International Journal of Molecular Sciences

21 pages, 4909 KiB

Open AccessArticle

Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen–Antioxidant Mutual Prodrugs

by Zaman Ashraf¹, Alamgeer², Raqiqatur Rasool¹, Mubashir Hassan³, Haseeb Ahsan², Samina Afzal⁴, Khurram Afzal⁴, Hongsik Cho^5,6

and Song Ja Kim^3,*

¹ Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan

² Department of Pharmacology, Faculty of Pharmacy University of Sargodha, Sargodha 40100, Pakistan

³ Department of Biology, College of Natural Sciences, Kongju National University, Gongju 314701, Korea

⁴ Faculty of Pharmacy, BahauddinZakria University, Multan 60800, Pakistan

⁵ Department of Orthopaedic Surgery & Biomedical Engineering, University of Tennessee Health Science Center-Campbell Clinic, Memphis, TN 38104, USA

⁶ Research 151, Veterans Affairs Medical Center, Memphis, TN 38104, USA

Int. J. Mol. Sci. 2016, 17(12), 2151; https://doi.org/10.3390/ijms17122151 - 21 Dec 2016

Cited by 12 | Viewed by 7217

Abstract

Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a–c were obtained by reacting its –COOH group with chloroacetyl derivatives 3a–c. The in vitro hydrolysis data confirmed that synthesized prodrugs [...] Read more.

Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a–c were obtained by reacting its –COOH group with chloroacetyl derivatives 3a–c. The in vitro hydrolysis data confirmed that synthesized prodrugs 5a–c were stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of 5c (p < 0.001) is more significant than the parent dexibuprofen. The prodrug 5c produced maximum inhibition (42.06%) of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs 5a and 5b showed significant inhibition of pyrexia (p < 0.001). The analgesic activity of 5a is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 5a was more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs 5a–c interacts with the residues present in active binding sites of target protein. The stability of drug–target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug. Full article

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

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13 pages, 3296 KiB

Open AccessArticle

Neuropeptide Y1 Receptor Regulates Glucocorticoid-Induced Inhibition of Osteoblast Differentiation in Murine MC3T3-E1 Cells via ERK Signaling

by Wei Yu^†, Chao Zhu^†, Wenning Xu, Leisheng Jiang^* and Shengdan Jiang^*

¹ Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2150; https://doi.org/10.3390/ijms17122150 - 21 Dec 2016

Cited by 18 | Viewed by 6895

Abstract

High dose glucocorticoid (GC) administration impairs the viability and function of osteoblasts, thus causing osteoporosis and osteonecrosis. Neuropeptide Y1 receptor (Y1 receptor) is expressed in bone tissues and cells, and regulates bone remodeling. However, the role of Y1 receptor in glucocorticoid-induced inhibition of [...] Read more.

High dose glucocorticoid (GC) administration impairs the viability and function of osteoblasts, thus causing osteoporosis and osteonecrosis. Neuropeptide Y1 receptor (Y1 receptor) is expressed in bone tissues and cells, and regulates bone remodeling. However, the role of Y1 receptor in glucocorticoid-induced inhibition of osteoblast differentiation remains unknown. In the present study, osteoblastic cell line MC3T3-E1 cultured in osteogenic differentiation medium was treated with or without of 10⁻⁷ M dexamethasone (Dex), Y1 receptor shRNA interference, Y1 receptor agonist [Leu³¹, Pro³⁴]-NPY, and antagonist BIBP3226. Cell proliferation and apoptosis were assessed by cell counting kit-8 (CCK-8) assay and cleaved caspase expression, respectively. Osteoblast differentiation was evaluated by Alizarin Red S staining and osteogenic marker gene expressions. Protein expression was detected by Western blot analysis. Dex upregulated the expression of Y1 receptor in MC3T3-E1 cells associated with reduced osteogenic gene expressions and mineralization. Blockade of Y1 receptor by shRNA transfection and BIBP3226 significantly attenuated the inhibitory effects of Dex on osteoblastic activity. Y1 receptor signaling modulated the activation of extracellular signal-regulated kinases (ERK) as well as the expressions of osteogenic genes. Y1 receptor agonist inhibited ERK phosphorylation and osteoblast differentiation, while Y1 receptor blockade exhibited the opposite effects. Activation of ERK signaling by constitutive active mutant of MEK1 (caMEK) abolished Y1 receptor-mediated Dex inhibition of osteoblast differentiation in MC3T3-E1 cells. Taken together, Y1 receptor regulates Dex-induced inhibition of osteoblast differentiation in murine MC3T3-E1 cells via ERK signaling. This study provides a novel role of Y1 receptor in the process of GC-induced suppression in osteoblast survival and differentiation. Full article

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

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9 pages, 2586 KiB

Open AccessArticle

A Novel Pathogenic BRCA1 Splicing Variant Produces Partial Intron Retention in the Mature Messenger RNA

by Maria Valeria Esposito¹, Marcella Nunziato^1,2, Flavio Starnone¹, Antonella Telese¹, Alessandra Calabrese^1,3, Giuseppe D’Aiuto³, Pietro Pucci¹, Massimiliano D’Aiuto³, Francisco Baralle⁴, Valeria D’Argenio^1,5,*

and Francesco Salvatore^1,5,6,*

¹ CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy

² Department of Movement Sciences and Wellness (DiSMEB), University of Naples Parthenope, via Medina 40, 80133 Naples, Italy

³ Department of Senology, Istituto Nazionale Tumori–IRCCS Fondazione Pascale, via Mariano Semmola, 52, 80131 Naples, Italy

⁴ International Centre for Genetic Engineering and Biotechnology, Science Park, Padriciano 99, 34149 Trieste, Italy

⁵ Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, via Sergio Pansini 5, 80131 Naples, Italy

⁶ IRCCS-Fondazione SDN, via Emanuele Gianturco 113, 80143 Naples, Italy

Int. J. Mol. Sci. 2016, 17(12), 2145; https://doi.org/10.3390/ijms17122145 - 21 Dec 2016

Cited by 12 | Viewed by 6109

Abstract

About 10% of all breast cancers arise from hereditary mutations that increase the risk of breast and ovarian cancers; and about 25% of these are associated with the BRCA1 or BRCA2 genes. The identification of BRCA1/BRCA2 mutations can enable physicians to [...] Read more.

About 10% of all breast cancers arise from hereditary mutations that increase the risk of breast and ovarian cancers; and about 25% of these are associated with the BRCA1 or BRCA2 genes. The identification of BRCA1/BRCA2 mutations can enable physicians to better tailor the clinical management of patients; and to initiate preventive measures in healthy carriers. The pathophysiological significance of newly identified variants poses challenges for genetic counseling. We characterized a new BRCA1 variant discovered in a breast cancer patient during BRCA1/2 screening by next-generation sequencing. Bioinformatic predictions; indicating that the variant is probably pathogenetic; were verified using retro-transcription of the patient’s RNA followed by PCR amplifications performed on the resulting cDNA. The variant causes the loss of a canonic donor splice site at position +2 in BRCA1 intron 21; and consequently the partial retention of 156 bp of intron 21 in the patient’s transcript; which demonstrates that this novel BRCA1 mutation plays a pathogenetic role in breast cancer. These findings enabled us to initiate appropriate counseling and to tailor the clinical management of this family. Lastly; these data reinforce the importance of studying the effects of sequence variants at the RNA level to verify their potential role in disease onset. Full article

(This article belongs to the Special Issue Next-Generation Sequencing for Clinical Application)

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13 pages, 1631 KiB

Open AccessArticle

Dermal Delivery of Constructs Encoding Cre Recombinase to Induce Skin Tumors in Pten^LoxP/LoxP;Braf^CA/+ Mice

by Marcel A. Deken¹, Ji-Ying Song², Jules Gadiot¹, Adriaan D. Bins³, Paula Kroon¹, Inge Verbrugge¹ and Christian U. Blank^1,4,*

¹ Department of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

² Department of Experimental Animal Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

³ Division of Medical Oncology, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

⁴ Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Int. J. Mol. Sci. 2016, 17(12), 2149; https://doi.org/10.3390/ijms17122149 - 20 Dec 2016

Cited by 2 | Viewed by 7453

Abstract

Current genetically-engineered mouse melanoma models are often based on Tyr::CreER^T2-controlled MAPK pathway activation by the BRAF^V600E mutation and PI3K pathway activation by loss of PTEN. The major drawback of these models is the occurrence of spontaneous tumors caused by leakiness [...] Read more.

