International Journal of Molecular Sciences

3748 KiB

Open AccessArticle

Influence of Secondary-Structure Folding on the Mutually Exclusive Folding Process of GL5/I27 Protein: Evidence from Molecular Dynamics Simulations

by Qing Wang, Yan Wang and Guangju Chen

Int. J. Mol. Sci. 2016, 17(11), 1962; https://doi.org/10.3390/ijms17111962 - 23 Nov 2016

Cited by 8 | Viewed by 5196

Abstract

Mutually exclusive folding proteins are a class of multidomain proteins in which the host domain remains folded while the guest domain is unfolded, and both domains achieve exchange of their folding status by a mutual exclusive folding (MEF) process. We carried out conventional [...] Read more.

Mutually exclusive folding proteins are a class of multidomain proteins in which the host domain remains folded while the guest domain is unfolded, and both domains achieve exchange of their folding status by a mutual exclusive folding (MEF) process. We carried out conventional and targeted molecular dynamics simulations for the mutually exclusive folding protein of GL5/I27 to address the MEF transition mechanisms. We constructed two starting models and two targeted models, i.e., the starting models GL5/I27-S and GL5/I27-ST in which the first model involves the host domain GL5 and the secondary-structure unfolded guest domain I27-S, while the second model involves the host domain GL5 and the secondary/tertiary-structure extending guest domain I27-ST, and the target models GL5-S/I27 and GL5-ST/I27 in which GL5-S and GL5-ST represent the secondary-structure unfolding and the secondary/tertiary-structure extending, respectively. We investigated four MEF transition processes from both starting models to both target models. Based on structural changes and the variations of the radius of gyration (R_g) and the fractions of native contacts (Q), the formation of the secondary structure of the I27-guest domain induces significant extending of the GL5-host domain; but the primary shrinking of the tertiary structure of the I27-guest domain causes insignificant extending of the GL5-host domain during the processes. The results indicate that only formation of the secondary structure in the I27-guest domain provides the main driving force for the mutually exclusive folding/unfolding between the I27-guest and GL5-host domains. A special structure as an intermediate with both host and guest domains being folded at the same time was found, which was suggested by the experiment. The analysis of hydrogen bonds and correlation motions supported the studied transition mechanism with the dynamical “tug-of-war” phenomenon. Full article

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

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6367 KiB

Open AccessArticle

HMGB1 Promotes Intraoral Palatal Wound Healing through RAGE-Dependent Mechanisms

by Salunya Tancharoen, Satoshi Gando, Shrestha Binita, Tomoka Nagasato, Kiyoshi Kikuchi, Yuko Nawa, Pornpen Dararat, Mika Yamamoto, Somphong Narkpinit and Ikuro Maruyama

Int. J. Mol. Sci. 2016, 17(11), 1961; https://doi.org/10.3390/ijms17111961 - 23 Nov 2016

Cited by 22 | Viewed by 7438

Abstract

High mobility group box 1 (HMGB1) is tightly connected to the process of tissue organization upon tissue injury. Here we show that HMGB1 controls epithelium and connective tissue regeneration both in vivo and in vitro during palatal wound healing. Heterozygous HMGB1 (Hmgb1 [...] Read more.

High mobility group box 1 (HMGB1) is tightly connected to the process of tissue organization upon tissue injury. Here we show that HMGB1 controls epithelium and connective tissue regeneration both in vivo and in vitro during palatal wound healing. Heterozygous HMGB1 (Hmgb1^+/−) mice and Wild-type (WT) mice were subjected to palatal injury. Maxillary tissues were stained with Mallory Azan or immunostained with anti-HMGB1, anti-proliferating cell nuclear antigen (PCNA), anti-nuclear factor-κB (NF-κB) p50 and anti-vascular endothelial growth factor (VEGF) antibodies. Palatal gingival explants were cultured with recombinant HMGB1 (rHMGB1) co-treated with siRNA targeting receptor for advanced glycation end products (RAGEs) for cell migration and PCNA expression analysis. Measurement of the wound area showed differences between Hmgb1^+/− and WT mice on Day 3 after wounding. Mallory Azan staining showed densely packed of collagen fibers in WT mice, whereas in Hmgb1^+/− mice weave-like pattern of low density collagen bundles were present. At three and seven days post-surgery, PCNA, NF-κB p50 and VEGF positive keratinocytes of WT mice were greater than that of Hmgb1^+/− mice. Knockdown of RAGE prevents the effect of rHMGB1-induced cell migration and PCNA expression in gingival cell cultures. The data suggest that HMGB1/RAGE axis has crucial roles in palatal wound healing. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration)

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796 KiB

Open AccessArticle

Fatty Acid and Phenolic Compound Concentrations in Eight Different Monovarietal Virgin Olive Oils from Extremadura and the Relationship with Oxidative Stability

by Alfonso Montaño, Marcos Hernández, Inmaculada Garrido, José Luís Llerena and Francisco Espinosa

Int. J. Mol. Sci. 2016, 17(11), 1960; https://doi.org/10.3390/ijms17111960 - 23 Nov 2016

Cited by 48 | Viewed by 6310

Abstract

Olive oils have been shown to be more resistant to oxidation than other vegetable fats, mainly due to their fatty acid (FA) profile which is rich in oleic acid and to their high content of antioxidants, principally phenols and tocopherols. This has situated [...] Read more.

Olive oils have been shown to be more resistant to oxidation than other vegetable fats, mainly due to their fatty acid (FA) profile which is rich in oleic acid and to their high content of antioxidants, principally phenols and tocopherols. This has situated virgin olive oils (VOOs) among the fats of high nutritional quality. However, it is important to stress that the oil’s commercial category (olive oil, virgin olive oil, extra-virgin olive oil), the variety of the source plant, and the extraction-conservation systems all decisively influence the concentration of these antioxidants and the oil’s shelf-life. The present work studied the fatty acid (FA) and phenolic composition and the oxidative stability (OS) of eight olive varieties grown in Extremadura (Arbequina, Cornicabra, Manzanilla Cacereña, Manzanilla de Sevilla, Morisca, Pico Limón, Picual, and Verdial de Badajoz), with the olives being harvested at different locations and dates. The Cornicabra, Picual, and Manzanilla Cacereña VOOs were found to have high oleic acid contents (>77.0%), while the VOOs of Morisca and Verdial de Badajoz had high linoleic acid contents (>14.5%). Regarding the phenol content, high values were found in the Cornicabra (633 mg·kg⁻¹) and Morisca (550 mg·kg⁻¹) VOOs, and low values in Arbequina (200 mg·kg⁻¹). The OS was found to depend upon both the variety and the date of harvesting. It was higher in the Cornicabra and Picual oils (>55 h), and lower in those of Verdial de Badajoz (26.3 h), Arbequina (29.8 h), and Morisca (31.5 h). In relating phenols and FAs with the OS, it was observed that, while the latter, particularly the linoleic content (R = −0.710, p < 0.001, n = 135), constitute the most influential factors, the phenolic compounds, especially o-diphenols, are equally influential when the oils’ linoleic content is ≥12.5% (R = 0.674, p < 0.001, n = 47). The results show that VOOs’ resistance to oxidation depends not only on the FA or phenolic profile, but also on the interaction of these compounds within the same matrix. Full article

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

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Open AccessArticle

Intracranial Thrombus Morphology and Composition Undergoes Time-Dependent Changes in Acute Ischemic Stroke: A CT Densitometry Study

by Slaven Pikija, Jozef Magdic, Vladimir Trkulja, Peter Unterkreuter, Johannes Sebastian Mutzenbach, Helmut F. Novak, Friedrich Weymayr, Larissa Hauer and Johann Sellner

Int. J. Mol. Sci. 2016, 17(11), 1959; https://doi.org/10.3390/ijms17111959 - 23 Nov 2016

Cited by 23 | Viewed by 5349

Abstract

The aim of our study was to assess whether cerebral artery clots undergo time-dependent morphological and compositional changes in acute ischemic stroke. We performed a retrospective chart review of patients admitted within 5 h from symptom onset to three European stroke centers and [...] Read more.

