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Breast cancer poses a significant health risk worldwide. However, the effectiveness of current chemotherapy is limited due to increasing drug resistance and side effects, making it crucial to develop new compounds with novel mechanism of action that can surpass these limitations. As a consequence of their reversible and targeted mechanism, DNA minor groove binders (MGBs) are considered as a relatively safer and more effective alternative. In this study, transcriptomic analysis was conducted to reveal the dysregulated genes and signaling pathways in MCF7 cancer cells following treatment with novel MGB ligands to gain insights into the mechanism of action of MGBs at the molecular level. The transcriptomic results were validated using real-time PCR. The findings of this study indicate that the investigated MGBs primarily inhibit the genes associated with the estrogen receptor. Remarkably, ligand 5 showed downregulation of 34 out of the 35 genes regulated by estrogen receptor, highlighting its potential as a promising candidate for breast cancer therapy.
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Spectroscopic, biochemical, and computational modelling studies have been used to assess the binding capability of a set of minor groove binding (MGB) ligands against the self-complementary DNA sequences 5'-d(CGCACTAGTGCG)-3' and 5'-d(CGCAGTACTGCG)-3'. The ligands were carefully designed to target the DNA response element, 5'-WGWWCW-3', the binding site for several nuclear receptors. Basic 1D 1H NMR spectra of the DNA samples prepared with three MGB ligands show subtle variations suggestive of how each ligand associates with the double helical structure of both DNA sequences. The variations among the investigated ligands were reflected in the line shape and intensity of 1D 1H and 31P-{1H} NMR spectra. Rapid visual inspection of these 1D NMR spectra proves to be beneficial in providing valuable insights on MGB binding molecules. The NMR results were consistent with the findings from both UV DNA denaturation and molecular modelling studies. Both the NMR spectroscopic and computational analyses indicate that the investigated ligands bind to the minor grooves as antiparallel side-by-side dimers in a head-to-tail fashion. Moreover, comparisons with results from biochemical studies offered valuable insights into the mechanism of action, and antitumor activity of MGBs in relation to their structures, essential pre-requisites for future optimization of MGBs as therapeutic agents.
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ADN , ADN/química , ADN/metabolismo , Ligandos , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Estructura Molecular , Conformación de Ácido Nucleico , Sitios de Unión , Relación Estructura-Actividad , Modelos Moleculares , Relación Dosis-Respuesta a Droga , Espectroscopía de Resonancia Magnética , Línea Celular TumoralRESUMEN
New 5-aminosalicylamide-4-thiazolinone hybrids (27) were efficiently synthesized, characterized, and evaluated to explore their structure-activity relationship as anticancer agents. The antiproliferative activities of the new hybrids were evaluated against eight cancer cell lines using the sulforhodamine B assay. The most potent compound (24b) possessed high selectivity on the tested cell lines in the low micromolar range, with much lower effects on normal fibroblast cells (IC50 > 50 µM). The cell lines derived from leukemia (Jurkat), cervix (HeLa), and colon (HCT116) cancers appeared to be the most sensitive, with IC50 of 2 µM. 24b is the N-ethylamide derivative with p-dimethylaminobenzylidene at position 5 of the 4-thiazolinone moiety. Other N-substituents or arylidene derivatives showed lower activity. Hybrids with salicylamides showed lower activity than with methyl salicylate. The results clearly show that the modifications of the carboxy group and arylidene moiety greatly affect the activity. Investigating the possible molecular mechanisms of these hybrids revealed that they act through cell-cycle arrest and induction of apoptosis and epidermal growth factor receptor (EGFR) inhibition. Molecular docking studies rationalize the molecular interactions of 24b with EGFR. This work expands our knowledge of the structural requirements to improve the anticancer activity of 5-aminosalicylic-thiazolinone hybrids and pave the way toward multitarget anticancer salicylates.
