International Journal of Molecular Sciences

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Open AccessReview

Environmental Stimuli Shape Biofilm Formation and the Virulence of Periodontal Pathogens

by Marja T. Pöllänen, Annamari Paino and Riikka Ihalin

Int. J. Mol. Sci. 2013, 14(8), 17221-17237; https://doi.org/10.3390/ijms140817221 - 20 Aug 2013

Cited by 28 | Viewed by 9363

Periodontitis is a common inflammatory disease affecting the tooth-supporting structures. It is initiated by bacteria growing as a biofilm at the gingival margin, and communication of the biofilms differs in health and disease. The bacterial composition of periodontitis-associated biofilms has been well documented [...] Read more.

Periodontitis is a common inflammatory disease affecting the tooth-supporting structures. It is initiated by bacteria growing as a biofilm at the gingival margin, and communication of the biofilms differs in health and disease. The bacterial composition of periodontitis-associated biofilms has been well documented and is under continual investigation. However, the roles of several host response and inflammation driven environmental stimuli on biofilm formation is not well understood. This review article addresses the effects of environmental factors such as pH, temperature, cytokines, hormones, and oxidative stress on periodontal biofilm formation and bacterial virulence. Full article

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

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Open AccessReview

Post-Transcriptional Controls by Ribonucleoprotein Complexes in the Acquisition of Drug Resistance

by Hoin Kang, Chongtae Kim, Heejin Lee, Wook Kim and Eun Kyung Lee

Int. J. Mol. Sci. 2013, 14(8), 17204-17220; https://doi.org/10.3390/ijms140817204 - 20 Aug 2013

Cited by 19 | Viewed by 7936

Abstract

Acquisition of drug resistance leads to failure of anti-cancer treatments and therapies. Although several successive chemotherapies are available, along with efforts towards clinical applications of new anti-cancer drugs, it is generally realized that there is a long way to go to treat cancers. [...] Read more.

Acquisition of drug resistance leads to failure of anti-cancer treatments and therapies. Although several successive chemotherapies are available, along with efforts towards clinical applications of new anti-cancer drugs, it is generally realized that there is a long way to go to treat cancers. Resistance to anti-cancer drugs results from various factors, including genetic as well as epigenetic differences in tumors. Determining the molecular and cellular mechanisms responsible for the acquisition of drug resistance may be a helpful approach for the development of new therapeutic strategies to overcome treatment failure. Several studies have shown that the acquisition of drug resistance is tightly regulated by post-transcriptional regulators such as RNA binding proteins (RBPs) and microRNAs (miRNAs), which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, epithelial-mesenchymal transition, and drug metabolism. Here, we review our current understanding of ribonucleoprotein complexes, including RBPs and miRNAs, which play critical roles in the acquisition of drug resistance and have potential clinical implications for cancer. Full article

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

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Open AccessArticle

Design, Synthesis and Antiviral Activity Studies of Schizonepetin Derivatives

by Beihua Bao, Zheng Meng, Nianguang Li, Zhengjie Meng, Li Zhang, Yudan Cao, Weifeng Yao, Mingqiu Shan and Anwei Ding

Int. J. Mol. Sci. 2013, 14(8), 17193-17203; https://doi.org/10.3390/ijms140817193 - 20 Aug 2013

Cited by 2 | Viewed by 6112

Abstract

A series of schizonepetin derivatives have been designed and synthesized in order to obtain potent antivirus agents. The antiviral activity against HSV-1 and influenza virus H3N2 as well as the cytotoxicity of these derivatives was evaluated by using cytopathic effect (CPE) inhibition assay [...] Read more.

A series of schizonepetin derivatives have been designed and synthesized in order to obtain potent antivirus agents. The antiviral activity against HSV-1 and influenza virus H3N2 as well as the cytotoxicity of these derivatives was evaluated by using cytopathic effect (CPE) inhibition assay in vitro. Compounds M2, M4, M5 and M34 showed higher inhibitory activity against HSV-1 virus with the TC₅₀ values being in micromole. Compounds M28, M33, and M35 showed higher inhibitory activity against influenza virus H3N2 with their TC₅₀ values being 96.4, 71.0 and 75.4 μM, respectively. Preliminary biological activity evaluation indicated that the anti-H3N2 and anti-HSV-1 activities improved obviously through the introduction of halogen into the structure of schizonepetin. Full article

(This article belongs to the Section Biochemistry)

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Open AccessReview

Preventive or Potential Therapeutic Value of Nutraceuticals against Ionizing Radiation-Induced Oxidative Stress in Exposed Subjects and Frequent Fliers

by Maria Teresa Giardi, Eleftherios Touloupakis, Delfina Bertolotto and Gabriele Mascetti

Int. J. Mol. Sci. 2013, 14(8), 17168-17192; https://doi.org/10.3390/ijms140817168 - 20 Aug 2013

Cited by 26 | Viewed by 8805

Abstract

Humans are constantly exposed to ionizing radiation deriving from outer space sources or activities related to medical care. Absorption of ionizing radiation doses over a prolonged period of time can result in oxidative damage and cellular dysfunction inducing several diseases, especially in ageing [...] Read more.

Humans are constantly exposed to ionizing radiation deriving from outer space sources or activities related to medical care. Absorption of ionizing radiation doses over a prolonged period of time can result in oxidative damage and cellular dysfunction inducing several diseases, especially in ageing subjects. In this report, we analyze the effects of ionizing radiation, particularly at low doses, in relation to a variety of human pathologies, including cancer, and cardiovascular and retinal diseases. We discuss scientific data in support of protection strategies by safe antioxidant formulations that can provide preventive or potential therapeutic value in response to long-term diseases that may develop following exposure. Full article

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

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Open AccessReview

Molecular Interactions in the Development of Brain Metastases

by Nina Martinez, Adrienne Boire and Lisa M. DeAngelis

Int. J. Mol. Sci. 2013, 14(8), 17157-17167; https://doi.org/10.3390/ijms140817157 - 20 Aug 2013

Cited by 11 | Viewed by 5998

Abstract

Brain metastases are a much-feared complication of cancer. The development of brain metastases requires a malignant cell to acquire characteristics that facilitate dissemination away from the primary site, entrance into the nervous system, and establishment in the brain. This review summarizes recent work [...] Read more.

