International Journal of Molecular Sciences

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Open AccessArticle

A Combination of Soybean and Haematococcus Extract Alleviates Ultraviolet B-Induced Photoaging

by Jieun Shin, Jong-Eun Kim, Kum-Ju Pak, Jung Il Kang, Tae-Seok Kim, Sang-Yoon Lee, Ik-Hyun Yeo, Jung Han Yoon Park, Jong Hun Kim, Nam Joo Kang and Ki Won Lee

Int. J. Mol. Sci. 2017, 18(3), 682; https://doi.org/10.3390/ijms18030682 - 22 Mar 2017

Cited by 21 | Viewed by 6740

Abstract

Soybean-derived isoflavones have been investigated for their preventative effects against UV-induced symptoms of skin damage including wrinkle formation and inflammation. Haematococcus pluvialis is a freshwater species of Chlorophyta that contains high concentrations of the natural carotenoid pigment astaxanthin. Astaxanthin is known to be [...] Read more.

Soybean-derived isoflavones have been investigated for their preventative effects against UV-induced symptoms of skin damage including wrinkle formation and inflammation. Haematococcus pluvialis is a freshwater species of Chlorophyta that contains high concentrations of the natural carotenoid pigment astaxanthin. Astaxanthin is known to be involved in retinoic acid receptor (RAR) signaling and previously been associated with the inhibition of activator protein (AP)-1 dependent transcription. Based on previous studies, we hypothesized that a combination of soy extract (SE) and Haematococcus extract (HE) may prevent UVB-induced photoaging through specific signaling pathways, as measured by UVB-induced wrinkling on hairless mice skin and expression changes in human dermal fibroblasts (HDFs). The 1:2 ratio of SE and HE mixture (SHM) showed the optimal benefit in vivo. SHM was found to inhibit wrinkle formation via the downregulation of matrix metalloproteinase (MMP)-1 mRNA and protein expression. SHM also inhibited mitogen-activated protein kinase (MAPK) phosphorylation and the transactivation of AP-1 which plays an important role in regulating MMP expression. These results highlight the potential for SHM to be developed as a therapeutic agent to prevent UVB-induced skin wrinkling. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Open AccessCase Report

Anti-Obesity Effect of Bombus ignitus Queen Glycosaminoglycans in Rats on a High-Fat Diet

by Mi Young Ahn, Ban Ji Kim, Ha Jeong Kim, Hyung Joo Yoon, Sang Duck Jee, Jae Sam Hwang and Kun-Koo Park

Int. J. Mol. Sci. 2017, 18(3), 681; https://doi.org/10.3390/ijms18030681 - 22 Mar 2017

Cited by 17 | Viewed by 5495

Abstract

The mechanism of functional insect glycosaminoglycan (GAG) on obesity caused a high fat diet has not yet been elucidated. Therefore, insect glycosaminoglycans derived from Isaria sinclairii, Bombus ignitus (a type of bumblebee) queen, and Gryllus bimaculatus were purified and investigated as a [...] Read more.

The mechanism of functional insect glycosaminoglycan (GAG) on obesity caused a high fat diet has not yet been elucidated. Therefore, insect glycosaminoglycans derived from Isaria sinclairii, Bombus ignitus (a type of bumblebee) queen, and Gryllus bimaculatus were purified and investigated as a potential functional food. 14-week old male Wistar rats were fed a high-fat diet (HFD) for 6 weeks. There were five groups that received daily intraperitoneal administration of phosphate buffered saline (PBS, control), GbG (GAG from Gryllus bimaculatus) 10 mg/kg, ISG (GAG from Isaria sinclairii) 10 mg/kg, IQG (GAG from Bombus ignites) 10 mg/kg, or Pravastatin (2 mg/kg). All treatments were performed for one month. IQG produced a potential anti-inflammatory effect with the inhibition of c-reactive protein and sero-biochemical parameters of phospholipids and free fatty acids indicative of an anti-hyperlipidemic effect. Abdominal and epididymidal fat weight were reduced in conjunction with a mild increase in body weight. The level of laminin in HMVEC-C cells or fibronectin in HFD rat hepatocytes was significantly affected by these GAG treatments, which regulated adipogenesis and adipocyte function. Compared to the control rats, IQG-treated rats displayed up-regulation of 87 genes (test:control ratio >2.0) including fatty acid synthase and 3-hydroxy-3-methylglutaryl-coenzyme A reductase, with the down-regulation of 47 genes including the uridine diphosphate (UDP) glycosyltransferase 2 families, polypeptidase B, and insulin-like growth factor binding protein 1. The data suggest that IQG could potentially prevent or treat fatty liver or hyperlipidemia. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Open AccessArticle

Survivin and NAIP in Human Benign Prostatic Hyperplasia: Protective Role of the Association of Serenoa repens, Lycopene and Selenium from the Randomized Clinical Study

by Giuseppe Morgia, Antonio Micali, Mariagrazia Rinaldi, Natasha Irrera, Herbert Marini, Domenico Puzzolo, Antonina Pisani, Salvatore Privitera, Giorgio I. Russo, Sebastiano Cimino, Antonio Ieni, Vincenzo Trichilo, Domenica Altavilla, Francesco Squadrito and Letteria Minutoli

Int. J. Mol. Sci. 2017, 18(3), 680; https://doi.org/10.3390/ijms18030680 - 22 Mar 2017

Cited by 15 | Viewed by 5711

Abstract

Benign prostatic hyperplasia (BPH) treatment includes the apoptosis machinery modulation through the direct inhibition of caspase cascade. We previously demonstrated that Serenoa repens (Ser) with lycopene (Ly) and selenium (Se) reawakened apoptosis by reducing survivin and neuronal apoptosis inhibitory protein (NAIP) levels in [...] Read more.

Benign prostatic hyperplasia (BPH) treatment includes the apoptosis machinery modulation through the direct inhibition of caspase cascade. We previously demonstrated that Serenoa repens (Ser) with lycopene (Ly) and selenium (Se) reawakened apoptosis by reducing survivin and neuronal apoptosis inhibitory protein (NAIP) levels in rats. The aim of this study was to evaluate the effectiveness of Ser-Se-Ly association on survivin and NAIP expression in BPH patients. Ninety patients with lower urinary tract symptoms (LUTS) due to clinical BPH were included in this randomized, double-blind, placebo-controlled trial. Participants were randomly assigned to receive placebo (Group BPH + placebo, n = 45) or Ser-Se-Ly association (Group BPH + Ser-Se-Ly; n = 45) for 3 months. At time 0, all patients underwent prostatic biopsies. After 3 months of treatment, they underwent prostatic re-biopsy and specimens were collected for molecular, morphological, and immunohistochemical analysis. After 3 months, survivin and NAIP were significantly decreased, while caspase-3 was significantly increased in BPH patients treated with Ser-Se-Ly when compared with the other group. In BPH patients treated with Ser-Se-Ly for 3 months, the glandular epithelium was formed by a single layer of cuboidal cells. PSA showed high immunoexpression in all BPH patients and a focal positivity in Ser-Se-Ly treated patients after 3 months. Evident prostate specific membrane antigen (PSMA) immunoexpression was shown in all BPH patients, while no positivity was present after Ser-Se-Ly administration. Ser-Se-Ly proved to be effective in promoting apoptosis in BPH patients. Full article

(This article belongs to the Special Issue Molecular Research on Urology)

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Open AccessArticle

Methodological Challenges in Protein Microarray and Immunohistochemistry for the Discovery of Novel Autoantibodies in Paediatric Acute Disseminated Encephalomyelitis

by Patrick Peschl, Melanie Ramberger, Romana Höftberger, Karin Jöhrer, Matthias Baumann, Kevin Rostásy and Markus Reindl

Int. J. Mol. Sci. 2017, 18(3), 679; https://doi.org/10.3390/ijms18030679 - 22 Mar 2017

Cited by 5 | Viewed by 4848

Abstract

Acute disseminated encephalomyelitis (ADEM) is a rare autoimmune-mediated demyelinating disease affecting mainly children and young adults. Differentiation to multiple sclerosis is not always possible, due to overlapping clinical symptoms and recurrent and multiphasic forms. Until now, immunoglobulins reactive to myelin oligodendrocyte glycoprotein (MOG [...] Read more.

