International Journal of Molecular Sciences

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Open AccessReview

Proteomics-Based Analysis of Protein Complexes in Pluripotent Stem Cells and Cancer Biology

by Putty-Reddy Sudhir and Chung-Hsuan Chen^*

Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan

Int. J. Mol. Sci. 2016, 17(3), 432; https://doi.org/10.3390/ijms17030432 - 22 Mar 2016

Cited by 5 | Viewed by 8321

A protein complex consists of two or more proteins that are linked together through protein–protein interactions. The proteins show stable/transient and direct/indirect interactions within the protein complex or between the protein complexes. Protein complexes are involved in regulation of most of the cellular [...] Read more.

A protein complex consists of two or more proteins that are linked together through protein–protein interactions. The proteins show stable/transient and direct/indirect interactions within the protein complex or between the protein complexes. Protein complexes are involved in regulation of most of the cellular processes and molecular functions. The delineation of protein complexes is important to expand our knowledge on proteins functional roles in physiological and pathological conditions. The genetic yeast-2-hybrid method has been extensively used to characterize protein-protein interactions. Alternatively, a biochemical-based affinity purification coupled with mass spectrometry (AP-MS) approach has been widely used to characterize the protein complexes. In the AP-MS method, a protein complex of a target protein of interest is purified using a specific antibody or an affinity tag (e.g., DYKDDDDK peptide (FLAG) and polyhistidine (His)) and is subsequently analyzed by means of MS. Tandem affinity purification, a two-step purification system, coupled with MS has been widely used mainly to reduce the contaminants. We review here a general principle for AP-MS-based characterization of protein complexes and we explore several protein complexes identified in pluripotent stem cell biology and cancer biology as examples. Full article

(This article belongs to the Special Issue Advances in Proteomic Research)

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Open AccessReview

Molecular Insight into Gut Microbiota and Rheumatoid Arthritis

by Xiaohao Wu^1,2,†

, Bing He^1,2,†, Jin Liu^1,2,†, Hui Feng^3,4,†, Yinghui Ma^3,4, Defang Li^1,2,5, Baosheng Guo^1,2,5, Chao Liang^1,2,5, Lei Dang^1,2, Luyao Wang^1,2, Jing Tian⁴, Hailong Zhu^1,2,*, Lianbo Xiao^3,4,*, Cheng Lu^1,2,6,*

, Aiping Lu^{1,2,3,4,5,6,*} and Ge Zhang^1,2,4,5,*

¹ Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China

² Institute of Integrated Bioinformedicine and Translational Science, Hong Kong Baptist University, Hong Kong SAR, China

³ Guanghua Integrative Hospital, Shanghai 200000, China

⁴ Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai 200000, China

⁵ Research Group of Bone and Joint Diseases, HKBU Institute of Science & Technology, Haimen 226100, China

⁶ Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100000, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(3), 431; https://doi.org/10.3390/ijms17030431 - 22 Mar 2016

Cited by 68 | Viewed by 13549

Abstract

Rheumatoid arthritis (RA) is a systemic, inflammatory, and autoimmune disorder. Gut microbiota play an important role in the etiology of RA. With the considerable progress made in next-generation sequencing techniques, the identified gut microbiota difference between RA patients and healthy individuals provides an [...] Read more.

Rheumatoid arthritis (RA) is a systemic, inflammatory, and autoimmune disorder. Gut microbiota play an important role in the etiology of RA. With the considerable progress made in next-generation sequencing techniques, the identified gut microbiota difference between RA patients and healthy individuals provides an updated overview of the association between gut microbiota and RA. We reviewed the reported correlation and underlying molecular mechanisms among gut microbiota, the immune system, and RA. It has become known that gut microbiota contribute to the pathogenesis of RA via multiple molecular mechanisms. The progressive understanding of the dynamic interaction between gut microbiota and their host will help in establishing a highly individualized management for each RA patient, and achieve a better efficacy in clinical practice, or even discovering new drugs for RA. Full article

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

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Open AccessArticle

Koumine Attenuates Lipopolysaccaride-Stimulated Inflammation in RAW264.7 Macrophages, Coincidentally Associated with Inhibition of NF-κB, ERK and p38 Pathways

by Zhihang Yuan^1,2,†, Froilan Bernard Matias^3,†, Jing Wu^1,2, Zengenni Liang⁴ and Zhiliang Sun^1,2,*

¹ Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China

² Hunan Co-Innovation Center for Utilization of Botanical Functional Ingredients, Changsha 410128, China

³ Department of Animal Management, College of Veterinary Science and Medicine, Central Luzon State University, Science City of Muñoz, Nueva Ecija 3120, Philippines

⁴ Department of Hunan Agricultural Product Processing Institute, Changsha 410128, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(3), 430; https://doi.org/10.3390/ijms17030430 - 22 Mar 2016

Cited by 42 | Viewed by 6503

Abstract

Medicinal herbal plants have been commonly used for intervention of different diseases and health enhancement worldwide. Koumine, an alkaloid monomer found abundantly in Gelsemium plants, can be effectively used as an anti-inflammatory medication. In this study, the mechanisms associated with the preventative effect [...] Read more.

Medicinal herbal plants have been commonly used for intervention of different diseases and health enhancement worldwide. Koumine, an alkaloid monomer found abundantly in Gelsemium plants, can be effectively used as an anti-inflammatory medication. In this study, the mechanisms associated with the preventative effect of koumine on lipopolysaccharide (LPS)-mediated inflammation in RAW264.7 macrophages were investigated. Koumine induced a decrease in the level of inducible nitric oxide synthase (iNOS) protein, concomitant reduction in the production of nitric oxide (NO) and reduction of the levels of interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and IL-1β. Furthermore, koumine decreased the phosphorylation of p65 and inhibited nuclear factor κ Bα (IκBα) proteins, resulting in lower production of nuclear factor (NF)-κB transactivation. Koumine also induced a decrease in the phosphorylation of extracellular-signal-regulated kinases (ERK) and p38 in RAW264 cells. In conclusion, these findings reveal that koumine decreases the productions of pro-inflammatory mediators though the suppression of p38 and ERK MAPK phosphorylation and the inhibition of NF-κB activation in RAW264.7 cells. Full article

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

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Open AccessReview

Caveolae and Caveolin-1 Integrate Reverse Cholesterol Transport and Inflammation in Atherosclerosis

by Li Qin¹, Neng Zhu², Bao-Xue Ao¹, Chan Liu¹, Ya-Ning Shi¹, Ke Du¹, Jian-Xiong Chen^1,3, Xi-Long Zheng^1,4

and Duan-Fang Liao^1,*

¹ School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China

² Department of Urology, The First Hospital of Hunan University of Chinese Medicine, Changsha 410208, China

³ Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS 39216, USA

⁴ Department of Biochemistry & Molecular Biology, the Libin Cardiovascular Institute of Alberta, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada

Int. J. Mol. Sci. 2016, 17(3), 429; https://doi.org/10.3390/ijms17030429 - 22 Mar 2016

Cited by 43 | Viewed by 14479

Abstract

Lipid disorder and inflammation play critical roles in the development of atherosclerosis. Reverse cholesterol transport is a key event in lipid metabolism. Caveolae and caveolin-1 are in the center stage of cholesterol transportation and inflammation in macrophages. Here, we propose that reverse cholesterol [...] Read more.

Lipid disorder and inflammation play critical roles in the development of atherosclerosis. Reverse cholesterol transport is a key event in lipid metabolism. Caveolae and caveolin-1 are in the center stage of cholesterol transportation and inflammation in macrophages. Here, we propose that reverse cholesterol transport and inflammation in atherosclerosis can be integrated by caveolae and caveolin-1. Full article

(This article belongs to the Section Biochemistry)

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Open AccessReview

Targeted Delivery Systems for Molecular Therapy in Skeletal Disorders

by Lei Dang^†, Jin Liu^†, Fangfei Li^†, Luyao Wang^†, Defang Li, Baosheng Guo, Xiaojuan He, Feng Jiang, Chao Liang, Biao Liu, Shaikh Atik Badshah, Bing He, Jun Lu, Cheng Lu

, Aiping Lu^* and Ge Zhang^*

¹ Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(3), 428; https://doi.org/10.3390/ijms17030428 - 22 Mar 2016

Cited by 36 | Viewed by 7122

Abstract

Abnormalities in the integral components of bone, including bone matrix, bone mineral and bone cells, give rise to complex disturbances of skeletal development, growth and homeostasis. Non-specific drug delivery using high-dose systemic administration may decrease therapeutic efficacy of drugs and increase the risk [...] Read more.

