International Journal of Molecular Sciences

388 KiB

Open AccessArticle

Transcriptome-Wide Single Nucleotide Polymorphisms (SNPs) for Abalone (Haliotis midae): Validation and Application Using GoldenGate Medium-Throughput Genotyping Assays

by Aletta Bester-Van Der Merwe, Sonja Blaauw, Jana Du Plessis and Rouvay Roodt-Wilding

Int. J. Mol. Sci. 2013, 14(9), 19341-19360; https://doi.org/10.3390/ijms140919341 - 23 Sep 2013

Cited by 17 | Viewed by 7919

Abstract

Haliotis midae is one of the most valuable commercial abalone species in the world, but is highly vulnerable, due to exploitation, habitat destruction and predation. In order to preserve wild and cultured stocks, genetic management and improvement of the species has become crucial. [...] Read more.

Haliotis midae is one of the most valuable commercial abalone species in the world, but is highly vulnerable, due to exploitation, habitat destruction and predation. In order to preserve wild and cultured stocks, genetic management and improvement of the species has become crucial. Fundamental to this is the availability and employment of molecular markers, such as microsatellites and Single Nucleotide Polymorphisms (SNPs) . Transcriptome sequences generated through sequencing-by-synthesis technology were utilized for the in vitro and in silico identification of 505 putative SNPs from a total of 316 selected contigs. A subset of 234 SNPs were further validated and characterized in wild and cultured abalone using two Illumina GoldenGate genotyping assays. Combined with VeraCode technology, this genotyping platform yielded a 65%−69% conversion rate (percentage polymorphic markers) with a global genotyping success rate of 76%−85% and provided a viable means for validating SNP markers in a non-model species. The utility of 31 of the validated SNPs in population structure analysis was confirmed, while a large number of SNPs (174) were shown to be informative and are, thus, good candidates for linkage map construction. The non-synonymous SNPs (50) located in coding regions of genes that showed similarities with known proteins will also be useful for genetic applications, such as the marker-assisted selection of genes of relevance to abalone aquaculture. Full article

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

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374 KiB

Open AccessReview

Choosing an Appropriate Infection Model to Study Quorum Sensing Inhibition in Pseudomonas Infections

by Evelina Papaioannou, Putri Dwi Utari and Wim J. Quax

Int. J. Mol. Sci. 2013, 14(9), 19309-19340; https://doi.org/10.3390/ijms140919309 - 23 Sep 2013

Cited by 40 | Viewed by 10580

Abstract

Bacteria, although considered for decades to be antisocial organisms whose sole purpose is to find nutrients and multiply are, in fact, highly communicative organisms. Referred to as quorum sensing, cell-to-cell communication mechanisms have been adopted by bacteria in order to co-ordinate their gene [...] Read more.

Bacteria, although considered for decades to be antisocial organisms whose sole purpose is to find nutrients and multiply are, in fact, highly communicative organisms. Referred to as quorum sensing, cell-to-cell communication mechanisms have been adopted by bacteria in order to co-ordinate their gene expression. By behaving as a community rather than as individuals, bacteria can simultaneously switch on their virulence factor production and establish successful infections in eukaryotes. Understanding pathogen-host interactions requires the use of infection models. As the use of rodents is limited, for ethical considerations and the high costs associated with their use, alternative models based on invertebrates have been developed. Invertebrate models have the benefits of low handling costs, limited space requirements and rapid generation of results. This review presents examples of such models available for studying the pathogenicity of the Gram-negative bacterium Pseudomonas aeruginosa. Quorum sensing interference, known as quorum quenching, suggests a promising disease-control strategy since quorum-quenching mechanisms appear to play important roles in microbe-microbe and host-pathogen interactions. Examples of natural and synthetic quorum sensing inhibitors and their potential as antimicrobials in Pseudomonas-related infections are discussed in the second part of this review. Full article

(This article belongs to the Special Issue Quorum Sensing Research in Microbial Systems)

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Graphical abstract

1711 KiB

Open AccessReview

Oxidative Stress in the Pathogenesis of Keratoconus and Fuchs Endothelial Corneal Dystrophy

by Katarzyna A. Wojcik, Anna Kaminska, Janusz Blasiak, Jerzy Szaflik and Jacek P. Szaflik

Int. J. Mol. Sci. 2013, 14(9), 19294-19308; https://doi.org/10.3390/ijms140919294 - 23 Sep 2013

Cited by 124 | Viewed by 17005

Abstract

Due to its localization and function, the cornea is regularly exposed to sunlight and atmospheric oxygen, mainly dioxygen, which produce reactive oxygen species (ROS). Therefore, corneal cells are particularly susceptible to oxidative stress. The accumulation of ROS in the cornea may affect signal [...] Read more.

Due to its localization and function, the cornea is regularly exposed to sunlight and atmospheric oxygen, mainly dioxygen, which produce reactive oxygen species (ROS). Therefore, corneal cells are particularly susceptible to oxidative stress. The accumulation of ROS in the cornea may affect signal transduction, proliferation and may also promote cell death. The cornea has several enzymatic and non-enzymatic antioxidants involved in ROS scavenging, but in certain conditions they may not cope with oxidative stress, leading to diseases of the eye. Keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD) are multifactorial diseases of the cornea, in which pathogenesis is not fully understood. However, increased levels of oxidative stress markers detected in these disorders indicate that oxidative stress may play an important role in their development and progression. These markers are: (i) decreased levels of non-enzymatic antioxidants, and (ii) decreased expression of genes encoding antioxidative enzymes, including thioredoxin reductase, peroxiredoxins, superoxide dismutase, glutathione S-transferase, and aldehyde dehydrogenase. Moreover, the FECD endothelium displays higher levels of oxidative DNA damage, especially in mitochondrial DNA (mtDNA), whereas KC cornea shows abnormal levels of some components of oxidative phosphorylation encoded by mtDNA. In this review we present some considerations and results of experiments supporting the thesis on the important role of oxidative stress in KC and FECD pathology. Full article

(This article belongs to the Section Biochemistry)

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2011 KiB

Open AccessArticle

Receptor-Targeted, Magneto-Mechanical Stimulation of Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells

by Bin Hu, Alicia J El Haj and Jon Dobson

Int. J. Mol. Sci. 2013, 14(9), 19276-19293; https://doi.org/10.3390/ijms140919276 - 23 Sep 2013

Cited by 68 | Viewed by 9565

Abstract

Mechanical cues are employed to promote stem cell differentiation and functional tissue formation in tissue engineering and regenerative medicine. We have developed a Magnetic Force Bioreactor (MFB) that delivers highly targeted local forces to cells at a pico-newton level, utilizing magnetic micro- and [...] Read more.