Current genetically-engineered mouse melanoma models are often based on Tyr::CreER^T2-controlled MAPK pathway activation by the BRAF^V600E mutation and PI3K pathway activation by loss of PTEN. The major drawback of these models is the occurrence of spontaneous tumors caused by leakiness of the Tyr::CreER^T2 system, hampering long-term experiments. To address this problem, we investigated several approaches to optimally provide local delivery of Cre recombinase, including injection of lentiviral particles, DNA tattoo administration and particle-mediated gene transfer, to induce melanomas in Pten^LoxP/LoxP;Braf^CA/+ mice lacking the Tyr::CreER^T2 allele. We found that dermal delivery of the Cre recombinase gene under the control of a non-specific CAG promoter induced the formation of melanomas, but also keratoacanthoma and squamous cell carcinomas. Delivery of Cre recombinase DNA under the control of melanocyte-specific promoters in Pten^LoxP/LoxP;Braf^CA/+ mice resulted in sole melanoma induction. The growth rate and histological features of the induced tumors were similar to 4-hydroxytamoxifen-induced tumors in Tyr::CreER^T2;Pten^LoxP/LoxP;Braf^CA/+ mice, while the onset of spontaneous tumors was prevented completely. These novel induction methods will allow long-term experiments in mouse models of skin malignancies. Full article

(This article belongs to the Special Issue Animal Models of Melanoma)

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16 pages, 1057 KiB

Open AccessArticle

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

by Andrea Párniczky^1,†, Eszter Hegyi^1,†, Anna Zsófia Tóth¹, Ákos Szücs², Andrea Szentesi^3,4, Áron Vincze⁵, Ferenc Izbéki⁶, Balázs Csaba Németh⁴, Péter Hegyi^3,4 and Miklós Sahin-Tóth^1,*

¹ Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA

² First Department of Surgery, Semmelweis University, 1082 Budapest, Hungary

³ Institute for Translational Medicine, University of Pécs, 7624 Pécs, Hungary

⁴ First Department of Medicine, University of Szeged, 6720 Szeged, Hungary

⁵ First Department of Medicine, University of Pécs, 7624 Pécs, Hungary

⁶ Department of Gastroenterology, St. George Teaching Hospital of County Fejér, 8000 Székesfehérvár, Hungary

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2148; https://doi.org/10.3390/ijms17122148 - 20 Dec 2016

Cited by 14 | Viewed by 6003

Abstract

Human chymotrypsin-like elastases 3A and 3B (CELA3A and CELA3B) are the products of gene duplication and share 92% identity in their primary structure. CELA3B forms stable complexes with procarboxypeptidases A1 and A2 whereas CELA3A binds poorly due to the evolutionary substitution of Ala241 [...] Read more.

Human chymotrypsin-like elastases 3A and 3B (CELA3A and CELA3B) are the products of gene duplication and share 92% identity in their primary structure. CELA3B forms stable complexes with procarboxypeptidases A1 and A2 whereas CELA3A binds poorly due to the evolutionary substitution of Ala241 with Gly in exon 7. Since position 241 is polymorphic both in CELA3A (p.G241A) and CELA3B (p.A241G), genetic analysis can directly assess whether individual variability in complex formation might alter risk for chronic pancreatitis. Here we sequenced exon 7 of CELA3A and CELA3B in a cohort of 225 subjects with chronic pancreatitis (120 alcoholic and 105 non-alcoholic) and 300 controls of Hungarian origin. Allele frequencies were 2.5% for CELA3A p.G241A and 1.5% for CELA3B p.A241G in controls, and no significant difference was observed in patients. Additionally, we identified six synonymous variants, two missense variants, a gene conversion event and ten variants in the flanking intronic regions. Variant c.643-7G>T in CELA3B showed an association with alcoholic chronic pancreatitis with a small protective effect (OR = 0.59, 95% CI = 0.39–0.89, p = 0.01). Functional analysis of missense variants revealed no major defects in secretion or activity. We conclude that variants affecting amino-acid position 241 in CELA3A and CELA3B are not associated with chronic pancreatitis, indicating that changes in complex formation between proelastases and procarboxypeptidases do not alter pancreatitis risk. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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8 pages, 199 KiB

Open AccessReview

Neuroprotection via Reduction in Stress: Altered Menstrual Patterns as a Marker for Stress and Implications for Long-Term Neurologic Health in Women

by David Prokai and Sarah L. Berga^*

Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA

Int. J. Mol. Sci. 2016, 17(12), 2147; https://doi.org/10.3390/ijms17122147 - 20 Dec 2016

Cited by 22 | Viewed by 6696

Abstract

Individuals under chronic psychological stress can be difficult to identify clinically. There is often no outwardly visible phenotype. Chronic stress of sufficient magnitude not only impacts reproductive function, but also concomitantly elicits a constellation of neuroendocrine changes that may accelerate aging in general [...] Read more.

Individuals under chronic psychological stress can be difficult to identify clinically. There is often no outwardly visible phenotype. Chronic stress of sufficient magnitude not only impacts reproductive function, but also concomitantly elicits a constellation of neuroendocrine changes that may accelerate aging in general and brain aging in particular. Functional hypothalamic amenorrhea, a phenotypically recognizable form of stress, is due to stress-induced suppression of endogenous gonadotropin-releasing hormone secretion. Reversal of functional hypothalamic amenorrhea includes restoration of ovulatory ovarian function and fertility and amelioration of hypercortisolism and hypothyroidism. Taken together, recovery from functional hypothalamic amenorrhea putatively offers neuroprotection and ameliorates stress-induced premature brain aging and possibly syndromic Alzheimer’s disease. Amenorrhea may be viewed as a sentinel indicator of stress. Hypothalamic hypogonadism is less clinically evident in men and the diagnosis is difficult to establish. Whether there are other sex differences in the impact of stress on brain aging remains to be better investigated, but it is likely that both low estradiol from stress-induced anovulation and low testosterone from stress-induced hypogonadism compromise brain health. Full article

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

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36 pages, 1154 KiB

Open AccessReview

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

by Edith Charlier^*, Biserka Relic, Céline Deroyer, Olivier Malaise

, Sophie Neuville, Julie Collée, Michel G. Malaise and Dominique De Seny

Laboratory of Rheumatology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA) Research, Centre Hospitalier Universitaire (CHU) de Liège, University of Liège, 4000 Liège, Belgium

Int. J. Mol. Sci. 2016, 17(12), 2146; https://doi.org/10.3390/ijms17122146 - 20 Dec 2016

Cited by 271 | Viewed by 15718

Abstract

Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs [...] Read more.

Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs and participates to OA development. However, the relative contribution of apoptosis per se in OA pathogenesis appears complex to evaluate. Indeed, depending on technical approaches, OA stages, cartilage layers, animal models, as well as in vivo or in vitro experiments, the percentage of apoptosis and cell death types can vary. Apoptosis, chondroptosis, necrosis, and autophagic cell death are described in this review. The question of cell death causality in OA progression is also addressed, as well as the molecular pathways leading to cell death in response to the following inducers: Fas, Interleukin-1β (IL-1β), Tumor Necrosis factor-α (TNF-α), leptin, nitric oxide (NO) donors, and mechanical stresses. Furthermore, the protective role of autophagy in chondrocytes is highlighted, as well as its decline during OA progression, enhancing chondrocyte cell death; the transition being mainly controlled by HIF-1α/HIF-2α imbalance. Finally, we have considered whether interfering in chondrocyte apoptosis or promoting autophagy could constitute therapeutic strategies to impede OA progression. Full article

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

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15 pages, 1370 KiB

Open AccessReview

Apoptosis in Cellular Society: Communication between Apoptotic Cells and Their Neighbors

by Yuhei Kawamoto^1,2, Yu-ichiro Nakajima^3,4 and Erina Kuranaga^1,2,3,*

¹ Laboratory for Histogenetic Dynamics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara 630-0192, Japan

² Laboratory for Histogenetic Dynamics, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan

³ Laboratory for Histogenetic Dynamics, Graduate School of Life Sciences, Tohoku University, Sendai 980-8578, Japan

⁴ Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai 980-8578, Japan

Int. J. Mol. Sci. 2016, 17(12), 2144; https://doi.org/10.3390/ijms17122144 - 20 Dec 2016

Cited by 47 | Viewed by 12984

Abstract

Apoptosis is one of the cell-intrinsic suicide programs and is an essential cellular behavior for animal development and homeostasis. Traditionally, apoptosis has been regarded as a cell-autonomous phenomenon. However, recent in vivo genetic studies have revealed that apoptotic cells actively influence the behaviors [...] Read more.

Apoptosis is one of the cell-intrinsic suicide programs and is an essential cellular behavior for animal development and homeostasis. Traditionally, apoptosis has been regarded as a cell-autonomous phenomenon. However, recent in vivo genetic studies have revealed that apoptotic cells actively influence the behaviors of surrounding cells, including engulfment, proliferation, and production of mechanical forces. Such interactions can be bidirectional, and apoptosis is non-autonomously induced in a cellular community. Of note, it is becoming evident that active communication between apoptotic cells and living cells contributes to physiological processes during tissue remodeling, regeneration, and morphogenesis. In this review, we focus on the mutual interactions between apoptotic cells and their neighbors in cellular society and discuss issues relevant to future studies of apoptosis. Full article

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

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12 pages, 1589 KiB

Open AccessArticle

Prediction of Hepatocellular Carcinoma Development after Hepatitis C Virus Eradication Using Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein

by Shunsuke Sato¹, Takuya Genda^1,*, Takafumi Ichida², Nozomi Amano¹, Sho Sato¹, Ayato Murata¹, Hironori Tsuzura¹, Yutaka Narita¹, Yoshio Kanemitsu¹, Katsuharu Hirano², Yuji Shimada¹, Katsuyori Iijima¹, Ryo Wada³, Akihito Nagahara¹ and Sumio Watanabe⁴

¹ Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka 410-2295, Japan

² Department of Hepatology, East Shonan General Hospital, Kanagawa 253-0083, Japan

³ Department of Pathology, Juntendo University Shizuoka Hospital, Shizuoka 410-2295, Japan

⁴ Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8431, Japan

Int. J. Mol. Sci. 2016, 17(12), 2143; https://doi.org/10.3390/ijms17122143 - 20 Dec 2016

Cited by 30 | Viewed by 5549

Abstract

We aimed to clarify the association between a novel serum fibrosis marker, Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA⁺-M2BP), and hepatocellular carcinoma (HCC) development in 355 patients with chronic hepatitis C who achieved sustained virologic response (SVR) through interferon-based antiviral therapy. Pretreatment [...] Read more.

We aimed to clarify the association between a novel serum fibrosis marker, Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA⁺-M2BP), and hepatocellular carcinoma (HCC) development in 355 patients with chronic hepatitis C who achieved sustained virologic response (SVR) through interferon-based antiviral therapy. Pretreatment serum WFA⁺-M2BP levels were quantified and the hazard ratios (HRs) for HCC development were retrospectively analyzed by Cox proportional hazard analysis. During the median follow-up time of 2.9 years, 12 patients developed HCC. Multivariate analysis demonstrated that high serum WFA⁺-M2BP (≥2.80 cut off index (COI), HR = 15.20, p = 0.013) and high fibrosis-4 (FIB-4) index (≥3.7, HR = 5.62, p = 0.034) were independent risk factors for HCC development. The three- and five-year cumulative incidence of HCC in patients with low WFA⁺-M2BP were 0.4% and 0.4%, respectively, whereas those of patients with high WFA⁺-M2BP were 7.7% and 17.6%, respectively (p < 0.001). In addition, combination of serum WFA⁺-M2BP and FIB-4 indices successfully stratified the risk of HCC: the five-year cumulative incidences of HCC were 26.9%, 6.8%, and 0.0% in patients with both, either, and none of these risk factors, respectively (p < 0.001). In conclusion, pretreatment serum WFA⁺-M2BP level is a useful predictor for HCC development after achieving SVR. Full article

(This article belongs to the Special Issue Hepatitis Virus Infection and Research)

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19 pages, 1180 KiB

Open AccessReview

Tumour Heterogeneity: The Key Advantages of Single-Cell Analysis

by Marta Tellez-Gabriel^1,*

, Benjamin Ory², Francois Lamoureux², Marie-Francoise Heymann^2,3,4 and Dominique Heymann^2,3,4,*

¹ Laboratorio Hematologia Oncologica y de Transplantes, Institut Investigacions Biomèdiques (IBB) Sant Pau, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain

² Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 957, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, Equipe Ligue 2012, Faculty of Medicine, University of Nantes, Nantes 44035, France

³ Department of Oncology and Metabolism, Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK

⁴ European Associated Laboratory, INSERM, Sarcoma Research Unit, Medical School, University of Sheffield, Sheffield S10 2RX, UK

Int. J. Mol. Sci. 2016, 17(12), 2142; https://doi.org/10.3390/ijms17122142 - 20 Dec 2016

Cited by 136 | Viewed by 17102

Abstract

Tumour heterogeneity refers to the fact that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity), and it [...] Read more.

Tumour heterogeneity refers to the fact that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity), and it is caused by genetic and non-genetic factors. The heterogeneity of cancer cells introduces significant challenges in using molecular prognostic markers as well as for classifying patients that might benefit from specific therapies. Thus, research efforts for characterizing heterogeneity would be useful for a better understanding of the causes and progression of disease. It has been suggested that the study of heterogeneity within Circulating Tumour Cells (CTCs) could also reflect the full spectrum of mutations of the disease more accurately than a single biopsy of a primary or metastatic tumour. In previous years, many high throughput methodologies have raised for the study of heterogeneity at different levels (i.e., RNA, DNA, protein and epigenetic events). The aim of the current review is to stress clinical implications of tumour heterogeneity, as well as current available methodologies for their study, paying specific attention to those able to assess heterogeneity at the single cell level. Full article

(This article belongs to the Special Issue Circulating Tumor Cells)

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14 pages, 416 KiB

Open AccessReview

Moringa oleifera Seeds and Oil: Characteristics and Uses for Human Health

by Alessandro Leone^1,2,*,†

, Alberto Spada^3,†

, Alberto Battezzati^1,2, Alberto Schiraldi², Junior Aristil³ and Simona Bertoli^1,2

¹ International Center for the Assessment of Nutritional Status (ICANS), University of Milan, Via Sandro Botticelli 21, 20133 Milan, Italy

² Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Mangiagalli 25, 20133 Milan, Italy

³ Department of Agricultural and Environmental Sciences-Production, Landscape, Agroenergy (DISAA), University of Milan, Via Celoria 2, 20133 Milan, Italy

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2141; https://doi.org/10.3390/ijms17122141 - 20 Dec 2016

Cited by 275 | Viewed by 30264

Abstract

Moringa oleifera seeds are a promising resource for food and non-food applications, due to their content of monounsaturated fatty acids with a high monounsaturated/saturated fatty acids (MUFA/SFA) ratio, sterols and tocopherols, as well as proteins rich in sulfated amino acids. The rapid growth [...] Read more.