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Antineoplásicos , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos/química , Receptores ErbB , Células HeLa , Estructura Molecular , Línea Celular TumoralRESUMEN
Throughout the process of carcinogenesis, cancer cells develop intricate networks to adapt to a variety of stressful conditions including DNA damage, nutrient deprivation, and hypoxia. These molecular networks encounter genomic instability and mutations coupled with changes in the gene expression programs due to genetic and epigenetic alterations. Histone deacetylases (HDACs) are important modulators of the epigenetic constitution of cancer cells. It has become increasingly known that HDACs have the capacity to regulate various cellular systems through the deacetylation of histone and bounteous nonhistone proteins that are rooted in complex pathways in cancer cells to evade death pathways and immune surveillance. Elucidation of the signaling pathways involved in the adaptive responses to cellular stress and the role of HDACs may lead to the development of novel therapeutic agents. In this article, we overview the dominant stress types including metabolic, oxidative, genotoxic, and proteotoxic stress imposed on cancer cells in the context of HDACs, which guide stress adaptation responses. Next, we expose a closer view on the therapeutic interventions and clinical trials that involve HDACs inhibitors, in addition to highlighting the impact of using HDAC inhibitors in combination with stress-inducing agents for the management of cancer and to overcome the resistance to current cancer therapy.
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Histona Desacetilasas , Neoplasias , Daño del ADN , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/metabolismo , Histonas , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismoRESUMEN
Cancer of the central nervous system (CNS) is ranked as the 19th most prevalent form of the disease in 2020. This study aims to identify candidate biomarkers and metabolic pathways affected by paclitaxel and etoposide, which serve as potential treatments for glioblastoma, and are linked to the pathogenesis of glioblastoma. We utilized an untargeted metabolomics approach using the highly sensitive ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS) for identification. In this study, 92 and 94 metabolites in U87 and U373 cell lines were profiled, respectively. The produced metabolites were then analyzed utilizing t-tests, volcano plots, and enrichment analysis modules. Our analysis revealed distinct metabolites to be significantly dysregulated (nutriacholic acid, L-phenylalanine, L-arginine, guanosine, ADP, hypoxanthine, and guanine), and to a lesser extent, mevalonic acid in paclitaxel and/or etoposide treated cells. Furthermore, both urea and citric acid cycles, and metabolism of polyamines and amino acids (aspartate, arginine, and proline) were significantly enriched. These findings can be used to create a map that can be utilized to assess the antitumor effect of paclitaxel and/or etoposide within the studied cancer cells.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Etopósido/farmacología , Paclitaxel/farmacología , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodos , Neoplasias Encefálicas/tratamiento farmacológicoRESUMEN
Selective inhibition of histone deacetylases (HDACs) is an important strategy in the field of anticancer drug discovery. However, lack of inhibitors that possess high selectivity toward certain HDACs isozymes is associated with adverse side effects that limits their clinical applications. We have initiated a collaborative initiatives between multi-institutions aimed at the discovery of novel and selective HDACs inhibitors. To this end, a phenotypic screening of an in-house pilot library of about 70 small molecules against various HDAC isozymes led to the discovery of five compounds that displayed varying degrees of HDAC isozyme selectivity. The anticancer activities of these molecules were validated using various biological assays including transcriptomic studies. Compounds 15, 14, and 19 possessed selective inhibitory activity against HDAC5, while 28 displayed selective inhibition of HDAC1 and HDAC2. Compound 22 was found to be a selective inhibitor for HDAC3 and HDAC9. Importantly, we discovered a none-hydroxamate based HDAC inhibitor, compound 28, representing a distinct chemical probe of HDAC inhibitors. It contains a trifluoromethyloxadiazolyl moiety (TFMO) as a non-chelating metal-binding group. The new compounds showed potent anti-proliferative activity when tested against MCF7 breast cancer cell line, as well as increased acetylation of histones and induce cells apoptosis. The new compounds apoptotic effects were validated through the upregulation of proapoptotic proteins caspases3 and 7 and downregulation of the antiapoptotic biomarkers C-MYC, BCL2, BCL3 and NFĸB genes. Furthermore, the new compounds arrested cell cycle at different phases, which was confirmed through downregulation of the CDK1, 2, 4, 6, E2F1 and RB1 proteins. Taken together, our findings provide the foundation for the development of new chemical probes as potential lead drug candidates for the treatment of cancer.