Mechanical cues are employed to promote stem cell differentiation and functional tissue formation in tissue engineering and regenerative medicine. We have developed a Magnetic Force Bioreactor (MFB) that delivers highly targeted local forces to cells at a pico-newton level, utilizing magnetic micro- and nano-particles to target cell surface receptors. In this study, we investigated the effects of magnetically targeting and actuating specific two mechanical-sensitive cell membrane receptors—platelet-derived growth factor receptor α (PDGFRα) and integrin α_νβ₃. It was found that a higher mineral-to-matrix ratio was obtained after three weeks of magneto-mechanical stimulation coupled with osteogenic medium culture by initially targeting PDGFRα compared with targeting integrin α_νβ₃ and non-treated controls. Moreover, different initiation sites caused a differentiated response profile when using a 2-day-lagged magneto-mechanical stimulation over culture periods of 7 and 12 days). However, both resulted in statistically higher osteogenic marker genes expression compared with immediate magneto-mechanical stimulation. These results provide insights into important parameters for designing appropriate protocols for ex vivo induced bone formation via magneto-mechanical actuation. Full article

(This article belongs to the Special Issue Magnetic Nanoparticles 2013)

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Open AccessReview

The Consequence of Oncomorphic TP53 Mutations in Ovarian Cancer

by Pavla Brachova, Kristina W. Thiel and Kimberly K. Leslie

Int. J. Mol. Sci. 2013, 14(9), 19257-19275; https://doi.org/10.3390/ijms140919257 - 23 Sep 2013

Cited by 78 | Viewed by 13794

Abstract

Ovarian cancer is the most lethal gynecological malignancy, with an alarmingly poor prognosis attributed to late detection and chemoresistance. Initially, most tumors respond to chemotherapy but eventually relapse due to the development of drug resistance. Currently, there are no biological markers that can [...] Read more.

Ovarian cancer is the most lethal gynecological malignancy, with an alarmingly poor prognosis attributed to late detection and chemoresistance. Initially, most tumors respond to chemotherapy but eventually relapse due to the development of drug resistance. Currently, there are no biological markers that can be used to predict patient response to chemotherapy. However, it is clear that mutations in the tumor suppressor gene TP53, which occur in 96% of serous ovarian tumors, alter the core molecular pathways involved in drug response. One subtype of TP53 mutations, widely termed gain-of-function (GOF) mutations, surprisingly converts this protein from a tumor suppressor to an oncogene. We term the resulting change an oncomorphism. In this review, we discuss particular TP53 mutations, including known oncomorphic properties of the resulting mutant p53 proteins. For example, several different oncomorphic mutations have been reported, but each mutation acts in a distinct manner and has a different effect on tumor progression and chemoresistance. An understanding of the pathological pathways altered by each mutation is necessary in order to design appropriate drug interventions for patients suffering from this deadly disease. Full article

(This article belongs to the Special Issue Genes and Pathways in the Pathogenesis of Ovarian Cancer)

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Open AccessReview

Voltage-Gated Potassium Channel Kv1.3 Is Highly Expressed in Human Osteosarcoma and Promotes Osteosarcoma Growth

by Jin Wu, Daixing Zhong, Xinyu Wu, Mo Sha, Liangqi Kang and Zhenqi Ding

Int. J. Mol. Sci. 2013, 14(9), 19245-19256; https://doi.org/10.3390/ijms140919245 - 23 Sep 2013

Cited by 17 | Viewed by 6078

Abstract

Deregulation of voltage-gated potassium channel subunit Kv1.3 has been reported in many tumors. Kv1.3 promotes tumorigenesis by enhancing cell proliferation while suppressing apoptosis. However, the expression and function of Kv1.3 in osteosarcoma are unknown. In the present study, we detected the expression of [...] Read more.

Deregulation of voltage-gated potassium channel subunit Kv1.3 has been reported in many tumors. Kv1.3 promotes tumorigenesis by enhancing cell proliferation while suppressing apoptosis. However, the expression and function of Kv1.3 in osteosarcoma are unknown. In the present study, we detected the expression of Kv1.3 in human osteosarcoma cells and tissues by RT-PCR, Western blot and immunohistochemistry. We further examined cell proliferation and apoptosis in osteosarcoma MG-63 cells and xenografts following knockdown of Kv1.3 by short hairpin RNA (shRNA). We found that Kv1.3 was upregulated in human osteosarcoma. Knockdown of Kv1.3 significantly suppressed cell proliferation and increased apoptosis as demonstrated by enhanced cleavage of poly (ADP-ribose) polymerase (PARP) and the activation of Caspase-3/7. Furthermore, adenovirus delivered shRNA targeting Kv1.3 significantly inhibited the growth of MG-63 xenografts. Taken together, our results suggest that Kv1.3 is a novel molecular target for osterosarcoma therapy. Full article

(This article belongs to the Section Biochemistry)

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296 KiB

Open AccessArticle

Analysis of Gln223Agr Polymorphism of Leptin Receptor Gene in Type II Diabetic Mellitus Subjects among Malaysians

by Ali Etemad, Vasudevan Ramachandran, Seyyed Reza Pishva, Farzad Heidari, Ahmad Fazli Abdul Aziz, Ahmad Khairuddin Mohamed Yusof, Chong Pei Pei and Patimah Ismail

Int. J. Mol. Sci. 2013, 14(9), 19230-19244; https://doi.org/10.3390/ijms140919230 - 18 Sep 2013

Cited by 30 | Viewed by 7750

Abstract

Leptin is known as the adipose peptide hormone. It plays an important role in the regulation of body fat and inhibits food intake by its action. Moreover, it is believed that leptin level deductions might be the cause of obesity and may play [...] Read more.

Leptin is known as the adipose peptide hormone. It plays an important role in the regulation of body fat and inhibits food intake by its action. Moreover, it is believed that leptin level deductions might be the cause of obesity and may play an important role in the development of Type 2 Diabetes Mellitus (T2DM), as well as in cardiovascular diseases (CVD). The Leptin Receptor (LEPR) gene and its polymorphisms have not been extensively studied in relation to the T2DM and its complications in various populations. In this study, we have determined the association of Gln223Agr loci of LEPR gene in three ethnic groups of Malaysia, namely: Malays, Chinese and Indians. A total of 284 T2DM subjects and 281 healthy individuals were recruited based on International Diabetes Federation (IDF) criteria. Genomic DNA was extracted from the buccal specimens of the subjects. The commercial polymerase chain reaction (PCR) method was carried out by proper restriction enzyme MSP I to both amplify and digest the Gln223Agr polymorphism. The p-value among the three studied races was 0.057, 0.011 and 0.095, respectively. The values such as age, WHR, FPG, H_bA_1C, LDL, HDL, Chol and Family History were significantly different among the subjects with Gln223Agr polymorphism of LEPR (p < 0.05). Full article

(This article belongs to the Section Biochemistry)

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Open AccessReview

Posttranscriptional Regulation of Insulin Family Ligands and Receptors

by Amaresh C. Panda, Ioannis Grammatikakis, Je-Hyun Yoon and Kotb Abdelmohsen

Int. J. Mol. Sci. 2013, 14(9), 19202-19229; https://doi.org/10.3390/ijms140919202 - 18 Sep 2013

Cited by 19 | Viewed by 9827

Abstract

Insulin system including ligands (insulin and IGFs) and their shared receptors (IR and IGFR) are critical regulators of insulin signaling and glucose homeostasis. Altered insulin system is associated with major pathological conditions like diabetes and cancer. The mRNAs encoding for these ligands and [...] Read more.

