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Background Acquired resistance to 5-fluorouracil (5-FU) frequently results in chemotherapy failure and disease recurrence in advanced colorectal cancer (CRC) patients. Research has demonstrated that dysregulation of long non-coding RNAs (lncRNAs) mediates the development of chemotherapy resistance in cancerous cells. The present study aims to identify key lncRNAs associated with 5-FU resistance in CRC using bioinformatic and experimental validation approaches. Methods The Gene Expression Omnibus (GEO) dataset GSE119481, which contains miRNA expression profiles of the parental CRC HCT116 cell line (HCT116/P) and its in-vitro established 5-FU-resistant sub-cell line (HCT116/FUR), was downloaded. Firstly, differentially expressed microRNAs (DEmiRNAs) between the parental and 5-FU resistance cells were identified. LncRNAs and mRNAs were then predicted using online databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to uncover relevant biological mechanisms and pathways. Networks integrating lncRNAs, miRNAs, and mRNAs interactions were constructed, and topological analyses were used to identify key lncRNAs associated with 5-FU resistance. An in-vitro model of the HCT116/FUR sub-cell line was developed by exposing the HCT116/P cell line to increasing concentrations of 5-FU. Finally, real-time quantitative PCR (RT-qPCR) was performed on total RNA extracted from the HCT116/P cell line and the HCT116/FUR sub-cell line to validate the in-silico predictions of key lncRNAs. Results A total of 32 DEmiRNAs were identified. Enrichment analysis demonstrated that these DEmiRNAs were mainly enriched in several cancer hallmark pathways that regulate cell growth, cell cycle, cell survival, inflammation, immune response, and apoptosis. The predictive analysis identified 237 unique lncRNAs and 123 mRNAs interacting with these DEmiRNAs. The pathway analysis indicated that most of these predicted genes were enriched in the cellular response to starvation, protein polyubiquitination, chromatin remodeling, and negative regulation of gene expression. Topological analyses of the lncRNA-miRNA-mRNA network highlighted the nuclear enriched abundant transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and Opa interacting protein 5 antisense RNA 1 (OIP5-AS1) as central lncRNAs. Experimental analysis by RT-qPCR confirmed that the expression levels of NEAT1 and MALAT1 were significantly increased in HCT116/FUR cells compared to HCT116/P cells. However, no significant difference was observed in the OIP5-AS1 expression level between the two cells. Conclusion Our findings specifically highlight MALAT1 and NEAT1 as significant contributors to 5-FU resistance in CRC. These lncRNAs are promising biomarkers for diagnosing and predicting outcomes in CRC.

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The gram-negative bacterium Escherichia coli Nissle 1917 (EcN) has long been recognized for its therapeutic potential in treating various intestinal diseases. Bacterial ghosts (BGs) are empty shells of non-living bacterial cells that demonstrate enormous potential for medicinal applications. Genetic and chemical techniques can create these BGs. In the current study, we produced Escherichia coli Nissle 1917 ghosts (EcNGs) for the first time using benzoic acid (BA) and sodium hydroxide (SH). BA is a feeble acidic chemical that enhances gram-negative bacteria's external membrane permeability, reduces energy production, and decreases internal pH. SH has shown success in producing BGs from some gram-negative and gram-positive organisms. This research aims to produce EcNGs using the minimum inhibitory concentration (MIC) of SH and BA, specifically 3.125 mg/mL. We assessed the bacterial quality of the BGs produced using quantitative PCR (qPCR) and Bradford protein assays. Field emission scanning electron microscopy (FE-SEM) showed the three-dimensional structure of EcNGs. The study confirmed the presence of tunnel-like pores on the outer surface, indicating the preservation of cell membrane integrity. Importantly, this investigation introduces BA as a novel chemical inducer of EcNGs, suggesting its potential alongside SH for efficient EcNG formation.