Abnormalities in the integral components of bone, including bone matrix, bone mineral and bone cells, give rise to complex disturbances of skeletal development, growth and homeostasis. Non-specific drug delivery using high-dose systemic administration may decrease therapeutic efficacy of drugs and increase the risk of toxic effects in non-skeletal tissues, which remain clinical challenges in the treatment of skeletal disorders. Thus, targeted delivery systems are urgently needed to achieve higher drug delivery efficiency, improve therapeutic efficacy in the targeted cells/tissues, and minimize toxicities in non-targeted cells/tissues. In this review, we summarize recent progress in the application of different targeting moieties and nanoparticles for targeted drug delivery in skeletal disorders, and also discuss the advantages, challenges and perspectives in their clinical translation. Full article

(This article belongs to the Special Issue Molecule- and Cell-Targeted Drug Design and Screening and Identification of Natural Product)

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Open AccessArticle

Arsenite Regulates Prolongation of Glycan Residues of Membrane Glycoprotein: A Pivotal Study via Wax Physisorption Kinetics and FTIR Imaging

by Chih-Hung Lee¹

, Chia-Yen Hsu², Pei-Yu Huang², Ching-Iue Chen³, Yao-Chang Lee^2,4,*,†

and Hsin-Su Yu^5,6,*,†

¹ Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan

² Biomedical and Molecular Imaging Lab, X-ray and IR Imaging Group, National Synchrotron Radiation Research Center, 101 Hsin-Ann Road, Hsinchu Science Park, Hsinchu 30076, Taiwan

³ Beamline Group, National Synchrotron Radiation Research Center, Hsinchu 30076, Taiwan

⁴ Department of Optics and Photonics, National Central University, Chung-Li 32001, Taiwan

⁵ National Institute of Environmental Health Sciences, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Zhunan 35053, Taiwan

⁶ Department of Dermatology, Kaohsiung Medical University, Kaohsiung, No. 100, Shih-Chuan 1st Road, Kaohsiung 807, Taiwan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(3), 427; https://doi.org/10.3390/ijms17030427 - 22 Mar 2016

Cited by 6 | Viewed by 6314

Abstract

Arsenic exposure results in several human cancers, including those of the skin, lung, and bladder. As skin cancers are the most common form, epidermal keratinocytes (KC) are the main target of arsenic exposure. The mechanisms by which arsenic induces carcinogenesis remains unclear, but [...] Read more.

Arsenic exposure results in several human cancers, including those of the skin, lung, and bladder. As skin cancers are the most common form, epidermal keratinocytes (KC) are the main target of arsenic exposure. The mechanisms by which arsenic induces carcinogenesis remains unclear, but aberrant cell proliferation and dysregulated energy homeostasis play a significant role. Protein glycosylation is involved in many key physiological processes, including cell proliferation and differentiation. To evaluate whether arsenite exposure affected protein glycosylation, the alteration of chain length of glycan residues in arsenite treated skin cells was estimated. Herein we demonstrated that the protein glycosylation was adenosine triphosphate (ATP)-dependent and regulated by arsenite exposure by using Fourier transform infrared (FTIR) reflectance spectroscopy, synchrotron-radiation-based FTIR (SR-FTIR) microspectroscopy, and wax physisorption kinetics coupled with focal-plane-array-based FTIR (WPK-FPA-FTIR) imaging. We were able to estimate the relative length of surface protein-linked glycan residues on arsenite-treated skin cells, including primary KC and two skin cancer cell lines, HSC-1 and HaCaT cells. Differential physisorption of wax adsorbents adhered to long-chain (elongated type) and short-chain (regular type) glycan residues of glycoprotein of skin cell samples treated with various concentration of arsenite was measured. The physisorption ratio of beeswax remain/n-pentacosane remain for KC cells was increased during arsenite exposure. Interestingly, this increase was reversed after oligomycin (an ATP synthase inhibitor) pretreatment, suggesting the chain length of protein-linked glycan residues is likely ATP-dependent. This is the first study to demonstrate the elongation and termination of surface protein-linked glycan residues using WPK-FPA-FTIR imaging in eukaryotes. Herein the result may provide a scientific basis to target surface protein-linked glycan residues in the process of arsenic carcinogenesis. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessReview

Nocturnal Pruritus: The Battle for a Peaceful Night’s Sleep

by Michael Joseph Lavery¹

, Carolyn Stull¹, Michael Owen Kinney² and Gil Yosipovitch^1,*

¹ Department of Dermatology/Temple Itch Center, Lewis Katz School of Medicine, Temple University, 3322 North Broad Street-Suite 212, Philadelphia, PA 19140, USA

² Department of Neurosciences, Royal Victoria Hospital, 274 Grosvenor Road, Belfast, Northern Ireland BT12 6BA, UK

Int. J. Mol. Sci. 2016, 17(3), 425; https://doi.org/10.3390/ijms17030425 - 22 Mar 2016

Cited by 95 | Viewed by 13849

Abstract

Chronic pruritus is a debilitating condition with numerous etiologies. Many patients suffer from nocturnal pruritus, which can decrease quality of life and affect mortality in hemodialysis patients. Nocturnal pruritus may occur in all sleep stages but is most prevalent in stages N1 and [...] Read more.

Chronic pruritus is a debilitating condition with numerous etiologies. Many patients suffer from nocturnal pruritus, which can decrease quality of life and affect mortality in hemodialysis patients. Nocturnal pruritus may occur in all sleep stages but is most prevalent in stages N1 and N2. Further research is needed to elucidate the pathophysiology of nocturnal itch, which will aid in the development of tailored management strategies. Full article

(This article belongs to the Special Issue Sleep, Circadian Rhythm and Skin)

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Open AccessReview

Emerging Role of miRNAs in the Drug Resistance of Gastric Cancer

by Ismael Riquelme^1,†, Pablo Letelier^2,†, Angela L. Riffo-Campos¹, Priscilla Brebi¹ and Juan Carlos Roa^3,*

¹ Molecular Pathology Laboratory, Department of Pathology, CEGIN-BIOREN, Universidad de La Frontera, Avenida Alemania 0458, 3th Floor, Temuco 4810296, Chile

² School of Health Sciences, Universidad Católica de Temuco, Manuel Montt 56, Temuco 4813302, Chile

³ Department of Pathology, UC Centre for Investigational Oncology (CITO), Advanced Centre for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Marcoleta 377, 7th Floor, Santiago 8330024, Chile

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(3), 424; https://doi.org/10.3390/ijms17030424 - 22 Mar 2016

Cited by 89 | Viewed by 9080

Abstract

Gastric cancer is the third leading cause of cancer mortality worldwide. Unfortunately, most gastric cancer cases are diagnosed in an advanced, non-curable stage and with a limited response to chemotherapy. Drug resistance is one of the most important causes of therapy failure in [...] Read more.

Gastric cancer is the third leading cause of cancer mortality worldwide. Unfortunately, most gastric cancer cases are diagnosed in an advanced, non-curable stage and with a limited response to chemotherapy. Drug resistance is one of the most important causes of therapy failure in gastric cancer patients. Although the mechanisms of drug resistance have been broadly studied, the regulation of these mechanisms has not been completely understood. Accumulating evidence has recently highlighted the role of microRNAs in the development and maintenance of drug resistance due to their regulatory features in specific genes involved in the chemoresistant phenotype of malignancies, including gastric cancer. This review summarizes the current knowledge about the miRNAs’ characteristics, their regulation of the genes involved in chemoresistance and their potential as targeted therapies for personalized treatment in resistant gastric cancer. Full article

(This article belongs to the Special Issue MicroRNA in Various Disease States as Biomarkers)

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Open AccessReview

A Review of Ribonuclease 7’s Structure, Regulation, and Contributions to Host Defense

by Brian Becknell^1,2 and John David Spencer^1,2,*

¹ Center for Clinical and Translational Research, The Research Institute at Nationwide Children’s, Columbus, OH 43205, USA

² Division of Pediatric Nephrology, Nationwide Children’s, Columbus, OH 43205, USA

Int. J. Mol. Sci. 2016, 17(3), 423; https://doi.org/10.3390/ijms17030423 - 22 Mar 2016

Cited by 38 | Viewed by 6802

Abstract

The Ribonuclease A Superfamily is composed of a group of structurally similar peptides that are secreted by immune cells and epithelial tissues. Several members of the Ribonuclease A Superfamily demonstrate antimicrobial activity, and it has been suggested that some of these ribonucleases play [...] Read more.