Insulin system including ligands (insulin and IGFs) and their shared receptors (IR and IGFR) are critical regulators of insulin signaling and glucose homeostasis. Altered insulin system is associated with major pathological conditions like diabetes and cancer. The mRNAs encoding for these ligands and their receptors are posttranscriptionally controlled by three major groups of regulators; (i) alternative splicing regulatory factors; (ii) turnover and translation regulator RNA-binding proteins (TTR-RBPs); and (iii) non-coding RNAs including miRNAs and long non-coding RNAs (lncRNAs). In this review, we discuss the influence of these regulators on alternative splicing, mRNA stability and translation. Due to the pathological impacts of insulin system, we also discussed the possibilities of discovering new potential regulators which will improve understanding of insulin system and associated diseases. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Open AccessArticle

Cinnamomum cassia Essential Oil Inhibits α-MSH-Induced Melanin Production and Oxidative Stress in Murine B16 Melanoma Cells

by Su-Tze Chou, Wen-Lun Chang, Chen-Tien Chang, Shih-Lan Hsu, Yu-Che Lin and Ying Shih

Int. J. Mol. Sci. 2013, 14(9), 19186-19201; https://doi.org/10.3390/ijms140919186 - 18 Sep 2013

Cited by 109 | Viewed by 12931

Abstract

Essential oils extracted from aromatic plants exhibit important biological activities and have become increasingly important for the development of aromatherapy for complementary and alternative medicine. The essential oil extracted from Cinnamomum cassia Presl (CC-EO) has various functional properties; however, little information is available [...] Read more.

Essential oils extracted from aromatic plants exhibit important biological activities and have become increasingly important for the development of aromatherapy for complementary and alternative medicine. The essential oil extracted from Cinnamomum cassia Presl (CC-EO) has various functional properties; however, little information is available regarding its anti-tyrosinase and anti-melanogenic activities. In this study, 16 compounds in the CC-EO have been identified; the major components of this oil are cis-2-methoxycinnamic acid (43.06%) and cinnamaldehyde (42.37%). CC-EO and cinnamaldehyde exhibited anti-tyrosinase activities; however, cis-2-methoxycinnamic acid did not demonstrate tyrosinase inhibitory activity. In murine B16 melanoma cells stimulated with α-melanocyte-stimulating hormone (α-MSH), CC-EO and cinnamaldehyde not only reduced the melanin content and tyrosinase activity of the cells but also down-regulated tyrosinase expression without exhibiting cytotoxicity. Moreover, CC-EO and cinnamaldehyde decreased thiobarbituric acid-reactive substance (TBARS) levels and restored glutathione (GSH) and catalase activity in the α-MSH-stimulated B16 cells. These results demonstrate that CC-EO and its major component, cinnamaldehyde, possess potent anti-tyrosinase and anti-melanogenic activities that are coupled with antioxidant properties. Therefore, CC-EO may be a good source of skin-whitening agents and may have potential as an antioxidant in the future development of complementary and alternative medicine-based aromatherapy. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Involvement of Calcium-Mediated Reactive Oxygen Species in Inductive GRP78 Expression by Geldanamycin in 9L Rat Brain Tumor Cells

by Fang-Chun Sun, Hsin-Yi Shyu, Meng-Shiou Lee, Meng-Shiunn Lee and Yiu-Kay Lai

Int. J. Mol. Sci. 2013, 14(9), 19169-19185; https://doi.org/10.3390/ijms140919169 - 18 Sep 2013

Cited by 6 | Viewed by 8511

Abstract

Treatment with geldanamycin (GA) leads to an increase in [Ca²⁺]_c and the production of reactive oxygen species (ROS) in rat brain tumor 9L RBT cells. GA-exerted calcium signaling was blocked by BAPTA/AM and EGTA. The effect of GA on [Ca [...] Read more.

Treatment with geldanamycin (GA) leads to an increase in [Ca²⁺]_c and the production of reactive oxygen species (ROS) in rat brain tumor 9L RBT cells. GA-exerted calcium signaling was blocked by BAPTA/AM and EGTA. The effect of GA on [Ca²⁺]_c was significantly reduced in the presence of thapsigargin (TG) and ruthenium red (RR). GA-induced GRP78 expression is significantly decreased in the presence of BAPTA/AM, EGTA and RR, suggesting that the calcium influx from the extracellular space and intracellular calcium store oscillations are contributed to by the calcium mobilization and GRP78 expression induced by GA. The induced GRP78 expression is sensitive to added U73122 and Ro-31-8425, pinpointing the involvement of phospholipase C (PLC) and protein kinase C (PKC) in GA-induced endoplasmic reticulum (ER) stress. The antioxidants N-acetylcysteine (NAC), BAPTA/AM, EGTA and H7 also have significant inhibitory effects on ROS generation. Finally, neither H7 nor NAC was able to affect the calcium response elicited by GA. Our results suggest that the causal signaling cascade during GA-inducted GRP78 expression occurs via a pathway that connects PLC to cytoplasmic calcium increase, PKC activation and, then, finally, ROS generation. Our data provides new insights into the influence of GA on ER stress response in 9L RBT cells. Full article

(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)

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Open AccessArticle

Formation of Apatite Coatings on an Artificial Ligament Using a Plasma- and Precursor-Assisted Biomimetic Process

by Hirotaka Mutsuzaki, Yoshiro Yokoyama, Atsuo Ito and Ayako Oyane

Int. J. Mol. Sci. 2013, 14(9), 19155-19168; https://doi.org/10.3390/ijms140919155 - 17 Sep 2013

Cited by 21 | Viewed by 6623

Abstract

A plasma- and precursor-assisted biomimetic process utilizing plasma and alternate dipping treatments was applied to a Leed-Keio artificial ligament to produce a thin coating of apatite in a supersaturated calcium phosphate solution. Following plasma surface modification, the specimen was alternately dipped in calcium [...] Read more.

A plasma- and precursor-assisted biomimetic process utilizing plasma and alternate dipping treatments was applied to a Leed-Keio artificial ligament to produce a thin coating of apatite in a supersaturated calcium phosphate solution. Following plasma surface modification, the specimen was alternately dipped in calcium and phosphate ion solutions three times (alternate dipping treatment) to create a precoating containing amorphous calcium phosphate (ACP) which is an apatite precursor. To grow an apatite layer on the ACP precoating, the ACP-precoated specimen was immersed for 24 h in a simulated body fluid with ion concentrations approximately equal to those in human blood plasma. The plasma surface modification was necessary to create an adequate apatite coating and to improve the coating adhesion depending on the plasma power density. The apatite coating prepared using the optimized conditions formed a thin-film that covered the entire surface of the artificial ligament. The resulting apatite-coated artificial ligament should exhibit improved osseointegration within the bone tunnel and possesses great potential for use in ligament reconstructions. Full article

(This article belongs to the Special Issue Biologic Coatings for Orthopaedic Implant)

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369 KiB

Open AccessArticle

Probing Antigen-Antibody Interaction Using Fluorescence Coupled Capillary Electrophoresis

by Jianhao Wang, Lin Qiu, Cheli Wang, Yue Zhang, Jingyan Li, Jiang Xia and Pengju Jiang

Int. J. Mol. Sci. 2013, 14(9), 19146-19154; https://doi.org/10.3390/ijms140919146 - 17 Sep 2013

Cited by 11 | Viewed by 7413

Abstract

In this report, the use of fluorescence detection coupled capillary electrophoresis (CE-FL) allowed us to fully characterize the antigen-antibody interaction. CE-FL allowed separation of unbound quantum dots (QDs) and ligand bound QDs and also revealed an ordered assembly of biomolecules on QDs. Further, [...] Read more.