Brain metastases are a much-feared complication of cancer. The development of brain metastases requires a malignant cell to acquire characteristics that facilitate dissemination away from the primary site, entrance into the nervous system, and establishment in the brain. This review summarizes recent work focused on the molecular derangements leading to brain metastases and outlines areas in need of greater understanding. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Cucurbitacin E as Inducer of Cell Death and Apoptosis in Human Oral Squamous Cell Carcinoma Cell Line SAS

by Chao-Ming Hung, Chi-Chang Chang, Chen-Wei Lin, Shun-Yao Ko and Yi-Chiang Hsu

Int. J. Mol. Sci. 2013, 14(8), 17147-17156; https://doi.org/10.3390/ijms140817147 - 20 Aug 2013

Cited by 34 | Viewed by 7345

Abstract

Human oral squamous cell carcinoma (OSCC) is a common form of malignant cancer, for which radiotherapy or chemotherapy are the main treatment methods. Cucurbitacin E (CuE) is a natural compound previously shown to be an antifeedant as well as a potent chemopreventive agent [...] Read more.

Human oral squamous cell carcinoma (OSCC) is a common form of malignant cancer, for which radiotherapy or chemotherapy are the main treatment methods. Cucurbitacin E (CuE) is a natural compound previously shown to be an antifeedant as well as a potent chemopreventive agent against several types of cancer. The present study investigates anti-proliferation (using MTT assay, CuE demonstrated cytotoxic activity against SAS cell with IC₅₀ values at 3.69 µM) and induced apoptosis of human oral squamous cell carcinoma SAS cells after 24 h treatment with CuE. Mitochondrial membrane potential (MMP) and caspase activity were studied and our results indicate that CuE inhibits cell proliferation as well as the activation of apoptois in SAS cells. Both effects increased in proportion to the dosage of CuE and apoptosis was induced via mitochondria- and caspase-dependent pathways. CuE can induce cell death by a mechanism that is not dependent on apoptosis induction, and thus represents a promising anticancer agent for prevention and treatment of OSCC. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Homoserine Lactones Influence the Reaction of Plants to Rhizobia

by Azhar A. Zarkani, Elke Stein, Christian R. Röhrich, Marek Schikora, Elena Evguenieva-Hackenberg, Thomas Degenkolb, Andreas Vilcinskas, Gabriele Klug, Karl-Heinz Kogel and Adam Schikora

Int. J. Mol. Sci. 2013, 14(8), 17122-17146; https://doi.org/10.3390/ijms140817122 - 20 Aug 2013

Cited by 69 | Viewed by 10690

Abstract

Bacterial quorum sensing molecules not only grant the communication within bacterial communities, but also influence eukaryotic hosts. N-acyl-homoserine lactones (AHLs) produced by pathogenic or beneficial bacteria were shown to induce diverse reactions in animals and plants. In plants, the reaction to AHLs [...] Read more.

Bacterial quorum sensing molecules not only grant the communication within bacterial communities, but also influence eukaryotic hosts. N-acyl-homoserine lactones (AHLs) produced by pathogenic or beneficial bacteria were shown to induce diverse reactions in animals and plants. In plants, the reaction to AHLs depends on the length of the lipid side chain. Here we investigated the impact of two bacteria on Arabidopsis thaliana, which usually enter a close symbiosis with plants from the Fabaceae (legumes) family and produce a long-chain AHL (Sinorhizobium meliloti) or a short-chain AHL (Rhizobium etli). We demonstrate that, similarly to the reaction to pure AHL molecules, the impact, which the inoculation with rhizosphere bacteria has on plants, depends on the type of the produced AHL. The inoculation with oxo-C14-HSL-producing S. meliloti strains enhanced plant resistance towards pathogenic bacteria, whereas the inoculation with an AttM lactonase-expressing S. meliloti strain did not. Inoculation with the oxo-C8-HSL-producing R. etli had no impact on the resistance, which is in agreement with our previous hypothesis. In addition, plants seem to influence the availability of AHLs in the rhizosphere. Taken together, this report provides new insights in the role of N-acyl-homoserine lactones in the inter-kingdom communication at the root surface. Full article

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

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Open AccessReview

NF90 in Posttranscriptional Gene Regulation and MicroRNA Biogenesis

by Kiyoshi Masuda, Yuki Kuwano, Kensei Nishida, Kazuhito Rokutan and Issei Imoto

Int. J. Mol. Sci. 2013, 14(8), 17111-17121; https://doi.org/10.3390/ijms140817111 - 19 Aug 2013

Cited by 37 | Viewed by 9414

Abstract

Gene expression patterns are effectively regulated by turnover and translation regulatory (TTR) RNA-binding proteins (RBPs). The TTR-RBPs control gene expression at posttranscriptional levels, such as pre-mRNA splicing, mRNA cytoplasmic export, turnover, storage, and translation. Double-stranded RNA binding proteins (DSRBPs) are known to regulate [...] Read more.

Gene expression patterns are effectively regulated by turnover and translation regulatory (TTR) RNA-binding proteins (RBPs). The TTR-RBPs control gene expression at posttranscriptional levels, such as pre-mRNA splicing, mRNA cytoplasmic export, turnover, storage, and translation. Double-stranded RNA binding proteins (DSRBPs) are known to regulate many processes of cellular metabolism, including transcriptional control, translational control, mRNA processing and localization. Nuclear factor 90 (NF90), one of the DSRBPs, is abundantly expressed in vertebrate tissue and participates in many aspects of RNA metabolism. NF90 was originally purified as a component of a DNA binding complex which binds to the antigen recognition response element 2 in the interleukin 2 promoter. Recent studies have provided us with interesting insights into its possible physiological roles in RNA metabolism, including transcription, degradation, and translation. In addition, it was shown that NF90 regulates microRNA expression. In this review, we try to focus on the function of NF90 in posttranscriptional gene regulation and microRNA biogenesis. Full article

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

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Open AccessReview

Non-Coding RNAs and Cancer

by Federica Calore, Francesca Lovat and Michela Garofalo

Int. J. Mol. Sci. 2013, 14(8), 17085-17110; https://doi.org/10.3390/ijms140817085 - 19 Aug 2013

Cited by 48 | Viewed by 12047

Abstract

The discovery of the biological relevance of non-coding RNA (ncRNAs) molecules represents one of the most significant advances in contemporary molecular biology. Expression profiling of human tumors, based on the expression of miRNAs and other short or long ncRNAs, has identified signatures associated [...] Read more.