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Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Células MCF-7 , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Berries are natural sources of anthocyanins, especially cyanidin-3-glucoside (C3G), and exhibit significant antioxidant, antidiabetic, anti-inflammatory, and cytoprotective effects against various oxidative stress-induced disorders. C3G and its metabolites possess higher absorption and bioavailability, and interaction with gut microbiota may enhance their health benefits. Various in vitro studies have shown the reactive oxygen species (ROS)-mitigating potential of C3G. However, in in vivo models, C3G exerts its cytoprotective properties by regulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant-responsive element (ARE) pathway. Despite existing reports stating various health benefits of C3G, its antioxidant potential by modulating the Nrf2 pathway remains less identified. This review discusses the Nrf2-mediated antioxidant response of C3G in modulating oxidative stress against DNA damage, apoptosis, carcinogen toxicity, and inflammatory conditions. Furthermore, we have reviewed the recent clinical trial data to establish cross talk between a berry-rich diet and disease prevention.
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Antocianinas/farmacología , Antocianinas/uso terapéutico , Frutas/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Humanos , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Neoplasias/metabolismo , Neoplasias/prevención & control , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Breast and lung cancers are among the top cancer types in terms of incidence and mortality burden worldwide. One of the challenges in the treatment of breast and lung cancers is their resistance to administered drugs, as observed with angiogenesis inhibitors. Based on clinical and pre-clinical findings, these two types of cancers have gained the ability to resist angiogenesis inhibitors through several mechanisms that rely on cellular and extracellular factors. This resistance is mediated through angiogenesis-independent vascularization, and it is related to cancer cells and their microenvironment. The mechanisms that cancer cells utilize include metabolic symbiosis and invasion, and they also take advantage of neighboring cells like macrophages, endothelial cells, myeloid and adipose cells. Overcoming resistance is of great interest, and researchers are investigating possible strategies to enhance sensitivity towards angiogenesis inhibitors. These strategies involved targeting multiple players in angiogenesis, epigenetics, hypoxia, cellular metabolism and the immune system. This review aims to discuss the mechanisms of resistance to angiogenesis inhibitors and to highlight recently developed approaches to overcome this resistance.
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Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos , Neoplasias Pulmonares/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/genética , Epigenómica/métodos , Femenino , Humanos , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/genética , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Neovascularización Patológica/genética , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genéticaRESUMEN
Renin-angiotensin system exerted deleterious effects on learning and cognitive functions through different mechanisms. The present study has been designed to evaluate the protective effect of perindopril and azilsartan as monotherapy or in combination on aluminum chloride (AlCl3) induced neurobehavioral and pathological changes in Alzheimeric rats. Male Wistar rats were divided into nine groups (n = 6); negative control, AlCl3 treated, vehicle, AlCl3 and Azilsartan (3.5 mg/kg, 7 mg/kg) co-treated, AlCl3 and perindopril (0.5 mg/kg, 1 mg/kg) co-treated, AlCl3 and (Azilsartan 3.5 mg/kg + perindopril 0.5 mg/kg), and AlCl3 and (Azilsartan 7 mg/kg + perindopril 1 mg/kg), all groups were treated for consecutive 60 days. Then, memory function was evaluated by the Y- maze test. Amyloid Peptide - 42 (Aß-42), Acetylcholinesterase (AChE), Malondialdehyde (MDA), Tumor necrosis factor (TNF-α) and Nitric Oxide (NO) levels in the hippocampus were assessed with (ELISA) kits. The histopathological studies of the hippocampal dentate gyrus (DG) and Cornu Ammonis-3 (CA3) were also performed. Oral administration of either azilsartan and perindopril alone or in combined for 60 days have shown; improvement of cognitive function, significant reduction in the hippocampal levels of Aß-42, Acetylcholinesterase, Malondialdehyde (MDA), Tumor necrosis factor (TNF-α) and reserved most of histopathological changes in dentate gyrus (DG) and Cornu Ammonis-3 (CA3) that mediated by Alcl3. Our behavioral, biochemical, and histopathological studies indicate that perindopril and azilsartan have neuroprotective effects on the AD model of rats induced by AlCl3, suggesting that perindopril and azilsartan may be a candidate drugs for the treatment of AD.