Asunto(s)

Escherichia coli , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Pruebas de Sensibilidad Microbiana , Ácido Benzoico/farmacología , Ácido Benzoico/química , Hidróxido de Sodio/farmacología , Hidróxido de Sodio/química , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Microscopía Electrónica de Rastreo , Antibacterianos/farmacología , Antibacterianos/química

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This study investigated the efficacy of using chitosan/alginate nanoparticles loaded with recombinant human bone morphogenetic-2 (rhBMP-2) and SMAD4 encoding plasmid to enhance the chondrogenesis of human bone marrow mesenchymal stem cells (hBM-MSCs) seeded on an extracellular matrix (ECM). The research treatments included the stem cells treated with the biological cocktail (BC), negative control (NC), hBM-MSCs with chondrogenic medium (MCM), hBM-MSCs with naked rhBMP-2 and chondrogenic medium (NB/C), and hBM-MSCs with naked rhBMP-2 and chondrogenic medium plus SMAD4 encoding plasmid transfected with polyethyleneimine (PEI) (NB/C/S/P). The cartilage differentiation was performed with real-time quantitative PCR analysis and alizarin blue staining. The data indicated that the biological cocktail (BC) exhibited significantly higher expression of cartilage-related genes compared to significant differences with MCM and negative control (NC) on chondrogenesis. In the (NB/C/S/P), the expression levels of SOX9 and COLX were lower than those in the BC group. The expression pattern of the ACAN gene was similar to COL2A1 changes suggesting that it holds promising potential for cartilage regeneration.

Asunto(s)

Alginatos , Proteína Morfogenética Ósea 2 , Cartílago Articular , Quitosano , Condrogénesis , Matriz Extracelular , Células Madre Mesenquimatosas , Nanopartículas , Regeneración , Transducción de Señal , Proteína Smad4 , Andamios del Tejido , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Quitosano/química , Quitosano/farmacología , Alginatos/química , Alginatos/farmacología , Humanos , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Cartílago Articular/citología , Proteína Morfogenética Ósea 2/metabolismo , Proteína Morfogenética Ósea 2/genética , Nanopartículas/química , Condrogénesis/efectos de los fármacos , Andamios del Tejido/química , Proteína Smad4/metabolismo , Proteína Smad4/genética , Transducción de Señal/efectos de los fármacos , Matriz Extracelular/metabolismo , Regeneración/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Factor de Transcripción SOX9/metabolismo , Factor de Transcripción SOX9/genética , Proteínas Recombinantes/farmacología , Factor de Crecimiento Transformador beta

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The use of NPS compounds is increasing, and impairment in spatial learning and memory is a growing concern. Alpha-pyrrolidinovalerophenone (α-PVP) consumption, as a commonly used NPS, can impair spatial learning and memory via the brain mitochondrial dysfunction mechanism. Liraglutide isone of the most well-known Glucagon-Like Peptide 1 (GLP-1) agonists that is used as an anti-diabetic and anti-obesity drug. According to current research, Liraglutide likely ameliorates cognitive impairment in neurodegenerative conditions and substance use disorders. Hence, the purpose of this study is examining the effect of Liraglutide on α-PVP-induced spatial learning and memory problems due to brain mitochondrial dysfunction. Wistar rats (8 in each group) received α-PVP (20 mg/kg/d for 10 consecutive days, intraperitoneally (I.P.)). Then, Liraglutide was administered at 47 and 94 µg/kg/d, I.P., for 4 weeks following the α-PVP administration. The Morris Water Maze (MWM) task evaluated spatial learning and memory 24 h after Liraglutide treatment. Bedside, brain mitochondrial activity parameters, including reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), cytochrome c release, mitochondrial outer membrane damage and swelling, and brain ADP/ATP ratio, were studied. Our results showed that Liraglutide ameliorated α-PVP-induced spatial learning and memory impairments through alleviating brain mitochondrial dysfunction (which is indicated by increasing ROS formation, collapsed MMP, mitochondrial outer membrane damage, cytochrome c release, mitochondrial swelling, and increased brain ADP/ATP ratio). This study could be used as a starting point for future studies about the possible role of Liraglutide in ameliorating mitochondrial dysfunction leading to substance use disorder- induced cognitive impairment.