The Ribonuclease A Superfamily is composed of a group of structurally similar peptides that are secreted by immune cells and epithelial tissues. Several members of the Ribonuclease A Superfamily demonstrate antimicrobial activity, and it has been suggested that some of these ribonucleases play an essential role in host defense. Ribonuclease 7 (RNase 7) is an epithelial-derived secreted peptide with potent broad-spectrum antimicrobial activity. This review summarizes the published literature on RNase 7’s antimicrobial properties, structure, regulation, and contributions to host defense. In doing so, we conclude by highlighting key knowledge gaps that must be investigated to completely understand the potential of developing RNase 7 as a novel therapeutic for human infectious diseases. Full article

(This article belongs to the Special Issue Antimicrobial RNases in Host Defense)

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Open AccessArticle

Myricetin Prevents Alveolar Bone Loss in an Experimental Ovariectomized Mouse Model of Periodontitis

by Jialiang Huang^1,†, Chuanlong Wu^2,†, Bo Tian^2,†, Xiao Zhou¹, Nian Ma¹ and Yufen Qian^1,*

¹ Department of Orthodontics, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China

² Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(3), 422; https://doi.org/10.3390/ijms17030422 - 22 Mar 2016

Cited by 27 | Viewed by 8421

Abstract

Periodontitis is a common chronic inflammatory disease, which leads to alveolar bone resorption. Healthy and functional alveolar bone, which can support the teeth and enable their movement, is very important for orthodontic treatment. Myricetin inhibited osteoclastogenesis by suppressing the expression of some genes, [...] Read more.

Periodontitis is a common chronic inflammatory disease, which leads to alveolar bone resorption. Healthy and functional alveolar bone, which can support the teeth and enable their movement, is very important for orthodontic treatment. Myricetin inhibited osteoclastogenesis by suppressing the expression of some genes, signaling pathways, and cytokines. This study aimed to investigate the effects of myricetin on alveolar bone loss in an ovariectomized (OVX) mouse model of periodontitis as well as in vitro osteoclast formation and bone resorption. Twenty-four healthy eight-week-old C57BL/J6 female mice were assigned randomly to four groups: phosphate-buffered saline (PBS) control (sham) OVX + ligature + PBS (vehicle), and OVX + ligature + low or high (2 or 5 mg∙kg⁻¹∙day⁻¹, respectively) doses of myricetin. Myricetin or PBS was injected intraperitoneally (i.p.) every other day for 30 days. The maxillae were collected and subjected to further examination, including micro-computed tomography (micro-CT), hematoxylin and eosin (H&E) staining, and tartrate-resistant acid phosphatase (TRAP) staining; a resorption pit assay was also performed in vitro to evaluate the effects of myricetin on receptor activator of nuclear factor κ-B ligand (RANKL)-induced osteoclastogenesis. Myricetin, at both high and low doses, prevented alveolar bone resorption and increased alveolar crest height in the mouse model and inhibited osteoclast formation and bone resorption in vitro. However, myricetin was more effective at high dose than at low dose. Our study demonstrated that myricetin had a positive effect on alveolar bone resorption in an OVX mouse model of periodontitis and, therefore, may be a potential agent for the treatment of periodontitis and osteoporosis. Full article

(This article belongs to the Section Biochemistry)

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Open AccessReview

MicroRNAs as Biomarkers for Diagnosis, Prognosis and Theranostics in Prostate Cancer

by Gloria Bertoli^*

, Claudia Cava

and Isabella Castiglioni

Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), Segrate 20090, Segrate (Mi), Italy

Int. J. Mol. Sci. 2016, 17(3), 421; https://doi.org/10.3390/ijms17030421 - 22 Mar 2016

Cited by 125 | Viewed by 10894

Abstract

Prostate cancer (PC) includes several phenotypes, from indolent to highly aggressive cancer. Actual diagnostic and prognostic tools have several limitations, and there is a need for new biomarkers to stratify patients and assign them optimal therapies by taking into account potential genetic and [...] Read more.

Prostate cancer (PC) includes several phenotypes, from indolent to highly aggressive cancer. Actual diagnostic and prognostic tools have several limitations, and there is a need for new biomarkers to stratify patients and assign them optimal therapies by taking into account potential genetic and epigenetic differences. MicroRNAs (miRNAs) are small sequences of non-coding RNA regulating specific genes involved in the onset and development of PC. Stable miRNAs have been found in biofluids, such as serum and plasma; thus, the measurement of PC-associated miRNAs is emerging as a non-invasive tool for PC detection and monitoring. In this study, we conduct an in-depth literature review focusing on miRNAs that may contribute to the diagnosis and prognosis of PC. The role of miRNAs as a potential theranostic tool in PC is discussed. Using a meta-analysis approach, we found a group of 29 miRNAs with diagnostic properties and a group of seven miRNAs with prognostic properties, which were found already expressed in both biofluids and PC tissues. We tested the two miRNA groups on The Cancer Genome Atlas dataset of PC tissue samples with a machine-learning approach. Our results suggest that these 29 miRNAs should be considered as potential panel of biomarkers for the diagnosis of PC, both as in vivo non-invasive test and ex vivo confirmation test. Full article

(This article belongs to the Special Issue MicroRNA in Various Disease States as Biomarkers)

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Open AccessArticle

Transcranial Magnetic Stimulation of the Supplementary Motor Area in the Treatment of Obsessive-Compulsive Disorder: A Multi-Site Study

by Emily R. Hawken^1,2,†, Dancho Dilkov^3,†, Emil Kaludiev³, Selcuk Simek⁴, Felicia Zhang¹ and Roumen Milev^1,*

¹ Departments of Psychiatry, Queen’s University, Kingston, ON K7L 4X3, Canada

² Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 4X3, Canada

³ Department of Psychiatry, Military Medical Academy, Sofia 1000, Bulgaria

⁴ Department of Psychiatry, Sincan State Hospital, Istanbul 34400, Turkey

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(3), 420; https://doi.org/10.3390/ijms17030420 - 22 Mar 2016

Cited by 72 | Viewed by 8147

Abstract

Recently, strategies beyond pharmacological and psychological treatments have been developed for the management of obsessive-compulsive disorder (OCD). Specifically, repetitive transcranial magnetic stimulation (rTMS) has been employed as an adjunctive treatment in cases of treatment-refractory OCD. Here, we investigate six weeks of low frequency [...] Read more.

Recently, strategies beyond pharmacological and psychological treatments have been developed for the management of obsessive-compulsive disorder (OCD). Specifically, repetitive transcranial magnetic stimulation (rTMS) has been employed as an adjunctive treatment in cases of treatment-refractory OCD. Here, we investigate six weeks of low frequency rTMS, applied bilaterally and simultaneously over the sensory motor area, in OCD patients in a randomized, double-blind placebo-controlled clinical trial. Twenty-two participants were randomly enrolled into the treatment (ACTIVE = 10) or placebo (SHAM = 12) groups. At each of seven visits (baseline; day 1 and weeks 2, 4, and 6 of treatment; and two and six weeks after treatment) the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was administered. At the end of the six weeks of rTMS, patients in the ACTIVE group showed a clinically significant decrease in Y-BOCS scores compared to both the baseline and the SHAM group. This effect was maintained six weeks following the end of rTMS treatment. Therefore, in this sample, rTMS appeared to significantly improve the OCD symptoms of the treated patients beyond the treatment window. More studies need to be conducted to determine the generalizability of these findings and to define the duration of rTMS’ clinical effect on the Y-BOCS. Clinical Trial Registration Number (NCT) at www.clinicaltrials.gov: NCT00616486. Full article

(This article belongs to the Special Issue The Pathophysiology of Neuropsychiatric Disorders and New Therapeutic Targets)

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Open AccessReview

LARP6 Meets Collagen mRNA: Specific Regulation of Type I Collagen Expression

by Yujie Zhang and Branko Stefanovic^*

Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA

Int. J. Mol. Sci. 2016, 17(3), 419; https://doi.org/10.3390/ijms17030419 - 22 Mar 2016

Cited by 62 | Viewed by 9499

Abstract

Type I collagen is the most abundant structural protein in all vertebrates, but its constitutive rate of synthesis is low due to long half-life of the protein (60–70 days). However, several hundred fold increased production of type I collagen is often seen in [...] Read more.