The aim of our study was to assess whether cerebral artery clots undergo time-dependent morphological and compositional changes in acute ischemic stroke. We performed a retrospective chart review of patients admitted within 5 h from symptom onset to three European stroke centers and evaluated non-contrast-enhanced CT (NECT) for hyperdense artery signs (HAS) in 2565 scans. The occlusion site, density of HAS expressed in Hounsfield units (HU), area of HAS, and relative density (rHU) (HU clot/HU non-affected artery) were studied and related to time from symptom onset, clinical severity, stroke etiology, and laboratory parameters. A HAS was present in the middle cerebral artery (MCA) in 185 (7.2%) and further explored. The mean time from symptom onset to CT was 100 min (range 17–300). We found a time-dependent loss of density in the occluded M1 segment within the first 5 h (N = 118, 95% CI [−15, −2], p = 0.01). Further, the thrombus area in the M2 segment decreased with time (cubic trend N = 67, 95% CI [−63, −8], p = 0.02). Overall, and especially in the M2 segment, a lower clot area was associated with higher fibrinogen (−21.7%, 95% CI [−34.8, −5.8], p = 0.009). In conclusion, our results disclosed time-dependent changes of intracranial thrombi with regard to occlusion site, density and area. Full article

(This article belongs to the Special Issue Atherosclerosis and Vascular Imaging 2016)

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Open AccessReview

Pro-Tumoral Inflammatory Myeloid Cells as Emerging Therapeutic Targets

by Gabor J. Szebeni, Csaba Vizler, Lajos I. Nagy, Klara Kitajka and Laszlo G. Puskas

Int. J. Mol. Sci. 2016, 17(11), 1958; https://doi.org/10.3390/ijms17111958 - 23 Nov 2016

Cited by 43 | Viewed by 7982

Abstract

Since the observation of Virchow, it has long been known that the tumor microenvironment constitutes the soil for the infiltration of inflammatory cells and for the release of inflammatory mediators. Under certain circumstances, inflammation remains unresolved and promotes cancer development. Here, we review [...] Read more.

Since the observation of Virchow, it has long been known that the tumor microenvironment constitutes the soil for the infiltration of inflammatory cells and for the release of inflammatory mediators. Under certain circumstances, inflammation remains unresolved and promotes cancer development. Here, we review some of these indisputable experimental and clinical evidences of cancer related smouldering inflammation. The most common myeloid infiltrate in solid tumors is composed of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). These cells promote tumor growth by several mechanisms, including their inherent immunosuppressive activity, promotion of neoangiogenesis, mediation of epithelial-mesenchymal transition and alteration of cellular metabolism. The pro-tumoral functions of TAMs and MDSCs are further enhanced by their cross-talk offering a myriad of potential anti-cancer therapeutic targets. We highlight these main pro-tumoral mechanisms of myeloid cells and give a general overview of their phenotypical and functional diversity, offering examples of possible therapeutic targets. Pharmacological targeting of inflammatory cells and molecular mediators may result in therapies improving patient condition and prognosis. Here, we review experimental and clinical findings on cancer-related inflammation with a major focus on creating an inventory of current small molecule-based therapeutic interventions targeting cancer-related inflammatory cells: TAMs and MDSCs. Full article

(This article belongs to the Special Issue Inflammation and Cancer)

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Open AccessArticle

Dual Function of Glucosamine in Gelatin/Hyaluronic Acid Cryogel to Modulate Scaffold Mechanical Properties and to Maintain Chondrogenic Phenotype for Cartilage Tissue Engineering

by Chih-Hao Chen, Chang-Yi Kuo, Yan-Jie Wang and Jyh-Ping Chen

Int. J. Mol. Sci. 2016, 17(11), 1957; https://doi.org/10.3390/ijms17111957 - 23 Nov 2016

Cited by 51 | Viewed by 7800

Abstract

Glucosamine (GlcN) fulfills many of the requirements as an ideal component in scaffolds used in cartilage tissue engineering. The incorporation of GlcN in a gelatin/hyaluronic acid (GH) cryogel scaffold could provide biological cues in maintaining the phenotype of chondrocytes. Nonetheless, substituting gelatin with [...] Read more.

Glucosamine (GlcN) fulfills many of the requirements as an ideal component in scaffolds used in cartilage tissue engineering. The incorporation of GlcN in a gelatin/hyaluronic acid (GH) cryogel scaffold could provide biological cues in maintaining the phenotype of chondrocytes. Nonetheless, substituting gelatin with GlcN may also decrease the crosslinking density and modulate the mechanical properties of the cryogel scaffold, which may be beneficial as physical cues for chondrocytes in the scaffold. Thus, we prepared cryogel scaffolds containing 9% GlcN (GH-GlcN9) and 16% GlcN (GH-GlcN16) by carbodiimide-mediated crosslinking reactions at −16 °C. The crosslinking density and the mechanical properties of the cryogel matrix could be tuned by adjusting the content of GlcN used during cryogel preparation. In general, incorporation of GlcN did not influence scaffold pore size and ultimate compressive strain but increased porosity. The GH-GlcN16 cryogel showed the highest swelling ratio and degradation rate in hyaluronidase and collagenase solutions. On the contrary, the Young’s modulus, storage modulus, ultimate compressive stress, energy dissipation level, and rate of stress relaxation decreased by increasing the GlcN content in the cryogel. The release of GlcN from the scaffolds in the culture medium of chondrocytes could be sustained for 21 days for GH-GlcN16 in contrast to only 7 days for GH-GlcN9. In vitro cell culture experiments using rabbit articular chondrocytes revealed that GlcN incorporation affected cell proliferation, morphology, and maintenance of chondrogenic phenotype. Overall, GH-GlcN16 showed the best performance in maintaining chondrogenic phenotype with reduced cell proliferation rate but enhanced glycosaminoglycans (GAGs) and type II collagen (COL II) secretion. Quantitative real-time polymerase chain reaction also showed time-dependent up-regulation of cartilage-specific marker genes (COL II, aggrecan and Sox9) for GH-GlcN16. Implantation of chondrocytes/GH-GlcN16 constructs into full-thickness articular cartilage defects of rabbits could regenerate neocartilage with positive staining for GAGs and COL II. The GH-GlcN16 cryogel will be suitable as a scaffold for the treatment of articular cartilage defects. Full article

(This article belongs to the Section Materials Science)

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Open AccessArticle

Microarray Expression Profiling of Long Non-Coding RNAs Involved in Nasopharyngeal Carcinoma Metastasis

by Xin Wen, Xinran Tang, Yingqin Li, Xianyue Ren, Qingmei He, Xiaojing Yang, Jian Zhang, Yaqin Wang, Jun Ma and Na Liu

Int. J. Mol. Sci. 2016, 17(11), 1956; https://doi.org/10.3390/ijms17111956 - 23 Nov 2016

Cited by 31 | Viewed by 6677

Abstract

Increasing evidence has demonstrated a significant role for long non-coding RNAs (lncRNAs) in tumorigenesis. However, their functions in nasopharyngeal carcinoma (NPC) metastasis remain largely unknown. In this study, a model comparing high and low metastatic NPC cell lines (5-8F vs. 6-10B and S18 [...] Read more.

