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1.
J Biol Chem ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690629

RESUMO

Hypoxia inducible transcription factors (HIFs) directly dictate the expression of multiple RNA species including novel and as yet uncharacterized long non-coding transcripts with unknown function. We used pan-genomic HIF-binding and transcriptomic data to identify a novel long non-coding RNA NICI (Non-coding Intergenic Co-Induced transcript) on chromosome 12p13.31 which is regulated by hypoxia via HIF-1 promoter-binding in multiple cell types. CRISPR/Cas9-mediated deletion of the hypoxia-response element revealed co-regulation of NICI and the neighboring protein-coding gene, solute carrier family 2 member 3 (SLC2A3) which encodes the high-affinity glucose transporter 3 (GLUT3). Knock-down or knock-out of NICI attenuated hypoxic induction of SLC2A3 indicating a direct regulatory role of NICI in SLC2A3 expression, which was further evidenced by CRISPR/Cas9-VPR mediated activation of NICI expression. We also demonstrate that regulation of SLC2A3 is mediated through transcriptional activation rather than post-transcriptional mechanisms since knock-out of NICI leads to reduced recruitment of RNA polymerase 2 to the SLC2A3 promoter. Consistent with this we observe NICI-dependent regulation of glucose consumption and cell proliferation. Furthermore, NICI expression is regulated by the VHL tumour suppressor and is highly expressed in clear cell renal cancer, where SLC2A3 expression is associated with patient prognosis, implying an important role for the HIF/NICI/SLC2A3 axis in this malignancy.

2.
Anal Cell Pathol (Amst) ; 2019: 1598182, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31482051

RESUMO

Human hepatocellular carcinoma (HCC) is the most common and recurrent type of primary adult liver cancer without any effective therapy. Plant-derived compounds acting as anticancer agents can induce apoptosis by targeting several signaling pathways. Strigolactone (SL) is a novel class of phytohormone, whose analogues have been reported to possess anticancer properties on a panel of human cancer cell lines through inducing cell cycle arrest, destabilizing microtubular integrity, reducing damaged in the DNA repair machinery, and inducing apoptosis. In our previous study, we reported that a novel SL analogue, TIT3, reduces HepG2 cell proliferation, inhibits cell migration, and induces apoptosis. To decipher the mechanisms of TIT3-induced anticancer activity in HepG2, we performed RNA sequencing and the differential expression of genes was analyzed using different tools. RNA-Seq data showed that the genes responsible for microtubule organization such as TUBB, BUB1B, TUBG2, TUBGCP6, TPX2, and MAP7 were significantly downregulated. Several epigenetic modulators such as UHRF1, HDAC7, and DNMT1 were also considerably downregulated, and this effect was associated with significant upregulation of various proapoptotic genes including CASP3, TNF-α, CASP7, and CDKN1A (p21). Likewise, damaged DNA repair genes such as RAD51, RAD52, and DDB2 were also significantly downregulated. This study indicates that TIT3-induced antiproliferative and proapoptotic activities on HCC cells could involve several signaling pathways. Our results suggest that TIT3 might be a promising drug to treat HCC.

3.
Genet Test Mol Biomarkers ; 23(8): 509-514, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31328973

RESUMO

Background: Long noncoding RNAs (lncRNAs) have recently been recognized as a new layer of biological regulation. They participate in mRNA regulation and may be useful as prognostic factors and drug targets. Colorectal cancer (CRC) is a common tumor that is characterized by its high mortality rate. Despite improvements in screening of CRC, the prognosis is still poor. Therefore, there is an urgent need to develop effective biomarkers for the detection of CRC. This study was designed to measure the expression of several oncogenic lncRNAs, including PANDAR, MALAT1, PCAT6, CCAT1, UCA1, MEG3, CCAT2, and BCAR4, in blood samples of healthy individuals and CRC patients. Methods: Total RNA was isolated from whole blood of 63 CRC patients and 40 controls and the expression of the lncRNAs was determined by real-time polymerase chain reaction and measured by REST2009 software. All p-values <0.05 were considered statistically significant. Results: The results showed that the expression levels of MALAT1, CCAT1, and PANDAR were significantly upregulated with 1.86, 4.54, and 4.68-fold higher levels (p < 0.05), respectively, in the blood of CRC patients compared to the controls. However, the other lncRNAs examined were not significantly expressed differentially in CRC blood samples. Conclusion: The findings of this study suggest that the expression of MALAT1, CCAT1, and PANDAR in blood could serve as potential biomarkers for CRC prognosis.