Asunto(s)

Encéfalo , Disfunción Cognitiva , Liraglutida , Mitocondrias , Pirrolidinas , Ratas Wistar , Animales , Liraglutida/farmacología , Liraglutida/uso terapéutico , Pirrolidinas/farmacología , Pirrolidinas/uso terapéutico , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Masculino , Ratas , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/inducido químicamente , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo

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Although humans are frequently exposed to multiple pollutants simultaneously, research on their harmful effects on health has typically focused on studying each pollutant individually. Inorganic arsenic (As) and benzo[a]pyrene (BaP) are well-known pollutants with carcinogenic potential, but their co-exposure effects on breast cancer cell progression remain incompletely understood. This study aimed to assess the combined impact of BaP and As on the viability and migration of MDA-MB-231 cells. The results indicated that even at low levels, both inorganic As (0.01 µM, 0.1 µM, and 1 µM) and BaP (1 µM, 2.5 µM), individually or in combination, enhanced the viability and migration of the cells. However, the cell cycle analysis revealed no significant differences between the control group and the cells exposed to BaP and As. Specifically, exposure to BaP alone or in combination with As (As 0.01 µM + BaP 1 µM) for 24 h led to a significant increase in vimentin gene expression. Interestingly, short-term exposure to As not only did not induce EMT but also modulated the effects of BaP on vimentin gene expression. However, there were no observable changes in the expression of E-cadherin mRNA. Consequently, additional research is required to evaluate the prolonged effects of co-exposure to As and BaP on the initiation of EMT and the progression of breast cancer.

RESUMEN

PURPOSE: In the present study, biodegradable poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) nanoparticles (NPs) containing insulin were loaded in sodium alginate/jeffamine (ALG/jeff) hydrogel for prolonged delivery of insulin. The main aim of this work was to fabricate an efficient insulin delivery system to improve patient adherence by decreasing the repetition of injections. METHODS: Swelling and morphological properties and crosslinking efficiency of ALG/jeff hydrogel were assessed. The composite hydrogel was prepared by adding PHBV NPs to ALG/jeff hydrogel concurrently with crosslinking process. The morphology and loading capacity of composite hydrogel were analyzed. RESULTS: Circular dichroism measurement demonstrated that insulin remains stable following fabrication process. The release profile exhibited 54.6 % insulin release from composite hydrogel within 31 days with minor initial burst release equated to nanoparticles and hydrogels. MTT cell viability analysis was performed by applying L-929 cell line and no cytotoxic effect was observed. CONCLUSIONS: Favorable results clearly introduced fabricated composite hydrogel as an excellent candidate for drug delivery systems and also paves the route for prolonged delivery systems of other proteins.

Asunto(s)

Alginatos , Supervivencia Celular , Preparaciones de Acción Retardada , Hidrogeles , Insulina , Nanopartículas , Poliésteres , Alginatos/química , Insulina/administración & dosificación , Insulina/química , Hidrogeles/química , Nanopartículas/química , Supervivencia Celular/efectos de los fármacos , Poliésteres/química , Animales , Preparaciones de Acción Retardada/química , Ratones , Línea Celular , Ácido Glucurónico/química , Ácidos Hexurónicos/química , Sistemas de Liberación de Medicamentos/métodos , Portadores de Fármacos/química , Liberación de Fármacos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Polihidroxibutiratos

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This systematic study deals with the amount of bisphenol A (BPA) in milk and dairy products, its analytical methods, and risk assessment. Milk is one of the drinks that has a high consumption. Bisphenol A can be present both in raw milk and its amount undergoes changes during the pasteurization process. This review was conducted by searching for the keywords Bisphenol A, BPA milk, dairy product, cheese, cream, butter, yogurt, measurement, detection, and analysis in different databases. The search was done in three databases, Scopus, PubMed and Science Direct. The largest number of studies on the determination of bisphenol A belonged to Asian and European countries. The amount of bisphenol A in milks was observed in the range from ND to 640 ng/mL. Furthermore, the amount of BPA in the tested cheese samples was observed in the ND range up to 6.1 ng/g and in the yogurt samples in the ND range up to 4.4 ng/g. The most used analytical method was based on liquid chromatography. The most used solvent for extraction was methanol or acetonitrile. HQ (Hazard Quotient) was also calculated in some studies. There was no risk in terms of milk consumption due to BPA contamination in extracted data.