The discovery of the biological relevance of non-coding RNA (ncRNAs) molecules represents one of the most significant advances in contemporary molecular biology. Expression profiling of human tumors, based on the expression of miRNAs and other short or long ncRNAs, has identified signatures associated with diagnosis, staging, progression, prognosis, and response to treatment. In this review we will discuss the recent remarkable advancement in the understanding the biological functions of human ncRNAs in cancer, the mechanisms of expression and the therapeutic potential. Full article

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

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Open AccessArticle

Effects of Reduced Prolamin on Seed Storage Protein Composition and the Nutritional Quality of Rice

by Hyun-Jung Kim, Jong-Yeol Lee, Ung-Han Yoon, Sun-Hyung Lim and Young-Mi Kim

Int. J. Mol. Sci. 2013, 14(8), 17073-17084; https://doi.org/10.3390/ijms140817073 - 19 Aug 2013

Cited by 28 | Viewed by 9441

Abstract

Rice seed storage proteins accumulate in two types of protein body (PB-I and PB-II) that are nutrient sources for animals. PB-I is indigestible and negatively affects rice protein quality. To improve the nutritional value of rice seeds we are aiming to engineer the [...] Read more.

Rice seed storage proteins accumulate in two types of protein body (PB-I and PB-II) that are nutrient sources for animals. PB-I is indigestible and negatively affects rice protein quality. To improve the nutritional value of rice seeds we are aiming to engineer the composition and accumulation of endogenous seed storage proteins. In this study we generated transgenic rice plants in which 13 kD prolamin genes were suppressed by RNA interference (13 kD pro-RNAi). Analysis based on qRT-PCR confirmed that the targeted 13 kD prolamins were markedly suppressed, and were compensated for by an increase in other storage proteins including 10 kD prolamin, glutelins, and chaperone proteins. The storage protein profiles further revealed that the levels of 13 kD prolamins were significantly reduced, while that of the glutelin precursor was slightly increased and the remaining storage proteins did not change. Amino acid analysis showed that the reduction of 13 kD prolamins resulted in a 28% increase in the lysine content relative to the wild type, indicating that the 13 kD pro-RNAi rice seeds are more nutritious. Furthermore, a reduction in the levels of 13 kD prolamins resulted in abnormal formation of PB-I, which was small and had no lamellar structure. These results suggest that alteration of prolamins can contribute to improving the nutritional quality of rice. Full article

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Open AccessArticle

Molecular Cloning, Characterization and mRNA Expression of a Chitin Synthase 2 Gene from the Oriental Fruit Fly, Bactrocera dorsalis (Diptera: Tephritidae)

by Li Chen, Wen-Jia Yang, Lin Cong, Kang-Kang Xu and Jin-Jun Wang

Int. J. Mol. Sci. 2013, 14(8), 17055-17072; https://doi.org/10.3390/ijms140817055 - 19 Aug 2013

Cited by 17 | Viewed by 6938

Abstract

Chitin synthase (CHS), a potential target for eco-friendly insecticides, plays an essential role in chitin formation in insects. In this study, a full-length cDNA encoding chitin synthase 2 (BdCHS2) was cloned and characterized in the oriental fruit fly, Bactrocera dorsalis. [...] Read more.

Chitin synthase (CHS), a potential target for eco-friendly insecticides, plays an essential role in chitin formation in insects. In this study, a full-length cDNA encoding chitin synthase 2 (BdCHS2) was cloned and characterized in the oriental fruit fly, Bactrocera dorsalis. The BdCHS2 cDNA had 4417 nucleotides, containing an open reading frame of 4122 nucleotides, which encoded 1373 amino acid residues with a predicted molecular weight of 158.5 kDa. Phylogenetic analysis with other insect CHSs suggested that BdCHS2 belongs to insect CHS2. The BdCHS2 transcript was predominately found in midgut but was detected at low levels in fat body, Malpighian tubules, integument, and trachea. Moreover, BdCHS2 was expressed in all developmental stages, and highly expressed in the feeding stages. There was a positive relationship between BdCHS2 expression and total chitin content during development. Furthermore, both the gene expression and chitin content in midgut decreased when the insect was fed for 24 h, then starved for 24 h, while they increased dramatically and rapidly under the condition of starvation for 24 h then feeding for 24 h. These results suggest that BdCHS2 may play an important role in regulating chitin content of the midgut, and subsequently affect the growth and development of B. dorsalis. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

UVB-Stimulated TNFα Release from Human Melanocyte and Melanoma Cells Is Mediated by p38 MAPK

by Visalini Muthusamy and Terrence J. Piva

Int. J. Mol. Sci. 2013, 14(8), 17029-17054; https://doi.org/10.3390/ijms140817029 - 19 Aug 2013

Cited by 9 | Viewed by 7878

Abstract

Ultraviolet (UV) radiation activates cell signaling pathways in melanocytes. As a result of altered signaling pathways and UV-induced cellular damage, melanocytes can undergo oncogenesis and develop into melanomas. In this study, we investigated the effect of UV-radiation on p38 MAPK (mitogen-activated protein kinase), [...] Read more.

Ultraviolet (UV) radiation activates cell signaling pathways in melanocytes. As a result of altered signaling pathways and UV-induced cellular damage, melanocytes can undergo oncogenesis and develop into melanomas. In this study, we investigated the effect of UV-radiation on p38 MAPK (mitogen-activated protein kinase), JNK and NFκB pathways to determine which plays a major role in stimulating TNFα secretion in human HEM (melanocytes) and MM96L (melanoma) cells. MM96L cells exhibited 3.5-fold higher p38 activity than HEM cells at 5 min following UVA + B radiation and 1.6-fold higher JNK activity at 15–30 min following UVB+A radiation, while NFκB was minimally activated in both cells. Irradiated HEM cells had the greatest fold of TNFα secretion (UVB: 109-fold, UVA + B: 103-fold & UVB+A: 130-fold) when co-exposed to IL1α. The p38 inhibitor, SB202190, inhibited TNFα release by 93% from UVB-irradiated HEM cells. In the UVB-irradiated MM96L cells, both SB202190 and sulfasalazine (NFκB inhibitor) inhibited TNFα release by 52%. Although, anisomycin was a p38 MAPK activator, it inhibited TNFα release in UV-irradiated cells. This suggests that UV-mediated TNFα release may occur via different p38 pathway intermediates compared to those stimulated by anisomycin. As such, further studies into the functional role p38 MAPK plays in regulating TNFα release in UV-irradiated melanocyte-derived cells are warranted. Full article

(This article belongs to the Collection Radiation Toxicity in Cells)

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Open AccessArticle

Inhibition of NADPH Oxidase by Apocynin Attenuates Progression of Atherosclerosis

by Kara Kinkade, Jennifer Streeter and Francis J. Miller

Int. J. Mol. Sci. 2013, 14(8), 17017-17028; https://doi.org/10.3390/ijms140817017 - 19 Aug 2013

Cited by 48 | Viewed by 9064

Abstract

Of the multiple sources of reactive oxygen species (ROS) in the blood vessel, NADPH oxidases are the primary source. Whereas several studies have implicated NADPH oxidases in the initiation of atherosclerosis, their roles in disease progression are incompletely understood. Our objective was to [...] Read more.

