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1.
Sci Rep ; 9(1): 9038, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227780

RESUMO

Junctophilin-2 (JPH2) is a part of the junctional membrane complex that facilitates calcium-handling in the cardiomyocyte. Previously, missense variants in JPH2 have been linked to hypertrophic cardiomyopathy; however, pathogenic "loss of function" (LOF) variants have not been described. Family-based genetic analysis of GME individuals with cardiomyopathic disease identified an Iranian patient with dilated cardiomyopathy (DCM) as a carrier of a novel, homozygous single nucleotide insertion in JPH2 resulting in a stop codon (JPH2-p.E641*). A second Iranian family with consanguineous parents hosting an identical heterozygous variant had 2 children die in childhood from cardiac failure. To characterize ethnicity-dependent genetic variability in JPH2 and to identify homozygous JPH2 variants associated with cardiac disease, we identified variants in JPH2 in a worldwide control cohort (gnomAD) and 2 similar cohorts from the Greater Middle East (GME Variome, Iranome). These were compared against ethnicity-matched clinical whole exome sequencing (WES) referral tests and a case cohort of individuals with hypertrophic cardiomyopathy (HCM) based on comprehensive review of the literature. Worldwide, 1.45% of healthy individuals hosted a rare JPH2 variant with a significantly higher proportion among GME individuals (4.45%); LOF variants were rare overall (0.04%) yet were most prevalent in GME (0.21%). The increased prevalence of LOF variants in GME individuals was corroborated among region-specific, clinical WES cohorts. In conclusion, we report ethnic-specific differences in JPH2 rare variants, with GME individuals being at higher risk of hosting homozygous LOF variants. This conclusion is supported by the identification of a novel JPH2 LOF variant confirmed by segregation analysis resulting in autosomal recessive pediatric DCM due to presumptive JPH2 truncation.

2.
Arch Iran Med ; 20(2): 101-104, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28193084

RESUMO

BACKGROUND: Assisted reproductive  treatment  (ART)  cycle  is an  expensive  procedure with low implantation and pregnancy rate; therefore, it is necessary to evaluate the predictors of success in these patients. OBJECTIVE: The relationship between endometrial echopattern and pregnancy rate was evaluated. METHODS: The endometrial  echopattern  was  analyzed  prospectively  on  the  day  of  human chorionic  gonadotropin  (HCG) administration  in  280  in  vitro  fertilization/intracytoplasmic  sperm  injection (IVF/ICSI) cycles with 8-14 mm endometrial thickness at Royan institute in 2013-2014. Based on echopattern, three groups were developed: pattern A (Triple line), pattern B (Heterogeneous-echogen) and pattern C (Homogeneous-echogen). Pregnancy rate (PR) was compared between all groups. Data was analyzed using SPSS (v.18, Chicago, IL, USA), and descriptive tests such as Chi-square and analytical tests like logistic regression, for controlling confounder variables like age. RESULTS: Among 280 patients finally evaluable, the distribution of endometrial echopattern on the day of HCG administration was 127 patients (45.4%) in group A, 98 patients (35%) in group B and 55 patients (19.6%) in group C. The highest PR per transfer pertained to group A (49.6%), and the lowest to group B (32.7%). CONCLUSION: The presence of pattern A (Triple line) appears more likely to favor pregnancy. Therefore, ultrasonographic evaluation of endometrial echopattern on the day of HCG administration has prognostic value in clinical settings for predicting implantation in ART cycle.


Assuntos
Gonadotropina Coriônica/administração & dosagem , Endométrio/diagnóstico por imagem , Taxa de Gravidez , Injeções de Esperma Intracitoplásmicas , Adulto , Estudos Transversais , Transferência Embrionária , Feminino , Humanos , Irã (Geográfico) , Modelos Logísticos , Gravidez , Prognóstico , Ultrassonografia , Adulto Jovem
3.
Mol Syndromol ; 9(1): 25-29, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29456480