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In this study, surface modified mesoporous silica nanoparticles (MSNs) were prepared for the targeted delivery of the anticancer agents, daunorubicin (DNR) and cytarabine (CTR), against K562 leukemia cancer cell lines. The MSNs were surface-modified with pH-sensitive chitosan (CS) to prevent the burst release of anticancer agents at the physiological pH of 7.4 and to enable a higher drug release at lower pH and higher concentration of glutathione. Finally, the MSNs were surface modified with KK1B10 aptamer (Apt) to enhance their uptake by K562 cells through ligand-receptor interactions. The MSNs were characterized using different methods and both in vitro and in vivo experiments were utilized to demonstrate their suitability as targeted anticancer agents. The resultant MSNs exhibited an average particle size of 295 nm, a surface area of 39.06 m2/g, and a cumulative pore volume of 0.09 cm3/g. Surface modification of MSNs with chitosan (CS) resulted in a more regulated and acceptable continuous release rate of DNR. The drug release rate was significantly higher at pH 5 media enriched with glutathione, compared to pH 7.4. Furthermore, MSNs coated with CS and conjugated with aptamer (MSN-DNR + CTR@CS-Apt) exhibited a lower IC50 value of 2.34 µg/ml, compared to MSNs without aptamer conjugation, which displayed an IC50 value of 12.27 µg/ml. The results of the cell cycle analysis indicated that the administration of MSN-DNR + CTR@CS-Apt led to a significant increase in the population of apoptotic cells in the sub-G1 phase. Additionally, the treatment arrested the remaining cells in various other phases of the cell cycle. Furthermore, the interactions between Apt-receptors were found to enhance the uptake of MSNs by cancer cells. The results of in vivo studies demonstrated that the administration of MSN-DNR + CTR@CS-Apt led to a significant reduction in the expression levels of CD71 and CD235a markers, as compared to MSN-DNR + CTR@CS (p < 0.001). In conclusion, the surface modified MSNs prepared in this study showed lower IC50 against cancer cell lines and higher anticancer activity in animal models.

Asunto(s)

Antineoplásicos , Quitosano , Leucemia , Nanopartículas , Animales , Daunorrubicina , Quitosano/química , Citarabina , Dióxido de Silicio/química , Antineoplásicos/química , Nanopartículas/química , Glutatión , Porosidad , Sistemas de Liberación de Medicamentos/métodos , Portadores de Fármacos/química

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BACKGROUND: Colorectal Cancer (CC) is among the most prevalent cancers in elderly persons. Radiotherapy is usually prescribed as CC develops, however, radiation beams indiscriminately affect normal cells. Previous studies nominated that probiotics and their metabolites can be used to minimize the side effects of radiotherapy. Hereby, the aim of this study was to investigate the probable correlation between cell-free supernatant of Bacillus subtilis and radiation response in normal and cancerous cell lines. METHODS AND RESULTS: IEC-18 and SW-48 cells were treated with different concentrations of B. subtilis supernatant. To evaluate the effect of probiotic treatments under radiation and the normal situation, the cytotoxicity of the treatments was measured using the MTT method. The cell cycle status was analyzed by flow cytometry. The expression levels of Bax, Bcl-2, and Caspase 3 genes were also determined by real-time (RT) PCR. B. subtilis supernatant increased the viability of normal cells under radiation treatment, although this effect was not significant. 40% v/v of this mixture could amplify the lethal effect of radiation and decreased the viability of cancer cells. SW-48 cells that received 40% v/v of the supernatant had a significantly higher rate of apoptosis. Probiotic supernatant effectively induced the expression of proapoptotic Bax and Caspase 3 genes. CONCLUSION: Presented results confirmed that the supernatant of B. subtilis can be supposed as a clue to improve the efficacy of radiation therapy in CC patients as it increased the sensitivity of cancerous cells and protected normal epithelial cells from detrimental effects of radiation.