Increasing evidence has demonstrated a significant role for long non-coding RNAs (lncRNAs) in tumorigenesis. However, their functions in nasopharyngeal carcinoma (NPC) metastasis remain largely unknown. In this study, a model comparing high and low metastatic NPC cell lines (5-8F vs. 6-10B and S18 vs. S26) was constructed to determine the expression profile of lncRNAs using the microarray analysis, and we found 167 lncRNAs and 209 mRNAs were differentially expressed. Bioinformatic analysis indicated that the dysregulated mRNAs participated in important biological regulatory functions in NPC. Validation of 26 significantly dysregulated lncRNAs by qRT-PCR showed the expression patterns of 22 lncRNAs were in accordance with the microarray data. Furthermore, the expression level of ENST00000470135, which was the most upregulated lncRNA in high metastatic cell lines, was significantly higher in NPC cell lines and tissues with lymph node metastasis (LNM) and knocking down ENST00000470135 suppressed the migration, invasion and proliferation of NPC cells in vitro. In conclusion, our study revealed expression patterns of lncRNAs in NPC metastasis. The dysregulated lncRNAs may act as novel biomarkers and therapeutic targets for NPC. Full article

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

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Open AccessCommunication

Importance of Heat and Pressure for Solubilization of Recombinant Spider Silk Proteins in Aqueous Solution

by Justin A. Jones, Thomas I. Harris, Paula F. Oliveira, Brianne E. Bell, Abdulrahman Alhabib and Randolph V. Lewis

Int. J. Mol. Sci. 2016, 17(11), 1955; https://doi.org/10.3390/ijms17111955 - 23 Nov 2016

Cited by 8 | Viewed by 5819

Abstract

The production of recombinant spider silk proteins continues to be a key area of interest for a number of research groups. Several key obstacles exist in their production as well as in their formulation into useable products. The original reported method to solubilize [...] Read more.

The production of recombinant spider silk proteins continues to be a key area of interest for a number of research groups. Several key obstacles exist in their production as well as in their formulation into useable products. The original reported method to solubilize recombinant spider silk proteins (rSSp) in an aqueous solution involved using microwaves to quickly generate heat and pressure inside of a sealed vial containing rSSp and water. Fibers produced from this system are remarkable in their mechanical ability and demonstrate the ability to be stretched and recover 100 times. The microwave method dissolves the rSSPs with dissolution time increasing with higher molecular weight constructs, increasing concentration of rSSPs, protein type, and salt concentration. It has proven successful in solvating a number of different rSSPs including native-like sequences (MaSp1, MaSp2, piriform, and aggregate) as well as chimeric sequences (FlAS) in varied concentrations that have been spun into fibers and formed into films, foams, sponges, gels, coatings, macro and micro spheres and adhesives. The system is effective but inherently unpredictable and difficult to control. Provided that the materials that can be generated from this method of dissolution are impressive, an alternative means of applying heat and pressure that is controllable and predictable has been developed. Results indicate that there are combinations of heat and pressure (135 °C and 140 psi) that result in maximal dissolution without degrading the recombinant MaSp2 protein tested, and that heat and pressure are the key elements to the method of dissolution. Full article

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

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Open AccessReview

d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology

by Danilo De Gregorio, Stefano Comai, Luca Posa and Gabriella Gobbi

Int. J. Mol. Sci. 2016, 17(11), 1953; https://doi.org/10.3390/ijms17111953 - 23 Nov 2016

Cited by 92 | Viewed by 39398

Abstract

d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action [...] Read more.

d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles’ reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD’s mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT_2A receptor as a partial agonist and 5-HT_1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D₂, Trace Amine Associate receptor 1 (TAAR₁) and 5-HT_2A. More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD’s effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR₁ receptors. Full article

(This article belongs to the Special Issue Antipsychotics)

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Open AccessArticle

Regulation of Intrinsic and Extrinsic Apoptotic Pathways in Osteosarcoma Cells Following Oleandrin Treatment

by Yunlong Ma, Bin Zhu, Lei Yong, Chunyu Song, Xiao Liu, Huilei Yu, Peng Wang, Zhongjun Liu and Xiaoguang Liu

Int. J. Mol. Sci. 2016, 17(11), 1950; https://doi.org/10.3390/ijms17111950 - 23 Nov 2016

Cited by 31 | Viewed by 7869

Abstract

Our previous study has reported the anti-tumor effect of oleandrin on osteosarcoma (OS) cells. In the current study, we mainly explored its potential regulation on intrinsic and extrinsic apoptotic pathway in OS cells. Cells apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential [...] Read more.

Our previous study has reported the anti-tumor effect of oleandrin on osteosarcoma (OS) cells. In the current study, we mainly explored its potential regulation on intrinsic and extrinsic apoptotic pathway in OS cells. Cells apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected using fluorescence staining and flow cytometry. Caspase-3 activity was detected using a commercial kit. The levels of cytoplasmic cytochrome c, mitochondrial cytochrome c, bcl-2, bax, caspase-9, Fas, FasL, caspase-8 and caspase-3 were detected by Western blotting. z-VAD-fmk was applied to block both intrinsic and extrinsic apoptosis pathways, and cells apoptosis was also tested. Furthermore, we used z-LEHD-fmk and Fas blocking antibody to inhibit intrinsic and extrinsic pathways, separately, and the selectivity of oleandrin on these pathways was explored. Results showed that oleandrin induced the apoptosis of OS cells, which was accompanied by an increase in ROS and a decrease in MMP. Furthermore, cytochrome c level was reduced in mitochondria but elevated in the cytoplasm. Caspase-3 activity was enhanced by oleandrin in a concentration- and time-dependent manner. Oleandrin also down-regulated the expression of bcl-2, but up-regulated bax, caspase-9, Fas, FasL, caspase-8 and caspase-3. In addition, the suppression of both apoptotic pathways by z-VAD-fmk greatly reverted the oleandrin-induced apoptosis. Moreover, the suppression of one pathway by a corresponding inhibitor did not affect the regulation of oleandrin on another pathway. Taken together, we concluded that oleandrin induced apoptosis of OS cells via activating both intrinsic and extrinsic apoptotic pathways. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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1957 KiB

Open AccessArticle

Varietal Dependence of GLVs Accumulation and LOX-HPL Pathway Gene Expression in Four Vitis vinifera Wine Grapes

by Xu Qian, Xiao-Qing Xu, Ke-Ji Yu, Bao-Qing Zhu, Yi-Bin Lan, Chang-Qing Duan and Qiu-Hong Pan

Int. J. Mol. Sci. 2016, 17(11), 1924; https://doi.org/10.3390/ijms17111924 - 23 Nov 2016

Cited by 32 | Viewed by 6266

Abstract

Variety is one of the major factors influencing grape and wine aromatic characteristics. Green leaf volatiles (GLVs), derived from lipoxygenase-hydroperoxides lyase (LOX-HPL) pathway, are important components for the aromatic quality of grapes and wines. However, the varietal difference regarding GLVs accumulation and related [...] Read more.