In this report, the use of fluorescence detection coupled capillary electrophoresis (CE-FL) allowed us to fully characterize the antigen-antibody interaction. CE-FL allowed separation of unbound quantum dots (QDs) and ligand bound QDs and also revealed an ordered assembly of biomolecules on QDs. Further, we observed FRET from QDs donor to DyLight acceptor, which were covalently conjugated with human IgG and goat anti-human IgG, respectively. The immunocomplex was formed and the mutual affinity of the antigen and antibody brought QDs and DyLight close enough to allow FRET to occur. This novel CE-based technique can be easily extended to other FRET systems based on QDs and may have potential application in the detection of antibodies. Full article

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

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Graphical abstract

906 KiB

Open AccessArticle

Small Molecules Present in the Cerebrospinal Fluid Metabolome Influence Superoxide Dismutase 1 Aggregation

by Joana S. Cristóvão, Sónia S. Leal, Isabel Cardoso and Cláudio M. Gomes

Int. J. Mol. Sci. 2013, 14(9), 19128-19145; https://doi.org/10.3390/ijms140919128 - 17 Sep 2013

Cited by 5 | Viewed by 7667

Abstract

Superoxide dismutase 1 (SOD1) aggregation is one of the pathological markers of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. The underlying molecular grounds of SOD1 pathologic aggregation remains obscure as mutations alone are not exclusively the cause for the formation of protein [...] Read more.

Superoxide dismutase 1 (SOD1) aggregation is one of the pathological markers of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. The underlying molecular grounds of SOD1 pathologic aggregation remains obscure as mutations alone are not exclusively the cause for the formation of protein inclusions. Thus, other components in the cell environment likely play a key role in triggering SOD1 toxic aggregation in ALS. Recently, it was found that ALS patients present a specific altered metabolomic profile in the cerebrospinal fluid (CSF) where SOD1 is also present and potentially interacts with metabolites. Here we have investigated how some of these small molecules affect apoSOD1 structure and aggregation propensity. Our results show that as co-solvents, the tested small molecules do not affect apoSOD1 thermal stability but do influence its tertiary interactions and dynamics, as evidenced by combined biophysical analysis and proteolytic susceptibility. Moreover, these compounds influence apoSOD1 aggregation, decreasing nucleation time and promoting the formation of larger and less soluble aggregates, and in some cases polymeric assemblies apparently composed by spherical species resembling the soluble native protein. We conclude that some components of the ALS metabolome that shape the chemical environment in the CSF may influence apoSOD1 conformers and aggregation. Full article

(This article belongs to the Special Issue Protein Folding)

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Graphical abstract

1061 KiB

Open AccessReview

Single-Chain Fragment Variable Passive Immunotherapies for Neurodegenerative Diseases

by Liang Huang, Xiaomin Su and Howard J. Federoff

Int. J. Mol. Sci. 2013, 14(9), 19109-19127; https://doi.org/10.3390/ijms140919109 - 17 Sep 2013

Cited by 37 | Viewed by 11567

Abstract

Accumulation of misfolded proteins has been implicated in a variety of neurodegenerative diseases including prion diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). In the past decade, single-chain fragment variable (scFv) -based immunotherapies have been developed to target abnormal proteins [...] Read more.

Accumulation of misfolded proteins has been implicated in a variety of neurodegenerative diseases including prion diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). In the past decade, single-chain fragment variable (scFv) -based immunotherapies have been developed to target abnormal proteins or various forms of protein aggregates including Aβ, SNCA, Htt, and PrP proteins. The scFvs are produced by fusing the variable regions of the antibody heavy and light chains, creating a much smaller protein with unaltered specificity. Because of its small size and relative ease of production, scFvs are promising diagnostic and therapeutic reagents for protein misfolded diseases. Studies have demonstrated the efficacy and safety of scFvs in preventing amyloid protein aggregation in preclinical models. Herein, we discuss recent developments of these immunotherapeutics. We review efforts of our group and others using scFv in neurodegenerative disease models. We illustrate the advantages of scFvs, including engineering to enhance misfolded conformer specificity and subcellular targeting to optimize therapeutic action. Full article

(This article belongs to the Special Issue Protein Folding)

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Open AccessArticle

Adverse Impact of Diet-Induced Hypercholesterolemia on Cardiovascular Tissue Homeostasis in a Rabbit Model: Time-Dependent Changes in Cardiac Parameters

by Attila Kertész, Mariann Bombicz, Daniel Priksz, Jozsef Balla, Gyorgy Balla, Rudolf Gesztelyi, Balazs Varga, David D. Haines, Arpad Tosaki and Bela Juhasz

Int. J. Mol. Sci. 2013, 14(9), 19086-19108; https://doi.org/10.3390/ijms140919086 - 17 Sep 2013

Cited by 13 | Viewed by 8902

Abstract

The present study evaluates a hypothesis that diet-related hypercholesterolemia increases oxidative stress-related burden to cardiovascular tissue, resulting in progressively increased mortality, along with deterioration of electrophysiological and enzymatic function in rabbit myocardium. New Zealand white rabbits were divided into four groups, defined as [...] Read more.

The present study evaluates a hypothesis that diet-related hypercholesterolemia increases oxidative stress-related burden to cardiovascular tissue, resulting in progressively increased mortality, along with deterioration of electrophysiological and enzymatic function in rabbit myocardium. New Zealand white rabbits were divided into four groups, defined as follows: GROUP I, cholesterol-free rabbit chow for 12 weeks; GROUP II, cholesterol-free chow, 40 weeks; GROUP III, chow supplemented with 2% cholesterol, 12 weeks; GROUP IV, chow supplemented with 2% cholesterol, 40 weeks. At the 12 and 40 weeks time points, animals in each of the aforementioned cohorts were subjected to echocardiographic measurements, followed by sacrifice. Significant deterioration in major outcome variables measured in the present study were observed only in animals maintained for 40 weeks on 2% cholesterol-supplemented chow, with much lesser adverse effects noted in animals fed high cholesterol diets for only 12 weeks. It was observed that rabbits receiving high cholesterol diets for 40 weeks exhibited significantly increased mortality, worsened ejection fraction and general deterioration of cardiac functions, along with increased atherosclerotic plaque formation and infarct size. Additionally, myocardium of GROUP IV animals was observed to contain lower levels of heme oxygenase-1 (HO-1) and cytochrome c oxidase III (COX III) protein relative to the controls. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Open AccessArticle

Basic Amino Acid Residues of Human Eosinophil Derived Neurotoxin Essential for Glycosaminoglycan Binding

by Ta-Jen Hung, Wei-Tang Chang, Noboru Tomiya, Yuan-Chuan Lee, Hao-Teng Chang, Chien-Jung Chen, Ping-Hsueh Kuo, Tan-chi Fan and Margaret Dah-Tsyr Chang

Int. J. Mol. Sci. 2013, 14(9), 19067-19085; https://doi.org/10.3390/ijms140919067 - 16 Sep 2013

Cited by 2 | Viewed by 7028

Abstract

Human eosinophil derived neurotoxin (EDN), a granule protein secreted by activated eosinophils, is a biomarker for asthma in children. EDN belongs to the human RNase A superfamily possessing both ribonucleolytic and antiviral activities. EDN interacts with heparin oligosaccharides and heparin sulfate proteoglycans on [...] Read more.

