammation, neuronal cell death, and neurological dysfunction. Attenuating such secondary injury has provided the conceptual basis for neuroprotective treatments. Despite strong experimental data, more than 30 clinical trials of neuroprotection in [...] Read more.

Traumatic brain injury (TBI) induces secondary biochemical changes that contribute to delayed neuroinflammation, neuronal cell death, and neurological dysfunction. Attenuating such secondary injury has provided the conceptual basis for neuroprotective treatments. Despite strong experimental data, more than 30 clinical trials of neuroprotection in TBI patients have failed. In part, these failures likely reflect methodological differences between the clinical and animal studies, as well as inadequate pre-clinical evaluation and/or trial design problems. However, recent changes in experimental approach and advances in clinical trial methodology have raised the potential for successful clinical translation. Here we critically analyze the current limitations and translational opportunities for developing successful neuroprotective therapies for TBI. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2014)

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Open AccessArticle

Hispolon Decreases Melanin Production and Induces Apoptosis in Melanoma Cells through the Downregulation of Tyrosinase and Microphthalmia-Associated Transcription Factor (MITF) Expressions and the Activation of Caspase-3, -8 and -9

by Yi-Shyan Chen, Shu-Mei Lee, Chih-Chien Lin and Chia-Yi Liu

Int. J. Mol. Sci. 2014, 15(1), 1201-1215; https://doi.org/10.3390/ijms15011201 - 17 Jan 2014

Cited by 40 | Viewed by 10511

Abstract

Hispolon is one of the most important functional compounds that forms Phellinus linteus (Berkeley & Curtis) Teng. Hispolon has antioxidant, anti-inflammatory, antiproliferative and anticancer effects. In this study, we analyzed the functions of hispolon on melanogenesis and apoptosis in B16-F10 melanoma cells. The [...] Read more.

Hispolon is one of the most important functional compounds that forms Phellinus linteus (Berkeley & Curtis) Teng. Hispolon has antioxidant, anti-inflammatory, antiproliferative and anticancer effects. In this study, we analyzed the functions of hispolon on melanogenesis and apoptosis in B16-F10 melanoma cells. The results demonstrated that hispolon is not an enzymatic inhibitor for tyrosinase; rather, it represses the expression of tyrosinase and the microphthalmia-associated transcription factor (MITF) to reduce the production of melanin in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16-F10 cells at lower concentrations (less than 2 μM). In contrast, at higher concentration (greater than 10 μM), hispolon can induce activity of caspase-3, -8 and -9 to trigger apoptosis of B16-F10 cells but not of Detroit 551 normal fibroblast cells. Therefore, we suggest that hispolon has the potential to treat hyperpigmentation diseases and melanoma skin cancer in the future. Full article

(This article belongs to the Section Biochemistry)

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