Of the multiple sources of reactive oxygen species (ROS) in the blood vessel, NADPH oxidases are the primary source. Whereas several studies have implicated NADPH oxidases in the initiation of atherosclerosis, their roles in disease progression are incompletely understood. Our objective was to determine the potential clinical relevance of inhibiting NADPH oxidase in established atherosclerosis. Using a hypercholesteremic murine model of atherosclerosis (ApoE^−/−/LDLR^−/− (AS) mice on normal chow diet), we first established a time-dependent relationship between superoxide levels and lesion size in AS mice. Next, we identified NADPH oxidase as the primary source of ROS in atherosclerotic lesions. Treatment of aortic segments from AS mice with apocynin, which interferes with NADPH oxidase activation in part by preventing translocation of the subunit p47^phox, significantly reduced superoxide levels. Moreover, addition of apocynin to the drinking water of AS mice produced a decrease in lesion size as compared to untreated AS mice, with the effect most pronounced in the thoracoabdominal aorta but absent from the aortic arch. Granulocyte function in AS+apocynin mice was suppressed, confirming efficacy of apocynin treatment. We conclude that apocynin attenuates the progression of atherosclerosis in hypercholesterolemic mice, potentially by its ability to inhibit generation of superoxide by NADPH oxidase. Full article

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

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Open AccessArticle

Regulation of Huntingtin Gene Expression by miRNA-137, -214, -148a, and Their Respective isomiRs

by Emilia Kozlowska, Wlodzimierz J. Krzyzosiak and Edyta Koscianska

Int. J. Mol. Sci. 2013, 14(8), 16999-17016; https://doi.org/10.3390/ijms140816999 - 19 Aug 2013

Cited by 44 | Viewed by 10122

Abstract

With the advent of deep sequencing technology, a variety of miRNA length and sequence variants, termed isomiRNAs (isomiRs), have been discovered. However, the functional roles of these commonly detected isomiRs remain unknown. In this paper, we demonstrated that miRNAs regulate the expression of [...] Read more.

With the advent of deep sequencing technology, a variety of miRNA length and sequence variants, termed isomiRNAs (isomiRs), have been discovered. However, the functional roles of these commonly detected isomiRs remain unknown. In this paper, we demonstrated that miRNAs regulate the expression of the HTT gene, whose mutation leads to Huntington’s disease (HD), a hereditary degenerative disorder. Specifically, we validated the interactions of canonical miRNAs, miR-137, miR-214, and miR-148a, with the HTT 3'UTR using a luciferase assay. Moreover, we applied synthetic miRNA mimics to examine whether a slight shifting of miRNA seed regions might alter the regulation of the HTT transcript. We also examined miR-137, miR-214, and miR-148a isomiRs and showed the activity of these isoforms on reporter constructs bearing appropriate sequences from the HTT 3'UTR. Hence, we demonstrated that certain 5'-end variants of miRNAs might be functional for the regulation of the same targets as canonical miRNAs. Full article

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

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Open AccessArticle

Decreased Expression of Alpha-L-Fucosidase Gene FUCA1 in Human Colorectal Tumors

by Olalla Otero-Estévez, Mónica Martínez-Fernández, Lorena Vázquez-Iglesias, María Páez de la Cadena, Francisco J. Rodríguez-Berrocal and Vicenta S. Martínez-Zorzano

Int. J. Mol. Sci. 2013, 14(8), 16986-16998; https://doi.org/10.3390/ijms140816986 - 19 Aug 2013

Cited by 26 | Viewed by 8649

Abstract

In previous studies we described a decreased alpha-L-fucosidase activity in colorectal tumors, appearing as a prognostic factor of tumoral recurrence. The aim of this work was to extend the knowledge about tissue alpha-L-fucosidase in colorectal cancer by quantifying the expression of its encoding [...] Read more.

In previous studies we described a decreased alpha-L-fucosidase activity in colorectal tumors, appearing as a prognostic factor of tumoral recurrence. The aim of this work was to extend the knowledge about tissue alpha-L-fucosidase in colorectal cancer by quantifying the expression of its encoding gene FUCA1 in tumors and healthy mucosa. FUCA1 mRNA levels were measured by RT-qPCR in paired tumor and normal mucosa tissues from 31 patients. For the accuracy of the RT-qPCR results, five candidate reference genes were validated in those samples. In addition, activity and expression of alpha-L-fucosidase in selected matched tumor and healthy mucosa samples were analyzed. According to geNorm and NormFinder algorithms, RPLP0 and HPRT1 were the best reference genes in colorectal tissues. These genes were used for normalization of FUCA1 expression levels. A significant decrease of more than 60% in normalized FUCA1 expression was detected in tumors compared to normal mucosa (p = 0.002). Moreover, a gradual decrease in FUCA1 expression was observed with progression of disease from earlier to advanced stages. These findings were confirmed by Western blot analysis of alpha-L-fucosidase expression. Our results demonstrated diminished FUCA1 mRNA levels in tumors, suggesting that expression of tissue alpha-L-fucosidase could be regulated at transcriptional level in colorectal cancer. Full article

(This article belongs to the Special Issue Glycosylation and Glycoproteins)

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Open AccessArticle

Structural Properties of Polyphenols Causing Cell Cycle Arrest at G1 Phase in HCT116 Human Colorectal Cancer Cell Lines

by Soon Young Shin, Hyuk Yoon, Seunghyun Ahn, Dong-Wook Kim, Dong-Ho Bae, Dongsoo Koh, Young Han Lee and Yoongho Lim

Int. J. Mol. Sci. 2013, 14(8), 16970-16985; https://doi.org/10.3390/ijms140816970 - 19 Aug 2013

Cited by 32 | Viewed by 9345

Abstract

Plant-derived polyphenols are being tested as chemopreventive agents; some polyphenols arrest the cell cycle at G1 phase, whereas others inhibit cell cycle proliferation at G2/M phase. Therefore, polyphenols have been proposed to inhibit cell cycle progression at different phases via distinct mechanisms. Indeed, [...] Read more.