4.
J Cell Biochem ; 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31232490

RESUMO

Escherichia coli is frequently exploited for genetic manipulations and heterologous gene expression studies. We have evaluated the metabolic profile of E. coli strain BL21 (DE3) RIL CodonPlus after genetic modifications and subjecting to the production of recombinant protein. Three genetically variable E. coli cell types were studied, normal cells (susceptible to antibiotics) cultured in simple LB medium, cells harboring ampicillin-resistant plasmid pET21a (+), grown under antibiotic stress, and cells having recombinant plasmid pET21a (+) ligated with bacterial lactate dehydrogenase gene grown under ampicillin and standard isopropyl thiogalactoside (IPTG)-induced gene expression conditions. A total of 592 metabolites were identified through liquid chromatography-mass spectrometry/mass spectrometry analysis, feature and peak detection using XCMS and CAMERA followed by precursor identification by METLIN-based procedures. Overall, 107 metabolites were found differentially regulated among genetically modified cells. Quantitative analysis has shown a significant modulation in DHNA-CoA, p-aminobenzoic acid, and citrulline levels, indicating an alteration in vitamin K, folic acid biosynthesis, and urea cycle of E. coli cells during heterologous gene expression. Modulations in energy metabolites including NADH, AMP, ADP, ATP, carbohydrate, terpenoids, fatty acid metabolites, diadenosine tetraphosphate (Ap4A), and l-carnitine advocate major metabolic rearrangements. Our study provides a broader insight into the metabolic adaptations of bacterial cells during gene manipulation experiments that can be prolonged to improve the yield of heterologous gene products and concomitant production of valuable biomolecules.

5.
Proc Natl Acad Sci U S A ; 116(25): 12452-12461, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31152137

RESUMO

Tumor hypoxia is associated with poor patient outcomes in estrogen receptor-α-positive (ERα+) breast cancer. Hypoxia is known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here, we show that the glutamine transporter, SNAT2, is the AA transporter most frequently induced by hypoxia in breast cancer, and is regulated by hypoxia both in vitro and in vivo in xenografts. SNAT2 induction in MCF7 cells was also regulated by ERα, but it became predominantly a hypoxia-inducible factor 1α (HIF-1α)-dependent gene under hypoxia. Relevant to this, binding sites for both HIF-1α and ERα overlap in SNAT2's cis-regulatory elements. In addition, the down-regulation of SNAT2 by the ER antagonist fulvestrant was reverted in hypoxia. Overexpression of SNAT2 in vitro to recapitulate the levels induced by hypoxia caused enhanced growth, particularly after ERα inhibition, in hypoxia, or when glutamine levels were low. SNAT2 up-regulation in vivo caused complete resistance to antiestrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlated with hypoxia profiles and worse outcome in patients given antiestrogen therapies. Our findings show a switch in the regulation of SNAT2 between ERα and HIF-1α, leading to endocrine resistance in hypoxia. Development of drugs targeting SNAT2 may be of value for a subset of hormone-resistant breast cancer.

