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1.
Hum Mutat ; 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31456290

RESUMO

Inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptors. These diseases show marked phenotypic and genetic heterogeneity. The Israeli IRD consortium (IIRDC) was established in 2013 with the goal of performing clinical and genetic mapping of the majority of Israeli IRD patients. To date we recruited 2,420 families including 3,413 individuals with IRDs. Based on our estimation, these patients represent approximately 40% of Israeli IRD patients. To the best of our knowledge, this is by far the largest reported IRD cohort, and one of the first studies addressing genetic analysis of IRD patients on a nation-wide scale. The most common inheritance pattern in our cohort is autosomal recessive (60% of families). The most common retinal phenotype is retinitis pigmentosa (43%), followed by Stargardt disease and cone/cone-rod dystrophy. We identified the cause of disease in 56% of the families. Overall, 605 distinct mutations were identified, of which 12% represent prevalent founder mutations. The most frequently mutated genes were ABCA4, USH2A, FAM161A, CNGA3 and EYS. The results of this study have important implications for molecular diagnosis, genetic screening and counseling, as well as for development of new therapeutic strategies for retinal diseases. This article is protected by copyright. All rights reserved.

2.
Stem Cell Res ; 39: 101491, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31326746

RESUMO

Retinal organoids (ROs) derived from human-induced pluripotent stem cells recapitulate the three-dimensional structure of retina, mimic human retinal development, and provide cell sources for pre-clinical retinal transplantation. Retinal pigment epithelium (RPE) is crucial for normal outer retinal physiology, including phagocytosis of shed photoreceptor outer segments and secretion of neurotrophic and vasculotrophic growth factors. However, whether ROs-RPE co-culture can improve the differentiation of photoreceptors in ROs in vitro remains unknown. Herein, primary mouse RPE cells were contact co-cultured with ROs at different time points. Our results revealed that the RPE cells accelerated photoreceptor differentiation in ROs, as the cross talk between the RPE and ROs promoted the stage specific expression of photoreceptor markers at different differentiation stages. Thus, we established an improved co-culture system based on modeling of human retina-RPE dynamics during retinogenesis for the evaluation of ocular therapies.

3.
Hum Mutat ; 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31212395

RESUMO

PURPOSE: Stargardt disease (STGD1) is caused by biallelic mutations in ABCA4, but many patients are genetically unsolved due to insensitive mutation-scanning methods. We aimed to develop a cost-effective sequencing method for ABCA4 exons and regions carrying known causal deep-intronic variants. METHODS: Fifty exons and 12 regions containing 14 deep-intronic variants of ABCA4 were sequenced using double-tiled single molecule Molecular Inversion Probe (smMIP)-based next-generation sequencing. DNAs of 16 STGD1 cases carrying 29 ABCA4 alleles and of four healthy persons were sequenced using 483 smMIPs. Thereafter, DNAs of 411 STGD1 cases with one or no ABCA4 variant were sequenced. The effect of novel noncoding variants on splicing was analyzed using in vitro splice assays. RESULTS: Thirty-four ABCA4 variants previously identified in 16 STGD1 cases were reliably identified. In 155/411 probands (38%), two causal variants were identified. We identified 11 deep-intronic variants present in 62 alleles. Two known and two new noncanonical splice site variants showed splice defects, and one novel deep-intronic variant (c.4539+2065C>G) resulted in a 170-nt mRNA pseudoexon insertion (p.[Arg1514Lysfs*35,=]). CONCLUSIONS: smMIPs-based sequence analysis of coding and selected noncoding regions of ABCA4 enabled cost-effective mutation detection in STGD1 cases in previously unsolved cases.