Acute disseminated encephalomyelitis (ADEM) is a rare autoimmune-mediated demyelinating disease affecting mainly children and young adults. Differentiation to multiple sclerosis is not always possible, due to overlapping clinical symptoms and recurrent and multiphasic forms. Until now, immunoglobulins reactive to myelin oligodendrocyte glycoprotein (MOG antibodies) have been found in a subset of patients with ADEM. However, there are still patients lacking autoantibodies, necessitating the identification of new autoantibodies as biomarkers in those patients. Therefore, we aimed to identify novel autoantibody targets in ADEM patients. Sixteen ADEM patients (11 seronegative, 5 seropositive for MOG antibodies) were analysed for potential new biomarkers, using a protein microarray and immunohistochemistry on rat brain tissue to identify antibodies against intracellular and surface neuronal and glial antigens. Nine candidate antigens were identified in the protein microarray analysis in at least two patients per group. Immunohistochemistry on rat brain tissue did not reveal new target antigens. Although no new autoantibody targets could be found here, future studies should aim to identify new biomarkers for therapeutic and prognostic purposes. The microarray analysis and immunohistochemistry methods used here have several limitations, which should be considered in future searches for biomarkers. Full article

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

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Open AccessArticle

Cytotoxicity, Bactericidal, and Antioxidant Activity of Sodium Alginate Hydrosols Treated with Direct Electric Current

by Żaneta Król, Krzysztof Marycz, Dominika Kulig, Monika Marędziak and Andrzej Jarmoluk

Int. J. Mol. Sci. 2017, 18(3), 678; https://doi.org/10.3390/ijms18030678 - 22 Mar 2017

Cited by 27 | Viewed by 6577

Abstract

The aim of the study was to investigate the effect of using direct electric current (DC) of 0, 200, and 400 mA for five minutes on the physiochemical properties, cytotoxicity, antibacterial, and antioxidant activity of sodium alginate hydrosols with different sodium chloride concentrations. [...] Read more.

The aim of the study was to investigate the effect of using direct electric current (DC) of 0, 200, and 400 mA for five minutes on the physiochemical properties, cytotoxicity, antibacterial, and antioxidant activity of sodium alginate hydrosols with different sodium chloride concentrations. The pH, oxidation-reduction potential (ORP), electrical conductivity (EC), and available chlorine concentration (ACC) were measured. The effect of sodium alginate hydrosols treated with DC on Staphylococcus aureus, Listeria monocytogenes, Bacillus cereus, Micrococcus luteus, Escherichia coli, Salmonella enteritidis, Yersinia enterocolitica, Pseudomonas fluorescence, and RAW 264.7 and L929 cells was investigated. Subsequently, the antioxidant properties of hydrosols were evaluated by determining the scavenging ability of 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH) and ferric reducing antioxidant power (FRAP). The results have shown that after applying 400 mA in hydrosol samples with 0.1% and 0.2% NaCl all tested bacteria were inactivated. The ACC concentration of C400 samples with NaCl was equal to 13.95 and 19.71 mg/L, respectively. The cytotoxicity analysis revealed that optimized electric field conditions and the addition of sodium chloride allow for the avoidance of toxicity effects on normal cells without disturbing the antibacterial effects. Due to the presence of oxidizing substances, the DPPH of variants treated with DC was lower than the DPPH of control samples. Full article

(This article belongs to the Section Materials Science)

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Open AccessArticle

Identification of Quantitative Trait Loci Conditioning the Main Biomass Yield Components and Resistance to Melampsora spp. in Salix viminalis × Salix schwerinii Hybrids

by Paweł Sulima, Jerzy A. Przyborowski, Anna Kuszewska, Dariusz Załuski, Małgorzata Jędryczka and Witold Irzykowski

Int. J. Mol. Sci. 2017, 18(3), 677; https://doi.org/10.3390/ijms18030677 - 22 Mar 2017

Cited by 6 | Viewed by 4327

Abstract

The biomass of Salix viminalis is the most highly valued source of green energy, followed by S. schwerinii, S. dasyclados and other species. Significant variability in productivity and leaf rust resistance are noted both within and among willow species, which creates new [...] Read more.

The biomass of Salix viminalis is the most highly valued source of green energy, followed by S. schwerinii, S. dasyclados and other species. Significant variability in productivity and leaf rust resistance are noted both within and among willow species, which creates new opportunities for improving willow yield parameters through selection of desirable recombinants supported with molecular markers. The aim of this study was to identify quantitative trait loci (QTLs) linked with biomass yield-related traits and the resistance/susceptibility of Salix mapping population to leaf rust. The experimental material comprised a mapping population developed based on S. viminalis × S. schwerinii hybrids. Phenotyping was performed on plants grown in a field experiment that had a balanced incomplete block design with 10 replications. Based on a genetic map, 11 QTLs were identified for plant height, 9 for shoot diameter, 3 for number of shoots and 11 for resistance/susceptibility to leaf rust. The QTLs identified in our study explained 3%–16% of variability in the analyzed traits. Our findings make significant contributions to the development of willow breeding programs and research into shrubby willow crops grown for energy. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Open AccessArticle

ATRAP Expression in Brown Adipose Tissue Does Not Influence the Development of Diet-Induced Metabolic Disorders in Mice

by Kohji Ohki, Hiromichi Wakui, Kengo Azushima, Kazushi Uneda, Sona Haku, Ryu Kobayashi, Kotaro Haruhara, Sho Kinguchi, Miyuki Matsuda, Masato Ohsawa, Akinobu Maeda, Shintaro Minegishi, Tomoaki Ishigami, Yoshiyuki Toya, Akio Yamashita, Satoshi Umemura and Kouichi Tamura

Int. J. Mol. Sci. 2017, 18(3), 676; https://doi.org/10.3390/ijms18030676 - 21 Mar 2017

Cited by 8 | Viewed by 6289

Abstract

Activation of tissue renin–angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R-associated protein (ATRAP), a specific binding protein of AT1R, functions [...] Read more.