Human eosinophil derived neurotoxin (EDN), a granule protein secreted by activated eosinophils, is a biomarker for asthma in children. EDN belongs to the human RNase A superfamily possessing both ribonucleolytic and antiviral activities. EDN interacts with heparin oligosaccharides and heparin sulfate proteoglycans on bronchial epithelial Beas-2B cells. In this study, we demonstrate that the binding of EDN to cells requires cell surface glycosaminoglycans (GAGs), and the binding strength between EDN and GAGs depends on the sulfation levels of GAGs. Furthermore, in silico computer modeling and in vitro binding assays suggest critical roles for the following basic amino acids located within heparin binding regions (HBRs) of EDN ³⁴QRRCKN³⁹ (HBR1), ⁶⁵NKTRKN⁷⁰ (HBR2), and ¹¹³NRDQRRD¹¹⁹ (HBR3) and in particular Arg³⁵, Arg³⁶, and Arg³⁸ within HBR1, and Arg¹¹⁴ and Arg¹¹⁷ within HBR3. Our data suggest that sulfated GAGs play a major role in EDN binding, which in turn may be related to the cellular effects of EDN. Full article

(This article belongs to the Special Issue Proteins and Protein-Ligand Interactions)

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Open AccessArticle

Exposure to Enriched Environment Decreases Neurobehavioral Deficits Induced by Neonatal Glutamate Toxicity

by Gabor Horvath, Dora Reglodi, Gyongyver Vadasz, Jozsef Farkas and Peter Kiss

Int. J. Mol. Sci. 2013, 14(9), 19054-19066; https://doi.org/10.3390/ijms140919054 - 16 Sep 2013

Cited by 25 | Viewed by 7905

Abstract

Environmental enrichment is a popular strategy to enhance motor and cognitive performance and to counteract the effects of various harmful stimuli. The protective effects of enriched environment have been shown in traumatic, ischemic and toxic nervous system lesions. Monosodium glutamate (MSG) is a [...] Read more.

Environmental enrichment is a popular strategy to enhance motor and cognitive performance and to counteract the effects of various harmful stimuli. The protective effects of enriched environment have been shown in traumatic, ischemic and toxic nervous system lesions. Monosodium glutamate (MSG) is a commonly used taste enhancer causing excitotoxic effects when given in newborn animals. We have previously demonstrated that MSG leads to a delay in neurobehavioral development, as shown by the delayed appearance of neurological reflexes and maturation of motor coordination. In the present study we aimed at investigating whether environmental enrichment is able to decrease the neurobehavioral delay caused by neonatal MSG treatment. Newborn pups were treated with MSG subcutaneously on postnatal days 1, 5 and 9. For environmental enrichment, we placed rats in larger cages, supplemented with different toys that were altered daily. Normal control and enriched control rats received saline treatment only. Physical parameters such as weight, day of eye opening, incisor eruption and ear unfolding were recorded. Animals were observed for appearance of reflexes such as negative geotaxis, righting reflexes, fore- and hindlimb grasp, fore- and hindlimb placing, sensory reflexes and gait. In cases of negative geotaxis, surface righting and gait, the time to perform the reflex was also recorded daily. For examining motor coordination, we performed grid walking, footfault, rope suspension, rota-rod, inclined board and walk initiation tests. We found that enriched environment alone did not lead to marked alterations in the course of development. On the other hand, MSG treatment caused a slight delay in reflex development and a pronounced delay in weight gain and motor coordination maturation. This delay in most signs and tests could be reversed by enriched environment: MSG-treated pups kept under enriched conditions showed no weight retardation, no reflex delay in some signs and performed better in most coordination tests. These results show that environmental enrichment is able to decrease the neurobehavioral delay caused by neonatal excitotoxicity. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology)

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Open AccessReview

Biochemistry and Molecular Biology of Carotenoid Biosynthesis in Chili Peppers (Capsicum spp.)

by María Del Rocío Gómez-García and Neftalí Ochoa-Alejo

Int. J. Mol. Sci. 2013, 14(9), 19025-19053; https://doi.org/10.3390/ijms140919025 - 16 Sep 2013

Cited by 165 | Viewed by 19815

Abstract

Capsicum species produce fruits that synthesize and accumulate carotenoid pigments, which are responsible for the fruits’ yellow, orange and red colors. Chili peppers have been used as an experimental model for studying the biochemical and molecular aspects of carotenoid biosynthesis. Most reports refer [...] Read more.

Capsicum species produce fruits that synthesize and accumulate carotenoid pigments, which are responsible for the fruits’ yellow, orange and red colors. Chili peppers have been used as an experimental model for studying the biochemical and molecular aspects of carotenoid biosynthesis. Most reports refer to the characterization of carotenoids and content determination in chili pepper fruits from different species, cultivars, varieties or genotypes. The types and levels of carotenoids differ between different chili pepper fruits, and they are also influenced by environmental conditions. Yellow-orange colors of chili pepper fruits are mainly due to the accumulation of α- and β-carotene, zeaxanthin, lutein and β-cryptoxanthin. Carotenoids such as capsanthin, capsorubin and capsanthin-5,6-epoxide confer the red colors. Chromoplasts are the sites of carotenoid pigment synthesis and storage. According to the most accepted theory, the synthesis of carotenoids in chili peppers is controlled by three loci: c1, c2 and y. Several enzymes participating in carotenoid biosynthesis in chili pepper fruits have been isolated and characterized, and the corresponding gene sequences have been reported. However, there is currently limited information on the molecular mechanisms that regulate this biosynthetic pathway. Approaches to gain more knowledge of the regulation of carotenoid biosynthesis are discussed. Full article

(This article belongs to the Special Issue Molecular Research in Plant Secondary Metabolism)

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Open AccessReview

hnRNP A1: The Swiss Army Knife of Gene Expression

by Jacques Jean-Philippe, Sean Paz and Massimo Caputi

Int. J. Mol. Sci. 2013, 14(9), 18999-19024; https://doi.org/10.3390/ijms140918999 - 16 Sep 2013

Cited by 221 | Viewed by 18190

Abstract

Eukaryotic cells express a large variety of RNA binding proteins (RBPs), with diverse affinities and specificities towards target RNAs. These proteins play a crucial role in almost every aspect of RNA biogenesis, expression and function. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a complex [...] Read more.