4.
PLoS One ; 14(6): e0218289, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31211817

RESUMO

This study scrutinized the asymmetric impact of oil prices on stock returns in Shanghai stock exchange with data (January 2000 to December 2018) by using asymmetric ARDL model. The examined results of asymmetric autoregressive distributed lag model indicate that cointegration exists between the oil prices and the stock returns. Results of asymmetric autoregressive distributed lag model confirm that both in the long run and the short run increase in oil prices have a negative impact on the stock returns of Shanghai stock exchange while decrease in the oil prices has a positive impact on the stock returns. The examined results of this study recommend that oil prices dynamically contribute incompetence in stock prices in such a way that impact the profits of investors in stock market.

5.
Environ Sci Pollut Res Int ; 26(23): 23480-23490, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201697

RESUMO

Environmental degradations are mainly caused by the use of different energy resources for economic growth. This research examined the influence of energy consumption (coal consumption, oil consumption, and gas consumption) and economic growth on environmental degradation in Pakistan. This research used newly developed method dynamic ARDL simulations to scrutinize the actual influence of positive and negative change in the use of coal consumption, oil consumption, and gas consumption for energy and economic growth on environmental degradation in Pakistan. The examined results of dynamic ARDL indicate that economic growth, coal consumption, oil consumption, and natural gas consumption have positive impact on the environmental degradations in Pakistan both in short run and long run. It is suggested that environmental degradations can be reduced by promoting renewable energy sources for energy.

6.
Sci Total Environ ; 686: 90-96, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31181530

RESUMO

In the present work, the fabrication of pyridinium functionalized anion exchange membranes (AEMs) for acid recovery using diffusion dialysis (DD) processes was developed using brominated poly (2,6-dimethyl-1,4-phenylene oxide) (BPPO) as a polymer backbone and 4-methylpyridine (MP) as an ion exchange element. The electrochemical and physiochemical properties of the developed AEMs were tested under various concentration of MP into the polymer matrix. Water uptake (WR) of 17.18% to 30.55%, ion exchange capacity (IEC) of 1.94-2.24 mmol/g and linear swelling ratio (LSR) of 6.87-14.89% were obtained. In addition, the new membranes exhibited dense morphology, higher thermal and chemical stability in addition to dimensional and mechanical sturdiness. Acid dialysis coefficient (UH) in the range of 0.011-0.066 m/h was obtained. In addition the developed AEMs had a separation factor (S) in range of 24.87-77.61 resulting in enhanced DD performance compared to commercial membrane DF-120B under comparable experimental conditions. The new prepared membranes showed potential for successful application in acid recovery via diffusion dialysis.

7.
Sci Total Environ ; 688: 424-436, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31247484

RESUMO

This research scrutinizes the impact of globalization, economic factors and energy consumption on CO2 emissions in Pakistan from 1971 to 2016 by utilizing dynamic ARDL simulations model Jordan and Philips (2018). Dynamic ARDL simulations model has capability to predict the actual positive and negative change in the independent variables and its effect on the dependent variable. The examined results of dynamic ARDL simulations indicates that Energy consumption, financial development, trade, foreign direct investment, economic globalization, social globalization and political globalization have positive effect on CO2 emissions in Pakistan while urbanization, economic growth and innovation have negative effect on CO2 emissions in Pakistan while in the short run the examined results of dynamic ARDL simulations indicate that energy consumption, urbanization, economic growth, financial development, economic globalization, social globalization and political globalization have positive effect on CO2 emissions in Pakistan while trade, innovation and foreign direct investment have negative effect on CO2 emissions. Based on the results of this study policy implications are suggested for Pakistan.

8.
Nat Commun ; 10(1): 2884, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253780

RESUMO

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10-5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.