Moringa oleifera seeds are a promising resource for food and non-food applications, due to their content of monounsaturated fatty acids with a high monounsaturated/saturated fatty acids (MUFA/SFA) ratio, sterols and tocopherols, as well as proteins rich in sulfated amino acids. The rapid growth of Moringa trees in subtropical and tropical areas, even under conditions of prolonged drought, makes this plant a reliable resource to enhance the nutritional status of local populations and, if rationalized cultivation practices are exploited, their economy, given that a biodiesel fuel could be produced from a source not in competition with human food crops. Despite the relatively diffuse use of Moringa seeds and their oil in traditional medicine, no pharmacological activity study has been conducted on humans. Some encouraging evidence, however, justifies new efforts to obtain clear and definitive information on the benefits to human health arising from seed consumption. A critical review of literature data concerning the composition of Moringa oil has set in motion a plan for future investigations. Such investigations, using the seeds and oil, will focus on cultivation conditions to improve plant production, and will study the health effects on human consumers of Moringa seeds and their oil. Full article

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

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17 pages, 1544 KiB

Open AccessReview

Effect of Lead (Pb) on Inflammatory Processes in the Brain

by Karina Chibowska¹, Irena Baranowska-Bosiacka^1,*

, Anna Falkowska¹, Izabela Gutowska²

, Marta Goschorska¹

and Dariusz Chlubek¹

¹ Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland

² Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Broniewskiego 24, 71-460 Szczecin, Poland

Int. J. Mol. Sci. 2016, 17(12), 2140; https://doi.org/10.3390/ijms17122140 - 19 Dec 2016

Cited by 122 | Viewed by 9863

Abstract

That the nervous system is the main target of lead (Pb) has long been considered an established fact until recent evidence has linked the Pb effect on the immune system to the toxic effects of Pb on the nervous system. In this paper, [...] Read more.

That the nervous system is the main target of lead (Pb) has long been considered an established fact until recent evidence has linked the Pb effect on the immune system to the toxic effects of Pb on the nervous system. In this paper, we present recent literature reports on the effect of Pb on the inflammatory processes in the brain, particularly the expression of selected cytokines in the brain (interleukin 6, TGF-β1, interleukin 16, interleukin 18, and interleukin 10); expression and activity of enzymes participating in the inflammatory processes, such as cyclooxygenase 2, caspase 1, nitrogen oxide synthase (NOS 2) and proteases (carboxypeptidases, metalloproteinases and chymotrypsin); and the expression of purine receptors P2X4 and P2X7. A significant role in the development of inflammatory processes in the brain is also played by microglia (residual macrophages in the brain and the spinal cord), which act as the first line of defense in the central nervous system, and astrocytes—Whose most important function is to maintain homeostasis for the proper functioning of neurons. In this paper, we also present evidence that exposure to Pb may result in micro and astrogliosis by triggering TLR4-MyD88-NF-κB signaling cascade and the production of pro-inflammatory cytokines. Full article

(This article belongs to the Section Bioinorganic Chemistry)

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16 pages, 12552 KiB

Open AccessArticle

Triptolide Combined with Radiotherapy for the Treatment of Nasopharyngeal Carcinoma via NF-κB-Related Mechanism

by Weiying Zhang, Min Kang, Tingting Zhang, Bo Li, Xueyin Liao and Rensheng Wang^*

Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, China

Int. J. Mol. Sci. 2016, 17(12), 2139; https://doi.org/10.3390/ijms17122139 - 19 Dec 2016

Cited by 19 | Viewed by 5785

Abstract

Advanced nasopharyngeal carcinoma (NPC) has a poor prognosis because of the lack of an effective treatment. Here we explored the efficiency and the molecular mechanisms of combined treatment with triptolide and ionizing radiation for treating NPC. Human nasopharyngeal carcinoma (CNE) cells were treated [...] Read more.

Advanced nasopharyngeal carcinoma (NPC) has a poor prognosis because of the lack of an effective treatment. Here we explored the efficiency and the molecular mechanisms of combined treatment with triptolide and ionizing radiation for treating NPC. Human nasopharyngeal carcinoma (CNE) cells were treated with triptolide, ionizing radiation, or triptolide plus ionizing radiation in vitro. Tumor potency was examined in an in vivo CNE cell xenograft mouse model, which was treated as above. Our results demonstrated that triptolide caused a significant reduction in cell growth and colony number, and induced a marked apoptosis that was further enhanced with increasing doses of ionizing radiation. Combination treatment synergistically reduced tumor weight and volume without obvious toxicity. Western blot analysis in vitro and in vivo showed that triptolide induced apoptotic protein Bax expression and inhibited phosph-NF-κB p65, Bcl-2 and VEGF proteins without affecting other NF-κB related protein expression. In conclusion, our findings revealed that triptolide plus ionizing radiation had synergistic anti-tumor and anti-angiogenesis effects in NPC via down-regulating NF-κB p65 phosphorylation. The combination therapy may provide novel mechanism insights into inhibit NPC. Full article

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

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18 pages, 815 KiB

Open AccessReview

Alterations of Epigenetic Regulators in Pancreatic Cancer and Their Clinical Implications

by Brittany R. Silverman and Jiaqi Shi^*

Department of Pathology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA

Int. J. Mol. Sci. 2016, 17(12), 2138; https://doi.org/10.3390/ijms17122138 - 19 Dec 2016

Cited by 26 | Viewed by 8478

Abstract

Pancreatic cancer is one of the most aggressive human cancer types with a five-year survival less than 7%. Emerging evidence revealed that many genetic alterations in pancreatic cancer target epigenetic regulators. Some of these mutations are driver mutations in cancer development. Several most [...] Read more.

Pancreatic cancer is one of the most aggressive human cancer types with a five-year survival less than 7%. Emerging evidence revealed that many genetic alterations in pancreatic cancer target epigenetic regulators. Some of these mutations are driver mutations in cancer development. Several most important mechanisms of epigenetic regulations include DNA methylation, histone modifications (methylation, acetylation, and ubiquitination), chromatin remodeling, and non-coding ribonucleic acids (RNAs). These modifications can alter chromatin structure and promoter accessibility, and thus lead to aberrant gene expression. However, exactly how these alterations affect epigenetic reprogramming in pancreatic cancer cells and in different stages of tumor development is still not clear. This mini-review summarizes the current knowledge of epigenetic alterations in pancreatic cancer development and progression, and discusses the clinical applications of epigenetic regulators as diagnostic biomarkers and therapeutic targets in pancreatic cancer. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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17 pages, 4406 KiB

Open AccessArticle

Neurotoxicity of a Biopesticide Analog on Zebrafish Larvae at Nanomolar Concentrations

by Ahmed Nasri^1,2,3,4, Audrey J. Valverde^1,2,3, Daniel B. Roche^5,6

, Catherine Desrumaux^1,2,3, Philippe Clair⁷, Hamouda Beyrem⁶, Laurent Chaloin⁸, Alain Ghysen^1,2,3,* and Véronique Perrier^1,2,3

¹ U1198 MMDN (Molecular Mechanisms of Neurodegenerative Diseases), Inserm (National Institute for Health and Medical Research), 34095 Montpellier, France

² BioCampus, University of Montpellier, 34095 Montpellier, France

³ EPHE (Ecole Pratique des Hautes Etudes), 75007 Paris, France

⁴ Laboratory of Environment Biomonitoring, Faculty of Sciences of Bizerta, University of Carthage, 7021 Zarzouna, Tunisia

⁵ IBC (Computational Biology Institute), CNRS (National Center for Scientific Research), University of Montpellier, 860 rue Saint Priest, 34095 Montpellier, France

⁶ CRBM (Research Center for Cell Biology in Montpellier), UMR 5237, CNRS, 1919 route de Mende, 34293 Montpellier, France

⁷ MGX (Montpellier GenomiX), BioCampus, University of Montpellier, 34095 Montpellier, France

⁸ CPBS (Center for Study of Pathogens and Biotechnologies for Health), FRE 3689, CNRS, University of Montpellier, 1919 route de Mende, 34293 Montpellier, France

Int. J. Mol. Sci. 2016, 17(12), 2137; https://doi.org/10.3390/ijms17122137 - 19 Dec 2016

Cited by 12 | Viewed by 6406

Abstract

Despite the ever-increasing role of pesticides in modern agriculture, their deleterious effects are still underexplored. Here we examine the effect of A6, a pesticide derived from the naturally-occurring α-terthienyl, and structurally related to the endocrine disrupting pesticides anilinopyrimidines, on living zebrafish larvae. We [...] Read more.