Activation of tissue renin–angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R-associated protein (ATRAP), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent excessive activation of tissue RAS. In the present study, we newly generated ATRAP/Agtrap-floxed (ATRAP^fl/fl) mice and adipose tissue-specific ATRAP downregulated (ATRAP^adipoq) mice by the Cre/loxP system using Adipoq-Cre. Using these mice, we examined the functional role of adipose ATRAP in the pathogenesis of obesity-related metabolic disorders. Compared with ATRAP^fl/fl mice, ATRAP^adipoq mice exhibited a decreased ATRAP expression in visceral white adipose tissue (WAT) and brown adipose tissue (BAT) by approximately 30% and 85%, respectively. When mice were fed a high-fat diet, ATRAP^fl/fl mice showed decreased endogenous ATRAP expression in WAT that was equivalent to ATRAP^adipoq mice, and there was no difference in the exacerbation of dietary obesity and glucose and lipid metabolism. These results indicate that ATRAP in BAT does not influence the pathogenesis of dietary obesity or metabolic disorders. Future studies that modulate ATRAP in WAT are necessary to assess its in vivo functions in the development of obesity-related metabolic disorders. Full article

(This article belongs to the Special Issue Selected Papers from the Renin–Angiotensin–Aldosterone System (RAAS)2016: Official Satellite of ISH2016, from September 23 to 24 in Tokyo, Japan)

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Open AccessArticle

Passage through the Ocular Barriers and Beneficial Effects in Retinal Ischemia of Topical Application of PACAP1-38 in Rodents

by Dora Werling, William A. Banks, Therese S. Salameh, Timea Kvarik, Laszlo Akos Kovacs, Alexandra Vaczy, Edina Szabo, Flora Mayer, Rita Varga, Andrea Tamas, Gabor Toth, Zsolt Biro, Tamas Atlasz and Dora Reglodi

Int. J. Mol. Sci. 2017, 18(3), 675; https://doi.org/10.3390/ijms18030675 - 21 Mar 2017

Cited by 29 | Viewed by 6070

Abstract

The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has two active forms, PACAP1-27 and PACAP1-38. Among the well-established actions are PACAP’s neurotrophic and neuroprotective effects, which have also been proven in models of different retinopathies. The route of delivery is usually intravitreal in [...] Read more.

The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has two active forms, PACAP1-27 and PACAP1-38. Among the well-established actions are PACAP’s neurotrophic and neuroprotective effects, which have also been proven in models of different retinopathies. The route of delivery is usually intravitreal in studies proving PACAP’s retinoprotective effects. Recently, we have shown that PACAP1-27 delivered as eye drops in benzalkonium-chloride was able to cross the ocular barriers and exert retinoprotection in ischemia. Since PACAP1-38 is the dominant form of the naturally occurring PACAP, our aim was to investigate whether the longer form is also able to cross the barriers and exert protective effects in permanent bilateral common carotid artery occlusion (BCCAO), a model of retinal hypoperfusion. Our results show that radioactive PACAP1-38 eye drops could effectively pass through the ocular barriers to reach the retina. Routine histological analysis and immunohistochemical evaluation of the Müller glial cells revealed that PACAP1-38 exerted retinoprotective effects. PACAP1-38 attenuated the damage caused by hypoperfusion, apparent in almost all retinal layers, and it decreased the glial cell overactivation. Overall, our results confirm that PACAP1-38 given in the form of eye drops is a novel protective therapeutic approach to treat retinal diseases. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2017)

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Open AccessArticle

ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition

by Santosh Lamichhane, Tonking Bastola, Ramesh Pariyar, Eun-Sol Lee, Ho-Sub Lee, Dae Ho Lee and Jungwon Seo

Int. J. Mol. Sci. 2017, 18(3), 674; https://doi.org/10.3390/ijms18030674 - 21 Mar 2017

Cited by 21 | Viewed by 8414

Abstract

Hypoglycemia, a complication of insulin or sulfonylurea therapy in diabetic patients, leads to brain damage. Furthermore, glucose replenishment following hypoglycemic coma induces neuronal cell death. In this study, we investigated the molecular mechanism underlying glucose deficiency-induced cytotoxicity and the protective effect of d [...] Read more.

Hypoglycemia, a complication of insulin or sulfonylurea therapy in diabetic patients, leads to brain damage. Furthermore, glucose replenishment following hypoglycemic coma induces neuronal cell death. In this study, we investigated the molecular mechanism underlying glucose deficiency-induced cytotoxicity and the protective effect of d-β-hydroxybutyrate (D-BHB) using SH-SY5Y cells. The cytotoxic mechanism of metformin under glucose deficiency was also examined. Cell viability under 1 mM glucose (glucose deficiency) was significantly decreased which was accompanied by increased production of reactive oxygen species (ROS) and decreased phosphorylation of extracellular signal-regulated kinase (ERK) and glycogen synthase 3 (GSK3β). ROS inhibitor reversed the glucose deficiency-induced cytotoxicity and restored the reduced phosphorylation of ERK and GSK3β. While metformin did not alter cell viability in normal glucose media, it further increased cell death and ROS production under glucose deficiency. However, D-BHB reversed cytotoxicity, ROS production, and the decrease in phosphorylation of ERK and GSK3β induced by the glucose deficiency. ERK inhibitor reversed the D-BHB-induced increase in cell viability under glucose deficiency, whereas GSK3β inhibitor did not restore glucose deficiency-induced cytotoxicity. Finally, the protective effect of D-BHB against glucose deficiency was confirmed in primary neuronal cells. We demonstrate that glucose deficiency-induced cytotoxicity is mediated by ERK inhibition through ROS production, which is attenuated by D-BHB and intensified by metformin. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2017)

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Open AccessReview

Molecular Basis for Modulation of Metabotropic Glutamate Receptors and Their Drug Actions by Extracellular Ca²⁺

by Juan Zou, Jason Y. Jiang and Jenny J. Yang

Int. J. Mol. Sci. 2017, 18(3), 672; https://doi.org/10.3390/ijms18030672 - 21 Mar 2017

Cited by 7 | Viewed by 9045

Abstract

Metabotropic glutamate receptors (mGluRs) associated with the slow phase of the glutamatergic signaling pathway in neurons of the central nervous system have gained importance as drug targets for chronic neurodegenerative diseases. While extracellular Ca²⁺ was reported to exhibit direct activation and modulation [...] Read more.

Metabotropic glutamate receptors (mGluRs) associated with the slow phase of the glutamatergic signaling pathway in neurons of the central nervous system have gained importance as drug targets for chronic neurodegenerative diseases. While extracellular Ca²⁺ was reported to exhibit direct activation and modulation via an allosteric site, the identification of those binding sites was challenged by weak binding. Herein, we review the discovery of extracellular Ca²⁺ in regulation of mGluRs, summarize the recent developments in probing Ca²⁺ binding and its co-regulation of the receptor based on structural and biochemical analysis, and discuss the molecular basis for Ca²⁺ to regulate various classes of drug action as well as its importance as an allosteric modulator in mGluRs. Full article

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

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Open AccessArticle

Preparation of Biodegradable and Elastic Poly(ε-caprolactone-co-lactide) Copolymers and Evaluation as a Localized and Sustained Drug Delivery Carrier

by Ji Hoon Park, Bo Keun Lee, Seung Hun Park, Mal Geum Kim, Jin Woo Lee, Hye Yun Lee, Hai Bang Lee, Jae Ho Kim and Moon Suk Kim

Int. J. Mol. Sci. 2017, 18(3), 671; https://doi.org/10.3390/ijms18030671 - 21 Mar 2017

Cited by 37 | Viewed by 5872

Abstract

To develop a biodegradable polymer possessing elasticity and flexibility, we synthesized MPEG-b-(PCL-co-PLA) copolymers (PC_xL_yA), which display specific rates of flexibility and elasticity. We synthesize the PC_xL_yA copolymers by ring-opening polymerization of ε-caprolactone and [...] Read more.