Plant-derived polyphenols are being tested as chemopreventive agents; some polyphenols arrest the cell cycle at G1 phase, whereas others inhibit cell cycle proliferation at G2/M phase. Therefore, polyphenols have been proposed to inhibit cell cycle progression at different phases via distinct mechanisms. Indeed, our previous studies showed that small structural differences in polyphenols cause large differences in their biological activities; however, the details of the structural properties causing G1 cell cycle arrest remain unknown. In this study, we prepared 27 polyphenols, including eight different scaffolds, to gain insight into the structural conditions that arrest the cell cycle at G1 phase in a quantitative structure–activity relationship study. We used cell cycle profiles to determine the biophores responsible for G1 cell cycle arrest and believe that the biophores identified in this study will help design polyphenols that cause G1 cell cycle arrest. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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MicroRNA-143 Downregulates Interleukin-13 Receptor Alpha1 in Human Mast Cells

by Shaoqing Yu, Ruxin Zhang, Chunshen Zhu, Jianqiu Cheng, Hong Wang and Jing Wu

Int. J. Mol. Sci. 2013, 14(8), 16958-16969; https://doi.org/10.3390/ijms140816958 - 19 Aug 2013

Cited by 25 | Viewed by 8201

Abstract

MicroRNA-143 (miR-143) was found to be downregulated in allergic rhinitis, and bioinformatics analysis predicted that IL-13Rα1 was a target gene of miR-143. To understand the molecular mechanisms of miR-143 involved in the pathogenesis of allergic inflammation, recombinant miR-143 plasmid vectors were constructed, and [...] Read more.

MicroRNA-143 (miR-143) was found to be downregulated in allergic rhinitis, and bioinformatics analysis predicted that IL-13Rα1 was a target gene of miR-143. To understand the molecular mechanisms of miR-143 involved in the pathogenesis of allergic inflammation, recombinant miR-143 plasmid vectors were constructed, and human mast cell-1(HMC-1) cells which play a central role in the allergic response were used for study. The plasmids were transfected into HMC-1 cells using a lentiviral vector. Expression of IL-13Rα1 mRNA was then detected by reverse transcriptase polymerase chain reaction (RT-PCR) and Western Blotting. The miR-143 lentiviral vector was successfully stably transfected in HMC-1 cells for target gene expression. Compared to the control, the target gene IL-13Rα1 was less expressed in HMC-1 transfected with miR-143 as determined by RT-PCR and Western Blotting (p < 0.05); this difference in expression was statistically significant and the inhibition efficiency was 71%. It indicates that miR-143 directly targets IL-13Rα1 and suppresses IL-13Rα1 expression in HMC-1 cells. Therefore, miR-143 may be associated with allergic reaction in human mast cells. Full article

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

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Open AccessArticle

The Association of IFI27 Expression and Fatigue Intensification during Localized Radiation Therapy: Implication of a Para-Inflammatory Bystander Response

by Chao-Pin Hsiao, Maria Araneta, Xiao Min Wang and Leorey N. Saligan

Int. J. Mol. Sci. 2013, 14(8), 16943-16957; https://doi.org/10.3390/ijms140816943 - 16 Aug 2013

Cited by 25 | Viewed by 8554

Abstract

The mechanisms behind fatigue intensification during cancer therapy remain elusive. The interferon alpha-inducible protein 27 (IFI27) was the most up-regulated gene based on our previous microarray data in fatigued men with non-metastatic prostate cancer receiving localized external beam radiation therapy (EBRT). [...] Read more.

The mechanisms behind fatigue intensification during cancer therapy remain elusive. The interferon alpha-inducible protein 27 (IFI27) was the most up-regulated gene based on our previous microarray data in fatigued men with non-metastatic prostate cancer receiving localized external beam radiation therapy (EBRT). The purpose of this study was to confirm the IFI27 up-regulation and determine its association with fatigue intensification during EBRT. Peripheral blood samples and fatigue scores were collected at three time points—prior to EBRT, at midpoint, and at completion of EBRT. Confirmatory quantitative real time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) were utilized to verify the microarray results. Subjects were a total of 40 Caucasian men with prostate cancer; 20 scheduled for EBRT (65.6 ± 7.5 years old), and 20 on active surveillance as controls (62.8 ± 6.1 years old). Significant IFI27 expression overtime during EBRT was confirmed by qPCR (p < 0.5), which correlated with fatigue scores during EBRT (R = −0.90, p = 0.006). Alterations in mechanisms associated with immune response and mitochondrial function that explain the up-regulation of IFI27 may provide an understanding of the pathways related to the intensification of fatigue during localized radiation therapy. Full article

(This article belongs to the Collection Radiation Toxicity in Cells)

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Open AccessArticle

ACE Inhibition with Captopril Retards the Development of Signs of Neurodegeneration in an Animal Model of Alzheimer’s Disease

by Said AbdAlla, Andreas Langer, Xuebin Fu and Ursula Quitterer

Int. J. Mol. Sci. 2013, 14(8), 16917-16942; https://doi.org/10.3390/ijms140816917 - 16 Aug 2013

Cited by 80 | Viewed by 12138

Abstract

Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer’s disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The [...] Read more.

Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer’s disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration. Full article

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

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Open AccessArticle

Bioinformatic Prediction of Gene Functions Regulated by Quorum Sensing in the Bioleaching Bacterium Acidithiobacillus ferrooxidans

by Alvaro Banderas and Nicolas Guiliani

Int. J. Mol. Sci. 2013, 14(8), 16901-16916; https://doi.org/10.3390/ijms140816901 - 16 Aug 2013

Cited by 23 | Viewed by 9550

Abstract

The biomining bacterium Acidithiobacillus ferrooxidans oxidizes sulfide ores and promotes metal solubilization. The efficiency of this process depends on the attachment of cells to surfaces, a process regulated by quorum sensing (QS) cell-to-cell signalling in many Gram-negative bacteria. At. ferrooxidans has a functional [...] Read more.