Assuntos
Ciliopatias/genética , Proteínas do Olho/genética , Predisposição Genética para Doença , Doenças Retinianas/genética , Elementos Alu/genética , Grupo com Ancestrais do Continente Asiático/genética , Genômica , Humanos , Japão , Mutação , Linhagem
9.
BMC Complement Altern Med ; 19(1): 100, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068163

RESUMO

BACKGROUND: Obesity is a risk factor for many diseases including diabetes, cancer, arthritis, and cardiovascular diseases. Angiogenesis nourishes adipose tissues and contributes to obesity; it can be prevented by suppressing the expression of associated signaling molecules. Natural products have garnered attention owing to their safety and efficacy in treating several diseases, including obesity. METHODS: Crude Microcystins were extracted from the blooming Microcystis aeruginosa under stress conditions, by ultrasonication following by solvent extraction. The microcystin extract was evaluated for its potential of inhibiting angiogenesis and adipogenesis. The antiangiogenic activity of the microcystins extract was investigated using human umbilical vein endothelial cells (HUVECs), and its anti-obesity activity was determined in vitro by quantification of the accumulated lipids in mouse 3 T3-L1 cells via Oil Red O staining method. RESULTS: The microcystin extract suppressed HUVECs proliferation and tubes formation in Matrigel in a dose-dependent manner. RT-PCR analysis revealed the downregulation of the mRNA expression of angiogenesis-related signaling molecules, such as PI3K, ß-catenin, vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial-cadherin, Akt1, and NF-κB. Additionally, it inhibited the differentiation of premature 3 T3 cells and lipid accumulation in a dose-dependent manner. It suppressed adipogenesis and lipogenesis by reducing the expression level of peroxisome proliferator-activated receptor γ, CCAAT/enhancer binding protein α, and sterol regulatory element-binding protein. CONCLUSIONS: Crude microcystin exerts anti-angiogenic and anti-obesity effects due to the inhibitory effects on the genes expression of associated signaling molecules and transcriptional factors.


Assuntos
Adipogenia/efeitos dos fármacos , Inibidores da Angiogênese/farmacologia , Fármacos Antiobesidade/farmacologia , Microcistinas/farmacologia , Microcystis/química , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Camundongos , Neovascularização Patológica/metabolismo
10.
Mol Vis ; 25: 106-117, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820146

RESUMO

Purpose: Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous showing progressive retinal cell death which results in vision loss. IRDs include a wide spectrum of disorders, such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), cone-rod dystrophy (CRD), and Stargardt disease (STGD1). Methods: In this study, we performed targeted next-generation sequencing based on molecular inversion probes (MIPs) that allowed the sequence analysis of 108 IRD-associated genes in 50 Iranian IRD probands. Results: The sequencing and variant filtering led to the identification of putative pathogenic variants in 36 out of 50 (72%) probands. Among 36 unique variants, we identified 20 novel variants in 15 genes. Four out of 36 probands carry compound heterozygous variants, and 32 probands carry homozygous variants. Conclusions: Employing a cost-effective targeted next-generation sequencing procedure, we identified the genetic causes of different retinal disorders in the majority of Iranian families in this study.


Assuntos
Distrofias de Cones e Bastonetes/genética , Proteínas do Olho/genética , Amaurose Congênita de Leber/genética , Degeneração Macular/congênito , Mutação , Retinite Pigmentosa/genética , Adolescente , Adulto , Criança , Distrofias de Cones e Bastonetes/metabolismo , Distrofias de Cones e Bastonetes/patologia , Proteínas do Olho/metabolismo , Feminino , Expressão Gênica , Estudos de Associação Genética , Genótipo , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/economia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Homozigoto , Humanos , Irã (Geográfico) , Amaurose Congênita de Leber/metabolismo , Amaurose Congênita de Leber/patologia , Degeneração Macular/genética , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Masculino , Linhagem , Fenótipo , Retina/metabolismo , Retina/patologia , Retinite Pigmentosa/congênito , Retinite Pigmentosa/metabolismo , Retinite Pigmentosa/patologia
11.
Cornea ; 38(6): 718-722, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30865045