6.
Bioorg Chem ; 88: 102937, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31048120

RESUMO

Naturally occurring polyamines like Putrescine, Spermidine, and Spermine are polycations which bind to the DNA, hence stabilizing it and promoting the essential cellular processes. Many synthetic polyamine analogues have been synthesized in the past few years, which have shown cytotoxic effects on different tumours. In the present study, we evaluated the antiproliferative effect of a novel, acylspermidine derivative, (N-(4-aminobutyl)-N-(3-aminopropyl)-8-hydroxy-dodecanamide) (AAHD) on HepG2 cells. Fluorescence staining was performed with nuclear stain (Hoechst 33342) and acridine orange/ethidium bromide double staining. Dose and the time-dependent antiproliferative effect were observed by WST-1 assays, and radical scavenging activity was measured by ROS. Morphological changes such as cell shrinkage & blebbing were analyzed by fluorescent microscopy. It was found that AAHD markedly suppressed the growth of HepG2 cells in a dose- and time-dependent manner. It was also noted that the modulation of ROS levels confirmed the radical scavenging activity. In the near future, AAHD can be a promising drug candidate in chalking out a neoplastic strategy to control the proliferation of tumour cells. This study indicated that AAHD induced anti-proliferative and pro-apoptotic activities on HCC. Since AAHD was active at micromolar concentrations without any adverse effects on the healthy cells (Fibroblasts), it is worthy of further clinical investigations.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30763917

RESUMO

ß-lactoglobulin (BLG) is a well characterized milk protein and a model for folding and aggregation studies. Rutin is a quercetin based-flavanoid and a famous dietary supplement. It is a potential protector from coronary heart disease, cancers, and inflammatory bowel disease. In this study, amyloid fibrillation is reported in BLG at pH 2.0 and temperature 358 K. It is inhibited to some extent by rutin with a rate of 99.3 h-1 M-1. Amyloid fibrillation started taking place after 10 h of incubation and completed near 40 h at a rate of 16.6 × 10-3 h-1, with a plateau during 40-108 h. Disruption of tertiary structure of BLG and increased solvent accessibility of hydrophobic core seem to trigger intermolecular assembly. Increase in 7% ß-sheet structure at the cost of 10% α-helical structures and the electron micrograph of BLG fibrils at 108 h further support the formation of amyloid. Although it could not block amyloidosis completely, and even the time required to reach plateau remains the same, a decrease of growth rate from 16.6 × 10-3 to 13.5 × 10-3 h-1 was observed in the presence of 30.0 µM rutin. Rutin seems to block solvent accessibility of the hydrophobic core of BLG. A decrease in the fibril population was observed in electron micrographs, with the increase in rutin concentration. All evidences indicate reversal of fibrillation in BLG in the presence of rutin.


Assuntos
Amiloide/química , Lactoglobulinas/química , Quercetina/química , Rutina/química , Animais , Bovinos , Concentração de Íons de Hidrogênio , Domínios Proteicos , Estrutura Secundária de Proteína
8.
Int J Biol Macromol ; 128: 54-60, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30682486

RESUMO

The aim of this study was to investigate the effects of sodium dodecyl benzenesulfonate (SDBS) on hen egg white lysozyme (HEWL) fibrillogenesis at pH 7.4. HEWL fibrillogenesis in the presence of SDBS was characterized using several spectroscopic techniques (turbidity, light scattering, intrinsic fluorescence, ThT binding assay, ThT kinetics, far-UV CD, and transmission electron mmicroscopy). The turbidity and light scattering data revealed that SDBS induces aggregation in HEWL in dose-dependent manner. HEWL aggregation was seen at low SDBS concentrations (0.03 to 0.5 mM) but it was not observed at concentrations of SDBS at >0.6 mM. The ThT and TEM data clearly showed that the aggregates formed in the presence of SDBS had an amyloid-like morphology. From the CD analysis it was clear that low SDBS concentrations decreases the α-helical content while the ß-sheet content increased. As the SDBS concentration further increased, the α-helical content increased again. The ThT kinetics analysis revealed that the HEWL monomer directly converted into the amyloid fibril without lag phase. All the spectroscopic and microscopic results support the finding that low concentrations of SDBS stimulate fibrillogenesis in HEWL, and that no fibrillogenesis occurs at higher SDBS concentrations.