The biomining bacterium Acidithiobacillus ferrooxidans oxidizes sulfide ores and promotes metal solubilization. The efficiency of this process depends on the attachment of cells to surfaces, a process regulated by quorum sensing (QS) cell-to-cell signalling in many Gram-negative bacteria. At. ferrooxidans has a functional QS system and the presence of AHLs enhances its attachment to pyrite. However, direct targets of the QS transcription factor AfeR remain unknown. In this study, a bioinformatic approach was used to infer possible AfeR direct targets based on the particular palindromic features of the AfeR binding site. A set of Hidden Markov Models designed to maintain palindromic regions and vary non-palindromic regions was used to screen for putative binding sites. By annotating the context of each predicted binding site (PBS), we classified them according to their positional coherence relative to other putative genomic structures such as start codons, RNA polymerase promoter elements and intergenic regions. We further used the Multiple EM for Motif Elicitation algorithm (MEME) to further filter out low homology PBSs. In summary, 75 target-genes were identified, 34 of which have a higher confidence level. Among the identified genes, we found afeR itself, zwf, genes encoding glycosyltransferase activities, metallo-beta lactamases, and active transport-related proteins. Glycosyltransferases and Zwf (Glucose 6-phosphate-1-dehydrogenase) might be directly involved in polysaccharide biosynthesis and attachment to minerals by At. ferrooxidans cells during the bioleaching process. Full article

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

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Open AccessArticle

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

by Vendula Sepsova, Jana Zdarova Karasova, Jan Korabecny, Rafael Dolezal, Filip Zemek, Brian J. Bennion and Kamil Kuca

Int. J. Mol. Sci. 2013, 14(8), 16882-16900; https://doi.org/10.3390/ijms140816882 - 16 Aug 2013

Cited by 42 | Viewed by 9720

Abstract

Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible [...] Read more.

Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring. 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

L/N-Type Calcium Channel Blocker Cilnidipine Added to Renin-Angiotensin Inhibition Improves Ambulatory Blood Pressure Profile and Suppresses Cardiac Hypertrophy in Hypertension with Chronic Kidney Disease

by Tomohiko Kanaoka, Kouichi Tamura, Hiromichi Wakui, Masato Ohsawa, Kengo Azushima, Kazushi Uneda, Ryu Kobayashi, Tetsuya Fujikawa, Yuko Tsurumi-Ikeya, Akinobu Maeda, Mai Yanagi, Yoshiyuki Toya and Satoshi Umemura

Int. J. Mol. Sci. 2013, 14(8), 16866-16881; https://doi.org/10.3390/ijms140816866 - 16 Aug 2013

Cited by 14 | Viewed by 9738

Abstract

Ambulatory blood pressure (BP) and heart rate (HR) profile are proposed to be related to renal deterioration and cardiovascular complication in hypertension and chronic kidney disease (CKD). In this study, we examined the beneficial effects cilnidipine, a unique L/N-type calcium channel blocker (CCB), [...] Read more.

Ambulatory blood pressure (BP) and heart rate (HR) profile are proposed to be related to renal deterioration and cardiovascular complication in hypertension and chronic kidney disease (CKD). In this study, we examined the beneficial effects cilnidipine, a unique L/N-type calcium channel blocker (CCB), in addition to renin-angiotensin system inhibitors, on ambulatory BP and HR profile, as well as cardiorenal function in hypertensive CKD patients. Forty-five patients were randomly assigned to the cilnidipine replacement group (n = 21) or the control CCBs group (n = 24) during a 24-week active treatment period. Although clinical BP values were similar in the cilnidipine and control CCBs groups after the treatment period, the results of ambulatory BP monitoring showed that the 24-h and daytime systolic BP levels in the cilnidipine group were significantly lower compared with the control group after the study. Furthermore, the left ventricular mass index (LVMI) was significantly decreased in the cilnidipine group compared to the control group after the study (LVMI, 135.3 ± 26.4 versus 181.2 ± 88.4, p = 0.031), with a significant difference in the changes in the LVMI between the cilnidipine and control groups (change in LVMI, −12.4 ± 23.7 versus 26.2 ± 64.4, p = 0.007). These results indicate that cilnidipine is beneficial for the suppression of pathological cardiac remodeling, at least partly, via a superior improving effect on ambulatory BP profile compared with control CCBs in hypertensive CKD patients. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Design, Synthesis and DNA Interaction Study of New Potential DNA Bis-Intercalators Based on Glucuronic Acid

by Jiuyang Zhao, Wei Li, Rui Ma, Shaopeng Chen, Sumei Ren and Tao Jiang

Int. J. Mol. Sci. 2013, 14(8), 16851-16865; https://doi.org/10.3390/ijms140816851 - 15 Aug 2013

Cited by 37 | Viewed by 7818

Abstract

A series of novel potential DNA bis-intercalators were designed and synthesized, in which two glucuronic acids were linked by ethylenediamine, and the glucuronic acid was coupled with various chromophores, including quinoline, acridine, indole and purine, at the C-1 position. The preliminary binding properties [...] Read more.

A series of novel potential DNA bis-intercalators were designed and synthesized, in which two glucuronic acids were linked by ethylenediamine, and the glucuronic acid was coupled with various chromophores, including quinoline, acridine, indole and purine, at the C-1 position. The preliminary binding properties of these compounds to calf thymus DNA (CT-DNA) have been investigated by UV-absorption and fluorescence spectroscopy. The results indicated that all the target compounds can interact with CT-DNA, and the acridine derivative, 3b, showed the highest key selection vector (KSV) value, which suggested that compound 3b binds most strongly to CT-DNA. Full article

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Open AccessArticle

Trastuzumab-Peptide Interactions: Mechanism and Application in Structure-Based Ligand Design

by Tian-Yang Sun, Qi Wang, Jin Zhang, Tao Wu and Fan Zhang

Int. J. Mol. Sci. 2013, 14(8), 16836-16850; https://doi.org/10.3390/ijms140816836 - 15 Aug 2013

Cited by 24 | Viewed by 9379

Abstract

Understanding of protein-ligand interactions and its influences on protein stability is necessary in the research on all biological processes and correlative applications, for instance, the appropriate affinity ligand design for the purification of bio-drugs. In this study, computational methods were applied to identify [...] Read more.

Understanding of protein-ligand interactions and its influences on protein stability is necessary in the research on all biological processes and correlative applications, for instance, the appropriate affinity ligand design for the purification of bio-drugs. In this study, computational methods were applied to identify binding site interaction details between trastuzumab and its natural receptor. Trastuzumab is an approved antibody used in the treatment of human breast cancer for patients whose tumors overexpress the HER2 (human epidermal growth factor receptor 2) protein. However, rational design of affinity ligands to keep the stability of protein during the binding process is still a challenge. Herein, molecular simulations and quantum mechanics were used on protein-ligand interaction analysis and protein ligand design. We analyzed the structure of the HER2-trastuzumab complex by molecular dynamics (MD) simulations. The interaction energies of the mutated peptides indicate that trastuzumab binds to ligand through electrostatic and hydrophobic interactions. Quantitative investigation of interactions shows that electrostatic interactions play the most important role in the binding of the peptide ligand. Prime/MM-GBSA calculations were carried out to predict the binding affinity of the designed peptide ligands. A high binding affinity and specificity peptide ligand is designed rationally with equivalent interaction energy to the wild-type octadecapeptide. The results offer new insights into affinity ligand design. Full article

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

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Open AccessReview

Gene Expression Profiling as a Tool to Investigate the Molecular Machinery Activated during Hippocampal Neurodegeneration Induced by Trimethyltin (TMT) Administration

by Wanda Lattanzi, Valentina Corvino, Valentina Di Maria, Fabrizio Michetti and Maria Concetta Geloso

Int. J. Mol. Sci. 2013, 14(8), 16817-16835; https://doi.org/10.3390/ijms140816817 - 15 Aug 2013

Cited by 31 | Viewed by 8832

Abstract

Trimethyltin (TMT) is an organotin compound exhibiting neurotoxicant effects selectively localized in the limbic system and especially marked in the hippocampus, in both experimental animal models and accidentally exposed humans. TMT administration causes selective neuronal death involving either the granular neurons of the [...] Read more.