RESUMO

PURPOSE: Brittle cornea syndrome (BCS) is a rare recessive disorder affecting connective tissues, most prominently in the eye. Pathogenic mutations causing BCS have been identified in PRDM5 and ZNF469 genes. This study investigates the genetic cause of BCS in a large, consanguineous Pakistani family with 4 affected and 3 unaffected individuals. METHODS: The coding region and exon-intron splice junctions of PRDM5 and ZNF469 genes were amplified by polymerase chain reaction, and bidirectional Sanger sequencing was performed to find the pathogenic change responsible for causing the disease in the family. RESULTS: A novel homozygous duplication c.9831dupC (p.Arg3278GlnfsX197) in the ZNF469 gene was identified, which was found to be co-segregating with the disease in the family. CONCLUSIONS: This is the first report of a ZNF469 homozygous mutation causing a BCS phenotype in a consanguineous Pakistani family. Our data extend the mutation spectrum of ZNF469 variants implicated in BCS.


Assuntos
Anormalidades do Olho/genética , Instabilidade Articular/congênito , Mutação , Anormalidades da Pele/genética , Fatores de Transcrição/genética , Criança , Pré-Escolar , Feminino , Humanos , Instabilidade Articular/genética , Masculino , Paquistão
12.
Microb Ecol ; 2019 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-30904989

RESUMO

Asian dust (AD) events have received significant attention due to their adverse effects on ecosystems and human health. However, detailed information about airborne pathogens associated with AD events is limited. This study monitored airborne bacterial communities and identified AD-specific bacteria and the potential hazards associated with these bacteria during AD events. Over a 33-month period, 40 air samples were collected under normal atmospheric conditions (non-AD events; n = 34) and during AD events (n = 6). The airborne bacterial communities in the air samples collected during non-AD events (non-AD sample) and AD events (AD sample) were evaluated using both culture-dependent and culture-independent methods. The bacterial diversity increased significantly, along with the 16S rRNA gene copy number, in AD samples (p < 0.05) and was positively correlated with PM10 concentration. High throughput sequencing of the 16S rRNA gene revealed that the relative abundance of the phylum Firmicutes increased substantially in AD samples (44.3 ± 5.0%) compared with non-AD samples (27.8 ± 4.3%). Within the phylum Firmicutes, AD samples included a greater abundance of Bacillus species (almost 23.8%) than non-AD samples (almost 13.3%). Both culture-dependent and culture-independent methods detected common predominant species closely related to Bacillus cereus during AD events. Subsequent multilocus sequence typing (MLST) and enterotoxin gene assays confirmed the presence of virulence factors in B. cereus isolates from AD samples. Furthermore, the abundance of bceT, encoding enterotoxin in B. cereus, was significantly higher in AD samples (p < 0.05). The systematic characterization of airborne bacterial communities in AD samples in this study suggests that B. cereus pose risks to public health.

13.
AAPS PharmSciTech ; 20(2): 81, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30645705

RESUMO

To achieve remotely directed delivery of anticancer drugs, surface-decorated nanoparticles with ligands are reported. In this study, folic acid- and thiol-decorated chitosan nanoparticles loaded with docetaxel (DTX-NPs) were prepared for enhanced cellular internalization in cancer cells and improved oral absorption. The DTX-NPs were explored through in vitro and in vivo parameters for various parameters. The DTX-NPs were found to be monodisperse nanoparticles with an average particle size of 158.50 ± 0.36 nm, a polydispersity index of 0.36 ± 0.0, a zeta potential of + 18.30 ± 2.52 mV, and an encapsulation efficiency of 71.47 ± 5.62%. The drug release from DTX-NPs followed the Korsmeyer-Peppas model with about 78% of drug release in 12 h. In in vitro cytotoxicity studies against folate receptor, positive MDA-MBB-231 cancerous cells showed improved cytotoxicity with IC50 of 0.58 µg/mL, which is significantly lower as compared to docetaxel (DTX). Ex vivo permeation enhancement showed an efflux ratio of 0.99 indicating successful transport across the intestine. Oral bioavailability was significantly improved as Cmax and AUC were higher than DTX suspension. Overall, the results suggest that DTX-NPs can be explored as a promising carrier for oral drug delivery.