Eukaryotic cells express a large variety of RNA binding proteins (RBPs), with diverse affinities and specificities towards target RNAs. These proteins play a crucial role in almost every aspect of RNA biogenesis, expression and function. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a complex and diverse family of RNA binding proteins. hnRNPs display multiple functions in the processing of heterogeneous nuclear RNAs into mature messenger RNAs. hnRNP A1 is one of the most abundant and ubiquitously expressed members of this protein family. hnRNP A1 plays multiple roles in gene expression by regulating major steps in the processing of nascent RNA transcripts. The transcription, splicing, stability, export through nuclear pores and translation of cellular and viral transcripts are all mechanisms modulated by this protein. The diverse functions played by hnRNP A1 are not limited to mRNA biogenesis, but extend to the processing of microRNAs, telomere maintenance and the regulation of transcription factor activity. Genomic approaches have recently uncovered the extent of hnRNP A1 roles in the development and differentiation of living organisms. The aim of this review is to highlight recent developments in the study of this protein and to describe its functions in cellular and viral gene expression and its role in human pathologies. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Open AccessShort Note

Minor Role of Mitochondrial Respiration for Fatty-Acid Induced Insulin Secretion

by Nadja Schulz, Oliver Kluth, Martin Jastroch and Annette Schürmann

Int. J. Mol. Sci. 2013, 14(9), 18989-18998; https://doi.org/10.3390/ijms140918989 - 16 Sep 2013

Cited by 14 | Viewed by 7816

Abstract

An appropriate insulin secretion by pancreatic beta-cells is necessary to maintain glucose homeostasis. A rise in plasma glucose leads to increased metabolism and an elevated cytoplasmic ATP/ADP ratio that finally triggers insulin granule exocytosis. In addition to this triggering pathway, one or more [...] Read more.

An appropriate insulin secretion by pancreatic beta-cells is necessary to maintain glucose homeostasis. A rise in plasma glucose leads to increased metabolism and an elevated cytoplasmic ATP/ADP ratio that finally triggers insulin granule exocytosis. In addition to this triggering pathway, one or more amplifying pathways—activated by amino acids or fatty acid—enhance secretion by promoting insulin granule recruitment to, and priming at, the plasma membrane. The aim of this study was to clarify the impact of the mitochondrial respiratory activity on fatty acid-induced insulin secretion that was assessed by an extracellular flux analyzer. Treatment of isolated mouse islets with glucose (20 mM) increased insulin secretion 18-fold and correlated with ATP-synthesizing respiration. Furthermore, oxygen consumption rate (OCR) significantly increased by 62% in response to glucose, whereas the addition of palmitate resulted only in a minor increase of OCR at both 2.8 mM (11%) and 20 mM glucose (21%). The addition of palmitate showed a pronounced increase of coupling efficiency (CE) at 2.8 mM glucose but no further insulin secretion. However, treatment with palmitate at 20 mM glucose increased insulin secretion about 32-fold accompanied by a small increase in CE. Thus, fatty acid induced respiration has a minor impact on insulin secretion. Our data clearly demonstrate that fatty acids in contrast to glucose play a minor role for respiration-mediated insulin secretion. In the presence of high glucose, fatty acids contribute partially to amplifying pathways of insulin secretion by further increasing mitochondrial activity in the islets of Langerhans. Full article

(This article belongs to the Section Molecular Recognition)

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Open AccessArticle

A Polymorphism at the 3'-UTR Region of the Aromatase Gene Is Associated with the Efficacy of the Aromatase Inhibitor, Anastrozole, in Metastatic Breast Carcinoma

by Lei Liu, Yu-Xian Bai, Jian-Hua Zhou, Xiu-Wei Sun, Hong Sui, Wen-Jie Zhang, Heng-Heng Yuan, Rui Xie, Xiao-Li Wei, Ting-Ting Zhang, Peng Huang, Yan-Jing Li, Jing-Xuan Wang, Shu Zhao and Qing-Yuan Zhang

Int. J. Mol. Sci. 2013, 14(9), 18973-18988; https://doi.org/10.3390/ijms140918973 - 13 Sep 2013

Cited by 31 | Viewed by 7208

Abstract

Estrogen-related genes and the fat mass and obesity-associated (FTO) gene play a critical role in estrogen metabolism, and those polymorphisms are associated with a poor prognosis in breast cancer. However, little is known about the association between these polymorphisms and the [...] Read more.

Estrogen-related genes and the fat mass and obesity-associated (FTO) gene play a critical role in estrogen metabolism, and those polymorphisms are associated with a poor prognosis in breast cancer. However, little is known about the association between these polymorphisms and the efficacy of anastrozole. The aim was to investigate the impact of the genetic polymorphisms, CYP19A1, 17-β-HSD-1 and FTO, on the response to anastrozole in metastatic breast carcinoma (MBC) and to evaluate the impact of those polymorphisms on various clinicopathologic features. Two-hundred seventy-two women with hormone receptor-positive MBC treated with anastrozole were identified retrospectively. DNA was extracted from peripheral blood and genotyped for five variants in three candidate genes. Time to progression was improved in patients carrying the variant alleles of rs4646 when compared to patients with the wild-type allele (16.40 months versus 13.52 months; p = 0.049). The rs4646 variant alleles were significantly associated with longer overall survival (37.3 months versus 31.6 months; p = 0.007). This relationship was not observed with the rs10046, rs2830, rs9926298 and rs9939609 polymorphisms. The findings of this study indicate that rs4646 polymorphism in the CYP19A1 gene may serve as a prognostic maker of the response to anastrozole in patients with MBC who are treated with anastrozole. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Emulsifying Activity and Stability of a Non-Toxic Bioemulsifier Synthesized by Microbacterium sp. MC3B-10

by Juan Carlos Camacho-Chab, Jean Guézennec, Manuel Jesús Chan-Bacab, Elvira Ríos-Leal, Corinne Sinquin, Raquel Muñiz-Salazar, Susana Del C. De la Rosa-García, Manuela Reyes-Estebanez and Benjamín Otto Ortega-Morales

Int. J. Mol. Sci. 2013, 14(9), 18959-18972; https://doi.org/10.3390/ijms140918959 - 13 Sep 2013

Cited by 54 | Viewed by 9663

Abstract

A previously reported bacterial bioemulsifier, here termed microbactan, was further analyzed to characterize its lipid component, molecular weight, ionic character and toxicity, along with its bioemulsifying potential for hydrophobic substrates at a range of temperatures, salinities and pH values. Analyses showed that microbactan [...] Read more.

