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

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Cover Story (view full-size image) Beyond their function of preventing water loss, cuticular lipids are also used as communication [...] Read more.
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Open AccessArticle Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen–Antioxidant Mutual Prodrugs
Int. J. Mol. Sci. 2016, 17(12), 2151; https://doi.org/10.3390/ijms17122151
Received: 1 November 2016 / Revised: 14 December 2016 / Accepted: 14 December 2016 / Published: 21 December 2016
Cited by 3 | PDF Full-text (4909 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5ac were obtained by reacting its –COOH group with chloroacetyl derivatives 3ac. The in vitro hydrolysis data confirmed that synthesized prodrugs
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Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5ac were obtained by reacting its –COOH group with chloroacetyl derivatives 3ac. The in vitro hydrolysis data confirmed that synthesized prodrugs 5ac 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 5ac 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
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Open AccessArticle Neuropeptide Y1 Receptor Regulates Glucocorticoid-Induced Inhibition of Osteoblast Differentiation in Murine MC3T3-E1 Cells via ERK Signaling
Int. J. Mol. Sci. 2016, 17(12), 2150; https://doi.org/10.3390/ijms17122150
Received: 26 October 2016 / Revised: 5 December 2016 / Accepted: 12 December 2016 / Published: 21 December 2016
Cited by 3 | PDF Full-text (3296 KB) | HTML Full-text | XML Full-text
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
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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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Open AccessArticle A Novel Pathogenic BRCA1 Splicing Variant Produces Partial Intron Retention in the Mature Messenger RNA
Int. J. Mol. Sci. 2016, 17(12), 2145; https://doi.org/10.3390/ijms17122145
Received: 28 October 2016 / Revised: 30 November 2016 / Accepted: 14 December 2016 / Published: 21 December 2016
Cited by 4 | PDF Full-text (2586 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
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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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Open AccessArticle Dermal Delivery of Constructs Encoding Cre Recombinase to Induce Skin Tumors in PtenLoxP/LoxP;BrafCA/+ Mice
Int. J. Mol. Sci. 2016, 17(12), 2149; https://doi.org/10.3390/ijms17122149
Received: 28 October 2016 / Revised: 28 November 2016 / Accepted: 6 December 2016 / Published: 20 December 2016
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Abstract
Current genetically-engineered mouse melanoma models are often based on Tyr::CreERT2-controlled MAPK pathway activation by the BRAFV600E mutation and PI3K pathway activation by loss of PTEN. The major drawback of these models is the occurrence of spontaneous tumors caused by leakiness
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Current genetically-engineered mouse melanoma models are often based on Tyr::CreERT2-controlled MAPK pathway activation by the BRAFV600E 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::CreERT2 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 PtenLoxP/LoxP;BrafCA/+ mice lacking the Tyr::CreERT2 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 PtenLoxP/LoxP;BrafCA/+ 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::CreERT2;PtenLoxP/LoxP;BrafCA/+ 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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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
Int. J. Mol. Sci. 2016, 17(12), 2148; https://doi.org/10.3390/ijms17122148
Received: 7 November 2016 / Revised: 14 December 2016 / Accepted: 14 December 2016 / Published: 20 December 2016
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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
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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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Open AccessReview Neuroprotection via Reduction in Stress: Altered Menstrual Patterns as a Marker for Stress and Implications for Long-Term Neurologic Health in Women
Int. J. Mol. Sci. 2016, 17(12), 2147; https://doi.org/10.3390/ijms17122147
Received: 18 October 2016 / Revised: 7 December 2016 / Accepted: 13 December 2016 / Published: 20 December 2016
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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
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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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Open AccessReview Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis
Int. J. Mol. Sci. 2016, 17(12), 2146; https://doi.org/10.3390/ijms17122146
Received: 29 October 2016 / Revised: 5 December 2016 / Accepted: 12 December 2016 / Published: 20 December 2016
Cited by 12 | PDF Full-text (1154 KB) | HTML Full-text | XML Full-text
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
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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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Open AccessReview Apoptosis in Cellular Society: Communication between Apoptotic Cells and Their Neighbors
Int. J. Mol. Sci. 2016, 17(12), 2144; https://doi.org/10.3390/ijms17122144
Received: 2 November 2016 / Revised: 7 December 2016 / Accepted: 15 December 2016 / Published: 20 December 2016
Cited by 7 | PDF Full-text (1370 KB) | HTML Full-text | XML Full-text
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
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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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Open AccessArticle Prediction of Hepatocellular Carcinoma Development after Hepatitis C Virus Eradication Using Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein
Int. J. Mol. Sci. 2016, 17(12), 2143; https://doi.org/10.3390/ijms17122143
Received: 12 October 2016 / Revised: 30 November 2016 / Accepted: 14 December 2016 / Published: 20 December 2016
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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
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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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Open AccessReview Tumour Heterogeneity: The Key Advantages of Single-Cell Analysis
Int. J. Mol. Sci. 2016, 17(12), 2142; https://doi.org/10.3390/ijms17122142
Received: 27 September 2016 / Revised: 12 December 2016 / Accepted: 13 December 2016 / Published: 20 December 2016
Cited by 12 | PDF Full-text (1180 KB) | HTML Full-text | XML Full-text
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
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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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Open AccessReview Moringa oleifera Seeds and Oil: Characteristics and Uses for Human Health
Int. J. Mol. Sci. 2016, 17(12), 2141; https://doi.org/10.3390/ijms17122141
Received: 26 October 2016 / Revised: 7 December 2016 / Accepted: 13 December 2016 / Published: 20 December 2016
Cited by 6 | PDF Full-text (416 KB) | HTML Full-text | XML Full-text
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
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Open AccessReview Effect of Lead (Pb) on Inflammatory Processes in the Brain
Int. J. Mol. Sci. 2016, 17(12), 2140; https://doi.org/10.3390/ijms17122140
Received: 1 September 2016 / Revised: 10 December 2016 / Accepted: 14 December 2016 / Published: 19 December 2016
Cited by 10 | PDF Full-text (1544 KB) | HTML Full-text | XML Full-text
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,
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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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Open AccessArticle Triptolide Combined with Radiotherapy for the Treatment of Nasopharyngeal Carcinoma via NF-κB-Related Mechanism
Int. J. Mol. Sci. 2016, 17(12), 2139; https://doi.org/10.3390/ijms17122139
Received: 13 October 2016 / Revised: 12 December 2016 / Accepted: 15 December 2016 / Published: 19 December 2016
Cited by 7 | PDF Full-text (12552 KB) | HTML Full-text | XML Full-text
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
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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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Open AccessReview Alterations of Epigenetic Regulators in Pancreatic Cancer and Their Clinical Implications
Int. J. Mol. Sci. 2016, 17(12), 2138; https://doi.org/10.3390/ijms17122138
Received: 15 November 2016 / Revised: 8 December 2016 / Accepted: 14 December 2016 / Published: 19 December 2016
Cited by 5 | PDF Full-text (815 KB) | HTML Full-text | XML Full-text
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
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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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Open AccessArticle Neurotoxicity of a Biopesticide Analog on Zebrafish Larvae at Nanomolar Concentrations
Int. J. Mol. Sci. 2016, 17(12), 2137; https://doi.org/10.3390/ijms17122137
Received: 6 October 2016 / Revised: 7 December 2016 / Accepted: 10 December 2016 / Published: 19 December 2016
Cited by 1 | PDF Full-text (4406 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
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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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