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Kinases and phosphatases are important players in growth signaling and are involved in cancer development. For development of targeted cancer therapy, attention is given to kinases rather than phosphatases inhibitors. Src homology region 2 domain-containing protein tyrosine phosphatase2 (SHP2) is overexpressed in different types of cancers. We investigated the SHP2-inhibitory effects of two new 5-aminosalicylate-4-thiazolinones in human cervical (HeLa) and breast (MCF-7 & MDA-MB-231) cancer cells. In-silico molecular docking showed preferential affinity of the two compounds towards the catalytic over the allosteric site of SHP2. An enzymatic assay confirmed the docking results whereby 0.01 µM of both compounds reduced SHP2 activity to 50%. On cellular level, the two compounds significantly reduced the expression of SHP2, KRAS, p-ERK and p-STAT3 in HeLa but not in the other two cell lines. Phosphorylation of AKT and JNK was enhanced in HeLa and MCF7. Both compounds exhibited anti-proliferative/anti-migratory effects on HeLa and MCF7 but not in MDA-MB-231 cells. These results indicate that inhibition of SHP2 and its downstream pathways by the two compounds might be a promising strategy for cancer therapy in some but not all cancer types.
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Inhibidores Enzimáticos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Tiazoles/farmacología , Apoptosis , Movimiento Celular , Proliferación Celular , Inhibidores Enzimáticos/química , Células HeLa , Humanos , Células MCF-7 , Mesalamina/química , Neoplasias/metabolismo , Neoplasias/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Tiazoles/química , Células Tumorales Cultivadas , Quinasas raf/metabolismo , Proteínas ras/metabolismoRESUMEN
BACKGROUND: Doxorubicin (DOX) is one of the most important anticancer agents used in treating breast cancer. However, chronic cardiotoxicity and multidrug resistance limit the chemotherapeutic use of DOX. METHODS: This study aimed to evaluate the capability of calcium channel blocker diltiazem (DIL) to reverse DOX resistance in breast cancer MCF-7 cells and to confer protection against DOX-induced cardiotoxicity in Wistar rats. For this purpose, we explored the effects of DOX on cell cycle phase distribution and expression of ABCB1, FOXO3a, and p53 genes in the presence and absence of DIL (20 µg/ml) and studied the ability of DIL to prevent DOX-induced cardiotoxicity after a single injection of DOX (15 mg/kg) in male Wister rats. RESULTS: We found that compared with DOX alone treatment, DIL + DOX treatment down regulated the ABCB1 gene expression by > fourfold but up regulated the FOXO3a and p53 genes expression by 1.5 fold. DIL treatment conferred protection against DOX-induced cardiotoxicity, as indicated by a decrease in the levels of the cardiac enzyme creatine kinase MB and malondialdehyde and an increase in the total antioxidant capacity and glutathione peroxidase levels. These biochemical results were further confirmed by the histopathological investigation of cardiac cells, which showed normal cardiac cells with central vesicular nuclei and prevention of DOX-induced disruption of normal cardiac architecture in the DIL to DOX group. CONCLUSIONS: Taken together, our results indicate that DIL treatment can reverse the resistance of breast cancer cells to the therapeutic effects of DOX and can protect against DOX-induced cardiotoxicity in rats.
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[This corrects the article DOI: 10.1186/s12935-014-0152-2.].
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To assess the value of endometrial thickness, volume, and sub-endometrial perfusion in women undergoing IVF. In 82 women candidate for ICSI, endometrial thickness and sub-endometrial perfusion were measured with a trans-vaginal 2 D ultrasound and 3 D power Doppler respectively on day of hCG trigger and Embryo transfer (ET). The primary outcome was the clinical pregnancy rate. Endometrial volume showing a statistically significant difference between pregnant and nonpregnant women (4.11 ± 1.19 vs. 3.4 ± 1.1 p = .019) on day of triggering and at ET (4.02 ± 1.15 vs. 3.45 ± 0.90, p = .022). VFI was significantly higher in pregnant group at both days of triggering and ET (0.54 ± 0.48 vs. 0.33 ± 0.31 and 0.47 ± 0.22 vs. 0.34 ± 0.2, p = .02). At cutoff values of 3.265 and 2.95 cm3 (70 & 80% sensitivity, specificity 64.5 & 51.6%, a positive predictive value 38.9 & 34.8%, and negative predictive value 87.0 & 88.9%) to predict pregnancy on the day of hCG trigger & ET respectively. Cutoff value for Endometrial VFI on the day of ET was 0.674 (sensitivity of 70%, specificity of 80.6%, PPV 53.8%, and NPV 89.3%). Higher endometrial volume and VFI were associated with pregnancy.