Despite the ever-increasing role of pesticides in modern agriculture, their deleterious effects are still underexplored. Here we examine the effect of A6, a pesticide derived from the naturally-occurring α-terthienyl, and structurally related to the endocrine disrupting pesticides anilinopyrimidines, on living zebrafish larvae. We show that both A6 and an anilinopyrimidine, cyprodinyl, decrease larval survival and affect central neurons at micromolar concentrations. Focusing on a superficial and easily observable sensory system, the lateral line system, we found that defects in axonal and sensory cell regeneration can be observed at much lower doses, in the nanomolar range. We also show that A6 accumulates preferentially in lateral line neurons and hair cells. We examined whether A6 affects the expression of putative target genes, and found that genes involved in apoptosis/cell proliferation are down-regulated, as well as genes reflecting estrogen receptor activation, consistent with previous reports that anilinopyrimidines act as endocrine disruptors. On the other hand, canonical targets of endocrine signaling are not affected, suggesting that the neurotoxic effect of A6 may be due to the binding of this compound to a recently identified, neuron-specific estrogen receptor. Full article

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

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10 pages, 381 KiB

Open AccessReview

Diabetic Cardiomyopathy: Does the Type of Diabetes Matter?

by Maximilian E. Hölscher, Christoph Bode and Heiko Bugger^*

Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany

Int. J. Mol. Sci. 2016, 17(12), 2136; https://doi.org/10.3390/ijms17122136 - 18 Dec 2016

Cited by 135 | Viewed by 13302

Abstract

In recent years, type 2 diabetes mellitus has evolved as a rapidly increasing epidemic that parallels the increased prevalence of obesity and which markedly increases the risk of cardiovascular disease across the globe. While ischemic heart disease represents the major cause of death [...] Read more.

In recent years, type 2 diabetes mellitus has evolved as a rapidly increasing epidemic that parallels the increased prevalence of obesity and which markedly increases the risk of cardiovascular disease across the globe. While ischemic heart disease represents the major cause of death in diabetic subjects, diabetic cardiomyopathy (DC) summarizes adverse effects of diabetes mellitus on the heart that are independent of coronary artery disease (CAD) and hypertension. DC increases the risk of heart failure (HF) and may lead to both heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). Numerous molecular mechanisms have been proposed to underlie DC that partially overlap with mechanisms believed to contribute to heart failure. Nevertheless, the existence of DC remains a topic of controversy, although the clinical relevance of DC is increasingly recognized by scientists and clinicians. In addition, relatively little attention has been attributed to the fact that both underlying mechanisms and clinical features of DC may be partially distinct in type 1 versus type 2 diabetes. In the following review, we will discuss clinical and preclinical literature on the existence of human DC in the context of the two different types of diabetes mellitus. Full article

(This article belongs to the Special Issue Diabetic Complications: Pathophysiology, Mechanisms, and Therapies)

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11 pages, 1338 KiB

Open AccessReview

Review of Toxic Epidermal Necrolysis

by Victoria Harris^1,*, Christopher Jackson²

and Alan Cooper³

¹ Sydney Medical School—Northern, University of Sydney, 2065 Sydney, Australia

² Sutton Arthritis Research Laboratory, Kolling Institute, University of Sydney, 2065 Sydney, Australia

³ Dermatology Department, Royal North Shore Hospital, 2065 Sydney, Australia

Int. J. Mol. Sci. 2016, 17(12), 2135; https://doi.org/10.3390/ijms17122135 - 18 Dec 2016

Cited by 46 | Viewed by 23927

Abstract

Toxic epidermal necrolysis (TEN) is a rare but life threatening mucocutaneous reaction to drugs or their metabolites. It is characterised by widespread keratinocyte apoptosis and sloughing of the skin, erosions of the mucous membranes, painful blistering, and severe systemic disturbance. The pathophysiology of [...] Read more.

Toxic epidermal necrolysis (TEN) is a rare but life threatening mucocutaneous reaction to drugs or their metabolites. It is characterised by widespread keratinocyte apoptosis and sloughing of the skin, erosions of the mucous membranes, painful blistering, and severe systemic disturbance. The pathophysiology of TEN is incompletely understood. Historically, it has been regarded as a drug-induced immune reaction initiated by cytotoxic lymphocytes via a human leukocyte antigen (HLA)-restricted pathway. Several mediators have been identified as contributors to the cell death seen in TEN, including; granulysin, soluble Fas ligand, perforin/granzyme, tumour necrosis factor-α (TNF-α), and TNF-related apoptosis-inducing ligand. Currently, granulysin is accepted as the most important mediator of T cell proliferation. There is uncertainty around the accepted management of TEN. The lack of definitive management guidelines for TEN is explained in part by the rarity of the disease and its high mortality rate, which makes it difficult to conduct randomised control trials on emerging therapies. Developments have been made in pharmacogenomics, with numerous HLA alleles identified; however, these have largely been ethnically specific. These associations have translated into screening recommendations for Han Chinese. Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions)

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16 pages, 570 KiB

Open AccessReview

Recent Methods for Purification and Structure Determination of Oligonucleotides

by Qiulong Zhang^1,3,4,†, Huanhuan Lv^1,3,4,†, Lili Wang^1,3,4, Man Chen^1,3,4, Fangfei Li^1,3,4, Chao Liang^1,3,4, Yuanyuan Yu^1,3,4, Feng Jiang^1,2,3,4,*, Aiping Lu^1,3,4,* and Ge Zhang^1,3,4,*

¹ Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong, China

² The State Key Laboratory Base of Novel Functional Materials and Preparation Science, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China

³ Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology, Haimen 226100, China

⁴ Shenzhen Lab of Combinatorial Compounds and Targeted Drug Delivery, HKBU Institute of Research and Continuing Education, Shenzhen 518000, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2134; https://doi.org/10.3390/ijms17122134 - 18 Dec 2016

Cited by 19 | Viewed by 8486

Abstract

Aptamers are single-stranded DNA or RNA oligonucleotides that can interact with target molecules through specific three-dimensional structures. The excellent features, such as high specificity and affinity for target proteins, small size, chemical stability, low immunogenicity, facile chemical synthesis, versatility in structural design and [...] Read more.

Aptamers are single-stranded DNA or RNA oligonucleotides that can interact with target molecules through specific three-dimensional structures. The excellent features, such as high specificity and affinity for target proteins, small size, chemical stability, low immunogenicity, facile chemical synthesis, versatility in structural design and engineering, and accessible for site-specific modifications with functional moieties, make aptamers attractive molecules in the fields of clinical diagnostics and biopharmaceutical therapeutics. However, difficulties in purification and structural identification of aptamers remain a major impediment to their broad clinical application. In this mini-review, we present the recently attractive developments regarding the purification and identification of aptamers. We also discuss the advantages, limitations, and prospects for the major methods applied in purifying and identifying aptamers, which could facilitate the application of aptamers. Full article

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

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16 pages, 2256 KiB

Open AccessArticle

Modulation of GLO1 Expression Affects Malignant Properties of Cells

by Antje Hutschenreuther^1,2, Marina Bigl¹, Nasr Y. A. Hemdan¹, Tewodros Debebe^3,4, Frank Gaunitz⁵

and Gerd Birkenmeier^1,*

¹ Institute of Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, Leipzig 04103, Germany

² Max Planck Institute of Evolutionary Anthropology, Deutscher Platz 6, Leipzig 04103, Germany

³ Institute of Medical Microbiology, Faculty of Medicine, University of Leipzig, Liebigstrasse 21, Leipzig 04103, Germany

⁴ College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar P.O. Box 79, Ethiopia

⁵ Department of Neurosurgery, University Hospital Leipzig, Liebigstrasse 20, Leipzig 04103, Germany

Int. J. Mol. Sci. 2016, 17(12), 2133; https://doi.org/10.3390/ijms17122133 - 18 Dec 2016

Cited by 27 | Viewed by 5257

Abstract

The energy metabolism of most tumor cells relies on aerobic glycolysis (Warburg effect) characterized by an increased glycolytic flux that is accompanied by the increased formation of the cytotoxic metabolite methylglyoxal (MGO). Consequently, the rate of detoxification of this reactive glycolytic byproduct needs [...] Read more.