Variety is one of the major factors influencing grape and wine aromatic characteristics. Green leaf volatiles (GLVs), derived from lipoxygenase-hydroperoxides lyase (LOX-HPL) pathway, are important components for the aromatic quality of grapes and wines. However, the varietal difference regarding GLVs accumulation and related gene expression are poorly studied. This work exhibited that the accumulation of various GLVs and the expression of LOX-HPL pathway genes in four Vitis vinifera wine grape cultivars: Syrah, Muscat Tchervine, Gewürztraminer and Chardonnay. The results showed a variety dependence of GLVs profile. Muscat Tchervine harvested grapes contained less C6 aldehydes and the most abundant esters, which corresponded to very low VvLOXA and VvHPL1 expression abundance as well as high VvAAT transcript in this variety. High expression level of both VvLOXA and VvHPL1 paralleled with higher level of C6 aldehydes together with higher alcohols in Syrah grape. Gewürztraminer and Chardonnay grapes had high aldehydes and alcohols as well as low esters, which were resulted from their higher expression level of VvLOXA or VvHPL1 and lower VvAAT. From these above corresponding relations, it is concluded that VvLOXA, VvHPL1 and VvAAT in the LOX-HPL pathway are targets for altering GLVs composition in the grape varieties. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Open AccessArticle

A Melting Curve-Based Multiplex RT-qPCR Assay for Simultaneous Detection of Four Human Coronaviruses

by Zhenzhou Wan, Ya’nan Zhang, Zhixiang He, Jia Liu, Ke Lan, Yihong Hu and Chiyu Zhang

Int. J. Mol. Sci. 2016, 17(11), 1880; https://doi.org/10.3390/ijms17111880 - 23 Nov 2016

Cited by 64 | Viewed by 14029

Abstract

Human coronaviruses HCoV-OC43, HCoV-229E, HCoV-NL63 and HCoV-HKU1 are common respiratory viruses associated with acute respiratory infection. They have a global distribution. Rapid and accurate diagnosis of HCoV infection is important for the management and treatment of hospitalized patients with HCoV infection. Here, we [...] Read more.

Human coronaviruses HCoV-OC43, HCoV-229E, HCoV-NL63 and HCoV-HKU1 are common respiratory viruses associated with acute respiratory infection. They have a global distribution. Rapid and accurate diagnosis of HCoV infection is important for the management and treatment of hospitalized patients with HCoV infection. Here, we developed a melting curve-based multiplex RT-qPCR assay for simultaneous detection of the four HCoVs. In the assay, SYTO 9 was used to replace SYBR Green I as the fluorescent dye, and GC-modified primers were designed to improve the melting temperature (Tm) of the specific amplicon. The four HCoVs were clearly distinguished by characteristic melting peaks in melting curve analysis. The detection sensitivity of the assay was 3 × 10² copies for HCoV-OC43, and 3 × 10¹ copies for HCoV-NL63, HCoV-229E and HCoV-HKU1 per 30 μL reaction. Clinical evaluation and sequencing confirmation demonstrated that the assay was specific and reliable. The assay represents a sensitive and reliable method for diagnosis of HCoV infection in clinical samples. Full article

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

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Open AccessArticle

by Edilene S. Soares, Leila M. Stávale, Monique C. P. Mendonça, Andressa Coope and Maria Alice da Cruz-Höfling

Int. J. Mol. Sci. 2016, 17(11), 1462; https://doi.org/10.3390/ijms17111462 - 23 Nov 2016

Cited by 3 | Viewed by 5445

Abstract

We have previously demonstrated that Phoneutria nigriventer venom (PNV) causes blood–brain barrier (BBB) breakdown, swelling of astrocytes end-feet and fluid permeation into brain interstitium in rats. Caveolae and water channels respond to BBB alterations by co-participation in shear stress response and edema formation/resolution. [...] Read more.

We have previously demonstrated that Phoneutria nigriventer venom (PNV) causes blood–brain barrier (BBB) breakdown, swelling of astrocytes end-feet and fluid permeation into brain interstitium in rats. Caveolae and water channels respond to BBB alterations by co-participation in shear stress response and edema formation/resolution. Herein, we showed post-natal developmental-related changes of two BBB-associated transporter proteins: the endothelial caveolin-1 (Cav-1), the major scaffolding protein from caveolae frame, and the astroglial aquaporin-4 (AQP4), the main water channel protein expressed in astrocytic peri-vascular end-feet processes, in the hippocampus of rats intraperitoneally-administered PNV. Western blotting protein levels; immunohistochemistry (IHC) protein distribution in CA1, CA2, and CA3 subfields; and gene expression by Real Time-Polymerase Chain Reaction (qPCR) were assessed in post-natal Day 14 (P14) and 8–10-week-old rats over critical periods of envenomation. The intensity and duration of the toxic manifestations indicate P14 neonate rats more vulnerable to PNV than adults. Histologically, the capillaries of P14 and 8–10-week-old rats treated with PNV showed perivascular edema, while controls did not. The intensity of the toxic manifestations in P14 decreases temporally (2 > 5 > 24 h), while inversely the expression of AQP4 and Cav-1 peaked at 24 h when clinically PNV-treated animals do not differ from saline controls. IHC of AQP4 revealed that hippocampal CA1 showed the least expression at 2 h when toxic manifestation was maximal. Subfield IHC quantification revealed that in P14 rats Cav-1 peaked at 24 h when toxic manifestations were absent, whereas in 8–10-week-old rats Cav-1 peaked at 2 h when toxic signs were highest, and progressively attenuated such increases until 24 h, remaining though significantly above baseline. Considering astrocyte-endothelial physical and functional interactions, we hypothesize that age-related modulations of AQP4 and Cav-1 might be linked both to changes in functional properties of astrocytes during post-natal development and in the BBB breakdown induced by the venom of P. nigriventer. Full article

(This article belongs to the Special Issue Aquaporin)

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Open AccessArticle

Pulmonary Function and Incidence of Selected Respiratory Diseases Depending on the Exposure to Ambient PM₁₀

by Artur Badyda, Anna Gayer, Piotr Oskar Czechowski, Grzegorz Majewski and Piotr Dąbrowiecki

Int. J. Mol. Sci. 2016, 17(11), 1954; https://doi.org/10.3390/ijms17111954 - 22 Nov 2016

Cited by 34 | Viewed by 5468

Abstract

It is essential in pulmonary disease research to take into account traffic-related air pollutant exposure among urban inhabitants. In our study, 4985 people were examined for spirometric parameters in the presented research which was conducted in the years 2008–2012. The research group was [...] Read more.