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Transferencia de Embrión , Endometrio/diagnóstico por imagen , Adulto , Endometrio/irrigación sanguínea , Femenino , Humanos , Valor Predictivo de las Pruebas , Embarazo , Ultrasonografía , Adulto JovenRESUMEN
The failure of mechanisms of natural anti-coagulation either due to genetic impairment or due to severe external injuries may result in a condition called thrombosis. This is believed to be the primary cause for a variety of life-threatening conditions such as: heart attack, stroke, pulmonary embolism, thrombophlebitis, and deep venous thrombosis (DVT). The growing number of these incidents requires an alternative anti-coagulant or anti-thrombotic agent that has minimal side effects and improved efficiency. For decades, plant polyphenols, especially flavonoids, were known for their vital role in preventing various diseases such as cancer. Mitigating excessive oxidative stress caused by reactive oxygen species (ROS) with anti-oxidant-rich flavonoids may reduce the risk of hyper-activation of platelets, cardiovascular diseases (CVD), pain, and thrombosis. Furthermore, flavonoids may mitigate endothelial dysfunction (ED), which generally correlates to the development of coronary artery and vascular diseases. Flavonoids also reduce the risk of atherosclerosis and atherothrombotic disease by inhibiting excessive tissue factor (TF) availability in the endothelium. Although the role of flavonoids in CVD is widely discussed, to the best of our knowledge, their role as anti-thrombotic lead has not been discussed. This review aims to focus on the biological uses of dietary flavonoids and their role in the treatment of various coagulation disorders, and may provide some potential lead to the drug discovery process in this area.
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Enfermedades Cardiovasculares/tratamiento farmacológico , Flavonoides/farmacología , Flavonoides/uso terapéutico , Inflamación/tratamiento farmacológico , Trombosis/tratamiento farmacológico , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Enfermedades Cardiovasculares/metabolismo , Humanos , Inflamación/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Trombosis/metabolismoRESUMEN
Temtamy syndrome is a syndromic form of intellectual disability characterized by ocular involvement, epilepsy and dysgenesis of the corpus callosum. After we initially mapped the disease to C12orf57, we noted a high carrier frequency of an ancient startloss founder mutation [c.1A>G; p.M1?] in our population, and variable phenotypic expressivity in newly identified cases. This study aims to combine 33 previously published patients with 23 who are described here for the first time to further delineate the phenotype of this syndrome. In addition to the known p.M1? founder, we describe four novel homozygous variants, thus increasing the number of Temtamy syndrome-related C12orf57 variants to seven, all but one predicted to be loss of function. While all patients presented with intellectual disability/developmental delay, the frequency of other phenotypic features was variable: 73.2% (41/56) had epilepsy, 63% (34/54) had corpus callosal abnormalities, 14.5% (8/55) had coloboma, and 16.4% (9/55) had microphthalmia. Our analysis also revealed a high frequency of less recognized features such as congenital heart disease (51.4%), and brain white matter abnormalities (38%, 19/50). We conclude that C12orf57 variants should be considered in the etiology of developmental delay/intellectual disability, even when typical syndromic features are lacking, especially in those who trace their ancestry to Saudi Arabia where a founder C12orf57 mutation is among the most common recessive causes of intellectual disability.