Assuntos
Antineoplásicos/química , Quitosana/química , Docetaxel/química , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Nanopartículas/química , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/farmacocinética , Docetaxel/farmacologia , Humanos , Coelhos , Ratos , Compostos de Sulfidrila/química
14.
J Coll Physicians Surg Pak ; 29(1): 16-18, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30630562

RESUMO

OBJECTIVE: To find out the diagnostic accuracy of MR Mammography in diagnosing malignant breast lesions taking histopathology as gold standard. STUDY DESIGN: Cross-sectional survey. PLACE AND DURATION OF STUDY: Department of Radiology in collaboration with Department of Pathology, Sir Ganga Ram Hospital, Lahore, from April 2015 to April 2016. METHODOLOGY: 150 female patients with either suspicious mammographic findings or palpable lesions suspicious for malignancy referred from surgical OPD of Sir Ganga Ram Hospital were assessed. Dynamic contrast enhanced MRI was done on 1.5 Tesla MRI machine and the images were evaluated on morphological and kinetic basis. MR findings were then compared with preoperative FNAC and biopsy findings. RESULTS: The mean age of the patients was 52.5 ±13.4 years with maximum patients of age group 46-55 years. Out of 150, 118 (78.6%) patients were found to have malignant lesions on MRM while 116 (77%) patients were proved to have malignant lesions on histopathology. There was 93.9% sensitivity, 73.5% specificity, 89.3% diagnostic accuracy, 92.3% PPV, and 78.1% NPV of MR mammography in diagnosing malignant breast lesions taking histopathology as gold standard. CONCLUSION: Breast MRI has high sensitivity, specificity, and diagnostic accuracy in diagnosis of malignant breast lesions and must be used as primary imaging tool for proper characterisation of the breast lumps.


Assuntos
Biópsia/métodos , Neoplasias da Mama/patologia , Mama/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Mamografia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Meios de Contraste , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Paquistão , Sensibilidade e Especificidade
15.
Genet Med ; 21(8): 1751-1760, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30643219

RESUMO

PURPOSE: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability. METHODS: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects. RESULTS: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects. CONCLUSION: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.

16.
Braz. j. pharm. sci ; 55: e18136, 2019. tab
Artigo em Inglês | LILACS | ID: biblio-1011645

RESUMO

The study was performed to estimate the association of hypertension and dyslipidaemia with increasing body weight and obesity in Type II diabetics of Lahore, Pakistan. An observational study was conducted by enrolling 2708 obese diabetics from four diabetes care centres of Lahore, Pakistan. Data was collected for a period of 7 months. Associations were estimated using chi-square, binary and multinomial logistic regression. Data suggested that blood pressure, systolic and diastolic, exhibited continual increase with increasing body weight and obesity class in diabetes patients with 41.8% increase in the prevalence of hypertension in obesity class III subjects (OR; 1.91, p=0.02). Likewise, triglycerides and total cholesterol exhibited continual increase in their mean values with increasing obesity, i-e., an overall increase in the prevalence of dyslipidaemia of 27.2% in obesity class 3 subjects (OR; 1.94, p=0.29). Taken together, this data suggested that hypertension is potentially associated with increasing obesity in diabetics, while dyslipidaemia demonstrated plausible association only with obesity class 3.


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/fisiopatologia , Dislipidemias/metabolismo , Manejo da Obesidade/classificação , Hipertensão/complicações , Paquistão/etnologia
17.
PLoS One ; 13(12): e0208556, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30521605