It is essential in pulmonary disease research to take into account traffic-related air pollutant exposure among urban inhabitants. In our study, 4985 people were examined for spirometric parameters in the presented research which was conducted in the years 2008–2012. The research group was divided into urban and rural residents. Traffic density, traffic structure and velocity, as well as concentrations of selected air pollutants (CO, NO₂ and PM₁₀) were measured at selected areas. Among people who live in the city, lower percentages of predicted values of spirometric parameters were noticed in comparison to residents of rural areas. Taking into account that the difference in the five-year mean concentration of PM₁₀ in the considered city and rural areas was over 17 μg/m³, each increase of PM₁₀ by 10 μg/m³ is associated with the decline in FEV₁ (forced expiratory volume during the first second of expiration) by 1.68%. These findings demonstrate that traffic-related air pollutants may have a significant influence on the decline of pulmonary function and the growing rate of respiratory diseases. Full article

(This article belongs to the Special Issue Molecular Research on Global Climate Change and Atmospheric Pollution)

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Open AccessReview

Calcium Dyshomeostasis in Tubular Aggregate Myopathy

by Jong-Mok Lee and Satoru Noguchi

Int. J. Mol. Sci. 2016, 17(11), 1952; https://doi.org/10.3390/ijms17111952 - 22 Nov 2016

Cited by 14 | Viewed by 8382

Abstract

Calcium is a crucial mediator of cell signaling in skeletal muscles for basic cellular functions and specific functions, including contraction, fiber-type differentiation and energy production. The sarcoplasmic reticulum (SR) is an organelle that provides a large supply of intracellular Ca²⁺ in myofibers. [...] Read more.

Calcium is a crucial mediator of cell signaling in skeletal muscles for basic cellular functions and specific functions, including contraction, fiber-type differentiation and energy production. The sarcoplasmic reticulum (SR) is an organelle that provides a large supply of intracellular Ca²⁺ in myofibers. Upon excitation, it releases Ca²⁺ into the cytosol, inducing contraction of myofibrils. During relaxation, it takes up cytosolic Ca²⁺ to terminate the contraction. During exercise, Ca²⁺ is cycled between the cytosol and the SR through a system by which the Ca²⁺ pool in the SR is restored by uptake of extracellular Ca²⁺ via a specific channel on the plasma membrane. This channel is called the store-operated Ca²⁺ channel or the Ca²⁺ release-activated Ca²⁺ channel. It is activated by depletion of the Ca²⁺ store in the SR by coordination of two main molecules: stromal interaction molecule 1 (STIM1) and calcium release-activated calcium channel protein 1 (ORAI1). Recently, myopathies with a dominant mutation in these genes have been reported and the pathogenic mechanism of such diseases have been proposed. This review overviews the calcium signaling in skeletal muscles and role of store-operated Ca²⁺ entry in calcium homeostasis. Finally, we discuss the phenotypes and the pathomechanism of myopathies caused by mutations in the STIM1 and ORAI1 genes. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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Open AccessCommunication

Transcriptome Analysis of mRNA and miRNA in Somatic Embryos of Larix leptolepis Subjected to Hydrogen Treatment

by Yali Liu, Suying Han, Xiangming Ding, Xinmin Li, Lifeng Zhang, Wanfeng Li, Haiyan Xu, Zhexin Li and Liwang Qi

Int. J. Mol. Sci. 2016, 17(11), 1951; https://doi.org/10.3390/ijms17111951 - 22 Nov 2016

Cited by 16 | Viewed by 5779

Abstract

Hydrogen is a therapeutic antioxidant that has been used extensively in clinical trials. It also acts as a bioactive molecule that can alleviate abiotic stress in plants. However, the biological effects of hydrogen in somatic embryos and the underlying molecular basis remain largely [...] Read more.

Hydrogen is a therapeutic antioxidant that has been used extensively in clinical trials. It also acts as a bioactive molecule that can alleviate abiotic stress in plants. However, the biological effects of hydrogen in somatic embryos and the underlying molecular basis remain largely unknown. In this study, the morphological and physiological influence of exogenous H₂ treatment during somatic embryogenesis was characterized in Larix leptolepis Gordon. The results showed that exposure to hydrogen increased the proportions of active pro-embryogenic cells and normal somatic embryos. We sequenced mRNA and microRNA (miRNA) libraries to identify global transcriptome changes at different time points during H₂ treatment of larch pro-embryogenic masses (PEMs). A total of 45,393 mRNAs and 315 miRNAs were obtained. Among them, 4253 genes and 96 miRNAs were differentially expressed in the hydrogen-treated libraries compared with the control. Further, a large number of the differentially expressed mRNAs and miRNAs were related to reactive oxygen species (ROS) homeostasis and cell cycle regulation. We also identified 4399 potential target genes for 285 of the miRNAs. The differential expression data and the mRNA-miRNA interaction network described here provide new insights into the molecular mechanisms that determine the performance of PEMs exposed to H₂ during somatic embryogenesis. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Open AccessReview

Structure-Functional Basis of Ion Transport in Sodium–Calcium Exchanger (NCX) Proteins

by Moshe Giladi, Reut Shor, Michal Lisnyansky and Daniel Khananshvili

Int. J. Mol. Sci. 2016, 17(11), 1949; https://doi.org/10.3390/ijms17111949 - 22 Nov 2016

Cited by 40 | Viewed by 8497

Abstract

The membrane-bound sodium–calcium exchanger (NCX) proteins shape Ca²⁺ homeostasis in many cell types, thus participating in a wide range of physiological and pathological processes. Determination of the crystal structure of an archaeal NCX (NCX_Mj) paved the way for a thorough and systematic [...] Read more.

The membrane-bound sodium–calcium exchanger (NCX) proteins shape Ca²⁺ homeostasis in many cell types, thus participating in a wide range of physiological and pathological processes. Determination of the crystal structure of an archaeal NCX (NCX_Mj) paved the way for a thorough and systematic investigation of ion transport mechanisms in NCX proteins. Here, we review the data gathered from the X-ray crystallography, molecular dynamics simulations, hydrogen–deuterium exchange mass-spectrometry (HDX-MS), and ion-flux analyses of mutants. Strikingly, the apo NCX_Mj protein exhibits characteristic patterns in the local backbone dynamics at particular helix segments, thereby possessing characteristic HDX profiles, suggesting structure-dynamic preorganization (geometric arrangements of catalytic residues before the transition state) of conserved α₁ and α₂ repeats at ion-coordinating residues involved in transport activities. Moreover, dynamic preorganization of local structural entities in the apo protein predefines the status of ion-occlusion and transition states, even though Na⁺ or Ca²⁺ binding modifies the preceding backbone dynamics nearby functionally important residues. Future challenges include resolving the structural-dynamic determinants governing the ion selectivity, functional asymmetry and ion-induced alternating access. Taking into account the structural similarities of NCX_Mj with the other proteins belonging to the Ca²⁺/cation exchanger superfamily, the recent findings can significantly improve our understanding of ion transport mechanisms in NCX and similar proteins. Full article

(This article belongs to the Special Issue Metalloproteins 2017)

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Open AccessArticle

Electric Signals Regulate the Directional Migration of Oligodendrocyte Progenitor Cells (OPCs) via β1 Integrin

by Bangfu Zhu, Matthew Nicholls, Yu Gu, Gaofeng Zhang, Chao Zhao, Robin J. M. Franklin and Bing Song

Int. J. Mol. Sci. 2016, 17(11), 1948; https://doi.org/10.3390/ijms17111948 - 22 Nov 2016

Cited by 16 | Viewed by 5617

Abstract

The guided migration of neural cells is essential for repair in the central nervous system (CNS). Oligodendrocyte progenitor cells (OPCs) will normally migrate towards an injury site to re-sheath demyelinated axons; however the mechanisms underlying this process are not well understood. Endogenous electric [...] Read more.