Type I collagen is the most abundant structural protein in all vertebrates, but its constitutive rate of synthesis is low due to long half-life of the protein (60–70 days). However, several hundred fold increased production of type I collagen is often seen in reparative or reactive fibrosis. The mechanism which is responsible for this dramatic upregulation is complex, including multiple levels of regulation. However, posttranscriptional regulation evidently plays a predominant role. Posttranscriptional regulation comprises processing, transport, stabilization and translation of mRNAs and is executed by RNA binding proteins. There are about 800 RNA binding proteins, but only one, La ribonucleoprotein domain family member 6 (LARP6), is specifically involved in type I collagen regulation. In the 5′untranslated region (5’UTR) of mRNAs encoding for type I and type III collagens there is an evolutionally conserved stem-loop (SL) structure; this structure is not found in any other mRNA, including any other collagen mRNA. LARP6 binds to the 5′SL in sequence specific manner to regulate stability of collagen mRNAs and their translatability. Here, we will review current understanding of how is LARP6 involved in posttranscriptional regulation of collagen mRNAs. We will also discuss how other proteins recruited by LARP6, including nonmuscle myosin, vimentin, serine threonine kinase receptor associated protein (STRAP), 25 kD FK506 binding protein (FKBP25) and RNA helicase A (RHA), contribute to this process. Full article

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

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Open AccessArticle

Melanocytes Affect Nodal Expression and Signaling in Melanoma Cells: A Lesson from Pediatric Large Congenital Melanocytic Nevi

by Naira V. Margaryan

, Alina Gilgur, Elisabeth A. Seftor, Chad Purnell, Nicoleta C. Arva, Arun K. Gosain, Mary J. C. Hendrix and Luigi Strizzi^*

Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA

Int. J. Mol. Sci. 2016, 17(3), 418; https://doi.org/10.3390/ijms17030418 - 22 Mar 2016

Cited by 6 | Viewed by 6619

Abstract

Expression of Nodal, a Transforming Growth Factor-beta (TGF-β) related growth factor, is associated with aggressive melanoma. Nodal expression in adult dysplastic nevi may predict the development of aggressive melanoma in some patients. A subset of pediatric patients diagnosed with giant or large congenital [...] Read more.

Expression of Nodal, a Transforming Growth Factor-beta (TGF-β) related growth factor, is associated with aggressive melanoma. Nodal expression in adult dysplastic nevi may predict the development of aggressive melanoma in some patients. A subset of pediatric patients diagnosed with giant or large congenital melanocytic nevi (LCMN) has shown increased risk for development of melanoma. Here, we investigate whether Nodal expression can help identify the rare cases of LCMN that develop melanoma and shed light on why the majority of these patients do not. Immunohistochemistry (IHC) staining results show varying degree of Nodal expression in pediatric dysplastic nevi and LCMN. Moreover, median scores from Nodal IHC expression analysis were not significantly different between these two groups. Additionally, none of the LCMN patients in this study developed melanoma, regardless of Nodal IHC levels. Co-culture experiments revealed reduced tumor growth and lower levels of Nodal and its signaling molecules P-SMAD2 and P-ERK1/2 when melanoma cells were grown in vivo or in vitro with normal melanocytes. The same was observed in melanoma cells cultured with melanocyte conditioned media containing pigmented melanocyte derived melanosomes (MDM). Since MDM contain molecules capable of inactivating radical oxygen species, to investigate potential anti-oxidant effect of MDM on Nodal expression and signaling in melanoma, melanoma cells were treated with either N-acetyl-l-cysteine (NAC), a component of the anti-oxidant glutathione or synthetic melanin, which in addition to providing pigmentation can also exert free radical scavenging activity. Melanoma cells treated with NAC or synthetic melanin showed reduced levels of Nodal, P-SMAD2 and P-ERK1/2 compared to untreated melanoma cells. Thus, the potential role for Nodal in melanoma development in LCMN is less evident than in adult dysplastic nevi possibly due to melanocyte cross-talk in LCMN capable of offsetting or delaying the pro-melanoma effects of Nodal via anti-oxidant effects of MDM. Full article

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

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Open AccessArticle

Alcohol Consumption during Pregnancy: Analysis of Two Direct Metabolites of Ethanol in Meconium

by Arantza Sanvisens^1,†, Neus Robert^2,†, José María Hernández^3,†, Paola Zuluaga^1,†, Magí Farré^4,†

, Wifredo Coroleu^5,†, Montserrat Serra^6,†, Jordi Tor^1,† and Robert Muga^1,*,†

¹ Departments of Internal Medicine, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain

² Emergency Medicine, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain

³ Proteomic and Metabolomic Unit, Fundació Institut d’Investigació Germans Trias i Pujol, 08916 Badalona, Spain

⁴ Clinical Pharmacology, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain

⁵ Paediatrics, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain

⁶ Obstetrics and Gyneacology, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(3), 417; https://doi.org/10.3390/ijms17030417 - 22 Mar 2016

Cited by 9 | Viewed by 7454

Abstract

Alcohol consumption in young women is a widespread habit that may continue during pregnancy and induce alterations in the fetus. We aimed to characterize prevalence of alcohol consumption in parturient women and to assess fetal ethanol exposure in their newborns by analyzing two [...] Read more.

Alcohol consumption in young women is a widespread habit that may continue during pregnancy and induce alterations in the fetus. We aimed to characterize prevalence of alcohol consumption in parturient women and to assess fetal ethanol exposure in their newborns by analyzing two direct metabolites of ethanol in meconium. This is a cross-sectional study performed in September 2011 and March 2012 in a series of women admitted to an obstetric unit following childbirth. During admission, socio-demographic and substance use (alcohol, tobacco, cannabis, cocaine, and opiates) during pregnancy were assessed using a structured questionnaire and clinical charts. We also recorded the characteristics of pregnancy, childbirth, and neonates. The meconium analysis was performed by liquid chromatography—tandem mass spectrometry (LC-MS/MS) to detect the presence of ethyl glucuronide (EtG) and ethyl sulfate (EtS). Fifty-one parturient and 52 neonates were included and 48 meconium samples were suitable for EtG and EtS detection. The median age of women was 30 years (interquartile range (IQR): 26–34 years); EtG was present in all meconium samples and median concentration of EtG was 67.9 ng/g (IQR: 36.0–110.6 ng/g). With respect to EtS, it was undetectable (<0.01 ng/g) in the majority of samples (79.1%). Only three (6%) women reported alcohol consumption during pregnancy in face-to-face interviews. However, prevalence of fetal exposure to alcohol through the detection of EtG and EtS was 4.2% and 16.7%, respectively. Prevention of alcohol consumption during pregnancy and the detection of substance use with markers of fetal exposure are essential components of maternal and child health. Full article

(This article belongs to the Special Issue Alcoholism: Molecular Mechanisms and Treatment Strategies)

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Immunogenicity and Cross-Protective Efficacy Induced by Outer Membrane Proteins from Salmonella Typhimurium Mutants with Truncated LPS in Mice

by Qiong Liu^1,†, Qing Liu^2,*,†, Xinxin Zhao¹, Tian Liu¹, Jie Yi¹, Kang Liang¹ and Qingke Kong^1,*

¹ Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China

² Department of Bioengineering, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(3), 416; https://doi.org/10.3390/ijms17030416 - 22 Mar 2016

Cited by 32 | Viewed by 11024

Abstract

Lipopolysaccharide (LPS) is a major virulence factor present in the outer membrane of Salmonella enterica serovar Typhimurium (S. Typhimurium). Outer membrane proteins (OMPs) from Salmonella show high immunogenicity and provide protection against Salmonella infection, and truncated LPS alters the outer membrane composition [...] Read more.