A previously reported bacterial bioemulsifier, here termed microbactan, was further analyzed to characterize its lipid component, molecular weight, ionic character and toxicity, along with its bioemulsifying potential for hydrophobic substrates at a range of temperatures, salinities and pH values. Analyses showed that microbactan is a high molecular weight (700 kDa), non-ionic molecule. Gas chromatography of the lipid fraction revealed the presence of palmitic, stearic, and oleic acids; thus microbactan may be considered a glycolipoprotein. Microbactan emulsified aromatic hydrocarbons and oils to various extents; the highest emulsification index was recorded against motor oil (96%). The stability of the microbactan-motor oil emulsion model reached its highest level (94%) at 50 °C, pH 10 and 3.5% NaCl content. It was not toxic to Artemia salina nauplii. Microbactan is, therefore, a non-toxic and non-ionic bioemulsifier of high molecular weight with affinity for a range of oily substrates. Comparative phylogenetic assessment of the 16S rDNA gene of Microbacterium sp. MC3B-10 with genes derived from other marine Microbacterium species suggested that this genus is well represented in coastal zones. The chemical nature and stability of the bioemulsifier suggest its potential application in bioremediation of marine environments and in cosmetics. Full article

(This article belongs to the Special Issue Biofilms: Extracellular Bastions of Bacteria)

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Open AccessReview

The Clinical Utilization of Circulating Cell Free DNA (CCFDNA) in Blood of Cancer Patients

by Yahya I. Elshimali, Husseina Khaddour, Marianna Sarkissyan, Yanyuan Wu and Jaydutt V. Vadgama

Int. J. Mol. Sci. 2013, 14(9), 18925-18958; https://doi.org/10.3390/ijms140918925 - 13 Sep 2013

Cited by 200 | Viewed by 16846

Abstract

Qualitative and quantitative testing of circulating cell free DNA (CCFDNA) can be applied for the management of malignant and benign neoplasms. Detecting circulating DNA in cancer patients may help develop a DNA profile for early stage diagnosis in malignancies. The technical issues of [...] Read more.

Qualitative and quantitative testing of circulating cell free DNA (CCFDNA) can be applied for the management of malignant and benign neoplasms. Detecting circulating DNA in cancer patients may help develop a DNA profile for early stage diagnosis in malignancies. The technical issues of obtaining, using, and analyzing CCFDNA from blood will be discussed. Full article

(This article belongs to the Special Issue Advances in Cancer Diagnosis)

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Open AccessReview

Potential of the Angiotensin Receptor Blockers (ARBs) Telmisartan, Irbesartan, and Candesartan for Inhibiting the HMGB1/RAGE Axis in Prevention and Acute Treatment of Stroke

by Kiyoshi Kikuchi, Salunya Tancharoen, Takashi Ito, Yoko Morimoto-Yamashita, Naoki Miura, Ko-ichi Kawahara, Ikuro Maruyama, Yoshinaka Murai and Eiichiro Tanaka

Int. J. Mol. Sci. 2013, 14(9), 18899-18924; https://doi.org/10.3390/ijms140918899 - 13 Sep 2013

Cited by 44 | Viewed by 11349 | Correction

Abstract

Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), telmisartan, [...] Read more.

Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), telmisartan, irbesartan and candesartan, inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is one of the pleiotropic effects of these drugs. High mobility group box 1 (HMGB1) is the ligand of RAGE, and has been recently identified as a lethal mediator of severe sepsis. HMGB1 is an intracellular protein, which acts as an inflammatory cytokine when released into the extracellular milieu. Extracellular HMGB1 causes multiple organ failure and contributes to the pathogenesis of hypertension, hyperlipidemia, diabetes mellitus, atherosclerosis, thrombosis, and stroke. This is the first review of the literature evaluating the potential of three ARBs for the HMGB1-RAGE axis on stroke therapy, including prevention and acute treatment. This review covers clinical and experimental studies conducted between 1976 and 2013. We propose that ARBs, which inhibit the HMGB1/RAGE axis, may offer a novel option for prevention and acute treatment of stroke. However, additional clinical studies are necessary to verify the efficacy of ARBs. Full article

(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)

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Open AccessArticle

Spectroscopic Studies of Model Photo-Receptors: Validation of a Nanosecond Time-Resolved Micro-Spectrophotometer Design Using Photoactive Yellow Protein and α-Phycoerythrocyanin

by Namrta Purwar, Jason Tenboer, Shailesh Tripathi and Marius Schmidt

Int. J. Mol. Sci. 2013, 14(9), 18881-18898; https://doi.org/10.3390/ijms140918881 - 13 Sep 2013

Cited by 8 | Viewed by 7409

Abstract

Time-resolved spectroscopic experiments have been performed with protein in solution and in crystalline form using a newly designed microspectrophotometer. The time-resolution of these experiments can be as good as two nanoseconds (ns), which is the minimal response time of the image intensifier used. [...] Read more.

Time-resolved spectroscopic experiments have been performed with protein in solution and in crystalline form using a newly designed microspectrophotometer. The time-resolution of these experiments can be as good as two nanoseconds (ns), which is the minimal response time of the image intensifier used. With the current setup, the effective time-resolution is about seven ns, determined mainly by the pulse duration of the nanosecond laser. The amount of protein required is small, on the order of 100 nanograms. Bleaching, which is an undesirable effect common to photoreceptor proteins, is minimized by using a millisecond shutter to avoid extensive exposure to the probing light. We investigate two model photoreceptors, photoactive yellow protein (PYP), and α-phycoerythrocyanin (α-PEC), on different time scales and at different temperatures. Relaxation times obtained from kinetic time-series of difference absorption spectra collected from PYP are consistent with previous results. The comparison with these results validates the capability of this spectrophotometer to deliver high quality time-resolved absorption spectra. Full article

(This article belongs to the Special Issue Frontiers of Micro-Spectroscopy in Biological Applications)

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Graphical abstract

1376 KiB

Open AccessArticle

Oleic Acid Increases Synthesis and Secretion of VEGF in Rat Vascular Smooth Muscle Cells: Role of Oxidative Stress and Impairment in Obesity

by Gabriella Doronzo, Michela Viretto, Cristina Barale, Isabella Russo, Luigi Mattiello, Giovanni Anfossi and Mariella Trovati

Int. J. Mol. Sci. 2013, 14(9), 18861-18880; https://doi.org/10.3390/ijms140918861 - 13 Sep 2013

Cited by 13 | Viewed by 8287

Abstract

Obesity is characterized by poor collateral vessel formation, a process involving vascular endothelial growth factor (VEGF) action on vascular smooth muscle cells (VSMC). Free fatty acids are involved in the pathogenesis of obesity vascular complications, and we have aimed to clarify whether oleic [...] Read more.