The guided migration of neural cells is essential for repair in the central nervous system (CNS). Oligodendrocyte progenitor cells (OPCs) will normally migrate towards an injury site to re-sheath demyelinated axons; however the mechanisms underlying this process are not well understood. Endogenous electric fields (EFs) are known to influence cell migration in vivo, and have been utilised in this study to direct the migration of OPCs isolated from neonatal Sprague-Dawley rats. The OPCs were exposed to physiological levels of electrical stimulation, and displayed a marked electrotactic response that was dependent on β1 integrin, one of the key subunits of integrin receptors. We also observed that F-actin, an important component of the cytoskeleton, was re-distributed towards the leading edge of the migrating cells, and that this asymmetric rearrangement was associated with β1 integrin function. Full article

(This article belongs to the Special Issue Pluripotent Stem Cell Technology for Disease Modeling, Drug Discovery and Regenerative Medicine)

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Open AccessArticle

Effects of Luteolin and Quercetin in Combination with Some Conventional Antibiotics against Methicillin-Resistant Staphylococcus aureus

by Muhammad Usman Amin, Muhammad Khurram, Taj Ali Khan, Hani S. Faidah, Zia Ullah Shah, Shafiq Ur Rahman, Abdul Haseeb, Muhammad Ilyas, Naseem Ullah, Sahibzada Muhammad Umar Khayam and Marcello Iriti

Int. J. Mol. Sci. 2016, 17(11), 1947; https://doi.org/10.3390/ijms17111947 - 22 Nov 2016

Cited by 63 | Viewed by 9908

Abstract

The present study was designed to evaluate the effects of flavonoids luteolin (L) and quercetin + luteolin (Q + L) in combination with commonly used antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates and S. aureus (ATCC 43300). Minimum inhibitory concentrations (MICs) [...] Read more.

The present study was designed to evaluate the effects of flavonoids luteolin (L) and quercetin + luteolin (Q + L) in combination with commonly used antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates and S. aureus (ATCC 43300). Minimum inhibitory concentrations (MICs) of L and Q + L, as well as the MICs of flavonoids in combination with antibiotics were determined and results showed an increased activity of flavonoids with antibiotics. The synergistic, additive, or antagonistic relationships between flavonoids (L and Q + L) and antibiotics were also evaluated, and additive and synergistic effects were observed for some antibiotic + flavonoid combinations. In addition, some combinations were also found to damage the bacterial cytoplasmic membrane, as assessed through potassium leakage assay. The effects of flavonoids and flavonoids + antibiotics on mecA gene mutations were also tested, and no functional variation was detected in the coding region. Full article

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

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Open AccessReview

Prediction of Protein–Protein Interactions by Evidence Combining Methods

by Ji-Wei Chang, Yan-Qing Zhou, Muhammad Tahir Ul Qamar, Ling-Ling Chen and Yu-Duan Ding

Int. J. Mol. Sci. 2016, 17(11), 1946; https://doi.org/10.3390/ijms17111946 - 22 Nov 2016

Cited by 28 | Viewed by 13357

Abstract

Most cellular functions involve proteins’ features based on their physical interactions with other partner proteins. Sketching a map of protein–protein interactions (PPIs) is therefore an important inception step towards understanding the basics of cell functions. Several experimental techniques operating in vivo or in [...] Read more.

Most cellular functions involve proteins’ features based on their physical interactions with other partner proteins. Sketching a map of protein–protein interactions (PPIs) is therefore an important inception step towards understanding the basics of cell functions. Several experimental techniques operating in vivo or in vitro have made significant contributions to screening a large number of protein interaction partners, especially high-throughput experimental methods. However, computational approaches for PPI predication supported by rapid accumulation of data generated from experimental techniques, 3D structure definitions, and genome sequencing have boosted the map sketching of PPIs. In this review, we shed light on in silico PPI prediction methods that integrate evidence from multiple sources, including evolutionary relationship, function annotation, sequence/structure features, network topology and text mining. These methods are developed for integration of multi-dimensional evidence, for designing the strategies to predict novel interactions, and for making the results consistent with the increase of prediction coverage and accuracy. Full article

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

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Open AccessArticle

Early Antipsychotic Treatment in Juvenile Rats Elicits Long-Term Alterations to the Dopamine Neurotransmitter System

by Michael De Santis, Jiamei Lian, Xu-Feng Huang and Chao Deng

Int. J. Mol. Sci. 2016, 17(11), 1944; https://doi.org/10.3390/ijms17111944 - 22 Nov 2016

Cited by 12 | Viewed by 5900

Abstract

Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term [...] Read more.

Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term changes to the adult dopamine (DA) system following aripiprazole, olanzapine and risperidone treatment in female and male juvenile rats. Levels of tyrosine hydroxylase (TH), phosphorylated-TH (p-TH), dopamine active transporter (DAT), and D₁ and D₂ receptors were measured via Western blot and/or receptor autoradiography. Aripiprazole decreased TH and D₁ receptor levels in the ventral tegmental area (VTA) and p-TH levels in the prefrontal cortex (PFC) of females, whilst TH levels decreased in the PFC of males. Olanzapine decreased PFC p-TH levels and increased D₂ receptor expression in the PFC and nucleus accumbens (NAc) in females only. Additionally, risperidone treatment increased D₁ receptor levels in the hippocampus of females, whilst, in males, p-TH levels increased in the PFC and hippocampus, D₁ receptor expression decreased in the NAc, and DAT levels decreased in the caudate putamen (CPu), and elevated in the VTA. These results suggest that early treatment with various APDs can cause different long-term alterations in the adult brain, across both treatment groups and genders. Full article

(This article belongs to the Special Issue Antipsychotics)

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Open AccessArticle

Hydrostatin-TL1, an Anti-Inflammatory Active Peptide from the Venom Gland of Hydrophis cyanocinctus in the South China Sea

by Ningyuan Wang, Yan Huang, An Li, Hailong Jiang, Jie Wang, Jianzhong Li, Lei Qiu, Ka Li and Yiming Lu

Int. J. Mol. Sci. 2016, 17(11), 1940; https://doi.org/10.3390/ijms17111940 - 22 Nov 2016

Cited by 21 | Viewed by 5603

Abstract

Tumor necrosis factor (TNF)-α is a pleiotropic cytokine with intense pro-inflammatory and immunomodulatory properties, and anti-TNF-α biologics are effective therapies for various inflammatory diseases such as inflammatory bowel disease (IBD) and sepsis. Snake venom, as a traditional Chinese medicine, has been used in [...] Read more.

Tumor necrosis factor (TNF)-α is a pleiotropic cytokine with intense pro-inflammatory and immunomodulatory properties, and anti-TNF-α biologics are effective therapies for various inflammatory diseases such as inflammatory bowel disease (IBD) and sepsis. Snake venom, as a traditional Chinese medicine, has been used in the treatment of inflammatory diseases in China for centuries. In this research, we constructed a venom gland T7 phage display library of the sea snake Hydrophis cyanocinctus to screen bioactive compounds that antagonize TNF-α and identified a novel nine-amino-acid peptide, termed hydrostatin-TL1 (H-TL1). In enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) analyses, H-TL1 inhibited the interaction between TNF-α and TNF receptor 1 (TNFR1). Further, H-TL1 attenuated the cytotoxicity of TNF-α in L929 cells as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. H-TL1 also decreased the mRNA expression of TNF-α/TNFR1 downstream targets and suppressed the phosphorylation of well-characterized proteins of downstream signal transduction pathways in HEK-293 cells. In vivo data demonstrated that H-TL1 protects animals against dextran sodium sulfate (DSS)-induced acute colitis and lipopolysaccharide (LPS)-induced acute shock. Given its significant anti-inflammatory activity in vitro and in vivo, H-TL1 is a potential peptide for the development of new agents to treat TNF-α-associated inflammatory diseases. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Anti-Inflammatory Effects of Chloranthalactone B in LPS-Stimulated RAW264.7 Cells

by Xueqin Li, Jun Shen, Yunyao Jiang, Ting Shen, Long You, Xiaobo Sun, Xudong Xu, Weicheng Hu, Haifeng Wu and Gongcheng Wang

Int. J. Mol. Sci. 2016, 17(11), 1938; https://doi.org/10.3390/ijms17111938 - 22 Nov 2016

Cited by 33 | Viewed by 7445

Abstract

Chloranthalactone B (CTB), a lindenane-type sesquiterpenoid, was obtained from the Chinese medicinal herb Sarcandra glabra, which is frequently used as a remedy for inflammatory diseases. However, the anti-inflammatory mechanisms of CTB have not been fully elucidated. In this study, we investigated the [...] Read more.