Lipopolysaccharide (LPS) is a major virulence factor present in the outer membrane of Salmonella enterica serovar Typhimurium (S. Typhimurium). Outer membrane proteins (OMPs) from Salmonella show high immunogenicity and provide protection against Salmonella infection, and truncated LPS alters the outer membrane composition of the cell wall. In our previous study, we demonstrated that Salmonella mutants carrying truncated LPS failed to induce strong immune responses and cross-reaction to other enteric bacteria, due to their high attenuation and low colonization in the host. Therefore, we plan to investigate whether outer membrane proteins from Salmonella mutants with truncated LPS resulting from a series of nonpolar mutations, including ∆waaC12, ∆waaF15, ∆waaG42, ∆rfaH49, ∆waaI43, ∆waaJ44, ∆waaL46, ∆wbaP45 and ∆wzy-48, affect immunogenicity and provide protection against diverse Salmonella challenge. In this study, the immunogenicity and cross-protection efficiency of purified OMPs from all mutants were investigated to explore a potential OMP vaccine to protect against homologous or heterologous serotype Salmonella challenge. The results demonstrated that OMPs from three Salmonella mutants (∆waaC12, ∆waaJ44 and ∆waaL46) induced higher immune responses and provided good protection against homologous S. Typhimurium. The OMPs from these three mutants were also selected to determine the cross-protective efficacy against homologous and heterologous serotype Salmonella. Our results indicated that the mutant ∆waaC12 can elicit higher cross-reactivity and can provide good protection against S. Choleraesuis and S. Enteritidis infection and that the cross-reactivity may be ascribed to an antigen of approximately 18.4–30 kDa. Full article

(This article belongs to the Special Issue Infectious Diseases: Pathophysiology, Diagnostics, Therapies, and Prevention)

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Open AccessConference Report

Ocular Stem Cell Research from Basic Science to Clinical Application: A Report from Zhongshan Ophthalmic Center Ocular Stem Cell Symposium

by Hong Ouyang¹, Jeffrey L. Goldberg², Shuyi Chen¹, Wei Li³, Guo-Tong Xu⁴, Wei Li⁵, Kang Zhang⁶, Robert B. Nussenblatt⁷, Yizhi Liu¹, Ting Xie^8,*, Chi-Chao Chan^1,7,* and Donald J. Zack^9,*

¹ State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China

² Department of Ophthalmology, Stanford University, Palo Alto, CA 94303, USA

³ Unit on Retinal Neurophysiology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA

⁴ Department of Ophthalmology, Tongji University, Shanghai 200092, China

⁵ Department of Ophthalmology, Xiamen University, Xiamen 361005, China

⁶ Department of Ophthalmology, University of California San Diego, San Diego, CA 92093, USA

⁷ Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA

⁸ Stowers Institute for Medical Research, Kansas City, MO 64110, USA

⁹ Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, MD 21231, USA

Int. J. Mol. Sci. 2016, 17(3), 415; https://doi.org/10.3390/ijms17030415 - 22 Mar 2016

Cited by 14 | Viewed by 12260

Abstract

Stem cells hold promise for treating a wide variety of diseases, including degenerative disorders of the eye. The eye is an ideal organ for stem cell therapy because of its relative immunological privilege, surgical accessibility, and its being a self-contained system. The eye [...] Read more.

Stem cells hold promise for treating a wide variety of diseases, including degenerative disorders of the eye. The eye is an ideal organ for stem cell therapy because of its relative immunological privilege, surgical accessibility, and its being a self-contained system. The eye also has many potential target diseases amenable to stem cell-based treatment, such as corneal limbal stem cell deficiency, glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa (RP). Among them, AMD and glaucoma are the two most common diseases, affecting over 200 million people worldwide. Recent results on the clinical trial of retinal pigment epithelial (RPE) cells from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) in treating dry AMD and Stargardt’s disease in the US, Japan, England, and China have generated great excitement and hope. This marks the beginning of the ocular stem cell therapy era. The recent Zhongshan Ophthalmic Center Ocular Stem Cell Symposium discussed the potential applications of various stem cell types in stem cell-based therapies, drug discoveries and tissue engineering for treating ocular diseases. Full article

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Open AccessArticle

Disrupted Homeostatic Cytokines Expression in Secondary Lymph Organs during HIV Infection

by Lintao Zhao^1,†, Jianbao Gao^1,†, Yan Li^2,†, Lina Liu¹, Yang Yang¹, Bo Guo^3,* and Bo Zhu^1,*

¹ Department of Oncology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China

² Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China

³ Department of Pathogenic Biology, Third Military Medical University, Chongqing 400037, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(3), 413; https://doi.org/10.3390/ijms17030413 - 22 Mar 2016

Cited by 6 | Viewed by 5095

Abstract

Research has firmly established that infection by human immunodeficiency virus (HIV) leads to structural disruption in secondary lymph organs (SLOs) and that IL-7 expression by SLOs is downregulated in simian immunodeficiency virus (SIV)-infected rhesus macaques. However, the foregoing has not been demonstrated in [...] Read more.

Research has firmly established that infection by human immunodeficiency virus (HIV) leads to structural disruption in secondary lymph organs (SLOs) and that IL-7 expression by SLOs is downregulated in simian immunodeficiency virus (SIV)-infected rhesus macaques. However, the foregoing has not been demonstrated in HIV-infected patients. As well, SLO-produced chemokines and cytokines, other than IL-7, have not been tested. In this study, SLOs in HIV-infected patients exhibit decreased levels of lymphoid cytokines, such as IL-7 and C–C motif chemokine ligand 21 (CCL21), due to lower expression of lymphotoxin (LT)-β. Previous research has shown that LT-β is produced mainly by CD4⁺T cells in rhesus macaques, while our study found the same level of LT-β expressed by CD4⁺T and CD8⁺T cells in humans. CD8⁺T cells substitute for depleted CD4⁺T cells LT-β production. Only the total number of CD3⁺T cells can account for the majority of LT-β in human SLOs. This study indicates a possible mechanism and a potential target for improvement of SLO function in HIV-infected patients, a novel adjuvant therapy for AIDS. Full article

(This article belongs to the Special Issue Immuno- and Neuropathogenesis of HIV Disease: Mechanisms, Prevention, Treatment, and Cure)

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Open AccessArticle

Biodegradation of Single-Walled Carbon Nanotubes in Macrophages through Respiratory Burst Modulation

by Jie Hou¹, Bin Wan^1,*, Yu Yang¹, Xiao-Min Ren¹, Liang-Hong Guo^1,2,* and Jing-Fu Liu¹

¹ State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China

² Institute of Environment and Health, Jianghan University, Wuhan 430056, China

Int. J. Mol. Sci. 2016, 17(3), 409; https://doi.org/10.3390/ijms17030409 - 22 Mar 2016

Cited by 34 | Viewed by 7357

Abstract

The biodegradation of carbon nanotubes (CNTs) may be one of major determinants of the toxic outcomes in exposed individuals. In this study, we employed a macrophage/monocyte model, Raw264.7, to investigate the feasibility of regulating the biodegradation of three types of single-walled carbon nanotubes [...] Read more.

The biodegradation of carbon nanotubes (CNTs) may be one of major determinants of the toxic outcomes in exposed individuals. In this study, we employed a macrophage/monocyte model, Raw264.7, to investigate the feasibility of regulating the biodegradation of three types of single-walled carbon nanotubes (SWCNTs) (pristine, ox-, and OH-SWCNTs) by respiratory burst modulation. An artificial fluid mimicking the enzymatic reactions of respiratory burst was constituted to reveal the role of respiratory burst played in SWCNT biodegradation. The biodegradation of SWCNTs were characterized by Raman, ultraviolet-visible-near-infrared spectroscopy, and transmission electron microscopy. Our results showed significantly accelerated biodegradation of ox-SWCNTs and OH-SWCNTs in macrophages activated by phorbol myristate acetate (PMA), which could be prevented by N-acetyl-l-cysteine (NAC), whereas p-SWCNTs were resistant to biodegradation. Similar tendencies were observed by using the in vitro enzymatic system, and the degradation rates of these SWCNTs are in the order of OH-SWCNTs > ox-SWCNTs >> p-SWCNTs, suggesting a pivotal role of respiratory burst in accelerating the biodegradation of SWCNTs and that defect sites on SWCNTs might be a prerequisite for the biodegradation to occur. Our findings might provide invaluable clues on the development of intervention measurements for relieving the side effects of SWCNTs and would help to design safer SWCNT products with higher biodegradability and less toxicity. Full article