Assuntos
Benzenossulfonatos/química , Benzenossulfonatos/farmacologia , Muramidase/química , Conformação Proteica/efeitos dos fármacos , Tensoativos/química , Tensoativos/farmacologia , Amiloide/química , Amiloide/metabolismo , Amiloide/ultraestrutura , Concentração de Íons de Hidrogênio , Agregados Proteicos , Análise Espectral
9.
Int J Biol Macromol ; 127: 297-305, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30654033

RESUMO

Allura red (AR) is an artificial azo dye mostly used in food industries and has potential health risks. We examined the role of AR in amyloidogenesis using hen egg white lysozyme (HEWL) at pH 7.0. The amyloidogenic induction properties of AR in HEWL were identified by circular dichroism (CD), turbidity, intrinsic fluorescence, light scattering, transmission electron microscopy (TEM), and molecular dynamic simulation studies. Turbidity and light scattering measurements showed that HEWL becomes aggregated in the presence of 0.03-15.0 mM of AR at pH 7.0 but not at very low AR concentrations (0.01-0.28 mM). However, AR-induced aggregation is a kinetically rapid process, with no observable lag phase and saturation within 6 s. The kinetics results suggested that the HEWL aggregation induced by AR is very rapid. The CD results demonstrated that the total ß-sheet content of HEWL was increased in the AR treated samples. The TEM results are established that AR-induced aggregates had amyloid-like structures. Molecular dynamics simulations analysis showed that the bound AR-HEWL structures were highly favored compared to unbound structures. The mechanism of AR-induced amyloid fibril formation may involve electrostatic, hydrogen bonding, and hydrophobic interactions.


Assuntos
Amiloide/química , Compostos Azo/química , Muramidase/química , Agregados Proteicos , Animais , Galinhas , Concentração de Íons de Hidrogênio , Domínios Proteicos , Estrutura Quaternária de Proteína
10.
Epigenet Insights ; 11: 2516865718814543, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30515476

RESUMO

Natural polyamines such as putrescine, spermidine, and spermine are crucial in the cell proliferation and maintenance in all the eukaryotes. However, the requirement of polyamines in tumor cells is stepped up to maintain tumorigenicity. Many synthetic polyamine analogues have been designed recently to target the polyamine metabolism in tumors to induce apoptosis. N4-Erucoyl spermidine (designed as N4-Eru), a novel acylspermidine derivative, has been shown to exert selective inhibitory effects on both hematological and solid tumors, but its mechanisms of action are unknown. In this study, RNA sequencing was performed to investigate the anticancer mechanisms of N4-Eru-treated T-cell acute lymphoblastic leukemia (ALL) cell line (Jurkat cells), and gene expression was examined through different tools. We could show that many key oncogenes including NDRG1, CACNA1G, TGFBR2, NOTCH1,2,3, UHRF1, DNMT1,3, HDAC1,3, KDM3A, KDM4B, KDM4C, FOS, and SATB1 were downregulated, whereas several tumor suppressor genes such as CDKN2AIPNL, KISS1, DDIT3, TP53I13, PPARG, FOXP1 were upregulated. Data obtained through RNA-Seq further showed that N4-Eru inhibited the NOTCH/Wnt/JAK-STAT axis. This study also indicated that N4-Eru-induced apoptosis could involve several key signaling pathways in cancer. Altogether, our results suggest that N4-Eru is a promising drug to treat ALL.

11.
Nat Commun ; 9(1): 4590, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389926

RESUMO

Here we introduce Protein-indexed Assay of Transposase Accessible Chromatin with sequencing (Pi-ATAC) that combines single-cell chromatin and proteomic profiling. In conjunction with DNA transposition, the levels of multiple cell surface or intracellular protein epitopes are recorded by index flow cytometry and positions in arrayed microwells, and then subject to molecular barcoding for subsequent pooled analysis. Pi-ATAC simultaneously identifies the epigenomic and proteomic heterogeneity in individual cells. Pi-ATAC reveals a casual link between transcription factor abundance and DNA motif access, and deconvolute cell types and states in the tumor microenvironment in vivo. We identify a dominant role for hypoxia, marked by HIF1α protein, in the tumor microvenvironment for shaping the regulome in a subset of epithelial tumor cells.