Chloranthalactone B (CTB), a lindenane-type sesquiterpenoid, was obtained from the Chinese medicinal herb Sarcandra glabra, which is frequently used as a remedy for inflammatory diseases. However, the anti-inflammatory mechanisms of CTB have not been fully elucidated. In this study, we investigated the molecular mechanisms underlying these effects in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. CTB strongly inhibited the production of nitric oxide and pro-inflammatory mediators such as prostaglandin E₂, tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6 in RAW264.7 cells stimulated with LPS. A reverse-transcription polymerase chain reaction assay and Western blot further confirmed that CTB inhibited the expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, and IL-1β at the transcriptional level, and decreased the luciferase activities of activator protein (AP)-1 reporter promoters. These data suggest that inhibition occurred at the transcriptional level. In addition, CTB blocked the activation of p38 mitogen-activated protein kinase (MAPK) but not c-Jun N-terminal kinase or extracellular signal-regulated kinase 1/2. Furthermore, CTB suppressed the phosphorylation of MKK3/6 by targeting the binding sites via formation of hydrogen bonds. Our findings clearly show that CTB inhibits the production of inflammatory mediators by inhibiting the AP-1 and p38 MAPK pathways. Therefore, CTB could potentially be used as an anti-inflammatory agent. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Open AccessArticle

Ziyuglycoside I Inhibits the Proliferation of MDA-MB-231 Breast Carcinoma Cells through Inducing p53-Mediated G2/M Cell Cycle Arrest and Intrinsic/Extrinsic Apoptosis

by Xue Zhu, Ke Wang, Kai Zhang, Ting Zhang, Yongxiang Yin and Fei Xu

Int. J. Mol. Sci. 2016, 17(11), 1903; https://doi.org/10.3390/ijms17111903 - 22 Nov 2016

Cited by 31 | Viewed by 6214

Abstract

Background: Due to the aggressive clinical behavior, poor outcome, and lack of effective specific targeted therapies, triple-negative breast cancer (TNBC) has currently been recognized as one of the most malignant types of tumors. In the present study, we investigated the cytotoxic effect of [...] Read more.

Background: Due to the aggressive clinical behavior, poor outcome, and lack of effective specific targeted therapies, triple-negative breast cancer (TNBC) has currently been recognized as one of the most malignant types of tumors. In the present study, we investigated the cytotoxic effect of ziyuglycoside I, one of the major components extracted from Chinese anti-tumor herbal Radix Sanguisorbae, on the TNBC cell line MDA-MB-231. Methods: The underlying molecular mechanism of the cytotoxic effect ziyuglycoside I on MDA-MB-231 cells was investigated with cell viability assay, flow cytometric analysis and Western blot. Results: Compared to normal mammary gland Hs 578Bst cells, treatment of ziyuglycoside I resulted in a significant growth inhibitory effect on MDA-MB-231 cells. Ziyuglycoside I induced the G2/M phase arrest and apoptosis of MDA-MB-231 cells in a dose-dependent manner. These effects were found to be partially mediated through the up-regulation of p53 and p21^WAF1, elevated Bax/Bcl-2 ratio, and the activation of both intrinsic (mitochondrial-initiated) and extrinsic (Fas/FasL-initiated) apoptotic pathways. Furthermore, the p53 specific siRNA attenuated these effects. Conclusion: Our study suggested that ziyuglycoside I-triggered MDA-MB-231 cell cycle arrest and apoptosis were probably mediated by p53. This suggests that ziyuglycoside I might be a potential drug candidate for treating TNBC. Full article

(This article belongs to the Section Molecular Toxicology)

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Open AccessReview

Role of Osteogenic Growth Peptide (OGP) and OGP(10–14) in Bone Regeneration: A Review

by Suzane C. Pigossi, Marcell C. Medeiros, Sybele Saska, Joni A. Cirelli and Raquel M. Scarel-Caminaga

Int. J. Mol. Sci. 2016, 17(11), 1885; https://doi.org/10.3390/ijms17111885 - 22 Nov 2016

Cited by 52 | Viewed by 9250

Abstract

Bone regeneration is a process that involves several molecular mediators, such as growth factors, which directly affect the proliferation, migration and differentiation of bone-related cells. The osteogenic growth peptide (OGP) and its C-terminal pentapeptide OGP(10–14) have been shown to stimulate the proliferation, differentiation, [...] Read more.

Bone regeneration is a process that involves several molecular mediators, such as growth factors, which directly affect the proliferation, migration and differentiation of bone-related cells. The osteogenic growth peptide (OGP) and its C-terminal pentapeptide OGP(10–14) have been shown to stimulate the proliferation, differentiation, alkaline phosphatase activity and matrix mineralization of osteoblastic lineage cells. However, the exact molecular mechanisms that promote osteoblastic proliferation and differentiation are not completely understood. This review presents the main chemical characteristics of OGP and/or OGP(10–14), and also discusses the potential molecular pathways induced by these growth factors to promote proliferation and differentiation of osteoblasts. Furthermore, since these peptides have been extensively investigated for bone tissue engineering, the clinical applications of these peptides for bone regeneration are discussed. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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Open AccessReview

Neuroprotective Strategies during Cardiac Surgery with Cardiopulmonary Bypass

by Aida Salameh, Stefan Dhein, Ingo Dähnert and Norbert Klein

Int. J. Mol. Sci. 2016, 17(11), 1945; https://doi.org/10.3390/ijms17111945 - 21 Nov 2016

Cited by 42 | Viewed by 11450

Abstract

Aortocoronary bypass or valve surgery usually require cardiac arrest using cardioplegic solutions. Although, in principle, in a number of cases beating heart surgery (so-called off-pump technique) is possible, aortic or valve surgery or correction of congenital heart diseases mostly require cardiopulmonary arrest. During [...] Read more.