Asunto(s)

Bacillus subtilis , Probióticos , Ratas , Animales , Bacillus subtilis/metabolismo , Caspasa 3/genética , Caspasa 3/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , Regulación hacia Arriba , Células Epiteliales/metabolismo , Apoptosis , Probióticos/farmacología

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Objectives: This study aimed to evaluate the effect of SSRIs on the expression of miRNAs and their protein targets. Materials and Methods: In a 100 day open-label study of citalopram (n=25) and sertraline (n=25), levels of miRNA 16, 132, and 124 and glucocorticoid receptor (GR), Brain-derived neurotrophic factor (BDNF), and serotonin transporter (SERT) protein expression were measured by QRT-PCR and western blot in healthy control (n=20), patients with depression at the baseline, and same patients after 100 days of treatment. Results: Expression levels of GR and BDNF proteins were lower in the depressed group before treatment as compared with the healthy group (P<0.0001). The SERT level was higher among the depressed group before treatment in comparison with the healthy group (P<0.0001). The level of GR and BDNF significantly increased, and SERT expression decreased after receiving sertraline (P<0.05). When the depressed group received citalopram, only SERT and GR were altered (P<0.05). Among the microRNAs' expression investigated, mir-124 and mir-132 were higher, and mir-16 was lower among the depressed compared with the healthy group (P<0.0001). Individuals receiving citalopram only showed an increase in the expression of mir-16 while administration of sertraline led to a significant increase in the expression of mir-16 and a decrease in mir-124 and mir-132 (P<0.05). Conclusion: This elucidated the relationship between antidepressant treatment and the expression of different microRNA that control gene expression in various pathways involved in depressed patients. Receiving SSRI can affect the level of these proteins and their relevant microRNAs.

RESUMEN

Novel psychoactive substances (NPS) consumption has increased in recent years, thus NPS-induced cognitive decline is a current source of concern. Alpha-pyrrolidinovalerophenone (α-PVP), as a member of NPS, is consumed throughout regions like Washington, D.C., Eastern Europe, and Central Asia. Mitochondrial dysfunction plays an essential role in NPS-induced cognitive impairment. Meanwhile, no investigations have been conducted regarding the α-PVP impact on spatial learning/memory and associated mechanisms. Consequently, our study investigated the α-PVP effect on spatial learning/memory and brain mitochondrial function. Wistar rats received different α-PVP doses (5, 10, and 20 mg/kg) intraperitoneally for 10 sequential days; 24 h after the last dose, spatial learning/memory was evaluated by the Morris Water Maze (MWM). Furthermore, brain mitochondrial protein yield and mitochondrial function variables (Mitochondrial swelling, succinate dehydrogenase (SDH) activity, lipid peroxidation, Mitochondrial Membrane Potential (MMP), Reactive oxygen species (ROS) level, brain ADP/ATP proportion, cytochrome c release, Mitochondrial Outer Membrane (MOM) damage) were examined. α-PVP higher dose (20 mg/kg) significantly impaired spatial learning/memory, mitochondrial protein yield, and brain mitochondrial function (caused reduced SDH activity, increased mitochondrial swelling, elevated ROS generation, increased lipid peroxidation, collapsed MMP, increased cytochrome c release, elevated brain ADP/ATP proportion, and MOM damage). Moreover, the lower dose of α-PVP (5 mg/kg) did not alter spatial learning/memory and brain mitochondrial function. These findings provide the first evidence regarding impaired spatial learning/memory following repeated administration of α-PVP and the possible role of brain mitochondrial dysfunction in these cognitive impairments.

Asunto(s)

Encefalopatías , Aprendizaje Espacial , Ratas , Animales , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Citocromos c/metabolismo , Aprendizaje por Laberinto , Mitocondrias , Encéfalo , Adenosina Trifosfato/metabolismo , Hipocampo , Estrés Oxidativo