Trimethyltin (TMT) is an organotin compound exhibiting neurotoxicant effects selectively localized in the limbic system and especially marked in the hippocampus, in both experimental animal models and accidentally exposed humans. TMT administration causes selective neuronal death involving either the granular neurons of the dentate gyrus or the pyramidal cells of the Cornu Ammonis, with a different pattern of localization depending on the different species studied or the dosage schedule. TMT is broadly used to realize experimental models of hippocampal neurodegeneration associated with cognitive impairment and temporal lobe epilepsy, though the molecular mechanisms underlying the associated selective neuronal death are still not conclusively clarified. Experimental evidence indicates that TMT-induced neurodegeneration is a complex event involving different pathogenetic mechanisms, probably acting differently in animal and cell models, which include neuroinflammation, intracellular calcium overload, and oxidative stress. Microarray-based, genome-wide expression analysis has been used to investigate the molecular scenario occurring in the TMT-injured brain in different in vivo and in vitro models, producing an overwhelming amount of data. The aim of this review is to discuss and rationalize the state-of-the-art on TMT-associated genome wide expression profiles in order to identify comparable and reproducible data that may allow focusing on significantly involved pathways. Full article

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

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Open AccessArticle

Protein Structures among Bio-Ethanol Co-Products and Its Relationships with Ruminal and Intestinal Availability of Protein in Dairy Cattle

by Arash Azarfar, Arjan Jonker and Peiqiang Yu

Int. J. Mol. Sci. 2013, 14(8), 16802-16816; https://doi.org/10.3390/ijms140816802 - 15 Aug 2013

Cited by 5 | Viewed by 6935

Abstract

The objectives of this study were to reveal molecular structures of protein among different types of the dried distillers grains with solubles (100% wheat DDGS (WDDGS); DDGS blend1 (BDDGS1, corn to wheat ratio 30:70%); DDGS blend2 (BDDGS2, corn to wheat ratio 50:50 percent)) [...] Read more.

The objectives of this study were to reveal molecular structures of protein among different types of the dried distillers grains with solubles (100% wheat DDGS (WDDGS); DDGS blend1 (BDDGS1, corn to wheat ratio 30:70%); DDGS blend2 (BDDGS2, corn to wheat ratio 50:50 percent)) and different batches within DDGS type using diffuse reflectance infrared Fourier transform spectroscopy (DRIFT). Compared with BDDGS1 and BDDGS2, wheat DDGS had higher (p < 0.05) peak area intensities of protein amide I and II and amide I to II intensity ratio. Increasing the corn to wheat ratio form 30:70 to 50:50 in the blend DDGS did not affect amide I and II area intensities and their ratio. Amide I to II peak intensity ratio differed (p < 0.05) among the different batches within WDDGS and BDDGS1. Compared with both blend DDGS types, WDDGS had higher α-helix and β-sheet ratio (p < 0.05), while α-helix to β-sheet ratio was similar among the three DDGS types. The α-helix to β-sheet ratio differed significantly among batches within WDDGS. Principal component analysis (PCA) revealed that protein molecular structures in WDDGS differed from those of BDDGS1 and between different batches within BDDGS1 and BDDGS2. The α-helix to β-sheet ratios of protein in all DDGS types had an influence on availability of protein at the ruminal level as well as at the intestinal level. The α-helix to β-sheet ratio was positively correlated to rumen undegraded protein (r = 0.41, p < 0.05) and unavailable protein (PC; r = 0.59, p < 0.05). Full article

(This article belongs to the Section Biochemistry)

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Open AccessReview

The Effects of Nanomaterials as Endocrine Disruptors

by Ivo Iavicoli, Luca Fontana, Veruscka Leso and Antonio Bergamaschi

Int. J. Mol. Sci. 2013, 14(8), 16732-16801; https://doi.org/10.3390/ijms140816732 - 14 Aug 2013

Cited by 181 | Viewed by 15870

Abstract

In recent years, nanoparticles have been increasingly used in several industrial, consumer and medical applications because of their unique physico-chemical properties. However, in vitro and in vivo studies have demonstrated that these properties are also closely associated with detrimental health effects. There is [...] Read more.

In recent years, nanoparticles have been increasingly used in several industrial, consumer and medical applications because of their unique physico-chemical properties. However, in vitro and in vivo studies have demonstrated that these properties are also closely associated with detrimental health effects. There is a serious lack of information on the potential nanoparticle hazard to human health, particularly on their possible toxic effects on the endocrine system. This topic is of primary importance since the disruption of endocrine functions is associated with severe adverse effects on human health. Consequently, in order to gather information on the hazardous effects of nanoparticles on endocrine organs, we reviewed the data available in the literature regarding the endocrine effects of in vitro and in vivo exposure to different types of nanoparticles. Our aim was to understand the potential endocrine disrupting risks posed by nanoparticles, to assess their underlying mechanisms of action and identify areas in which further investigation is needed in order to obtain a deeper understanding of the role of nanoparticles as endocrine disruptors. Current data support the notion that different types of nanoparticles are capable of altering the normal and physiological activity of the endocrine system. However, a critical evaluation of these findings suggests the need to interpret these results with caution since information on potential endocrine interactions and the toxicity of nanoparticles is quite limited. Full article

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

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Open AccessArticle

Endogenous Protease Nexin-1 Protects against Cerebral Ischemia

by Osvaldo Mirante, Melanie Price, Wilfredo Puentes, Ximena Castillo, Corinne Benakis, Jonathan Thevenet, Denis Monard and Lorenz Hirt

Int. J. Mol. Sci. 2013, 14(8), 16719-16731; https://doi.org/10.3390/ijms140816719 - 14 Aug 2013

Cited by 13 | Viewed by 8550

Abstract

The serine protease thrombin plays a role in signalling ischemic neuronal death in the brain. Paradoxically, endogenous neuroprotective mechanisms can be triggered by preconditioning with thrombin (thrombin preconditioning, TPC), leading to tolerance to cerebral ischemia. Here we studied the role of thrombin’s endogenous [...] Read more.