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Agenesia del Cuerpo Calloso/diagnóstico , Coloboma/diagnóstico , Anomalías Craneofaciales/diagnóstico , Anomalías del Ojo/diagnóstico , Agenesia del Cuerpo Calloso/epidemiología , Agenesia del Cuerpo Calloso/genética , Alelos , Coloboma/epidemiología , Coloboma/genética , Anomalías Craneofaciales/epidemiología , Anomalías Craneofaciales/genética , Anomalías del Ojo/genética , Facies , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética , Mutación , Fenotipo , PrevalenciaRESUMEN
BACKGROUND: Transient hyperprolactinemia was proven to adversely affect the outcome of IVF. We aimed to identify changes in serum prolactin levels in patients undergoing ICSI, and to evaluate the effect of these changes on the clinical pregnancy rate. METHODS: A prospective observational study included 90 patients scheduled for ICSI cycles. In each case 4 serum samples were collected during the cycle (midluteal, before ovum pick up procedure (OPU), 2 h after OPU, and before embryo transfer). Serum prolactin level was determined by immunoassay each time. RESULTS: The sample collected 2 h after OPU had a mean difference of 25.8 ± 2.8 ng/ml compared to the basal serum prolactin (p < 0.01). In comparison to other samples, this highlighted a significant hyperprolactinemia occurring after OPU, and resolving before embryo transfer. No statistically significant difference between the different serum prolactin samples amongst the pregnant and non pregnant patients. There was a significant positive pearson correlation between the prolactin levels before OPU, and the presence of higher quality embryos (r = 0.274, p = 0.019). CONCLUSION: In normoprolactinemic women transient hyperprolactinemia is identified in patients undergoing ICSI, and it doesn't affect the clinical pregnancy rates. A positive correlation was identified between higher quality embryos, and serum prolactin level before OPU. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02292953 , First received: November 10, 2014.
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Ciclo Menstrual/sangre , Índice de Embarazo , Prolactina/sangre , Inyecciones de Esperma Intracitoplasmáticas , Adulto , Femenino , Humanos , Hiperprolactinemia/sangre , Recuperación del Oocito , Embarazo , Estudios Prospectivos , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: To study the effect of intramural fibroids on uterine and endometrial vascularity in infertile women scheduled for in-vitro fertilization (IVF). METHODS: 3D power Doppler was used to measure the endometrial volume and blood flow indices in 182 women with intramural fibroids not affecting the uterine cavity and compared them to a matched control group without fibroids. RESULTS: There was significantly increased vascularity in the endometrium of the fibroid group as denoted by higher endometrial VI (p = 0.018), FI (p = 0.027) and Endometrial VFI. No significant difference in mean uterine artery RI (p = 0.277) or PI (p = 0.187). Among the fibroid group 62.6% had a fibroid > 4 cm. Women with fibroids > 4 cm had a significantly higher Endometrial FI (p = 0.037), and VFI (p = 0.02). Uterine artery blood flow was not affected, as uterine RI (p = 0.369) and PI (p = 0.321) were not statistically different. Compared with the control group (non fibroid), women with fibroids > 4 cm had significantly higher endometrial VI (p = 0.013), FI (p = 0.004), and VFI (p < 0.001), whereas women with fibroid ≤ 4 cm had no statistically significant differences in VI (p = 0.292), FI (p = 0.198), and VFI (p = 0.304). CONCLUSION: Intramural fibroids > 4 cm significantly increase endometrial vascularity. This increase in blood flow may be a factor that affects the outcome of IVF.
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Endometrio/irrigación sanguínea , Endometrio/diagnóstico por imagen , Fertilización In Vitro , Infertilidad Femenina/diagnóstico por imagen , Leiomioma/diagnóstico por imagen , Ultrasonografía Doppler/métodos , Neoplasias Uterinas/diagnóstico por imagen , Útero/irrigación sanguínea , Útero/diagnóstico por imagen , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Infertilidad Femenina/etiología , Infertilidad Femenina/terapia , Leiomioma/complicaciones , Flujo Sanguíneo Regional , Resultado del Tratamiento , Neoplasias Uterinas/complicacionesRESUMEN
BACKGROUND: Ultrasonography has been extensively used in women suspected of having a gynecological malignancy. The aim of this study is to evaluate the efficacy of 3D ultrasonography and power Doppler for discrimination between benign and malignant endometrium in premenopausal women with abnormal uterine bleeding. METHODS: This cross-sectional study included 78 premenopausal women with abnormal uterine bleeding scheduled for hysteroscopy and endometrial curettage. The endometrial thickness (ET), uterine artery pulsatility index (PI) and resistance index (RI), and endometrial volume (EV) and 3D power Doppler vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were measured and compared with hysteroscopic and histopathologic findings. RESULTS: The ET (P <0.001), EV (P <0.001), and endometrial VI (P <0.001) and VFI (P = 0.043) were significantly increased in patients with atypical endometrial hyperplasia and endometrial carcinoma (n = 10) than those with benign endometrium (n = 68); whereas, the uterine artery PI and RI and endometrial FI were not significantly different between the two groups. The best marker for discrimination between benign and malignant endometrium was the VI with an area under the ROC curve of 0.88 at a cutoff value of 0.81%. CONCLUSION: 3D ultrasonography and power Doppler, especially endometrial VI, may be useful for discrimination between benign and malignant endometrium in premenopausal women with abnormal uterine bleeding.