12.
FASEB J ; : fj201800265RR, 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30379590

RESUMO

Growth factor receptor-binding protein 10 (GRB10) is a well-known adaptor protein and a recently identified substrate of the mammalian target of rapamycin (mTOR). Depletion of GRB10 increases insulin sensitivity and overexpression suppresses PI3K/Akt signaling. Because the major reason for the limited efficacy of PI3K/Akt-targeted therapies in prostate cancer (PCa) is loss of mTOR-regulated feedback suppression, it is therefore important to assess the functional importance and regulation of GRB10 under these conditions. On the basis of these background observations, we explored the status and functional impact of GRB10 in PCa and found maximum expression in phosphatase and tensin homolog (PTEN)-deficient PCa. In human PCa samples, GRB10 inversely correlated with PTEN and positively correlated with pAKT levels. Knockdown of GRB10 in nontumorigenic PTEN null mouse embryonic fibroblasts and tumorigenic PCa cell lines reduced Akt phosphorylation and selectively activated a panel of receptor tyrosine kinases. Similarly, overexpression of GRB10 in PTEN wild-type PCa cell lines accelerated tumorigenesis and induced Akt phosphorylation. In PTEN wild-type PCa, GRB10 overexpression promoted mediated PTEN interaction and degradation. PI3K (but not mTOR) inhibitors reduced GRB10 expression, suggesting primarily PI3K-driven regulation of GRB10. In summary, our results suggest that GRB10 acts as a major downstream effector of PI3K and has tumor-promoting effects in prostate cancer.-Khan, M. I., Al Johani, A., Hamid, A., Ateeq, B., Manzar, N., Adhami, V. M., Lall, R. K., Rath, S., Sechi, M., Siddiqui, I. A., Choudhry, H., Zamzami, M. A., Havighurst, T. C., Huang, W., Ntambi, J. M., Mukhtar, H. Pro-proliferative function of adaptor protein GRB10 in prostate carcinoma.

13.
Mol Cancer Ther ; 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30446585

RESUMO

Hyperactivated AKT kinase due to loss of its negative regulator PTEN influences many aspects of cancer biology including chromatin. AKT primarily regulates acetyl-CoA production and phosphorylates many histone modulating enzymes resulting in their activation or inhibition. Therefore, understanding the therapeutic impact of AKT inhibition on chromatin related events is essential. Here, we report that AKT inhibition in prostate specific PTEN knockout mice significantly induces di- and tri-methylation of H3K4 with concomitant reduction in H3K9 acetylation. Mechanistically, we observed that AKT inhibition reduces expression of the H3K4 methylation specific histone demethylases KDM5 family, especially KDM5B expression at transcriptional levels. Further, we observed that AKT negatively regulates miR-137 levels, which transcriptionally represses KDM5B expression. Overexpression of miR-137 significantly reduced KDM5B and increased H3K4 methylation levels but failed to change AKT phosphorylation. Overall, we observed that AKT transcriptionally regulates KDM5B mainly via repression of miR-137. Our data identify a mechanism by which AKT kinase modulates the prostate cancer epigenome through regulating H3K4 methylation. Additional studies on AKT inhibition mediated induction of H3K4 methylation will help in designing strategies to enhance the therapeutic efficacy of PI3K/AKT inhibitors.

14.
Nanomedicine (Lond) ; 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30474494

RESUMO

AIM: The present work involves the development of Concavalin A-conjugated nanostructured lipidic carriers (NLCs) of olmesartan medoxomil for lectin receptor targeting. MATERIALS & METHODS: Excipient selection was performed by drug solubility in solid and liquid lipids. Factor screening was carried out by evaluating the impact of formulation and process variables on the critical quality attributes. Surface modification of NLCs was carried out using Concavalin A and extensively characterized. RESULTS & CONCLUSION: NLCs exhibited the particle size of 273.6 nm, Î¶-potential of -30.2 nm, encapsulation efficiency of 73.3% and sustained drug release profile. Nearly 4.2-fold improvement in cell uptake, four- to eightfold increase in Cmax and AUC, and 37% reduction in blood pressure was observed from NLCs over the pure drug.