To develop a biodegradable polymer possessing elasticity and flexibility, we synthesized MPEG-b-(PCL-co-PLA) copolymers (PC_xL_yA), which display specific rates of flexibility and elasticity. We synthesize the PC_xL_yA copolymers by ring-opening polymerization of ε-caprolactone and l-lactide. PC_xL_yA copolymers of various compositions were synthesized with 500,000 molecular weight. The PC_xL_yA copolymers mechanical properties were dependent on the mole ratio of the ε-caprolactone and l-lactide components. Cyclic tensile tests were carried out to investigate the resistance to creep of PC_xL_yA specimens after up to 20 deformation cycles to 50% elongation. After in vivo implantation, the PC_xL_yA implants exhibited biocompatibility, and gradually biodegraded over an eight-week experimental period. Immunohistochemical characterization showed that the PC_xL_yA implants provoked in vivo inflammation, which gradually decreased over time. The copolymer was used as a drug carrier for locally implantable drugs, the hydrophobic drug dexamethasone (Dex), and the water-soluble drug dexamethasone 21-phosphate disodium salt (Dex(p)). We monitored drug-loaded PC_xL_yA films for in vitro and in vivo drug release over 40 days and observed real-time sustained release of near-infrared (NIR) fluorescence over an extended period from hydrophobic IR-780- and hydrophilic IR-783-loaded PC_xL_yA implanted in live animals. Finally, we confirmed that PC_xL_yA films are usable as biodegradable, elastic drug carriers. Full article

(This article belongs to the Section Materials Science)

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Open AccessArticle

Study of Different Variants of Mo Enzyme crARC and the Interaction with Its Partners crCytb5-R and crCytb5-1

by Alejandro Chamizo-Ampudia, Aurora Galvan, Emilio Fernandez and Angel Llamas

Int. J. Mol. Sci. 2017, 18(3), 670; https://doi.org/10.3390/ijms18030670 - 21 Mar 2017

Cited by 8 | Viewed by 4149

Abstract

The mARC (mitochondrial Amidoxime Reducing Component) proteins are recently discovered molybdenum (Mo) Cofactor containing enzymes. They are involved in the reduction of several N-hydroxylated compounds (NHC) and nitrite. Some NHC are prodrugs containing an amidoxime structure or mutagens such as 6-hydroxylaminopurine (HAP). [...] Read more.

The mARC (mitochondrial Amidoxime Reducing Component) proteins are recently discovered molybdenum (Mo) Cofactor containing enzymes. They are involved in the reduction of several N-hydroxylated compounds (NHC) and nitrite. Some NHC are prodrugs containing an amidoxime structure or mutagens such as 6-hydroxylaminopurine (HAP). We have studied this protein in the green alga Chlamydomonas reinhardtii (crARC). Interestingly, all the ARC proteins need the reducing power supplied by other proteins. It is known that crARC requires a cytochrome b₅ (crCytb5-1) and a cytochrome b₅ reductase (crCytb5-R) that form an electron transport chain from NADH to the substrates. Here, we have investigated NHC reduction by crARC, the interaction with its partners and the function of important conserved amino acids. Interactions among crARC, crCytb5-1 and crCytb5-R have been studied by size-exclusion chromatography. A protein complex between crARC, crCytb5-1 and crCytb5-R was identified. Twelve conserved crARC amino acids have been substituted by alanine by in vitro mutagenesis. We have determined that the amino acids D182, F210 and R276 are essential for NHC reduction activity, R276 is important and F210 is critical for the Mo Cofactor chelation. Finally, the crARC C-termini were shown to be involved in protein aggregation or oligomerization. Full article

(This article belongs to the Special Issue Metalloproteins 2017)

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Open AccessArticle

Genomic Loads and Genotypes of Respiratory Syncytial Virus: Viral Factors during Lower Respiratory Tract Infection in Chilean Hospitalized Infants

by Yazmín Espinosa, Camila San Martín, Alejandro A. Torres, Mauricio J. Farfán, Juan P. Torres, Vasanthi Avadhanula, Pedro A. Piedra and Lorena I. Tapia

Int. J. Mol. Sci. 2017, 18(3), 654; https://doi.org/10.3390/ijms18030654 - 21 Mar 2017

Cited by 23 | Viewed by 5682

Abstract

The clinical impact of viral factors (types and viral loads) during respiratory syncytial virus (RSV) infection is still controversial, especially regarding newly described genotypes. In this study, infants with RSV bronchiolitis were recruited to describe the association of these viral factors with severity [...] Read more.

The clinical impact of viral factors (types and viral loads) during respiratory syncytial virus (RSV) infection is still controversial, especially regarding newly described genotypes. In this study, infants with RSV bronchiolitis were recruited to describe the association of these viral factors with severity of infection. RSV antigenic types, genotypes, and viral loads were determined from hospitalized patients at Hospital Roberto del Río, Santiago, Chile. Cases were characterized by demographic and clinical information, including days of lower respiratory symptoms and severity. A total of 86 patients were included: 49 moderate and 37 severe cases. During 2013, RSV-A was dominant (86%). RSV-B predominated in 2014 (92%). Phylogenetic analyses revealed circulation of GA2, Buenos Aires (BA), and Ontario (ON) genotypes. No association was observed between severity of infection and RSV group (p = 0.69) or genotype (p = 0.87). After a clinical categorization of duration of illness, higher RSV genomic loads were detected in infants evaluated earlier in their disease (p < 0.001) and also in infants evaluated later, but coursing a more severe infection (p = 0.04). Although types and genotypes did not associate with severity in our children, higher RSV genomic loads and delayed viral clearance in severe patients define a group that might benefit from new antiviral therapies. Full article

(This article belongs to the Special Issue Pneumonia: Pathogenesis, Diagnostics, Therapeutics, and Prevention)

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Open AccessReview

State of the Art on Functional Virgin Olive Oils Enriched with Bioactive Compounds and Their Properties

by Patricia Reboredo-Rodríguez, María Figueiredo-González, Carmen González-Barreiro, Jesús Simal-Gándara, María Desamparados Salvador, Beatriz Cancho-Grande and Giuseppe Fregapane

Int. J. Mol. Sci. 2017, 18(3), 668; https://doi.org/10.3390/ijms18030668 - 20 Mar 2017

Cited by 78 | Viewed by 10181

Abstract

Virgin olive oil, the main fat of the Mediterranean diet, is per se considered as a functional food—as stated by the European Food Safety Authority (EFSA)—due to its content in healthy compounds. The daily intake of endogenous bioactive phenolics from virgin olive oil [...] Read more.

Virgin olive oil, the main fat of the Mediterranean diet, is per se considered as a functional food—as stated by the European Food Safety Authority (EFSA)—due to its content in healthy compounds. The daily intake of endogenous bioactive phenolics from virgin olive oil is variable due to the influence of multiple agronomic and technological factors. Thus, a good strategy to ensure an optimal intake of polyphenols through habitual diet would be to produce enriched virgin olive oil with well-known bioactive polyphenols. Different sources of natural biological active substances can be potentially used to enrich virgin olive oil (e.g., raw materials derived from the same olive tree, mainly olive leaves and pomaces, and/or other compounds from plants and vegetables, mainly herbs and spices). The development of these functional olive oils may help in prevention of chronic diseases (such as cardiovascular diseases, immune frailty, ageing disorders and degenerative diseases) and improving the quality of life for many consumers reducing health care costs. In the present review, the most relevant scientific information related to the development of enriched virgin olive oil and their positive human health effects has been collected and discussed. 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

Novel Diagnostic and Predictive Biomarkers in Pancreatic Adenocarcinoma

by John C. Chang and Madappa Kundranda

Int. J. Mol. Sci. 2017, 18(3), 667; https://doi.org/10.3390/ijms18030667 - 20 Mar 2017