The serine protease thrombin plays a role in signalling ischemic neuronal death in the brain. Paradoxically, endogenous neuroprotective mechanisms can be triggered by preconditioning with thrombin (thrombin preconditioning, TPC), leading to tolerance to cerebral ischemia. Here we studied the role of thrombin’s endogenous potent inhibitor, protease nexin-1 (PN-1), in ischemia and in tolerance to cerebral ischemia induced by TPC. Cerebral ischemia was modelled in vitro in organotypic hippocampal slice cultures from rats or genetically engineered mice lacking PN-1 or with the reporter gene lacZ knocked into the PN-1 locus PN-1HAPN-1-lacZ/HAPN-1-lacZ (PN-1 KI) exposed to oxygen and glucose deprivation (OGD). We observed increased thrombin enzyme activity in culture homogenates 24 h after OGD. Lack of PN-1 increased neuronal death in the CA1, suggesting that endogenous PN-1 inhibits thrombin-induced neuronal damage after ischemia. OGD enhanced β-galactosidase activity, reflecting PN-1 expression, at one and 24 h, most strikingly in the stratum radiatum, a glial cell layer adjacent to the CA1 layer of ischemia sensitive neurons. TPC, 24 h before OGD, additionally increased PN-1 expression 1 h after OGD, compared to OGD alone. TPC failed to induce tolerance in cultures from PN-1^−/− mice confirming PN-1 as an important TPC target. PN-1 upregulation after TPC was blocked by the c-Jun N-terminal kinase (JNK) inhibitor, L-JNKI1, known to block TPC. This work suggests that PN-1 is an endogenous neuroprotectant in cerebral ischemia and a potential target for neuroprotection. Full article

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

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1301 KiB

Open AccessArticle

Using Synchrotron Radiation-Based Infrared Microspectroscopy to Reveal Microchemical Structure Characterization: Frost Damaged Wheat vs. Normal Wheat

by Hangshu Xin, Xuewei Zhang and Peiqiang Yu

Int. J. Mol. Sci. 2013, 14(8), 16706-16718; https://doi.org/10.3390/ijms140816706 - 14 Aug 2013

Cited by 22 | Viewed by 6990

Abstract

This study was conducted to compare: (1) protein chemical characteristics, including the amide I and II region, as well as protein secondary structure; and (2) carbohydrate internal structure and functional groups spectral intensities between the frost damaged wheat and normal wheat using synchrotron [...] Read more.

This study was conducted to compare: (1) protein chemical characteristics, including the amide I and II region, as well as protein secondary structure; and (2) carbohydrate internal structure and functional groups spectral intensities between the frost damaged wheat and normal wheat using synchrotron radiation-based Fourier transform infrared microspectroscopy (SR-FTIRM). Fingerprint regions of specific interest in our study involved protein and carbohydrate functional group band assignments, including protein amide I and II (ca. 1774–1475 cm⁻¹), structural carbohydrates (SCHO, ca. 1498–1176 cm⁻¹), cellulosic compounds (CELC, ca. 1295–1176 cm⁻¹), total carbohydrates (CHO, ca. 1191–906 cm⁻¹) and non-structural carbohydrates (NSCHO, ca. 954–809 cm⁻¹). The results showed that frost did cause variations in spectral profiles in wheat grains. Compared with healthy wheat grains, frost damaged wheat had significantly lower (p < 0.05) spectral intensities in height and area ratios of amide I to II and almost all the spectral parameters of carbohydrate-related functional groups, including SCHO, CHO and NSCHO. Furthermore, the height ratio of protein amide I to the third peak of CHO and the area ratios of protein amide (amide I + II) to carbohydrate compounds (CHO and SCHO) were also changed (p < 0.05) in damaged wheat grains. It was concluded that the SR-FTIR microspectroscopic technique was able to examine inherent molecular structure features at an ultra-spatial resolution (10 × 10 μm) between different wheat grains samples. The structural characterization of wheat was influenced by climate conditions, such as frost damage, and these structural variations might be a major reason for the decreases in nutritive values, nutrients availability and milling and baking quality in wheat grains. Full article

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

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Open AccessReview

Folding and Biogenesis of Mitochondrial Small Tim Proteins

by Efrain Ceh-Pavia, Michael P. Spiller and Hui Lu

Int. J. Mol. Sci. 2013, 14(8), 16685-16705; https://doi.org/10.3390/ijms140816685 - 13 Aug 2013

Cited by 19 | Viewed by 9673

Abstract

Correct and timely folding is critical to the function of all proteins. The importance of this is illustrated in the biogenesis of the mitochondrial intermembrane space (IMS) “small Tim” proteins. Biogenesis of the small Tim proteins is regulated by dedicated systems or pathways, [...] Read more.

Correct and timely folding is critical to the function of all proteins. The importance of this is illustrated in the biogenesis of the mitochondrial intermembrane space (IMS) “small Tim” proteins. Biogenesis of the small Tim proteins is regulated by dedicated systems or pathways, beginning with synthesis in the cytosol and ending with assembly of individually folded proteins into functional complexes in the mitochondrial IMS. The process is mostly centered on regulating the redox states of the conserved cysteine residues: oxidative folding is crucial for protein function in the IMS, but oxidized (disulfide bonded) proteins cannot be imported into mitochondria. How the redox-sensitive small Tim precursor proteins are maintained in a reduced, import-competent form in the cytosol is not well understood. Recent studies suggest that zinc and the cytosolic thioredoxin system play a role in the biogenesis of these proteins. In the IMS, the mitochondrial import and assembly (MIA) pathway catalyzes both import into the IMS and oxidative folding of the small Tim proteins. Finally, assembly of the small Tim complexes is a multistep process driven by electrostatic and hydrophobic interactions; however, the chaperone function of the complex might require destabilization of these interactions to accommodate the substrate. Here, we review how folding of the small Tim proteins is regulated during their biogenesis, from maintenance of the unfolded precursors in the cytosol, to their import, oxidative folding, complex assembly and function in the IMS. Full article

(This article belongs to the Special Issue Protein Folding)

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Int. J. Mol. Sci., Volume 14, Issue 8 (August 2013) – 106 articles , Pages 15199-17237

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