15.
EMBO Rep ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429208

RESUMO

Hypoxia-inducible factor (HIF) is the major transcriptional regulator of cellular responses to hypoxia. The two principal HIF-α isoforms, HIF-1α and HIF-2α, are progressively stabilized in response to hypoxia and form heterodimers with HIF-1ß to activate a broad range of transcriptional responses. Here, we report on the pan-genomic distribution of isoform-specific HIF binding in response to hypoxia of varying severity and duration, and in response to genetic ablation of each HIF-α isoform. Our findings reveal that, despite an identical consensus recognition sequence in DNA, each HIF heterodimer loads progressively at a distinct repertoire of cell-type-specific sites across the genome, with little evidence of redistribution under any of the conditions examined. Marked biases towards promoter-proximal binding of HIF-1 and promoter-distant binding of HIF-2 were observed under all conditions and were consistent in multiple cell type. The findings imply that each HIF isoform has an inherent property that determines its binding distribution across the genome, which might be exploited to therapeutically target the specific transcriptional output of each isoform independently.

16.
Integr Cancer Ther ; : 1534735418809901, 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30373413

RESUMO

BACKGROUND: The role of alkaloids isolated from Rhazya stricta Decne (Apocynaceae family) (RS) in targeting genes involved in cancer and metastasis remains to be elucidated. OBJECTIVE: Identify and characterize new compounds from RS, which inhibit gene(s) involved in the survival, invasion, self-renewal, and metastatic processes of cancer cells. METHODS: Bioinformatics study was performed using HISAT2, stringtie, and ballgown pipeline to understand expressional differences between a normal epithelial cell line-MCF10A and MCF7. NMR and ATR-FTIR were performed to elucidate the structure of rhazyaminine (R.A), isolated from R stricta. Cell viability assay was performed using 0, 25, and 50 µg/mL of total extract of R stricta (TERS) and R.A, respectively, for 0, 24, and 48 hours, followed by scratch assay. In addition, total RNA was isolated for RNA- seq analysis of MCF7 cell line treated with R.A followed by qRT-PCR analysis of Bcl-2 gene. RESULTS: Deptor, which is upregulated in MCF7 compared with MCF10A as found in our bioinformatics study was downregulated by R.A. Furthermore, R.A effectively reduced cell viability to around 50% ( P < .05) and restricted cell migration in scratch assay. Thirteen genes, related to metastasis and cancer stem cells, were downregulated by R.A according to RNA- seq analysis. Additionally, qRT-PCR validated the downregulation of Bcl-2 gene in R.A-treated cells by less than 0.5 folds ( P < .05). CONCLUSION: R.A successfully downregulated key genes involved in apoptosis, cell survival, epithelial-mesenchymal transition, cancer stem cell proliferation, and Wnt signal transduction pathway making it an excellent "lead candidate" molecule for in vivo proof-of-concept studies.

17.
J Pestic Sci ; 43(3): 168-172, 2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-30363122

RESUMO

Chemotherapy shows some promising results in the inhibition of cancer, but resistance to chemotherapy and its severe side effects may occur in due course, resulting in only restricted and narrow benefits. Therefore, there is a pressing need to find alternative chemotherapeutic drugs for combating cancers. Plants have been used since ages in medicine, and by the dawn of 19th century, various potent and promising anti-cancer products have been derived from plants. Strigolactones (SLs) are a novel class of phytohormones involved in regulating the branching of shoots. Recently, many novel synthesized SL analogues have been found to be effective against solid and non-solid tumours. These hormones have been reported to have a unique mechanism of inhibiting cancer cells by lowering their viability and promoting apoptosis and cell death at micromolar concentrations. Therefore, synthetic SL analogues could be future potent anti-cancer drug candidates. Further research is needed to identify and deduce the significance of these synthetic SL analogues.