RESUMO

Ryanodine receptor 1 (RYR1) is an intracellular calcium receptor primarily expressed in skeletal muscle with a role in excitation contraction. Both dominant and recessive mutations in the RYR1 gene cause a range of RYR1-related myopathies and/or susceptibility to malignant hyperthermia (MH). Recently, an atypical manifestation of ptosis, variably presenting with ophthalmoplegia, facial paralysis, and scoliosis but without significant muscle weakness, has been reported in 9 cases from 4 families with bialleic variants in RYR1. Two affected children from a consanguineous family with severe congenital ptosis, ophthalmoplegia, scoliosis, and distinctive long faces but without skeletal myopathy were studied. To identify the cause of the hereditary condition, DNA from the proband was subjected to whole exome sequencing (WES). WES revealed a novel homozygous missense variant in RYR1 (c.14066T>A; p.IIe4689Asn), which segregated within the family. Although the phenotype of the affected siblings in this study was similar to previously described cases, the clinical features were more severely expressed. Our findings contribute to the expansion of phenotypes related to RYR1 dysfunction. Additionally, it supports a new RYR1-related clinical presentation without musculoskeletal involvement. It is important that individuals with RYR1 mutations are considered susceptible to MH, as 70% of the MH cases are caused by mutations in the RYR1 gene.

4.
Phytomedicine ; 22(10): 961-7, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26321746

RESUMO

BACKGROUND: Hepatocellular carcinoma is the fifth most common cancer worldwide, with poor prognosis and resistance to chemotherapy. This gives novel cancer treatment methods an overwhelming significance. Epigenetic therapy of cancer is useful in reversing some of the cancer defects because of reversibility of the epigenetic alterations. Non-protein coding transcripts are the major part of our transcriptome. MEG3 is a tumor suppressor long non-coding RNA being expressed in many normal tissues. Methylation of MEG3 promoter region elicits the decrease in its expression in hepatocellular cancer cells. Bioactive nutrients including curcumin offer great potential in altering DNA methylation status which is catalyzed via DNMT1, DNMT3A and 3B. PURPOSE: Herein, we aimed to study RNA-based epigenetic effects of dendrosomal curcumin (DNC) on hepatocellular cancer (HCC). STUDY DESIGN: To this end miRNA-dependent regulation of MEG3 expression under treatment with DNC was studied by evaluating the modulatory involvement of miR-29a for DNMT3A and 3B and miR-185 for DNMT1. METHODS: We evaluated DNC entrance to HCC cells with the use of fluorescent characteristics of curcumin. Next we performed the MTT assay to evaluate DNC and dendrosome effects on HCC cell viability. The coding and non-coding genes expression analyses were done using quantitative-PCR. RESULTS: In result we found that the DNC dependent overexpression of miR-29a and miR-185 (P < 0.01) can down-regulate the expression of DNMT1, 3A and 3B (P < 0.05) and subsequently overexpresses MEG3 (P < 0.05). CONCLUSION: DNC potentially can induce DNA hypomethylation and reexpression of silenced tumor suppressor genes in HCC. These data suggest that DNC could be an effective choice for epigenetic therapy of HCC.


Assuntos
Curcumina/química , Metilação de DNA , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Células Hep G2/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Regulação para Cima
5.
Biomed Res Int ; 2015: 824746, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25793208

RESUMO

Application of nanoparticles has recently promising results for water insoluble agents like curcumin. In this study, we synthesized polymeric nanoparticle-curcumin (PNPC) and then showed its efficiency, drug loading, stability, and safety. Therapeutic effects of PNPC were also assessed on two cell lines and in an animal model of breast cancer. PNPC remarkably suppressed mammary and hepatocellular carcinoma cells proliferation (P < 0.05). Under the dosing procedure, PNPC was safe at 31.25 mg/kg and lower doses. Higher doses demonstrated minimal hepatocellular and renal toxicity in paraclinical and histopathological examinations. Tumor take rate in PNPC-treated group was 37.5% compared with 87.5% in control (P < 0.05). Average tumor size and weight were significantly lower in PNPC group than control (P < 0.05). PNPC increased proapoptotic Bax protein expression (P < 0.05). Antiapoptotic Bcl-2 protein expression, however, was lower in PNPC-treated animals than the control ones (P < 0.05). In addition, proliferative and angiogenic parameters were statistically decreased in PNPC-treated animals (P < 0.05). These results highlight the suppressing role for PNPC in in vitro and in vivo tumor growth models. Our findings provide credible evidence for superior biocompatibility of the polymeric nanocarrier in pharmacological arena together with an excellent tumor-suppressing response.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológico , Curcumina/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/administração & dosagem , Polímeros/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Portadores de Fármacos/administração & dosagem , Estabilidade de Medicamentos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Micelas
6.
Int J Nanomedicine ; 9: 5541-54, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25489242