The energy metabolism of most tumor cells relies on aerobic glycolysis (Warburg effect) characterized by an increased glycolytic flux that is accompanied by the increased formation of the cytotoxic metabolite methylglyoxal (MGO). Consequently, the rate of detoxification of this reactive glycolytic byproduct needs to be increased in order to prevent deleterious effects to the cells. This is brought about by an increased expression of glyoxalase 1 (GLO1) that is the rate-limiting enzyme of the MGO-detoxifying glyoxalase system. Here, we overexpressed GLO1 in HEK 293 cells and silenced it in MCF-7 cells using shRNA. Tumor-related properties of wild type and transformed cells were compared and key glycolytic enzyme activities assessed. Furthermore, the cells were subjected to hypoxic conditions to analyze the impact on cell proliferation and enzyme activities. Our results demonstrate that knockdown of GLO1 in the cancer cells significantly reduced tumor-associated properties such as migration and proliferation, whereas no functional alterations where found by overexpression of GLO1 in HEK 293 cells. In contrast, hypoxia caused inhibition of cell growth of all cells except of those overexpressing GLO1. Altogether, we conclude that GLO1 on one hand is crucial to maintaining tumor characteristics of malignant cells, and, on the other hand, supports malignant transformation of cells in a hypoxic environment when overexpressed. Full article

(This article belongs to the Special Issue Glyoxalase System)

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12 pages, 234 KiB

Open AccessArticle

EGFR and KRAS Mutations Predict the Incidence and Outcome of Brain Metastases in Non-Small Cell Lung Cancer

by Pascale Tomasini^1,2,*, Cindy Serdjebi^1,3, Nataliya Khobta¹, Philippe Metellus⁴, L’Houcine Ouafik^2,3, Isabelle Nanni³, Laurent Greillier^1,2, Anderson Loundou⁵, Frederic Fina³, Celine Mascaux^1,2 and Fabrice Barlesi^1,2

¹ Assistance Publique Hôpitaux de Marseille, Multidisciplinary Oncology & Therapeutic Innovations department. Aix Marseille University, Marseille 13015, France

² Inserm U911 CRO2 (Centre de Recherche en Oncologie biologique et Onco-pharmacologie), Aix Marseille University, Marseille 13005, France

³ Assistance Publique Hôpitaux de Marseille, Transfer Oncology Laboratory, Aix Marseille University, Marseille 13015, France

⁴ Department of Neurosurgery, Aix-Marseille University, Marseille 13005, France

⁵ Statistics Department, Aix Marseille University, Marseille 13005, France

Int. J. Mol. Sci. 2016, 17(12), 2132; https://doi.org/10.3390/ijms17122132 - 18 Dec 2016

Cited by 54 | Viewed by 8180

Abstract

Background: Lung cancer is the leading cause of brain metastases (BM). The identification of driver oncogenes and matched targeted therapies has improved outcome in non-small cell lung cancer (NSCLC) patients; however, a better understanding of BM molecular biology is needed to further drive [...] Read more.

Background: Lung cancer is the leading cause of brain metastases (BM). The identification of driver oncogenes and matched targeted therapies has improved outcome in non-small cell lung cancer (NSCLC) patients; however, a better understanding of BM molecular biology is needed to further drive the process in this field. Methods: In this observational study, stage IV NSCLC patients tested for EGFR and KRAS mutations were selected, and BM incidence, recurrence and patients’ outcome were assessed. Results: A total of 144 patients (142 Caucasian and two Asian) were selected, including 11.27% with EGFR-mutant and 33.10% with KRAS-mutant tumors, and 57.04% patients had developed BM. BM incidence was more frequent in patients with EGFR mutation according to multivariate analyses (MVA) (Odds ratio OR = 8.745 [1.743–43.881], p = 0.008). Among patients with treated BM, recurrence after local treatment was less frequent in patients with KRAS mutation (OR = 0.234 [0.078–0.699], p = 0.009). Among patients with untreated BM, overall survival (OS) was shorter for patients with KRAS mutation according to univariate analysis (OR = 7.130 [1.240–41.012], p = 0.028), but not MVA. Conclusions: EGFR and KRAS mutations have a predictive role on BM incidence, recurrence and outcome in Caucasian NSCLC patients. These results may impact the routine management of disease in these patients. Further studies are required to assess the influence of other biomarkers on NSCLC BM. Full article

(This article belongs to the Special Issue Brain Metastasis 2016)

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10 pages, 751 KiB

Open AccessArticle

Circulating Cell-Free DNA Levels Could Predict Oncological Outcomes of Patients Undergoing Esophagectomy for Esophageal Squamous Cell Carcinoma

by Chih-Cheng Hsieh^1,2,3, Han-Shui Hsu^2,4, Shih-Ching Chang^3,5 and Yann-Jang Chen^1,6,7,*

¹ Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan

² Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 11217, Taiwan

³ Department of Surgery, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan

⁴ Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan

⁵ Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 11217, Taiwan

⁶ Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 11221, Taiwan

⁷ Department of Pediatrics, Renai Branch, Taipei City Hospital, Taipei 10629, Taiwan

Int. J. Mol. Sci. 2016, 17(12), 2131; https://doi.org/10.3390/ijms17122131 - 17 Dec 2016

Cited by 44 | Viewed by 5317

Abstract

Circulating cell-free DNA (cfDNA) is a potential biomarker for cancer progression but its role is unclear in patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. We investigated relationships between plasma cfDNA levels and clinicopathological parameters in ESCC patients. Eighty-one ESCC patients who [...] Read more.

Circulating cell-free DNA (cfDNA) is a potential biomarker for cancer progression but its role is unclear in patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. We investigated relationships between plasma cfDNA levels and clinicopathological parameters in ESCC patients. Eighty-one ESCC patients who received esophagectomy were enrolled. Plasma samples from these patients and 95 normal controls were collected. DNA copy numbers were measured by real-time quantitative PCR. Subjects were divided into two groups by cfDNA level. Clinicopathological data were collected retrospectively and relationships between cfDNA levels and clinical parameters were evaluated. The cfDNA level in normal controls ranged from 0–4157 copies/mL. The cfDNA level of 96.3% ESCC patients was higher than the cutoff value (2447.26 copies/mL) with a specificity of 94.1%. The mean cfDNA concentration was 5918 copies/mL in lower and 53,311 copies/mL in higher cfDNA groups. No correlations were found between clinicopathological factors and cfDNA levels except for lymphovascular invasion. Higher cfDNA levels were associated with tumor relapse (p = 0.018). Five-year disease-free survival (DFS) and overall survival (OS) rates were 34.7% and 33.8%, respectively. Patients with higher cfDNA levels had poorer DFS (p = 0.013). Patients with higher cfDNA levels had poorer OS, but not significantly (p = 0.164). Circulating cfDNA could be a biomarker for tumor relapse of ESCC with high sensitivity and specificity. Higher cfDNA levels were associated with tumor relapse and shorter DFS after esophagectomy in ESCC patients. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment 2016)

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21 pages, 6077 KiB

Open AccessArticle

Identification of Heat Shock Transcription Factor Genes Involved in Thermotolerance of Octoploid Cultivated Strawberry

by Wan-Yu Liao^1,†, Lee-Fong Lin^2,†, Jing-Lian Jheng³, Chun-Chung Wang^4,5, Jui-Hung Yang⁵ and Ming-Lun Chou^2,*

¹ Institute of Medical Sciences, Tzu-Chi University, Hualien 97004, Taiwan

² Department of Life Sciences, Tzu-Chi University, Hualien 97004, Taiwan

³ Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 97004, Taiwan

⁴ Institute of Molecular Medicine, National Tsing-Hua University, Hsinchu 30013, Taiwan

⁵ Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 30011, Taiwan

^† These authors contributed equally to this study.