RESUMEN

Recently, electrochemiluminescent (ECL) immunosensors have received much attention in the field of biomarker detection. Here, a highly enhanced ECL immunosensing platform was designed for ultrasensitive detection of carcinoembryonic antigen (CEA). The surface of the glassy carbon electrode was enhanced by applying functional nanostructures such as thiolated graphene oxide (S-GO) and streptavidin-coated gold nanoparticles (SA-AuNPs). The selectivity and sensitivity of the designed immunosensor were improved by entrapping CEA biomolecules using a sandwich approach. Luminol/silver nanoparticles (Lu-SNPs) were applied as the main core of the signaling probe, which were then coated with streptavidin to provide overloading of the secondary antibody. The highly ECL signal enhancement was obtained due to the presence of horseradish peroxidase (HRP) in the signaling probe, in which the presence of H2O2 further amplified the intensity of the signals. The engineered immunosensor presented excellent sensitivity for CEA detection, with limit of detection (LOD) and linear detection range (LDR) values of 58 fg mL-1 and 0.1 pg mL-1 to 5 pg mL-1 (R2 = 0.9944), respectively. Besides its sensitivity, the fabricated ECL immunosensor presented outstanding selectivity for the detection of CEA in the presence of various similar agents. Additionally, the developed immunosensor showed an appropriate repeatability (RSD 3.8%) and proper stability (2 weeks). Having indicated a robust performance in the real human serum with stated LOD and LDR, the engineered immunosensor can be considered for the detection and monitoring of CEA in the clinic.

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Técnicas Biosensibles , Nanopartículas del Metal , Nanocompuestos , Humanos , Luminol/química , Antígeno Carcinoembrionario , Oro/química , Plata/química , Nanopartículas del Metal/química , Peróxido de Hidrógeno , Estreptavidina , Mediciones Luminiscentes , Inmunoensayo , Nanocompuestos/química

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Aim: To identify the DNA methylation status of related genes in major depressive disorder following selective serotonin-reuptake inhibitor treatment. Materials & methods: 45 patients with major depressive disorder and 45 healthy volunteers were considered experimental and control groups, respectively. High-resolution melting real-time PCR was implemented to evaluate DNA methylation. Results: After 100 days of selective serotonin-reuptake inhibitor treatment, methylation of promoter CpG sites of BDNF, NR3C1, FKBP5 and SLC6A4 was significantly reduced. Compared with before treatment, patients' Hamilton Depression Rating Scale scores were significantly reduced after selective serotonin-reuptake inhibitor treatment (p ≤ 0.0001). Conclusion: Based on the proven effect of antidepressants on DNA methylation and gene expression, these medications can improve the treatment process and reduce depression scores after treatment.

Asunto(s)

Metilación de ADN , Trastorno Depresivo Mayor , Inhibidores Selectivos de la Recaptación de Serotonina , Humanos , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Regiones Promotoras Genéticas , Receptores de Glucocorticoides/genética , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico

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Over the last 2 decades, induced pluripotent stem cells (iPSCs) have had various potential applications in various medical research areas, from personalized medicine to disease treatment. Different cellular resources are accessible for iPSC generation, such as keratinocytes, skin fibroblasts, and blood or urine cells. However, all these sources are somatic cells, and we must make several changes in a somatic cell's transcriptome and chromatin state to become a pluripotent cell. It has recently been revealed that cancer cells can be a new source of iPSCs production. Cancer cells show similarities with iPSCs in self-renewal capacity, reprogramming potency, and signaling pathways. Although genetic abnormalities and potential tumor formation in cancer cells pose a severe risk, reprogrammed cancer-induced pluripotent stem cells (cancer-iPSCs) indicate that pluripotency can transiently overcome the cancer phenotype. This review discusses whether cancer cells can be a preferable source to generate iPSCs.

Asunto(s)

Células Madre Pluripotentes Inducidas , Neoplasias , Diferenciación Celular , Reprogramación Celular/genética , Fibroblastos/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Queratinocitos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Transcriptoma