(This article belongs to the Special Issue Inorganic Nanostructures in Biological Systems)

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Open AccessArticle

Activin A-Smad Signaling Mediates Connective Tissue Growth Factor Synthesis in Liver Progenitor Cells

by Ze-Yang Ding¹, Guan-Nan Jin^1,2, Wei Wang¹, Yi-Min Sun¹, Wei-Xun Chen¹, Lin Chen¹, Hui-Fang Liang¹, Pran K. Datta³, Ming-Zhi Zhang⁴, Bixiang Zhang^1,* and Xiao-Ping Chen^1,*

¹ Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

² Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

³ Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA

⁴ Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University, Nashville, TN 37235, USA

Int. J. Mol. Sci. 2016, 17(3), 408; https://doi.org/10.3390/ijms17030408 - 22 Mar 2016

Cited by 15 | Viewed by 8120

Abstract

Liver progenitor cells (LPCs) are activated in chronic liver damage and may contribute to liver fibrosis. Our previous investigation reported that LPCs produced connective tissue growth factor (CTGF/CCN2), an inducer of liver fibrosis, yet the regulatory mechanism of the production of CTGF/CCN2 in [...] Read more.

Liver progenitor cells (LPCs) are activated in chronic liver damage and may contribute to liver fibrosis. Our previous investigation reported that LPCs produced connective tissue growth factor (CTGF/CCN2), an inducer of liver fibrosis, yet the regulatory mechanism of the production of CTGF/CCN2 in LPCs remains elusive. In this study, we report that Activin A is an inducer of CTGF/CCN2 in LPCs. Here we show that expression of both Activin A and CTGF/CCN2 were upregulated in the cirrhotic liver, and the expression of Activin A positively correlates with that of CTGF/CCN2 in liver tissues. We go on to show that Activin A induced de novo synthesis of CTGF/CCN2 in LPC cell lines LE/6 and WB-F344. Furthermore, Activin A contributed to autonomous production of CTGF/CCN2 in liver progenitor cells (LPCs) via activation of the Smad signaling pathway. Smad2, 3 and 4 were all required for this induction. Collectively, these results provide evidence for the fibrotic role of LPCs in the liver and suggest that the Activin A-Smad-CTGF/CCN2 signaling in LPCs may be a therapeutic target of liver fibrosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)

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Open AccessArticle

Isolation and Expression Analysis of STAT Members from Synechogobius hasta and Their Roles in Leptin Affecting Lipid Metabolism

by Kun Wu¹, Xiao-Ying Tan^1,2,*, Chuan-Chuan Wei¹, Wen-Jing You¹, Mei-Qin Zhuo¹ and Yu-Feng Song¹

¹ Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural University, Wuhan 430070, China

² Collaborative Innovation Center for Efficient and Health Production of Fisheries in Hunan Province, Changde 415000, China

Int. J. Mol. Sci. 2016, 17(3), 406; https://doi.org/10.3390/ijms17030406 - 22 Mar 2016

Cited by 13 | Viewed by 6509

Abstract

Signal transducers and activators of transcription proteins (STATs) act as important mediators in multiple biological processes induced by a large number of cytokines. In the present study, full-length cDNA sequences of seven STAT members, including some splicing variants different from those in mammals, [...] Read more.

Signal transducers and activators of transcription proteins (STATs) act as important mediators in multiple biological processes induced by a large number of cytokines. In the present study, full-length cDNA sequences of seven STAT members, including some splicing variants different from those in mammals, were obtained from Synechogobius hasta. The phylogenetic analysis revealed that the seven STAT members were derived from paralogous genes that might have arisen by whole genome duplication (WGD) events during vertebrate evolution. All of these members share similar domain structure compared with those of mammals, and were widely expressed across the tested tissues (brain, gill, heart, intestine, liver, muscle and spleen), but at variable levels. Incubation in vitro of recombinant human leptin changed the intracellular triglyceride (TG) content and mRNA levels of several STATs members, as well as expressions and activities of genes involved in lipid metabolism. Furthermore, Tyrphostin B42 (AG490), a specific inhibitor of the Janus Kinase 2(JAK2)-STAT pathway, partially reversed leptin-induced change on STAT3 and its two spliced isoforms expression, as well as expressions and activities of genes involved in lipid metabolism. As a consequence, the decrease of TG content was also reversed. Thus, our study suggests that STAT3 is the requisite for the leptin signal and the activation of the STAT3 member may account for the leptin-induced changes in lipid metabolism in S. hasta. Full article

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

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C/EBP β Mediates Endoplasmic Reticulum Stress Regulated Inflammatory Response and Extracellular Matrix Degradation in LPS-Stimulated Human Periodontal Ligament Cells

by Yudi Bai^1,*, Yi Wei¹, Lian Wu¹, Jianhua Wei², Xiaojing Wang¹ and Yuxiang Bai^3,*

¹ State Key Laboratory of Military Stomatology, Department of Pediatric Dentistry, School of Stomatology, the Fourth Military Medical University, Xi’an 710032, China

² Department of Oral and Maxillofacial Surgery, School of Stomatology, the Fourth Military Medical University, Xi’an 710032, China

³ Department of Health Statistics, the Fourth Military Medical University, Xi’an 710033, China

Int. J. Mol. Sci. 2016, 17(3), 385; https://doi.org/10.3390/ijms17030385 - 22 Mar 2016

Cited by 31 | Viewed by 7926

Abstract

Periodontitis is an oral inflammatory disease that not only affects the integrity of local tooth-supporting tissues but also impacts systemic health. A compositional shift in oral microbiota has been considered as the main cause of periodontitis; however, the potential mechanism has not been [...] Read more.

Periodontitis is an oral inflammatory disease that not only affects the integrity of local tooth-supporting tissues but also impacts systemic health. A compositional shift in oral microbiota has been considered as the main cause of periodontitis; however, the potential mechanism has not been fully defined. Herein, we investigated the role of CCAAT/enhancer-binding protein β (C/EBP β), a member of the C/EBP family of transcription factors, in human periodontal ligament cells (hPDLCs) exposed to Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS). RT-PCR and Western blotting analysis showed that the expression of C/EBP β was significantly increased in hPDLCs stimulated with LPS stimuli. Overexpression of C/EBP β by the recombinant adenoviral vector pAd/C/EBP β markedly increased the expression of the pro-inflammatory cytokines IL-6 and IL-8, and matrix metalloproteinases (MMP)-8 and -9 in hPDLCs in response to LPS. Furthermore, the activation of endoplasmic reticulum (ER) stress was confirmed in LPS-stimulated hPDLCs by measuring the expression of the ER stress marker molecules protein kinase-like ER kinase (PERK), eIF2α, GRP78/Bip, and C/EBP homologous protein (CHOP). The ER stress inhibitor salubrinal repressed, but inducer tunicamycin enhanced, the production of IL-6, IL-8, MMP-8, and MMP-9 in hPDLCs. Additionally, ER stress inducer tunicamycin significantly increased the expression level of C/EBP β in hPDLCs. Blocking of C/EBP β by siRNA resulted in a significant decrease in the secretion of IL-6 and IL-8 and expression of MMP-8 and MMP-9 induced by tunicamycin treatment in hPDLCs. Taken together, ER stress appears to play a regulatory role in the inflammatory response and extracellular matrix (ECM) degradation in hPDLCs in response to LPS stimuli by activating C/EBP β expression. This enhances our understanding of human periodontitis pathology. Full article

(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress)

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Open AccessArticle

Antiallergic Phorbol Ester from the Seeds of Aquilaria malaccensis

by Michal Korinek^1,2,†, Vitthal D. Wagh^1,†, I-Wen Lo¹

, Yu-Ming Hsu¹, Hsue-Yin Hsu³, Tsong-Long Hwang^4,5,6

, Yang-Chang Wu^1,7,8,9, Yuan-Bin Cheng^1,10

, Bing-Hung Chen^2,11,* and Fang-Rong Chang^1,10,12,13,*

¹ Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan

² Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan

³ Department of Life Sciences, Tzu Chi University, Hualien 970, Taiwan

⁴ Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan

⁵ Research Center for Industry of Human Ecology and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan

⁶ Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan

⁷ School of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan

⁸ Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 404, Taiwan

⁹ Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan

¹⁰ Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan

¹¹ The Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan

¹² Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

¹³ Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan

^† These authors contributed equally to this work.