RESUMO

Curcumin is a potent natural anticancer agent, but its effectiveness is limited by properties such as very low solubility, high rate of degradation, and low rate of absorption of its hydrophobic molecules in vivo. To date, various nanocarriers have been used to improve the bioavailability of this hydrophobic biomaterial. This study investigates the encapsulation of curcumin in a novel nanostructure of monomethoxy poly(ethylene glycol)-oleate (mPEG-OA) and its anticancer effect. Tests were done to determine the critical micelle concentration (CMC), encapsulation efficiency, drug-loading efficiency, and cytotoxicity (against U87MG brain carcinoma cells and HFSF-PI3 cells as normal human fibroblasts) of some nanodevice preparations. The results of fluorescence microscopy and cell-cycle analyses indicated that the in vitro bioavailability of the encapsulated curcumin was significantly greater than that of free curcumin. Cytotoxicity evaluations showed that half maximal inhibitory concentrations of free curcumin and curcumin-loaded mPEG-OA for the U87MG cancer cell line were 48 µM and 24 µM, respectively. The Annexin-V-FLUOS assay was used to quantify the apoptotic effect of the prepared nanostructures. Apoptosis induction was observed in a dose-dependent manner after curcumin-loaded mPEG-OA treatments. Two common self-assembling structures, micelles and polymersomes, were observed by atomic force microscopy and dynamic light scattering, and the abundance of each structure was dependent on the concentration of the diblock copolymer. The mPEG-OA micelles had a very low CMC (13.24 µM or 0.03 g/L). Moreover, atomic force microscopy and dynamic light scattering showed that the curcumin-loaded mPEG-OA polymersomes had very stable structures, and at concentrations 1,000 times less than the CMC, at which the micelles disappear, polymersomes were the dominant structures in the dispersion with a reduced size distribution below 150 nm. Overall, the results from these tests revealed that this nanocarrier can be considered as an appropriate drug delivery system for delivering curcumin to cancer cells.


Assuntos
Antineoplásicos/química , Curcumina/química , Portadores de Fármacos/química , Ácido Oleico/química , Polietilenoglicóis/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Micelas , Tamanho da Partícula
7.
Eur J Pharmacol ; 718(1-3): 1-9, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24051269

RESUMO

Alpha-solanine, a naturally steroidal glycoalkaloid, is found in leaves and fruits of plants as a defensive agent against fungi, bacteria and insects. Herein, we investigated solanine toxicity in vitro and in vivo, and assessed its protective and the therapeutic effects on a typical animal model of breast cancer. The study conducted in three series of experiments to obtain (i) solanine effects on cell viability of mammary carcinoma cells, (ii) in vivo toxicity of solanine, and (iv) the protective and therapeutic effects of solanine on animal model of breast cancer. Alpha-solanine significantly suppressed proliferation of mouse mammary carcinoma cells both in vitro and in vivo (P<0.05). Under the dosing procedure, 5 mg/kg solanine has been chosen for assessing its protective and therapeutic effects in mice breast cancer. Tumor take rate in the solanine-treated group was zero compared with a 75% rate in its respective control group (P<0.05). The average tumor size and weight were significantly lower in solanine-treated animals than its respective control ones (P<0.05). Proapoptotic Bax protein expression increased in breast tumor by solanine compared with its respective control group (P<0.05). Antiapoptotic Bcl-2 protein expression found to be lower in solanine-treated animals (P<0.05). Proliferative and angiogenic parameters greatly decreased in solanine-treated mice (P<0.05). Data provide evidence that solanine exerts a significant chemoprotective and chemotherapeutic effects on an animal model of breast cancer through apoptosis induction, cell proliferation and angiogenesis inhibition. These findings reveal a new therapeutic potential for solanine in cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/prevenção & controle , Solanina/farmacologia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/patologia , Camundongos , Metástase Neoplásica , Neovascularização Patológica/tratamento farmacológico , Solanina/uso terapêutico
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