RESUMEN

Melatonin (MT), a neurohormone with immunomodulatory properties, is one of the metabolites produced in the brain from tryptophan (TRP) that has already strong links with the neuropathogenesis of Multiple sclerosis (MS). However, the exact molecular mechanisms behind that are not fully understood. There is some evidence showing that MS and MT are interconnected via different pathways: Relapses of MS has a direct correlation with a low level of MT secretion and a growing body of evidence suggest that MT be therapeutic in Experimental Autoimmune Encephalomyelitis (EAE, a recognise animal model of MS) severity. Previous studies have demonstrated that the kynurenine pathway (KP), the main pathway of TRP catabolism, plays a key role in the pathogenesis of MS in humans and in EAE. The present study aimed to investigate whether MT can improve clinical signs in the EAE model by modulating the KP. C57BL/6 mice were induced with EAE and received different doses of MT. Then the onset and severity of EAE clinical symptoms were recorded. Two biological factors, aryl hydrocarbon receptor (AhR) and NAD+ which closely interact in the KP were also assessed. The results indicated that MT treatment at all tested doses significantly decrease the EAE clinical scores and the number of demyelinating plaques. Furthermore, MT treatment reduced the mRNA expression of the KP regulatory enzyme indoleamine 2,3-dioxygenase 1(IDO-1) and other KP enzymes. We also found that MT treatment reduces the mRNA expression of the AhR and inhibits the enzyme Nicotinamide N-Methyltransferase (Nnmt) overexpression leading to an increase in NAD+ levels. Collectively, this study suggests that MT treatment may significantly attenuates the severity of EAE by altering the KP, AhR and NAD+ metabolism.

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Encefalomielitis Autoinmune Experimental , Melatonina , Esclerosis Múltiple , Animales , Factores Biológicos/uso terapéutico , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Quinurenina/metabolismo , Melatonina/farmacología , Melatonina/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológico , NAD/uso terapéutico , Nicotinamida N-Metiltransferasa , ARN Mensajero/uso terapéutico , Receptores de Hidrocarburo de Aril/genética , Índice de Severidad de la Enfermedad , Triptófano/metabolismo

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Although stem cell therapy is a major area of interest in tissue engineering, providing proper oxygen tension, good viability, and cell differentiation remain challenges in tissue-engineered scaffolds. In this study, an osteogenic scaffold was fabricated using the 3D bio-printing technique. The bio-ink contained alginate hydrogel, encapsulated human bone marrow-derived mesenchymal stem cells (hBM-MSCs), calcium peroxide nanoparticles (CPO NPs) as an oxygen generating biomaterial, and bone morphogenic protein-2 nanoparticles (BMP2 NPs) as an osteoinductive growth factor. CPO NPs were synthesized with the hydrolysis-precipitation method, and their concentrations in the bio-ink were optimized. Scaffolds containing CPO 3% (w/w) were preferred, because they generated sufficient oxygen gas for 20 days, increased mechanical strength after 20 days, and had sufficient stability. The CPO NPs effect on the viability of embedded hBM-MSCs under hypoxic conditions was analyzed. Live/Dead staining results represented a 22% improvement in CPO 3% scaffold viability on day 7. Therefore, CPO NPs constituted a promising survival factor. BMP2 NPs were prepared with the double emulsification technique. The incorporation of both BMP2 and CPO NPs resulted in the upregulation of Runt-related transcription factor 2, Collagen type I alpha 1, and the osteocalcin genes compared to internal references in osteogenic media. Overall, the proposed 3D bio-printed osteogenic scaffold in this study has moved scientific research one step forward toward successful stem cell therapy and helped improve host tissue healing by biological activity enhancement, especially for low oxygen pressure tissues.

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Células Madre Mesenquimatosas , Nanopartículas , Médula Ósea , Proteína Morfogenética Ósea 2/metabolismo , Proteína Morfogenética Ósea 2/farmacología , Calcio/metabolismo , Diferenciación Celular , Humanos , Osteogénesis/genética , Oxígeno/metabolismo , Oxígeno/farmacología , Impresión Tridimensional , Ingeniería de Tejidos/métodos , Andamios del Tejido