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Int. J. Mol. Sci. 2016, 17(3), 398; https://doi.org/10.3390/ijms17030398 - 21 Mar 2016

Cited by 24 | Viewed by 8033

Abstract

The Aquilaria malaccensis (Thymelaeaceae) tree is a source of precious fragrant resin, called agarwood, which is widely used in traditional medicines in East Asia against diseases such as asthma. In our continuous search for active natural products, A. malaccensis seeds ethanolic extract demonstrated [...] Read more.

The Aquilaria malaccensis (Thymelaeaceae) tree is a source of precious fragrant resin, called agarwood, which is widely used in traditional medicines in East Asia against diseases such as asthma. In our continuous search for active natural products, A. malaccensis seeds ethanolic extract demonstrated antiallergic effect with an IC₅₀ value less than 1 µg/mL. Therefore, the present research aimed to purify and identify the antiallergic principle of A. malaccensis through a bioactivity-guided fractionation approach. We found that phorbol ester-rich fraction was responsible for the antiallergic activity of A. malaccensis seeds. One new active phorbol ester, 12-O-(2Z,4E,6E)-tetradeca-2,4,6-trienoylphorbol-13-acetate, aquimavitalin (1) was isolated. The structure of 1 was assigned by means of 1D and 2D NMR data and high-resolution mass spectrometry (HR-MS). Aquimavitalin (1) showed strong inhibitory activity in A23187- and antigen-induced degranulation assay with IC₅₀ values of 1.7 and 11 nM, respectively, with a therapeutic index up to 71,000. The antiallergic activities of A. malaccensis seeds and aquimavitalin (1) have never been revealed before. The results indicated that A. malaccensis seeds and the pure compound have the potential for use in the treatment of allergy. Full article

(This article belongs to the Special Issue The Mechanism of Action of Food Components in Disease Prevention)

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Open AccessEditorial

Announcing the International Journal of Molecular Sciences Junior Scientists Travel Awards 2016

by International Journal of Molecular Sciences Editorial Office

Klybeckstrasse 64, 4057 Basel, Switzerland

Int. J. Mol. Sci. 2016, 17(3), 405; https://doi.org/10.3390/ijms17030405 - 19 Mar 2016

Viewed by 3953

Abstract

With the goal of recognizing outstanding contributions to the field of molecular sciences by early-career investigators, including assistant professors, postdoctoral students and PhD students, [...] Full article

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Open AccessArticle

A Comparative Study of Molecular Structure, pKa, Lipophilicity, Solubility, Absorption and Polar Surface Area of Some Antiplatelet Drugs

by Milan Remko^1,*

, Anna Remková² and Ria Broer³

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, SK-832 32 Bratislava, Slovakia

² Department of Internal Medicine, Faculty of Medicine, Slovak Medical University, Limbová 12, SK–833 03 Bratislava, Slovakia

³ Department of Theoretical Chemistry, Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands

Int. J. Mol. Sci. 2016, 17(3), 388; https://doi.org/10.3390/ijms17030388 - 19 Mar 2016

Cited by 28 | Viewed by 9119

Abstract

Theoretical chemistry methods have been used to study the molecular properties of antiplatelet agents (ticlopidine, clopidogrel, prasugrel, elinogrel, ticagrelor and cangrelor) and several thiol-containing active metabolites. The geometries and energies of most stable conformers of these drugs have been computed at the Becke3LYP/6-311++G(d,p) [...] Read more.

Theoretical chemistry methods have been used to study the molecular properties of antiplatelet agents (ticlopidine, clopidogrel, prasugrel, elinogrel, ticagrelor and cangrelor) and several thiol-containing active metabolites. The geometries and energies of most stable conformers of these drugs have been computed at the Becke3LYP/6-311++G(d,p) level of density functional theory. Computed dissociation constants show that the active metabolites of prodrugs (ticlopidine, clopidogrel and prasugrel) and drugs elinogrel and cangrelor are completely ionized at pH 7.4. Both ticagrelor and its active metabolite are present at pH = 7.4 in neutral undissociated form. The thienopyridine prodrugs ticlopidine, clopidogrel and prasugrel are lipophilic and insoluble in water. Their lipophilicity is very high (about 2.5–3.5 logP values). The polar surface area, with regard to the structurally-heterogeneous character of these antiplatelet drugs, is from very large interval of values of 3–255 Å². Thienopyridine prodrugs, like ticlopidine, clopidogrel and prasugrel, with the lowest polar surface area (PSA) values, exhibit the largest absorption. A high value of polar surface area (PSA) of cangrelor (255 Å²) results in substantial worsening of the absorption in comparison with thienopyridine drugs. Full article

(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

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Open AccessArticle

The Role of K_V7.3 in Regulating Osteoblast Maturation and Mineralization

by Ji Eun Yang, Min Seok Song

, Yiming Shen, Pan Dong Ryu and So Yeong Lee^*

Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea

Int. J. Mol. Sci. 2016, 17(3), 407; https://doi.org/10.3390/ijms17030407 - 18 Mar 2016

Cited by 10 | Viewed by 6567

Abstract

KCNQ (K_V7) channels are voltage-gated potassium (K_V) channels, and the function of K_V7 channels in muscles, neurons, and sensory cells is well established. We confirmed that overall blockade of K_V channels with tetraethylammonium augmented the mineralization [...] Read more.

KCNQ (K_V7) channels are voltage-gated potassium (K_V) channels, and the function of K_V7 channels in muscles, neurons, and sensory cells is well established. We confirmed that overall blockade of K_V channels with tetraethylammonium augmented the mineralization of bone-marrow-derived human mesenchymal stem cells during osteogenic differentiation, and we determined that K_V7.3 was expressed in MG-63 and Saos-2 cells at the mRNA and protein levels. In addition, functional K_V7 currents were detected in MG-63 cells. Inhibition of K_V7.3 by linopirdine or XE991 increased the matrix mineralization during osteoblast differentiation. This was confirmed by alkaline phosphatase, osteocalcin, and osterix in MG-63 cells, whereas the expression of Runx2 showed no significant change. The extracellular glutamate secreted by osteoblasts was also measured to investigate its effect on MG-63 osteoblast differentiation. Blockade of K_V7.3 promoted the release of glutamate via the phosphorylation of extracellular signal-regulated kinase 1/2-mediated upregulation of synapsin, and induced the deposition of type 1 collagen. However, activation of K_V7.3 by flupirtine did not produce notable changes in matrix mineralization during osteoblast differentiation. These results suggest that K_V7.3 could be a novel regulator in osteoblast differentiation. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

First-Generation Antipsychotic Haloperidol Alters the Functionality of the Late Endosomal/Lysosomal Compartment in Vitro

by Alberto Canfrán-Duque¹, Luis C. Barrio², Milagros Lerma¹, Gema De la Peña¹, Jorge Serna³, Oscar Pastor³, Miguel A. Lasunción^1,4,*,†

and Rebeca Busto^1,4,*,†

¹ Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain

² Unidad de Neurología Experimental, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain

³ Servicio de Bioquímica-Clínica, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain

⁴ CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(3), 404; https://doi.org/10.3390/ijms17030404 - 18 Mar 2016

Cited by 17 | Viewed by 5990

Abstract

First- and second-generation antipsychotics (FGAs and SGAs, respectively), have the ability to inhibit cholesterol biosynthesis and also to interrupt the intracellular cholesterol trafficking, interfering with low-density lipoprotein (LDL)-derived cholesterol egress from late endosomes/lysosomes. In the present work, we examined the effects of FGA [...] Read more.