Cited by 109 | Viewed by 8767

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for a multitude of reasons including very late diagnosis. This in part is due to the lack of understanding of the biological behavior of PDAC and the ineffective screening for this disease. Significant efforts [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for a multitude of reasons including very late diagnosis. This in part is due to the lack of understanding of the biological behavior of PDAC and the ineffective screening for this disease. Significant efforts have been dedicated to finding the appropriate serum and imaging biomarkers to help early detection and predict response to treatment of PDAC. Carbohydrate antigen 19-9 (CA 19-9) has been the most validated serum marker and has the highest positive predictive value as a stand-alone marker. When combined with carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA 125), CA 19-9 can help predict the outcome of patients to surgery and chemotherapy. A slew of novel serum markers including multimarker panels as well as genetic and epigenetic materials have potential for early detection of pancreatic cancer, although these remain to be validated in larger trials. Imaging studies may not correlate with elevated serum markers. Critical features for determining PDAC include the presence of a mass, dilated pancreatic duct, and a duct cut-off sign. Features that are indicative of early metastasis includes neurovascular bundle involvement, duodenal invasion, and greater post contrast enhancement. 18-F-fluorodeoxyglucose (18-FDG) radiotracer uptake and changes following treatment may predict patient overall survival following treatment. Similarly, pretreatment apparent diffusion coefficient (ADC) values may predict prognosis with lower ADC lesions having worse outcome. Although these markers have provided significant improvement in the care of pancreatic cancer patients, further advancements can be made with perhaps better combination of markers or discovery of unique marker(s) to pancreatic cancer. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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Extracellular Vesicles Deliver Host and Virus RNA and Regulate Innate Immune Response

by Takahisa Kouwaki, Masaaki Okamoto, Hirotake Tsukamoto, Yoshimi Fukushima and Hiroyuki Oshiumi

Int. J. Mol. Sci. 2017, 18(3), 666; https://doi.org/10.3390/ijms18030666 - 20 Mar 2017

Cited by 92 | Viewed by 8896

Abstract

The innate immune system plays a crucial role in controlling viral infection. Pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-I-like receptors, sense viral components called pathogen-associated molecular patterns (PAMPs) and trigger signals to induce innate immune responses. Extracellular vesicles (EVs), including [...] Read more.

The innate immune system plays a crucial role in controlling viral infection. Pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-I-like receptors, sense viral components called pathogen-associated molecular patterns (PAMPs) and trigger signals to induce innate immune responses. Extracellular vesicles (EVs), including exosomes and microvesicles, deliver functional RNA and mediate intercellular communications. Recent studies have revealed that EVs released from virus-infected cells deliver viral RNA to dendritic cells and macrophages, thereby activating PRRs in recipient cells, which results in the expression of type I interferon and pro-inflammatory cytokines. On the other hand, EVs transfer not only viral RNA but also host microRNAs to recipient cells. Recently, infection of hepatocytes with hepatitis B virus (HBV) was shown to affect microRNA levels in EVs released from virus-infected cells, leading to attenuation of host innate immune response. This suggests that the virus utilizes the EVs and host microRNAs to counteract the antiviral innate immune responses. In this review, we summarize recent findings related to the role of EVs in antiviral innate immune responses. Full article

(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)

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Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

by Alexandria Hughes, Alexandra E. Oxford, Ken Tawara, Cheryl L. Jorcyk and Julia Thom Oxford

Int. J. Mol. Sci. 2017, 18(3), 665; https://doi.org/10.3390/ijms18030665 - 20 Mar 2017

Cited by 84 | Viewed by 8954

Abstract

Chondrocytes of the growth plate undergo apoptosis during the process of endochondral ossification, as well as during the progression of osteoarthritis. Although the regulation of this process is not completely understood, alterations in the precisely orchestrated programmed cell death during development can have [...] Read more.

Chondrocytes of the growth plate undergo apoptosis during the process of endochondral ossification, as well as during the progression of osteoarthritis. Although the regulation of this process is not completely understood, alterations in the precisely orchestrated programmed cell death during development can have catastrophic results, as exemplified by several chondrodystrophies which are frequently accompanied by early onset osteoarthritis. Understanding the mechanisms that underlie chondrocyte apoptosis during endochondral ossification in the growth plate has the potential to impact the development of therapeutic applications for chondrodystrophies and associated early onset osteoarthritis. In recent years, several chondrodysplasias and collagenopathies have been recognized as protein-folding diseases that lead to endoplasmic reticulum stress, endoplasmic reticulum associated degradation, and the unfolded protein response. Under conditions of prolonged endoplasmic reticulum stress in which the protein folding load outweighs the folding capacity of the endoplasmic reticulum, cellular dysfunction and death often occur. However, unfolded protein response (UPR) signaling is also required for the normal maturation of chondrocytes and osteoblasts. Understanding how UPR signaling may contribute to cartilage pathophysiology is an essential step toward therapeutic modulation of skeletal disorders that lead to osteoarthritis. Full article

(This article belongs to the Special Issue Apoptotic Chondrocytes and Osteoarthritis)

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Open AccessArticle

Gene-Transformation-Induced Changes in Chemical Functional Group Features and Molecular Structure Conformation in Alfalfa Plants Co-Expressing Lc-bHLH and C1-MYB Transcriptive Flavanoid Regulatory Genes: Effects of Single-Gene and Two-Gene Insertion

by Ravindra G. Heendeniya and Peiqiang Yu

Int. J. Mol. Sci. 2017, 18(3), 664; https://doi.org/10.3390/ijms18030664 - 20 Mar 2017

Cited by 5 | Viewed by 3766

Abstract

Alfalfa (Medicago sativa L.) genotypes transformed with Lc-bHLH and Lc transcription genes were developed with the intention of stimulating proanthocyanidin synthesis in the aerial parts of the plant. To our knowledge, there are no studies on the effect of single-gene and two-gene [...] Read more.

Alfalfa (Medicago sativa L.) genotypes transformed with Lc-bHLH and Lc transcription genes were developed with the intention of stimulating proanthocyanidin synthesis in the aerial parts of the plant. To our knowledge, there are no studies on the effect of single-gene and two-gene transformation on chemical functional groups and molecular structure changes in these plants. The objective of this study was to use advanced molecular spectroscopy with multivariate chemometrics to determine chemical functional group intensity and molecular structure changes in alfalfa plants when co-expressing Lc-bHLH and C1-MYB transcriptive flavanoid regulatory genes in comparison with non-transgenic (NT) and AC Grazeland (ACGL) genotypes. The results showed that compared to NT genotype, the presence of double genes (Lc and C1) increased ratios of both the area and peak height of protein structural Amide I/II and the height ratio of α-helix to β-sheet. In carbohydrate-related spectral analysis, the double gene-transformed alfalfa genotypes exhibited lower peak heights at 1370, 1240, 1153, and 1020 cm⁻¹ compared to the NT genotype. Furthermore, the effect of double gene transformation on carbohydrate molecular structure was clearly revealed in the principal component analysis of the spectra. In conclusion, single or double transformation of Lc and C1 genes resulted in changing functional groups and molecular structure related to proteins and carbohydrates compared to the NT alfalfa genotype. The current study provided molecular structural information on the transgenic alfalfa plants and provided an insight into the impact of transgenes on protein and carbohydrate properties and their molecular structure’s changes. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Open AccessArticle

Brain-Derived Neurotrophic Factor Loaded PS80 PBCA Nanocarrier for In Vitro Neural Differentiation of Mouse Induced Pluripotent Stem Cells

by Chiu-Yen Chung, Martin Hsiu-Chu Lin, I-Neng Lee, Tsong-Hai Lee, Ming-Hsueh Lee and Jen-Tsung Yang

Int. J. Mol. Sci. 2017, 18(3), 663; https://doi.org/10.3390/ijms18030663 - 19 Mar 2017

Cited by 17 | Viewed by 6987

Abstract

Brain derived neurotrophic factor (BDNF) can induce neural differentiation in stem cells and has the potential for repair of the nervous system. In this study, a polysorbate 80-coated polybutylcyanoacrylate nanocarrier (PS80 PBCA NC) was constructed to deliver plasmid DNAs (pDNAs) containing [...] Read more.