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BACKGROUND: Natural products comprise a large section of pharmaceutical agents in the field of cancer therapy. In the present study, the organic extracts and fractions of various parts of Ornithogalum bungei were investigated for in vitro cytotoxic properties on three human cancer cell lines, hepatocellular carcinoma (HepG2), prostate cancer (PC3), and leukemia (K562) cells. METHODS: The present experimental study was conducted at Tehran University of Medical Sciences (Tehran, Iran) during 2017-2019. Separately extracted plant materials, including bulbs, stems, and flowers of O. bungei were assessed by the tetrazolium dye-based colorimetric assay (MTT). The selected extracts were submitted to fractionation using vacuum liquid chromatography and after MTT assay, the half maximal inhibitory concentration (IC50 (value for each fraction was determined. The data were analyzed using One-way ANOVA followed by Tukey's post hoc test. P<0.05 was considered statistically significant. RESULTS: The cytotoxicity of the bulb's methanol extract and the dichloromethane extract of aerial parts increased in a concentration-dependent manner. Additionally, cell viability decreased in a dose-dependent manner. In the HepG2 cell line, the best IC50 values of fractions from DCM extracts of aerial parts were determined to be 19.8±10.2 µg/mL after 24 hours of exposure and 19.39±6.4 µg/mL following 48 hours of exposure. In the PC3 cell line, after 48 hours of exposure, the IC50 values of fractions were unaccountable, while the percentage of inhibition for A6 to A11 in 24 hours of exposure was more than 40 µg/mL. CONCLUSION: O. bungei growing in Iran showed significant potentials as a cytotoxic agent with selective effects on different cancer cell lines.

Asunto(s)

Neoplasias Hepáticas , Ornithogalum , Detección Precoz del Cáncer , Humanos , Irán , Masculino , Extractos Vegetales/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico

RESUMEN

Abstract Hypoxia-inducible factors (HIFs) and cancer stem cells (CSCs) are two challenging causes of radiotherapy and chemotherapy resistance, leading to most cases of failure and recurrence in breast cancer therapy. This study was conducted to investigated the inhibitory effect of combination therapy with doxorubicin (an anthracycline) and FM19G11 (an HIF inhibitor) on MCF-7 cells and their CSC-like cells (CSC-LCs). MCF-7 CSC-LCs with a CD44+/CD24- phenotype were sorted and characterized by flow cytometry. A combination of doxorubicin and FM19G11 caused more cytotoxic effects on MCF-7 and CSC-LCs compared to doxorubicin monotherapy. The largest synergistic effect was observed in CSC-LCs under hypoxic conditions; however, MCF-7 cells showed no synergism in normoxic conditions. The administration of doxorubicin and FM19G11 induced late apoptotic and necrotic cell death in MCF-7 and CSC-LCs. Additionally, G2 phase arrest was observed in both cells. Our results demonstrated that co-administration of FM19G11 and doxorubicin had a synergistic effect in hypoxia and improved drug resistance in breast cancer stem cells.

RESUMEN

The contribution of oxidative stress in several chronic and degenerative diseases suggests that antioxidant therapy can be a promising therapeutic strategy. However, in the case of many antioxidants, their biodistribution and bioactivity are restricted due to low water solubility. Curcumin is a powerful free radical scavenger that upon conjugation to gold nanoparticles results in the formation of stable gold nanoparticles that act as highly water-soluble carriers for the curcumin molecules. In the present study, the effect of curcumin-coated gold nanoparticles (Cur-GNPs) on the H2O2-treated human neuroblastoma (SK-N-SH) cell line was evaluated by using Fourier transform infrared (FTIR) microspectroscopy. Biochemical changes in cells resulting from exposure to reactive oxygen species (ROS) and antioxidant treatment on cells were investigated. Analyzing changes in PO2- bands and amide bands in the fingerprint region and also changes in the ratio of CH2(asym) to CH3(asym) bands in the lipid region revealed that post-treatment with Cur-GNPs could effectively decrease the damage on DNA caused by H2O2 treatment, whereas pre-treatment of cells with Cur-GNPs was found to be more effective at preventing lipid peroxidation than post-treatment. Further analysis of the CH2(asym) to CH3(asym) ratio provided information on not only the lipid peroxidation level in cells, but also the interaction of nanoparticles with the plasma membrane, as confirmed by lactate dehydrogenase assay.

Asunto(s)

Curcumina , Nanopartículas del Metal , Nanopartículas , Neuroblastoma , Curcumina/farmacología , Oro , Humanos , Peróxido de Hidrógeno/toxicidad , Nanopartículas del Metal/toxicidad , Estrés Oxidativo , Distribución Tisular