First- and second-generation antipsychotics (FGAs and SGAs, respectively), have the ability to inhibit cholesterol biosynthesis and also to interrupt the intracellular cholesterol trafficking, interfering with low-density lipoprotein (LDL)-derived cholesterol egress from late endosomes/lysosomes. In the present work, we examined the effects of FGA haloperidol on the functionality of late endosomes/lysosomes in vitro. In HepG2 hepatocarcinoma cells incubated in the presence of 1,1′-dioctadecyl-3,3,3,3′-tetramethylindocarbocyanineperchlorate (DiI)-LDL, treatment with haloperidol caused the enlargement of organelles positive for late endosome markers lysosome-associated membrane protein 2 (LAMP-2) and LBPA (lysobisphosphatidic acid), which also showed increased content of both free-cholesterol and DiI derived from LDL. This indicates the accumulation of LDL-lipids in the late endosomal/lysosomal compartment caused by haloperidol. In contrast, LDL traffic through early endosomes and the Golgi apparatus appeared to be unaffected by the antipsychotic as the distribution of both early endosome antigen 1 (EEA1) and coatomer subunit β (β-COP) were not perturbed. Notably, treatment with haloperidol significantly increased the lysosomal pH and decreased the activities of lysosomal protease and β-d-galactosidase in a dose-dependent manner. We conclude that the alkalinization of the lysosomes’ internal milieu induced by haloperidol affects lysosomal functionality. Full article

(This article belongs to the Special Issue Antipsychotics)

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Open AccessArticle

Evolving Diversity of Hepatitis C Viruses in Yunnan Honghe, China

by Lanhui Yang^1,2,*, Chenyan Jiang³, Song Hu⁴, Qiongni Diao³, Jia Li⁴, Wei Si¹, Mei Chen⁴ and Richard Y. Zhao^2,*

¹ Department of Clinical Laboratory, The First People’s Hospital of Honghe, Mengzi 661100, China

² Division of Molecular Pathology, Department of Pathology, University of Maryland School of Medicine, Baltimore, 21201 MD, USA

³ Division of Life Science, College of Life Science and Technology, Honghe University, Mengzi 661100, China

⁴ Department of Infectious Diseases, The First People’s Hospital of Honghe, Mengzi 661100, China

Int. J. Mol. Sci. 2016, 17(3), 403; https://doi.org/10.3390/ijms17030403 - 18 Mar 2016

Cited by 6 | Viewed by 5612

Abstract

The Chinese Honghe Autonomous Prefecture (Honghe) in Yunnan Province is a unique ethnic area because it is inhabited by more than ten different minority ethnic groups. Geographically, Honghe directly shares a border with Vietnam. The objective of this study was to investigate genetic [...] Read more.

The Chinese Honghe Autonomous Prefecture (Honghe) in Yunnan Province is a unique ethnic area because it is inhabited by more than ten different minority ethnic groups. Geographically, Honghe directly shares a border with Vietnam. The objective of this study was to investigate genetic diversity and distribution of the Hepatitis C virus (HCV) in Honghe. Ninety nine subjects who were infected with HCV or HCV/HIV (Human Immunodeficiency Virus Type 1) were recruited into this study. HCV genotypes and subtypes were determined based on the sequences of the core/envelope 1 (C/E1) and the nonstructural protein 5B (NS5B) genomic regions. The viral diversity and origins of dissemination were examined by phylogenetic analyses. Three HCV genotypes (1, 3 and 6) with six subtypes (1b, 3b, 3a, 6a, 6n and 6v) were identified. The most predominant form was genotype 3 (54.6%) followed by 6 (34.3%), and 1 (9.1%). The HCV subtype 3b appeared to be the most frequent form (38.4%) followed by 6n (20.2%) and 3a (16.2%). Statistical analyses suggested a possible rise of the genotype 6a in Honghe among intravenous drug users with HCV/HIV co-infections. Further phylogenetic analyses suggested that similar HCV-6a viruses might have been circulating in the Honghe area for more than a decade, which likely originated from Vietnam or vice versa. Two HCV samples with single HCV infection (SC34 and SC45) were isolated that could represent new recombinant variants. Although the genetic prevalence of HCV in Honghe is in general agreement with that of Southwest China and Yunnan Province, the diversity of HCV genotypes and subtypes in Honghe is somewhat unique and evolving. Information presented here should provide useful information for future health surveillance and prevention of HCV infection in this area. Full article

(This article belongs to the Special Issue Immuno- and Neuropathogenesis of HIV Disease: Mechanisms, Prevention, Treatment, and Cure)

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Open AccessArticle

A Novel Pretreatment-Free Duplex Chamber Digital PCR Detection System for the Absolute Quantitation of GMO Samples

by Pengyu Zhu¹, Chenguang Wang¹, Kunlun Huang^1,2, Yunbo Luo^1,2 and Wentao Xu^1,2,*

¹ Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China

² Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China

Int. J. Mol. Sci. 2016, 17(3), 402; https://doi.org/10.3390/ijms17030402 - 18 Mar 2016

Cited by 18 | Viewed by 6548

Abstract

Digital polymerase chain reaction (PCR) has developed rapidly since it was first reported in the 1990s. However, pretreatments are often required during preparation for digital PCR, which can increase operation error. The single-plex amplification of both the target and reference genes may cause [...] Read more.

Digital polymerase chain reaction (PCR) has developed rapidly since it was first reported in the 1990s. However, pretreatments are often required during preparation for digital PCR, which can increase operation error. The single-plex amplification of both the target and reference genes may cause uncertainties due to the different reaction volumes and the matrix effect. In the current study, a quantitative detection system based on the pretreatment-free duplex chamber digital PCR was developed. The dynamic range, limit of quantitation (LOQ), sensitivity and specificity were evaluated taking the GA21 event as the experimental object. Moreover, to determine the factors that may influence the stability of the duplex system, we evaluated whether the pretreatments, the primary and secondary structures of the probes and the SNP effect influence the detection. The results showed that the LOQ was 0.5% and the sensitivity was 0.1%. We also found that genome digestion and single nucleotide polymorphism (SNP) sites affect the detection results, whereas the unspecific hybridization within different probes had little side effect. This indicated that the detection system was suited for both chamber-based and droplet-based digital PCR. In conclusion, we have provided a simple and flexible way of achieving absolute quantitation for genetically modified organism (GMO) genome samples using commercial digital PCR detection systems. Full article

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

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Open AccessReview

Biosurfactants: Multifunctional Biomolecules of the 21st Century

by Danyelle Khadydja F. Santos^1,2, Raquel D. Rufino^2,3, Juliana M. Luna^2,3, Valdemir A. Santos^2,3 and Leonie A. Sarubbo^1,2,3,*

¹ Northeast Botechnology Network (RENORBIO), Federal Rural University of Pernambuco, Rua Dom Manoel de Medeiros, s/n, Dois Irmãos, 52171-900 Recife-PE, Brazil

² Center of Sciences and Technology, Catholic University of Pernambuco (UNICAP), Rua do Príncipe, 526, Boa Vista, 50050-900 Recife-PE, Brazil

³ Advanced Institute of Technology and Innovation (IATI), Rua Carlos Porto Carreiro, 70, Derby, 50070-090 Recife-PE, Brazil

Int. J. Mol. Sci. 2016, 17(3), 401; https://doi.org/10.3390/ijms17030401 - 18 Mar 2016

Cited by 804 | Viewed by 28898

Abstract

In the era of global industrialisation, the exploration of natural resources has served as a source of experimentation for science and advanced technologies, giving rise to the manufacturing of products with high aggregate value in the world market, such as biosurfactants. Biosurfactants are [...] Read more.

In the era of global industrialisation, the exploration of natural resources has served as a source of experimentation for science and advanced technologies, giving rise to the manufacturing of products with high aggregate value in the world market, such as biosurfactants. Biosurfactants are amphiphilic microbial molecules with hydrophilic and hydrophobic moieties that partition at liquid/liquid, liquid/gas or liquid/solid interfaces. Such characteristics allow these biomolecules to play a key role in emulsification, foam formation, detergency and dispersal, which are desirable qualities in different industries. Biosurfactant production is considered one of the key technologies for development in the 21st century. Besides exerting a strong positive impact on the main global problems, biosurfactant production has considerable importance to the implantation of sustainable industrial processes, such as the use of renewable resources and “green” products. Biodegradability and low toxicity have led to the intensification of scientific studies on a wide range of industrial applications for biosurfactants in the field of bioremediation as well as the petroleum, food processing, health, chemical, agricultural and cosmetic industries. In this paper, we offer an extensive review regarding knowledge accumulated over the years and advances achieved in the incorporation of biomolecules in different industries. Full article

(This article belongs to the Section Green Chemistry)

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Int. J. Mol. Sci., Volume 17, Issue 3 (March 2016) – 159 articles

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