Obesity is characterized by poor collateral vessel formation, a process involving vascular endothelial growth factor (VEGF) action on vascular smooth muscle cells (VSMC). Free fatty acids are involved in the pathogenesis of obesity vascular complications, and we have aimed to clarify whether oleic acid (OA) enhances VEGF synthesis/secretion in VSMC, and whether this effect is impaired in obesity. In cultured aortic VSMC from lean and obese Zucker rats (LZR and OZR, respectively) we measured the influence of OA on VEGF-A synthesis/secretion, signaling molecules and reactive oxygen species (ROS). In VSMC from LZR we found the following: (a) OA increases VEGF-A synthesis/secretion by a mechanism blunted by inhibitors of Akt, mTOR, ERK-1/2, PKC-beta, NADPH-oxidase and mitochondrial electron transport chain complex; (b) OA activates the above mentioned signaling pathways and increases ROS; (c) OA-induced activation of PKC-beta enhances oxidative stress, which activates signaling pathways responsible for the increased VEGF synthesis/secretion. In VSMC from OZR, which present enhanced baseline oxidative stress, the above mentioned actions of OA on VEGF-A, signaling pathways and ROS are impaired: this impairment is reproduced in VSMC from LZR by incubation with hydrogen peroxide. Thus, in OZR chronically elevated oxidative stress causes a resistance to the action on VEGF that OA exerts in LZR by increasing ROS. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)

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Open AccessArticle

A Facile and Efficient Synthesis of Diaryl Amines or Ethers under Microwave Irradiation at Presence of KF/Al₂O₃ without Solvent and Their Anti-Fungal Biological Activities against Six Phytopathogens

by Liang-Zhu Huang, Pan Han, You-Qiang Li, Ying-Meng Xu, Tao Zhang and Zhen-Ting Du

Int. J. Mol. Sci. 2013, 14(9), 18850-18860; https://doi.org/10.3390/ijms140918850 - 12 Sep 2013

Cited by 14 | Viewed by 7582

Abstract

A series of diaryl amines, ethers and thioethers were synthesized under microwave irradiation efficiently at presence of KF/Al₂O₃ in 83%–96% yields without any solvent. The salient characters of this method lie in short reaction time, high yields, general applicability to [...] Read more.

A series of diaryl amines, ethers and thioethers were synthesized under microwave irradiation efficiently at presence of KF/Al₂O₃ in 83%–96% yields without any solvent. The salient characters of this method lie in short reaction time, high yields, general applicability to substrates and simple workup procedure. At the same time, their antifungal biological activities against six phytopathogen were evaluated. Most of the compounds (3b, 3c, 3g–o) are more potent than thiophannate-methyl against to Magnaporthe oryzae. This implies that diaryl amine or ether moiety may be helpful in finding a fungicide against Magnaporthe oryzae. Full article

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Open AccessReview

ARID1A Mutations and PI3K/AKT Pathway Alterations in Endometriosis and Endometriosis-Associated Ovarian Carcinomas

by Eleftherios P. Samartzis, Aurelia Noske, Konstantin J. Dedes, Daniel Fink and Patrick Imesch

Int. J. Mol. Sci. 2013, 14(9), 18824-18849; https://doi.org/10.3390/ijms140918824 - 12 Sep 2013

Cited by 133 | Viewed by 15313

Abstract

Endometriosis is a common gynecological disease affecting 6%–10% of women of reproductive age and is characterized by the presence of endometrial-like tissue in localizations outside of the uterine cavity as, e.g., endometriotic ovarian cysts. Mainly, two epithelial ovarian carcinoma subtypes, the ovarian clear [...] Read more.

Endometriosis is a common gynecological disease affecting 6%–10% of women of reproductive age and is characterized by the presence of endometrial-like tissue in localizations outside of the uterine cavity as, e.g., endometriotic ovarian cysts. Mainly, two epithelial ovarian carcinoma subtypes, the ovarian clear cell carcinomas (OCCC) and the endometrioid ovarian carcinomas (EnOC), have been molecularly and epidemiologically linked to endometriosis. Mutations in the gene encoding the AT-rich interacting domain containing protein 1A (ARID1A) have been found to occur in high frequency in OCCC and EnOC. The majority of these mutations lead to a loss of expression of the ARID1A protein, which is a subunit of the SWI/SNF chromatin remodeling complex and considered as a bona fide tumor suppressor. ARID1A mutations frequently co-occur with mutations, leading to an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, such as mutations in PIK3CA encoding the catalytic subunit, p110α, of PI3K. In combination with recent functional observations, these findings strongly suggest cooperating mechanisms between the two pathways. The occurrence of ARID1A mutations and alterations in the PI3K/AKT pathway in endometriosis and endometriosis-associated ovarian carcinomas, as well as the possible functional and clinical implications are discussed in this review. Full article

(This article belongs to the Special Issue Genes and Pathways in the Pathogenesis of Ovarian Cancer)

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Open AccessArticle

Synthesis and Thermotropic Studies of a New Series of Teraryl Liquid Crystals 2-(4'-Alkoxybiphen-4-yl)-5-Cyanopyridines

by Win-Long Chia and Xue-Ming Lin

Int. J. Mol. Sci. 2013, 14(9), 18809-18823; https://doi.org/10.3390/ijms140918809 - 12 Sep 2013

Cited by 8 | Viewed by 6282

Abstract

A new series of teraryl 2-(4'-alkoxybiphen-4-yl)-5-cyanopyridines (nO-PPPyCN, n = 2–8) compounds, bearing a cyanopyridine terminus, were synthesized using a short 2-step reaction with overall yields between 33% and 69%. Spectral analyses were in accord with the expected structures. Thermotropic behavior of [...] Read more.

A new series of teraryl 2-(4'-alkoxybiphen-4-yl)-5-cyanopyridines (nO-PPPyCN, n = 2–8) compounds, bearing a cyanopyridine terminus, were synthesized using a short 2-step reaction with overall yields between 33% and 69%. Spectral analyses were in accord with the expected structures. Thermotropic behavior of the teraryl compounds was investigated using polarised optical microscopy and differential scanning calorimetry. All compounds exhibited both enantiotropic nematic and smectic A phases, with an additional enantiotropic smectic C phase when n = 7 and 8. Polymesomorphism appears to be a common behavior in this series of linear liquid crystal compounds. Full article

(This article belongs to the Special Issue Experimental and Theoretical Studies of Liquid Crystalline Materials: Where Do We Stand after 120 Years?)

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Open AccessReview

Long Non-Coding RNAs and Complex Human Diseases

by Jing Li, Zhenyu Xuan and Changning Liu

Int. J. Mol. Sci. 2013, 14(9), 18790-18808; https://doi.org/10.3390/ijms140918790 - 12 Sep 2013

Cited by 172 | Viewed by 12926

Abstract

Long non-coding RNAs (lncRNAs) are a heterogeneous class of RNAs that are generally defined as non-protein-coding transcripts longer than 200 nucleotides. Recently, an increasing number of studies have shown that lncRNAs can be involved in various critical biological processes, such as chromatin remodeling, [...] Read more.

Long non-coding RNAs (lncRNAs) are a heterogeneous class of RNAs that are generally defined as non-protein-coding transcripts longer than 200 nucleotides. Recently, an increasing number of studies have shown that lncRNAs can be involved in various critical biological processes, such as chromatin remodeling, gene transcription, and protein transport and trafficking. Moreover, lncRNAs are dysregulated in a number of complex human diseases, including coronary artery diseases, autoimmune diseases, neurological disorders, and various cancers, which indicates their important roles in these diseases. Here, we reviewed the current understanding of lncRNAs, including their definition and subclassification, regulatory functions, and potential roles in different types of complex human diseases. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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Int. J. Mol. Sci., Volume 14, Issue 9 (September 2013) – 111 articles , Pages 17238-19360

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