Aortocoronary bypass or valve surgery usually require cardiac arrest using cardioplegic solutions. Although, in principle, in a number of cases beating heart surgery (so-called off-pump technique) is possible, aortic or valve surgery or correction of congenital heart diseases mostly require cardiopulmonary arrest. During this condition, the heart-lung machine also named cardiopulmonary bypass (CPB) has to take over the circulation. It is noteworthy that the invention of a machine bypassing the heart and lungs enabled complex cardiac operations, but possible negative effects of the CPB on other organs, especially the brain, cannot be neglected. Thus, neuroprotection during CPB is still a matter of great interest. In this review, we will describe the impact of CPB on the brain and focus on pharmacological and non-pharmacological strategies to protect the brain. Full article

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

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Open AccessArticle

The Role of Deoxycytidine Kinase (dCK) in Radiation-Induced Cell Death

by Rui Zhong, Rui Xin, Zongyan Chen, Nan Liang, Yang Liu, Shumei Ma and Xiaodong Liu

Int. J. Mol. Sci. 2016, 17(11), 1939; https://doi.org/10.3390/ijms17111939 - 21 Nov 2016

Cited by 10 | Viewed by 6526

Abstract

Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in [...] Read more.

Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in order to activate the cell cycle G2/M checkpoint. However, whether dCK plays a role in radiation-induced cell death is less clear. In this study, we genetically modified dCK expression by knocking down or expressing a WT (wild-type), S74A (abrogates phosphorylation) and S74E (mimics phosphorylation) of dCK. We found that dCK could decrease IR-induced total cell death and apoptosis. Moreover, dCK increased IR-induced autophagy and dCK-S74 is required for it. Western blotting showed that the ratio of phospho-Akt/Akt, phospho-mTOR/mTOR, phospho-P70S6K/P70S6K significantly decreased in dCK-WT and dCK-S74E cells than that in dCK-S74A cells following IR treatment. Reciprocal experiment by co-immunoprecipitation showed that mTOR can interact with wild-type dCK. IR increased polyploidy and decreased G2/M arrest in dCK knock-down cells as compared with control cells. Taken together, phosphorylated and activated dCK can inhibit IR-induced cell death including apoptosis and mitotic catastrophe, and promote IR-induced autophagy through PI3K/Akt/mTOR pathway. Full article

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

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Open AccessArticle

Transcriptome Analysis Identifies Key Candidate Genes Mediating Purple Ovary Coloration in Asiatic Hybrid Lilies

by Leifeng Xu, Panpan Yang, Suxia Yuan, Yayan Feng, Hua Xu, Yuwei Cao and Jun Ming

Int. J. Mol. Sci. 2016, 17(11), 1881; https://doi.org/10.3390/ijms17111881 - 20 Nov 2016

Cited by 16 | Viewed by 8376

Abstract

Lily tepals have a short lifespan. Once the tepals senesce, the ornamental value of the flower is lost. Some cultivars have attractive purple ovaries and fruits which greatly enhance the ornamental value of Asiatic hybrid lilies. However, little is known about the molecular [...] Read more.

Lily tepals have a short lifespan. Once the tepals senesce, the ornamental value of the flower is lost. Some cultivars have attractive purple ovaries and fruits which greatly enhance the ornamental value of Asiatic hybrid lilies. However, little is known about the molecular mechanisms of anthocyanin biosynthesis in Asiatic hybrid lily ovaries. To investigate the transcriptional network that governs purple ovary coloration in Asiatic hybrid lilies, we obtained transcriptome data from green ovaries (S1) and purple ovaries (S2) of Asiatic “Tiny Padhye”. Comparative transcriptome analysis revealed 4228 differentially expressed genes. Differential expression analysis revealed that ten unigenes including four CHS genes, one CHI gene, one F3H gene, one F3′H gene, one DFR gene, one UFGT gene, and one 3RT gene were significantly up-regulated in purple ovaries. One MYB gene, LhMYB12-Lat, was identified as a key transcription factor determining the distribution of anthocyanins in Asiatic hybrid lily ovaries. Further qPCR results showed unigenes related to anthocyanin biosynthesis were highly expressed in purple ovaries of three purple-ovaried Asiatic hybrid lilies at stages 2 and 3, while they showed an extremely low level of expression in ovaries of three green-ovaried Asiatic hybrid lilies during all developmental stages. In addition, shading treatment significantly decreased pigment accumulation by suppressing the expression of several unigenes related to anthocyanin biosynthesis in ovaries of Asiatic “Tiny Padhye”. Lastly, a total of 15,048 Simple Sequence Repeats (SSRs) were identified in 13,710 sequences, and primer pairs for SSRs were designed. The results could further our understanding of the molecular mechanisms of anthocyanin biosynthesis in Asiatic hybrid lily ovaries. Full article

(This article belongs to the Special Issue Anthocyanins)

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Open AccessReview

Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment

by Yan Cui and Gang Guo

Int. J. Mol. Sci. 2016, 17(11), 1942; https://doi.org/10.3390/ijms17111942 - 19 Nov 2016

Cited by 94 | Viewed by 20684

Abstract

The tumor suppressor p53 is the most frequently mutated gene in human cancers. Most of the mutations are missense leading to loss of p53 function in inducing apoptosis and senescence. In addition to these autonomous effects of p53 inactivation/dysfunction on tumorigenesis, compelling evidence [...] Read more.

The tumor suppressor p53 is the most frequently mutated gene in human cancers. Most of the mutations are missense leading to loss of p53 function in inducing apoptosis and senescence. In addition to these autonomous effects of p53 inactivation/dysfunction on tumorigenesis, compelling evidence suggests that p53 mutation/inactivation also leads to gain-of-function or activation of non-autonomous pathways, which either directly or indirectly promote tumorigenesis. Experimental and clinical results suggest that p53 dysfunction fuels pro-tumor inflammation and serves as an immunological gain-of-function driver of tumorigenesis via skewing immune landscape of the tumor microenvironment (TME). It is now increasingly appreciated that p53 dysfunction in various cellular compartments of the TME leads to immunosuppression and immune evasion. Although our understanding of the cellular and molecular processes that link p53 activity to host immune regulation is still incomplete, it is clear that activating/reactivating the p53 pathway in the TME also represents a compelling immunological strategy to reverse immunosuppression and enhance antitumor immunity. Here, we review our current understanding of the potential cellular and molecular mechanisms by which p53 participates in immune regulation and discuss how targeting the p53 pathway can be exploited to alter the immunological landscape of tumors for maximizing therapeutic outcome. Full article

(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)

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Zebrafish: A Model for the Study of Toxicants Affecting Muscle Development and Function

by Magda Dubińska-Magiera, Małgorzata Daczewska, Anna Lewicka, Marta Migocka-Patrzałek, Joanna Niedbalska-Tarnowska and Krzysztof Jagla

Int. J. Mol. Sci. 2016, 17(11), 1941; https://doi.org/10.3390/ijms17111941 - 19 Nov 2016

Cited by 57 | Viewed by 13179

Abstract

The rapid progress in medicine, agriculture, and allied sciences has enabled the development of a large amount of potentially useful bioactive compounds, such as drugs and pesticides. However, there is another side of this phenomenon, which includes side effects and environmental pollution. To [...] Read more.

The rapid progress in medicine, agriculture, and allied sciences has enabled the development of a large amount of potentially useful bioactive compounds, such as drugs and pesticides. However, there is another side of this phenomenon, which includes side effects and environmental pollution. To avoid or minimize the uncontrollable consequences of using the newly developed compounds, researchers seek a quick and effective means of their evaluation. In achieving this goal, the zebrafish (Danio rerio) has proven to be a highly useful tool, mostly because of its fast growth and development, as well as the ability to absorb the molecules diluted in water through its skin and gills. In this review, we focus on the reports concerning the application of zebrafish as a model for assessing the impact of toxicants on skeletal muscles, which share many structural and functional similarities among vertebrates, including zebrafish and humans. Full article

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

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