Brain derived neurotrophic factor (BDNF) can induce neural differentiation in stem cells and has the potential for repair of the nervous system. In this study, a polysorbate 80-coated polybutylcyanoacrylate nanocarrier (PS80 PBCA NC) was constructed to deliver plasmid DNAs (pDNAs) containing BDNF gene attached to a hypoxia-responsive element (HRE-cmvBDNF). The hypoxia-sensing mechanism of BDNF expression and inductiveness of the nano-formulation on mouse induced pluripotent stem cells (iPSCs) to differentiate into neurons following hypoxia was tested in vitro with immunofluorescent staining and Western blotting. The HRE-cmvBDNF appeared to adsorb onto the surface of PS80 PBCA NC, with a resultant mean diameter of 92.6 ± 1.0 nm and zeta potential of −14.1 ± 1.1 mV. HIF-1α level in iPSCs was significantly higher in hypoxia, which resulted in a 51% greater BDNF expression when transfected with PS80 PBCA NC/HRE-cmvBDNF than those without hypoxia. TrkB and phospho-Akt were also elevated which correlated with neural differentiation. The findings suggest that PS80 PBCA NC too can be endocytosed to serve as an efficient vector for genes coupled to the HRE in hypoxia-sensitive cells, and activation of the PI3/Akt pathway in iPSCs by BDNF is capable of neural lineage specification. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)

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Open AccessArticle

Melatonin MT₁ and MT₂ Receptors in the Ram Reproductive Tract

by Marta González-Arto, David Aguilar, Elena Gaspar-Torrubia, Margarita Gallego, Melissa Carvajal-Serna, Luis V. Herrera-Marcos, Edith Serrano-Blesa, Thais Rose dos Santos Hamilton, Rosaura Pérez-Pé, Teresa Muiño-Blanco, José A. Cebrián-Pérez and Adriana Casao

Int. J. Mol. Sci. 2017, 18(3), 662; https://doi.org/10.3390/ijms18030662 - 19 Mar 2017

Cited by 38 | Viewed by 5694

Abstract

Some melatonin functions in mammals are exerted through MT₁ and MT₂ receptors. However, there are no reports of their presence in the reproductive tract of the ram, a seasonal species. Thus, we have investigated their existence in the ram testis, epididymis, [...] Read more.

Some melatonin functions in mammals are exerted through MT₁ and MT₂ receptors. However, there are no reports of their presence in the reproductive tract of the ram, a seasonal species. Thus, we have investigated their existence in the ram testis, epididymis, accessory glands and ductus deferens. Real-time polymerase chain reaction (qPCR) revealed higher levels of m-RNA for both receptors in the testis, ampulla, seminal vesicles, and vas deferens, than in the other organs of the reproductive tract (p < 0.05). Western blot analyses showed protein bands compatible with the MT₁ in the testis and cauda epididymis, and for the MT₂ in the cauda epididymis and deferent duct. Immunohistochemistry analyses revealed the presence of MT₁ receptors in spermatogonias, spermatocytes, and spermatids, and MT₂ receptors in the newly-formed spermatozoa in the testis, whereas both receptors were located in the epithelial cells of the ampulla, seminal vesicles, and ductus deferens. Indirect immunofluorescence showed significant differences in the immunolocation of both receptors in spermatozoa during their transit in the epididymis. In conclusion, it was demonstrated that melatonin receptors are present in the ram reproductive tract. These results open the way for new studies on the molecular mechanism of melatonin and the biological significance of its receptors. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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Genetic Variants Contributing to Colistin Cytotoxicity: Identification of TGIF1 and HOXD10 Using a Population Genomics Approach

by Michael T. Eadon, Ronald J. Hause, Amy L. Stark, Ying-Hua Cheng, Heather E. Wheeler, Kimberly S. Burgess, Eric A. Benson, Patrick N. Cunningham, Robert L. Bacallao, Pierre C. Dagher, Todd C. Skaar and M. Eileen Dolan

Int. J. Mol. Sci. 2017, 18(3), 661; https://doi.org/10.3390/ijms18030661 - 18 Mar 2017

Cited by 3 | Viewed by 5253

Abstract

Colistin sulfate (polymixin E) is an antibiotic prescribed with increasing frequency for severe Gram-negative bacterial infections. As nephrotoxicity is a common side effect, the discovery of pharmacogenomic markers associated with toxicity would benefit the utility of this drug. Our objective was to identify [...] Read more.

Colistin sulfate (polymixin E) is an antibiotic prescribed with increasing frequency for severe Gram-negative bacterial infections. As nephrotoxicity is a common side effect, the discovery of pharmacogenomic markers associated with toxicity would benefit the utility of this drug. Our objective was to identify genetic markers of colistin cytotoxicity that were also associated with expression of key proteins using an unbiased, whole genome approach and further evaluate the functional significance in renal cell lines. To this end, we employed International HapMap lymphoblastoid cell lines (LCLs) of Yoruban ancestry with known genetic information to perform a genome-wide association study (GWAS) with cellular sensitivity to colistin. Further association studies revealed that single nucleotide polymorphisms (SNPs) associated with gene expression and protein expression were significantly enriched in SNPs associated with cytotoxicity (p ≤ 0.001 for gene and p = 0.015 for protein expression). The most highly associated SNP, chr18:3417240 (p = 6.49 × 10⁻⁸), was nominally a cis-expression quantitative trait locus (eQTL) of the gene TGIF1 (transforming growth factor β (TGFβ)-induced factor-1; p = 0.021) and was associated with expression of the protein HOXD10 (homeobox protein D10; p = 7.17 × 10⁻⁵). To demonstrate functional relevance in a murine colistin nephrotoxicity model, HOXD10 immunohistochemistry revealed upregulated protein expression independent of mRNA expression in response to colistin administration. Knockdown of TGIF1 resulted in decreased protein expression of HOXD10 and increased resistance to colistin cytotoxicity. Furthermore, knockdown of HOXD10 in renal cells also resulted in increased resistance to colistin cytotoxicity, supporting the physiological relevance of the initial genomic associations. Full article

(This article belongs to the Special Issue Nephrotoxicity)

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Assessment of Antioxidant and Cytoprotective Potential of Jatropha (Jatropha curcas) Grown in Southern Italy

by Teresa Papalia, Davide Barreca and Maria Rosaria Panuccio

Int. J. Mol. Sci. 2017, 18(3), 660; https://doi.org/10.3390/ijms18030660 - 18 Mar 2017

Cited by 29 | Viewed by 6519

Abstract

Jatropha (Jatropha curcas L.) is a plant native of Central and South America, but widely distributed in the wild or semi-cultivated areas in Africa, India, and South East Asia. Although studies are available in literature on the polyphenolic content and bioactivity of [...] Read more.

Jatropha (Jatropha curcas L.) is a plant native of Central and South America, but widely distributed in the wild or semi-cultivated areas in Africa, India, and South East Asia. Although studies are available in literature on the polyphenolic content and bioactivity of Jatropha curcas L., no information is currently available on plants grown in pedoclimatic and soil conditions different from the autochthon regions. The aim of the present work was to characterize the antioxidant system developed by the plant under a new growing condition and to evaluate the polyphenol amount in a methanolic extract of leaves. Along with these analyses we have also tested the antioxidant and cytoprotective activities on lymphocytes. RP-HPLC-DAD analysis of flavonoids revealed a chromatographic profile dominated by the presence of flavone C-glucosydes. Vitexin is the most abundant identified compound followed by vicenin-2, stellarin-2, rhoifolin, and traces of isovitexin and isorhoifolin. Methanolic extract had high scavenging activity in all antioxidant assays tested and cytoprotective activity on lymphocytes exposed to tertz-buthylhydroperoxide. The results highlighted a well-defined mechanism of adaptation of the plant and a significant content of secondary metabolites with antioxidant properties, which are of interest for their potential uses, especially as a rich source of biologically active products. Full article

(This article belongs to the Special Issue Biological Activity of Natural Secondary Metabolite Products)

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Dysfunctional mTORC1 Signaling: A Convergent Mechanism between Syndromic and Nonsyndromic Forms of Autism Spectrum Disorder?

by Juliana Magdalon, Sandra M. Sánchez-Sánchez, Karina Griesi-Oliveira and Andréa L. Sertié

Int. J. Mol. Sci. 2017, 18(3), 659; https://doi.org/10.3390/ijms18030659 - 18 Mar 2017

Cited by 38 | Viewed by 9506

Abstract

Whereas autism spectrum disorder (ASD) exhibits striking heterogeneity in genetics and clinical presentation, dysfunction of mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway has been identified as a molecular feature common to several well-characterized syndromes with high prevalence of ASD. Additionally, recent [...] Read more.