18.
Food Sci Nutr ; 6(6): 1341-1351, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30258574

RESUMO

Iodine, a dynamic nutrient present in thyroid hormones, is responsible for regulating thyroid function, supporting a healthy metabolism, and aiding growth and development. Iodine is also essential for brain development during specific time windows influencing neurogenesis, neuronal and glial cell differentiation, myelination, neuronal migration, and synaptogenesis. About 1.5 billion people in 130 countries live in areas at risk of iron deficiencies (IDs). Reduced mental ability due to IDs occurs in almost 300 million people. Ensuring the consumption of minimum recommended daily allowances of iodine remains challenging. The effects of ID disorders range from high mortality of fetuses and children to inhibited mental development (cretinism). Poor socioeconomic development and impaired school performance are also notable. Currently, ID disorders are the single greatest contributor to preventable brain damage in fetuses and infants and arrested psychomotor development in children. Iodized salt may help fulfill iodine requirements. Increases in food salt iodization programs can help overcome ID disorders. Dietary plans can be well adjusted to incorporate iodinated foods. Maternal iodine supplementation for offspring requires adequate attention. Fruits, vegetables, bread, eggs, legumes (beans and peas), nuts, seeds, seafood, lean meats and poultry, and soy products provide small quantities of iodine. Nutrient-dense foods containing essential vitamins and minerals such as iodine may confer positive effects. To some extent, fortified foods and daily dietary supplements can be provided for different nutrients including iodine; otherwise, iodine may be consumed in less than the recommended amounts. This review focuses on aspects of adequate iodine consumption to avoid cognitive impairments.

19.
Breast Cancer ; 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30255294

RESUMO

p21Waf1/Cip1, the cyclin-dependent kinase (CDK) inhibitor belonging to the KIP/CIP family, was initially regarded as a tumor suppressor protein because it was recognized as the chief mediator of p53-dependent cell cycle arrest elicited by DNA damage. Conversely, it has been proposed that p21Waf1/Cip1 may also function as an oncogene because it can inhibit apoptosis. Thus, p21Waf1/Cip1 is regarded as a protein with a dual behavior, as its expression might cause potential benefits or dangerous effects in breast cancer. Consequently, careful planning is required in targeting p21Waf1/Cip1 expression for therapy of breast cancer patients. This review illustrates the discovery and mechanisms of induction of p21Waf1/Cip1. Then, we focus on elucidating the paradoxical effect of p21Waf1/Cip1 expression on human breast carcinogenesis and explaining how the subcellular localization (nuclear or cytoplasmic) of p21Waf1/Cip1 has an impact on both determining its fate as either cell-growth inhibitor or antiapoptotic molecule and, its effect on clinicopathological factors and prognosis of breast cancer patients. Moreover, we explore how the pattern of the p21Waf1/Cip1 could affect the responsiveness of human breast cancer to chemotherapy. Furthermore, the pharmacological approaches to target p21Waf1/Cip1 expression for therapy of breast cancer are clarified.

20.
Sci Rep ; 8(1): 11674, 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30076320

RESUMO

The use of anti-cancer adjuvant therapy is rationalized by potentiating the efficacy, and/or protecting from major side effects of chemotherapeutics. Thymoquinone (TQ) is a naturally occurring compound with cumulative evidence of anti-cancer properties. In this study, we assessed the chemomodulatory potential of TQ to gemcitabine (GCB) against human breast adenocarcinoma (MCF-7), and ductal carcinoma (T47D) cells. TQ showed cytotoxic effects against MCF-7 and T47D with IC50's of 64.9 ± 14 µM and 165 ± 2 µM, respectively. The IC50's of GCB against MCF-7 and T47D were 0.9 ± 0.18 µM and 14.3 ± 2.8 µM and were significantly reduced after combination with TQ to 0.058 ± 12 µM and 2.3 ± 0.2 µM, respectively. The CI- values were indicative of synergism in MCF-7 and T47D cells (0.15 and 0.30, respectively). Further investigation showed that GCB caused significant anti-proliferative effect reflected by increasing cell population in S-phase in both cell lines. TQ potentiated GCB-induced anti-proliferative activity in both cell lines. GCB induced considerable apoptosis in T47D cell line, and TQ significantly increased GCB-induced apoptotic effects by 1.5 to 3.6 folds. Interestingly, GCB, TQ and their combination induced significant autophagic cell death in the apoptosis defected MCF-7 cells. In addition, TQ, GCB and their combination depleted breast cancer associated stem cell (CD44(+)/CD24(-)/(low)) clone within MCF-7 and T47D cells by 3.8% to 27.5%. In conclusion, TQ showed promising chemomodulatory effects to GCB against breast cancer cells via inducing apoptosis, necrosis and autophagy, in addition to depleting tumor associated resistant stem cell fraction.

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