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Neoplasias Endometriales/complicaciones , Neoplasias Endometriales/diagnóstico , Endometrio/diagnóstico por imagen , Imagenología Tridimensional , Ultrasonografía Doppler/instrumentación , Ultrasonografía Doppler/estadística & datos numéricos , Hemorragia Uterina/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Endometrio/patología , Femenino , Humanos , Persona de Mediana Edad , Ultrasonografía Doppler/métodosRESUMEN
BACKGROUND: Cisplatin (CIS) is one of the most effective anticancer drug used in the treatment of several solid tumors .Its use is limited by its nephrotoxicity. The present study was designed to assess the role of a natural product resveratrol (RSVL) on sensitization of mammary carcinoma (Ehrlich ascites carcinoma) to the action of CIS and the possible protective effect against CIS-induced nephrotoxicity in rats. METHODS: The percent survival of female tumor bearing mice was used for determination the cytotoxic activity of CIS in the presence or the absence of RSVL. Uptake and cell cycle effect, serum creatinine (CREA), blood urea nitrogen (BUN), Reduced Glutathione (GSH) and histopatholgical examination of kidney tissues after CIS and/or RSVL therapy were also investigated. RESULTS: RSVL increased the intracellular level of CIS in EAC cells and there was a strong correlation between the high cellular level of CIS and its cytotoxicity. CIS at a dose level of 5 mg/kg increased the mean survival time of female tumor bearing mice to 25 days compared with 17 days for tumor-bearing control mice. Administration of RSVL at a dose level of 25 mg/kg simultaneously with CIS increased the mean survival time to 48 days with 60% survival of the tumor-bearing animals. Cell cycle analysis of tumor cells showed that CIS treatment decreases the proliferation index of tumor cells while in presence of RSVL there was more significant inhibitions. Also, CIS treatment caused increase in level of creatinine and blood urea with significant decrease in the GSH level. While, in the presence of RSVL, level of creatinine and blood urea restored to control level. CONCLUSION: This study suggests that RSVL could increase the cytotoxic activity of CIS and protect against its nephrotoxicity.
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BACKGROUND: Cisplatin (CIS) is a potent antineoplastic agent with high therapeutic efficacy against many kinds of tumors. Its use is limited by its nephrotoxicity. The aim of this work was to minimize cisplatin effective dose and the possible reduction of its severe side effects. The present study was designed to assess the role of sulfur containing agent dimethyl sulfoxide (DMSO) on sensitization of mammary carcinoma, Ehrlich ascites carcinoma (EAC), to the action of cisplatin and at the same time the possible protective effect against cisplatin induced nephrotoxicity in experimental animals. METHODS: To evaluate these effects we have explored the cisplatin effect on the survival time of tumor-bearing animals, tumor weight, cisplatin cellular uptake, apoptosis induction and cell cycle distribution and renal function in presence and absence of DMSO. RESULTS: Cisplatin at dose of 4.5 mg/kg increased the mean survival time of tumor bearing mice to 37 days compared with tumor bearing control mice. Pretreatment of tumor bearing mice with DMSO 50 % (2 ml/kg equal to 1 gm/kg) 2 h. before cisplatin showed a significant increase in their mean survival time 43 days compared to cisplatin treated animals. DMSO pretreatment retained rat's serum urea and creatinine levels to normal compared to animals treated with cisplatin alone. CONCLUSION: DMSO pretreatment enhanced the cytotoxic activity of cisplatin against the growth of EAC in vivo and showed protective effects against cisplatin-induce nephrotoxicity.