Whereas autism spectrum disorder (ASD) exhibits striking heterogeneity in genetics and clinical presentation, dysfunction of mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway has been identified as a molecular feature common to several well-characterized syndromes with high prevalence of ASD. Additionally, recent findings have also implicated mTORC1 signaling abnormalities in a subset of nonsyndromic ASD, suggesting that defective mTORC1 pathway may be a potential converging mechanism in ASD pathology across different etiologies. However, the mechanistic evidence for a causal link between aberrant mTORC1 pathway activity and ASD neurobehavioral features varies depending on the ASD form involved. In this review, we first discuss six monogenic ASD-related syndromes, including both classical and potentially novel mTORopathies, highlighting their contribution to our understanding of the neurobiological mechanisms underlying ASD, and then we discuss existing evidence suggesting that aberrant mTORC1 signaling may also play a role in nonsyndromic ASD. Full article

(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders 2017)

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Knee Viscosupplementation: Cost-Effectiveness Analysis between Stabilized Hyaluronic Acid in a Single Injection versus Five Injections of Standard Hyaluronic Acid

by Francisco J. Estades-Rubio, Alvaro Reyes-Martín, Victor Morales-Marcos, Mercedes García-Piriz, Juan J. García-Vera, Macarena Perán, Juan A. Marchal and Elvira Montañez-Heredia

Int. J. Mol. Sci. 2017, 18(3), 658; https://doi.org/10.3390/ijms18030658 - 17 Mar 2017

Cited by 18 | Viewed by 6475

Abstract

Given the wide difference in price per vial between various presentations of hyaluronic acid, this study seeks to compare the effectiveness and treatment cost of stabilized hyaluronic acid (NASHA) in a single injection with standard preparations of hyaluronic acid (HA) in five injections [...] Read more.

Given the wide difference in price per vial between various presentations of hyaluronic acid, this study seeks to compare the effectiveness and treatment cost of stabilized hyaluronic acid (NASHA) in a single injection with standard preparations of hyaluronic acid (HA) in five injections in osteoarthritis (OA) of the knee. Fifty-four patients with knee osteoarthritis (Kellgren–Lawrence Grade II and III) and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score greater than 7, with a homogeneous distribution of age, sex, BMI, and duration of disease, were included in this study. Patients were randomized into two groups: Group I was treated with NASHA (Durolane^®) and Group II with HA (Go-ON^®). Patient’s evolution was followed up at the 1st, 2nd, 4th, 8th, 12th, and 26th week after treatment. A statistically significant improvement in WOMAC score was observed for patients treated with NASHA versus those who received HA at Week 26. In addition, the need for analgesia was significantly reduced at Week 26 in the NASHA-treated group. Finally, the economic analysis showed an increased cost of overall treatment with HA injections. Our data support the use of the NASHA class of products in the treatment of knee OA. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases Therapy)

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The Glyoxalase System and Methylglyoxal-Derived Carbonyl Stress in Sepsis: Glycotoxic Aspects of Sepsis Pathophysiology

by Thomas Schmoch, Florian Uhle, Benedikt H. Siegler, Thomas Fleming, Jakob Morgenstern, Peter P. Nawroth, Markus A. Weigand and Thorsten Brenner

Int. J. Mol. Sci. 2017, 18(3), 657; https://doi.org/10.3390/ijms18030657 - 17 Mar 2017

Cited by 29 | Viewed by 9077

Abstract

Sepsis remains one of the leading causes of death in intensive care units. Although sepsis is caused by a viral, fungal or bacterial infection, it is the dysregulated generalized host response that ultimately leads to severe dysfunction of multiple organs and death. The [...] Read more.

Sepsis remains one of the leading causes of death in intensive care units. Although sepsis is caused by a viral, fungal or bacterial infection, it is the dysregulated generalized host response that ultimately leads to severe dysfunction of multiple organs and death. The concomitant profound metabolic changes are characterized by hyperglycemia, insulin resistance, and profound transformations of the intracellular energy supply in both peripheral and immune cells. A further hallmark of the early phases of sepsis is a massive formation of reactive oxygen (ROS; e.g., superoxide) as well as nitrogen (RNS; e.g., nitric oxide) species. Reactive carbonyl species (RCS) form a third crucial group of highly reactive metabolites, which until today have been not the focus of interest in sepsis. However, we previously showed in a prospective observational clinical trial that patients suffering from septic shock are characterized by significant methylglyoxal (MG)-derived carbonyl stress, with the glyoxalase system being downregulated in peripheral blood mononuclear cells. In this review, we give a detailed insight into the current state of research regarding the metabolic changes that entail an increased MG-production in septicemia. Thus, we point out the special role of the glyoxalase system in the context of sepsis. Full article

(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)

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Understanding the Effectiveness of Natural Compound Mixtures in Cancer through Their Molecular Mode of Action

by Thazin Nwe Aung, Zhipeng Qu, R. Daniel Kortschak and David L. Adelson

Int. J. Mol. Sci. 2017, 18(3), 656; https://doi.org/10.3390/ijms18030656 - 17 Mar 2017

Cited by 257 | Viewed by 12697

Abstract

Many approaches to cancer management are often ineffective due to adverse reactions, drug resistance, or inadequate target specificity of single anti-cancer agents. In contrast, a combinatorial approach with the application of two or more anti-cancer agents at their respective effective dosages can achieve [...] Read more.

Many approaches to cancer management are often ineffective due to adverse reactions, drug resistance, or inadequate target specificity of single anti-cancer agents. In contrast, a combinatorial approach with the application of two or more anti-cancer agents at their respective effective dosages can achieve a synergistic effect that boosts cytotoxicity to cancer cells. In cancer, aberrant apoptotic pathways allow cells that should be killed to survive with genetic abnormalities, leading to cancer progression. Mutations in apoptotic mechanism arising during the treatment of cancer through cancer progression can consequently lead to chemoresistance. Natural compound mixtures that are believed to have multiple specific targets with minimal acceptable side-effects are now of interest to many researchers due to their cytotoxic and chemosensitizing activities. Synergistic interactions within a drug mixture enhance the search for potential molecular targets in cancer cells. Nonetheless, biased/flawed scientific evidence from natural products can suggest false positive therapeutic benefits during drug screening. In this review, we have taken these factors into consideration when discussing the evidence for these compounds and their synergistic therapeutic benefits in cancer. While there is limited evidence for clinical efficacy for these mixtures, in vitro data suggest that these preparations merit further investigation, both in vitro and in vivo. Full article

(This article belongs to the Special Issue Biological Activity of Natural Secondary Metabolite Products)

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BDNF Variants May Modulate Long-Term Visual Memory Performance in a Healthy Cohort

by Nesli Avgan, Heidi G. Sutherland, Lauren K. Spriggens, Chieh Yu, Omar Ibrahim, Claire Bellis, Larisa M. Haupt, David H. K. Shum and Lyn R. Griffiths

Int. J. Mol. Sci. 2017, 18(3), 655; https://doi.org/10.3390/ijms18030655 - 17 Mar 2017

Cited by 18 | Viewed by 9177

Abstract

Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive functions including learning and memory. BDNF plays an important role in synaptic plasticity in humans and rats with BDNF shown to be essential for the formation of long-term memories. We previously identified a significant [...] Read more.

Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive functions including learning and memory. BDNF plays an important role in synaptic plasticity in humans and rats with BDNF shown to be essential for the formation of long-term memories. We previously identified a significant association between the BDNF Val66Met polymorphism (rs6265) and long-term visual memory (p-value = 0.003) in a small cohort (n = 181) comprised of healthy individuals who had been phenotyped for various aspects of memory function. In this study, we have extended the cohort to 597 individuals and examined multiple genetic variants across both the BDNF and BDNF-AS genes for association with visual memory performance as assessed by the Wechsler Memory Scale—Fourth Edition subtests Visual Reproduction I and II (VR I and II). VR I assesses immediate visual memory, whereas VR II assesses long-term visual memory. Genetic association analyses were performed for 34 single nucleotide polymorphisms genotyped on Illumina OmniExpress BeadChip arrays with the immediate and long-term visual memory phenotypes. While none of the BDNF and BDNF-AS variants were shown to be significant for immediate visual memory, we found 10 variants (including the Val66Met polymorphism (p-value = 0.006)) that were nominally associated, and three variants (two variants in BDNF and one variant in the BDNF-AS locus) that were significantly associated with long-term visual memory. Our data therefore suggests a potential role for BDNF, and its anti-sense transcript BDNF-AS, in long-term visual memory performance. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)

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In Vitro Anti-Inflammatory and Cytotoxic Effects of Aqueous Extracts from the Edible Sea Anemones Anemonia sulcata and Actinia equina

by Tânia Costa Silva, Paula Branquinho De Andrade, Fátima Paiva-Martins, Patrícia Valentão and David Micael Pereira

Int. J. Mol. Sci. 2017, 18(3), 653; https://doi.org/10.3390/ijms18030653 - 17 Mar 2017

Cited by 23 | Viewed by 5925

Abstract

Marine invertebrates have been attracting the attention of researchers for their application in nutrition, agriculture, and the pharmaceutical industry, among others. Concerning sea anemones (Cnidaria), little is known regarding their metabolic profiles and potential value as a source of pharmacologically-active agents. In this [...] Read more.

Marine invertebrates have been attracting the attention of researchers for their application in nutrition, agriculture, and the pharmaceutical industry, among others. Concerning sea anemones (Cnidaria), little is known regarding their metabolic profiles and potential value as a source of pharmacologically-active agents. In this work, the chemical profiles of two species of sea anemones Actinia equina and Anemonia sulcata, were studied by high-performance liquid chromatography with diode-array detection (HPLC-DAD) and its impact upon immune and gastric cells was evaluated. In both species, the methylpyridinium alkaloid homarine was the major compound in aqueous extracts. The extracts were effective in reducing lipopolysaccharide (LPS)-induced levels of nitric oxide (NO) and intracellular reactive oxygen species (ROS) in a macrophage model of inflammation. Both the extracts and the alkaloid homarine were effective in inhibiting phospholipase A₂ (PLA₂), a pivotal enzyme in the initial steps of the inflammatory cascade. In order to mimic the oral consumption of these extracts; their effect upon human gastric cells was evaluated. While no caspase-9 activation was detected, the fact that the endoplasmic reticulum-resident caspase-4, and also caspase-3, were activated points to a non-classical mechanism of apoptosis in human gastric cells. This work provides new insights on the toxicity and biological potential of sea anemones increasingly present in human nutrition. Full article

(This article belongs to the Special Issue Natural Anti-Inflammatory Agents)

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Plausible Roles for RAGE in Conditions Exacerbated by Direct and Indirect (Secondhand) Smoke Exposure

by Joshua B. Lewis, Kelsey M. Hirschi, Juan A. Arroyo, Benjamin T. Bikman, David L. Kooyman and Paul R. Reynolds

Int. J. Mol. Sci. 2017, 18(3), 652; https://doi.org/10.3390/ijms18030652 - 17 Mar 2017

Cited by 19 | Viewed by 7076

Abstract

Approximately 1 billion people smoke worldwide, and the burden placed on society by primary and secondhand smokers is expected to increase. Smoking is the leading risk factor for myriad health complications stemming from diverse pathogenic programs. First- and second-hand cigarette smoke contains thousands [...] Read more.

Approximately 1 billion people smoke worldwide, and the burden placed on society by primary and secondhand smokers is expected to increase. Smoking is the leading risk factor for myriad health complications stemming from diverse pathogenic programs. First- and second-hand cigarette smoke contains thousands of constituents, including several carcinogens and cytotoxic chemicals that orchestrate chronic inflammatory responses and destructive remodeling events. In the current review, we outline details related to compromised pulmonary and systemic conditions related to smoke exposure. Specifically, data are discussed relative to impaired lung physiology, cancer mechanisms, maternal-fetal complications, cardiometabolic, and joint disorders in the context of smoke exposure exacerbations. As a general unifying mechanism, the receptor for advanced glycation end-products (RAGE) and its signaling axis is increasingly considered central to smoke-related pathogenesis. RAGE is a multi-ligand cell surface receptor whose expression increases following cigarette smoke exposure. RAGE signaling participates in the underpinning of inflammatory mechanisms mediated by requisite cytokines, chemokines, and remodeling enzymes. Understanding the biological contributions of RAGE during cigarette smoke-induced inflammation may provide critically important insight into the pathology of lung disease and systemic complications that combine during the demise of those exposed. Full article

(This article belongs to the Special Issue Inhaled Pollutants Modulate Respiratory and Systemic Diseases)

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Neuroinflammation and Oxidative Stress in Psychosis and Psychosis Risk

by Henry Barron, Sina Hafizi, Ana C. Andreazza and Romina Mizrahi

Int. J. Mol. Sci. 2017, 18(3), 651; https://doi.org/10.3390/ijms18030651 - 17 Mar 2017

Cited by 128 | Viewed by 10940

Abstract

Although our understanding of psychotic disorders has advanced substantially in the past few decades, very little has changed in the standard of care for these illnesses since the development of atypical anti-psychotics in the 1990s. Here, we integrate new insights into the pathophysiology [...] Read more.

Although our understanding of psychotic disorders has advanced substantially in the past few decades, very little has changed in the standard of care for these illnesses since the development of atypical anti-psychotics in the 1990s. Here, we integrate new insights into the pathophysiology with the increasing interest in early detection and prevention. First, we explore the role of N-methyl-d-aspartate receptors in a subpopulation of cortical parvalbumin-containing interneurons (PVIs). Postmortem and preclinical data has implicated these neurons in the positive and negative symptoms, as well as the cognitive dysfunction present in schizophrenia. These neurons also appear to be sensitive to inflammation and oxidative stress during the perinatal and peripubertal periods, which may be mediated in large part by aberrant synaptic pruning. After exploring some of the molecular mechanisms through which neuroinflammation and oxidative stress are thought to exert their effects, we highlight the progress that has been made in identifying psychosis prior to onset through the identification of individuals at clinical high risk for psychosis (CHR). By combining our understanding of psychosis pathogenesis with the increasing characterization of endophenotypes that precede frank psychosis, it may be possible to identify patients before they present with psychosis and intervene to reduce the burden of the disease to both patients and families. Full article

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

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Int. J. Mol. Sci., Volume 18, Issue 3 (March 2017) – 207 articles

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