Int. J. Mol. Sci. 2016, 17(12), 2130; https://doi.org/10.3390/ijms17122130 - 17 Dec 2016

Cited by 17 | Viewed by 7433

Abstract

Heat shock transcription factors (HSFs) are mainly involved in the activation of genes in response to heat stress as well as other abiotic and biotic stresses. The growth, development, reproduction, and yield of strawberry are strongly limited by extreme temperatures and droughts. In [...] Read more.

Heat shock transcription factors (HSFs) are mainly involved in the activation of genes in response to heat stress as well as other abiotic and biotic stresses. The growth, development, reproduction, and yield of strawberry are strongly limited by extreme temperatures and droughts. In this study, we used Illumina sequencing and obtained transcriptome data set from Fragaria × ananassa Duchessne cv. Toyonoka. Six contigs and three unigenes were confirmed to encode HSF proteins (FaTHSFs). Subsequently, we characterized the biological functions of two particularly selected unigenes, FaTHSFA2a and FaTHSFB1a, which were classified into class A2 and B HSFs, respectively. Expression assays revealed that FaTHSFA2a and FaTHSFB1a expression was induced by heat shock and correlated well with elevated ambient temperatures. Overexpression of FaTHSFA2a and FaTHSFB1a resulted in the activation of their downstream stress-associated genes, and notably enhanced the thermotolerance of transgenic Arabidopsis plants. Besides, both FaTHSFA2a and FaTHSFB1a fusion proteins localized in the nucleus, indicating their similar subcellular distributions as transcription factors. Our yeast one-hybrid assay suggested that FaTHSFA2a has trans-activation activity, whereas FaTHSFB1a expresses trans-repression function. Altogether, our annotated transcriptome sequences provide a beneficial resource for identifying most genes expressed in octoploid strawberry. Furthermore, HSF studies revealed the possible insights into the molecular mechanisms of thermotolerance, thus rendering valuable molecular breeding to improve the tolerance of strawberry in response to high-temperature stress. Full article

(This article belongs to the Section Molecular Plant Sciences)

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12 pages, 2035 KiB

Open AccessArticle

Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid

by Hai-Zhi Jiang, Shu-Yu Wang, Xiang Yin, Hong-Quan Jiang, Xu-Dong Wang, Jing Wang, Tian-Hang Wang, Yan Qi, Yue-Qing Yang, Ying Wang, Chun-Ting Zhang and Hong-Lin Feng^*

Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China

Int. J. Mol. Sci. 2016, 17(12), 2129; https://doi.org/10.3390/ijms17122129 - 17 Dec 2016

Cited by 15 | Viewed by 7604

Abstract

Background: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important [...] Read more.

Background: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important roles in neurological diseases. In this study, we explored whether Homer1b/c was involved in SOD1 mutation-linked ALS. Results: In vitro studies showed that the SOD1 G93A mutation induced an increase of Homer1b/c expression at both the mRNA and protein levels in NSC34 cells. Knockdown of Homer1b/c expression using its short interfering RNA (siRNA) (si-Homer1) protected SOD1 G93A NSC34 cells from apoptosis. The expressions of Homer1b/c and apoptosis-related protein Bax were also suppressed, while Bcl-2 was increased by lithium and valproic acid (VPA) in SOD1 G93A NSC34 cells. In vivo, both the mRNA and protein levels of Homer1b/c were increased significantly in the lumbar spinal cord in SOD1 G93A transgenic mice compared with wild type (WT) mice. Moreover, lithium and VPA treatment suppressed the expression of Homer1b/c in SOD1 G93A mice. Conclusion: The suppression of SOD1 G93A mutation-induced Homer1b/c upregulation protected ALS against neuronal apoptosis, which is a novel mechanism of the neuroprotective effect of lithium and VPA. This study provides new insights into pathogenesis and treatment of ALS. Full article

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

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16 pages, 8570 KiB

Open AccessArticle

Metabolomic Approaches to Explore Chemical Diversity of Human Breast-Milk, Formula Milk and Bovine Milk

by Linxi Qian^1,2,†, Aihua Zhao^3,†, Yinan Zhang³, Tianlu Chen³, Steven H. Zeisel⁴, Wei Jia^3,* and Wei Cai^1,2,*

¹ Shanghai Institute for Pediatric Research, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai 200092, China

² Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai 200092, China

³ Center for Translational Medicine, Six People’s Hospital, Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, China

⁴ Nutrition Research Institute, University of North Carolina, Chapel Hill, Kannapolis, NC 28081, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2128; https://doi.org/10.3390/ijms17122128 - 17 Dec 2016

Cited by 45 | Viewed by 7934

Abstract

Although many studies have been conducted on the components present in human breast milk (HM), research on the differences of chemical metabolites between HM, bovine milk (BM) and formula milk (FM) is limited. This study was to explore the chemical diversity of HM, [...] Read more.

Although many studies have been conducted on the components present in human breast milk (HM), research on the differences of chemical metabolites between HM, bovine milk (BM) and formula milk (FM) is limited. This study was to explore the chemical diversity of HM, BM and FM by metabolomic approaches. GC-TOFMS and UPLC-QTOFMS were applied to investigate the metabolic compositions in 30 HM samples, 20 FM samples and 20 BM samples. Metabolite profiling identified that most of the non-esterified fatty acids, which reflected the hydrolysis of triglycerides, were much more abundant in HM than those in FM and BM, except for palmitic acid and stearic acid. The levels of tricarboxylic acid (TCA) intermediates were much higher in FM and BM than those in HM. Each type of milk also showed its unique composition of free amino acids and free carbohydrates. In conclusion, higher levels of non-esterified saturated fatty acids with aliphatic tails <16 carbons, monounsaturated fatty acids and polyunsaturated fatty acids and lower levels of TCA intermediates are characteristic of HM, as compared with FM and BM. The content of non-esterified fatty acids may reflect the hydrolysis of triglycerides in different milk types. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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17 pages, 843 KiB

Open AccessReview

A Possible Role of Intestinal Microbiota in the Pathogenesis of Ankylosing Spondylitis

by Lianjun Yang^1,†, Liping Wang^1,2,†

, Xin Wang³, Cory J. Xian^1,2,*

and Hai Lu^1,*

¹ Academy of Orthopedics of Guangdong Province, Orthopaedic Hospital of Guangdong Province, Department of Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China

² Sansom Institute for Health Research and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide SA5001, Australia

³ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane QLD4059, Australia

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(12), 2126; https://doi.org/10.3390/ijms17122126 - 17 Dec 2016

Cited by 51 | Viewed by 16699

Abstract

Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the sacroiliac joints and the spine, for which the pathogenesis is thought to be a result of the combination of host genetic factors and environmental triggers. However, the precise factors that determine one’s [...] Read more.

Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the sacroiliac joints and the spine, for which the pathogenesis is thought to be a result of the combination of host genetic factors and environmental triggers. However, the precise factors that determine one’s susceptibility to AS remain to be unraveled. With 100 trillion bacteria residing in the mammalian gut having established a symbiotic relation with their host influencing many aspects of host metabolism, physiology, and immunity, a growing body of evidence suggests that intestinal microbiota may play an important role in AS. Several mechanisms have been suggested to explain the potential role of the microbiome in the etiology of AS, such as alterations of intestinal permeability, stimulation of immune responses, and molecular mimicry. In this review, the existing evidence for the involvement of the microbiome in AS pathogenesis was discussed and the potential of intestinal microbiome-targeting strategies in the prevention and treatment of AS was evaluated. Full article

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

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28 pages, 1029 KiB

Open AccessReview

Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer’s Disease

by Andrea Kwakowsky^1,*

, Michael R. Milne², Henry J. Waldvogel¹ and Richard L. Faull¹

¹ Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand

² School of Biomedical Sciences, Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane 4072, QLD, Australia

Int. J. Mol. Sci. 2016, 17(12), 2122; https://doi.org/10.3390/ijms17122122 - 17 Dec 2016

Cited by 35 | Viewed by 7887

Abstract

The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological [...] Read more.

The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer’s disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer’s disease. Full article

(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)

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9 pages, 1144 KiB

Open AccessArticle

Characterization of the Microenvironment of Nodular Lymphocyte Predominant Hodgkin Lymphoma

by Ahmad Sattarzadeh^*, Lydia Visser^*, Bea Rutgers^*, Arjan Diepstra^*

and Anke Van den Berg^*

Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands

Int. J. Mol. Sci. 2016, 17(12), 2127; https://doi.org/10.3390/ijms17122127 - 16 Dec 2016

Cited by 24 | Viewed by 5365

Abstract

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is characterized by a low percentage of neoplastic lymphocyte predominant (LP) cells in a background of lymphocytes. The goal of this study is to characterize the microenvironment in NLPHL. Ten NLPHL cases and seven reactive lymph nodes [...] Read more.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is characterized by a low percentage of neoplastic lymphocyte predominant (LP) cells in a background of lymphocytes. The goal of this study is to characterize the microenvironment in NLPHL. Ten NLPHL cases and seven reactive lymph nodes (RLN) were analyzed by flow cytometry for the main immune cells and multiple specific subpopulations. To discriminate between cells in or outside the tumor cell area, we used CD26. We observed significantly lower levels of CD20+ B-cells and CD56+ NK cells and higher levels of CD4+ T-cells in NLPHL in comparison to RLN. In the subpopulations, we observed increased numbers of PD-1+CD4+ T follicular helper cells (TFH), CD69+CD4+ and CD69+CD8+ T-cells and CCR7-CD45RA-CD4+ effector memory T-cells, while FoxP3+CD4+ T regulatory cells (Tregs) and CCR7-CD45RA+ terminally differentiated CD4+ T-cells were decreased in NLPHL compared to RLN. CD69+ cells were increased in the tumor cell area in CD4+ and CD8+ T-cells, while FoxP3+CD25+CD4+ Tregs and CD25+CD8+ T-cells were significantly increased outside the tumor area. Thus, we show a markedly altered microenvironment in NLPHL, with lower numbers of NK cells and Tregs. PD-1+CD4+ and CD69+ T-cells were located inside, and Tregs and CD25+CD8+ cells outside the tumor cell area. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)

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16 pages, 4152 KiB

Open AccessArticle

Testosterone Deficiency Induces Changes of the Transcriptomes of Visceral Adipose Tissue in Miniature Pigs Fed a High-Fat and High-Cholesterol Diet

by Lifan Zhang^1,*, Yueqin Cai², Shengjuan Wei¹, Yun Ling², Liang Zhu², Dongfeng Li¹ and Zhaowei Cai^2,*

¹ College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China

² Laboratory Animal Research Center, Zhejiang Chinese Medical University, Hangzhou 310053, China

Int. J. Mol. Sci. 2016, 17(12), 2125; https://doi.org/10.3390/ijms17122125 - 16 Dec 2016

Cited by 5 | Viewed by 6646

Abstract

Testosterone deficiency causes fat deposition, particularly in visceral fat, and its replacement might reverse fat accumulation, however, the underlying mechanisms of such processes under diet-induced adiposity are largely unknown. To gain insights into the genome-wide role of androgen on visceral adipose tissue (VAT), [...] Read more.

Testosterone deficiency causes fat deposition, particularly in visceral fat, and its replacement might reverse fat accumulation, however, the underlying mechanisms of such processes under diet-induced adiposity are largely unknown. To gain insights into the genome-wide role of androgen on visceral adipose tissue (VAT), RNA-Seq was used to investigate testosterone deficiency induced changes of VAT in miniature pigs fed a high-fat and high-cholesterol (HFC) diet among intact male pigs (IM), castrated male pigs (CM), and castrated male pigs with testosterone replacement (CMT) treatments. The results showed that testosterone deficiency significantly increased VAT deposition and serum leptin concentrations. Moreover, a total of 1732 differentially expressed genes (DEGs) were identified between any two groups. Compared with gene expression profiles in IM and CMT pigs, upregulated genes in CM pigs, i.e., LOC100520753 (CD68), LCN2, EMR1, S100A9, NCF1 (p47phox), and LEP, were mainly involved in inflammatory response, oxidation-reduction process, and lipid metabolic process, while downregulated genes in CM pigs, i.e., ABHD5, SPP1, and GAS6, were focused on cell differentiation and cell adhesion. Taken together, our study demonstrates that testosterone deficiency alters the expression of numerous genes involved in key biological processes of VAT accumulation under HFC diet and provides a novel genome-wide view on the role of androgen on VAT deposition under HFC diet, thus improving our understanding of the molecular mechanisms involved in VAT changes induced by testosterone deficiency. Full article

(This article belongs to the Section Biochemistry)

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21 pages, 1536 KiB

Open AccessReview

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

by Dun-Xian Tan^*, Lucien C. Manchester, Lilan Qin and Russel J. Reiter^*

Department of Cell System and Anatomy, The University of Texas Health Science Center, San Antonio, TX 78229, USA

Int. J. Mol. Sci. 2016, 17(12), 2124; https://doi.org/10.3390/ijms17122124 - 16 Dec 2016

Cited by 320 | Viewed by 15207

Abstract

Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin [...] Read more.

Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria. Full article

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

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16 pages, 1232 KiB

Open AccessReview

Zebrafish as a Vertebrate Model System to Evaluate Effects of Environmental Toxicants on Cardiac Development and Function

by Swapnalee Sarmah^* and James A. Marrs^*

Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA

Int. J. Mol. Sci. 2016, 17(12), 2123; https://doi.org/10.3390/ijms17122123 - 16 Dec 2016

Cited by 128 | Viewed by 10097

Abstract

Environmental pollution is a serious problem of the modern world that possesses a major threat to public health. Exposure to environmental pollutants during embryonic development is particularly risky. Although many pollutants have been verified as potential toxicants, there are new chemicals in the [...] Read more.

Environmental pollution is a serious problem of the modern world that possesses a major threat to public health. Exposure to environmental pollutants during embryonic development is particularly risky. Although many pollutants have been verified as potential toxicants, there are new chemicals in the environment that need assessment. Heart development is an extremely sensitive process, which can be affected by environmentally toxic molecule exposure during embryonic development. Congenital heart defects are the most common life-threatening global health problems, and the etiology is mostly unknown. The zebrafish has emerged as an invaluable model to examine substance toxicity on vertebrate development, particularly on cardiac development. The zebrafish offers numerous advantages for toxicology research not found in other model systems. Many laboratories have used the zebrafish to study the effects of widespread chemicals in the environment on heart development, including pesticides, nanoparticles, and various organic pollutants. Here, we review the uses of the zebrafish in examining effects of exposure to external molecules during embryonic development in causing cardiac defects, including chemicals ubiquitous in the environment and illicit drugs. Known or potential mechanisms of toxicity and how zebrafish research can be used to provide mechanistic understanding of cardiac defects are discussed. Full article

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

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Int. J. Mol. Sci., Volume 17, Issue 12 (December 2016) – 195 articles

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