RESUMO

Cornus kousa the Korean dogwood has been traditionally used in East Asia as therapeutic traditional medicine however biological activities of Cornus kousa have not been investigated previously. The aim of the present study was to evaluate anti-obesity activities coupled with anti-angiogenic activities of anthocyanins rich fraction of ethanolic leaf extract of Cornus kousa (ELECk) in HUVECs and 3T3- L1 cells. Dried plants leaves were extracted with 70% ethanol and anthocyanin fraction (AnT Fr) was obtained by eluting the ethanolic extract through non-polar macroporous resin and further purification by HPLC. Antiangiogenic activities were determined by antiproliferative effect of AnT Fr on HUVECs. In the presence of various concentrations of AnT Fr, 3T3-L1 preadipocytes were induced to differentiate. Lipid accumulation in differentiated adipocytes were quantified by Oil-Red O staining. AnT Fr significantly suppressed angiogenesis by inhibiting proliferation and tube formation of HUVECs via downregulating VEGRF 2, PI3K, ß-catenin, NF-kB, and Akt1 in a dose dependent manner. AnT Fr inhibited lipid accumulation by down-regulating adipogenesis and lipogenesis promoting signaling proteins, PPARγ, CCAAT, C/EBPα, aP2, FAS, and LPL, however enhanced AMPK activation to p-AMPK in 3T3 cells quantified and expressed by western blotting. AnT Fr inhibit lipid accumulation by regulating adipogenesis and lipogenesis related genes and signaling proteins. The anti-obesity activities exerted by Cornus kousa are associated with antiangiogenic activities of anthocyanins rich fraction of Cornus kousa. Hence the presence of bioactive anthocyanins, Cornus kosa, is a good candidate for nutraceutical and pharmaceutical formulation for treating or controlling obesity.

18.
PLoS One ; 13(12): e0205380, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30576320

RESUMO

Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies (IRD) and the most frequent cause of inherited blindness in children. The phenotypic overlap with other early-onset and severe IRDs as well as difficulties associated with the ophthalmic examination of infants can complicate the clinical diagnosis. To date, 25 genes have been implicated in the pathogenesis of LCA. The disorder is usually inherited in an autosomal recessive fashion, although rare dominant cases have been reported. We report the mutation spectra and frequency of genes in 27 German index patients initially diagnosed with LCA. A total of 108 LCA- and other genes implicated in IRD were analysed using a cost-effective targeted next-generation sequencing procedure based on molecular inversion probes (MIPs). Sequencing and variant filtering led to the identification of putative pathogenic variants in 25 cases, thereby leading to a detection rate of 93%. The mutation spectrum comprises 34 different alleles, 17 of which are novel. In line with previous studies, the genetic results led to a revision of the initial clinical diagnosis in a substantial proportion of cases, demonstrating the importance of genetic testing in IRD. In addition, our detection rate of 93% shows that MIPs are a cost-efficient and sensitive tool for targeted next-generation sequencing in IRD.


Assuntos
Alelos , Sequenciamento de Nucleotídeos em Larga Escala , Amaurose Congênita de Leber/genética , Mutação , Análise Mutacional de DNA , Feminino , Alemanha , Humanos , Masculino
19.
Pak J Pharm Sci ; 31(6 (Supplementary): 2623-2628, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30587470

RESUMO

Among immunosuppressive agents cyclosporine A is drug of unique importance. This drug has a low therapeutic index, and it has many toxic effects. After oral administration its absolute bioavailability is variable due to poor absorption. Niosomes are new and versatile carriers to deliver drug. The bioavailability of immunosuppressant drug cyclosporine A can be increased by niosomal drug delivery system. So our basic theme was to prepare niosomes of immunosuppressant drug using cholesterol, span 60 and tween 60 etc. Niosomes were characterized for zeta potential, size, poly dispersivity index(PDI), entrapment efficiency and In vitrorelease profiles. Six niosomal formulations (F1-F6) were successfully developed using thin film hydration technique. Among various formulations F2 showed the highest entrapment efficiency 77.29 %. The DSC thermograms of physical mixtures and niosomal formulations indicated the presence of drug in crystalline form. In vitro drug release study demonstrated higher drug release values as compared to drug aqueous dispersion. Niosomal formulations were capable of releasing drug in sustained manner. The overall results demonstrated that developed niosomal carriers are competitive candidates for improving dissolution profile of cyclosporine A leading to increased bioavailability at the site of action.


Assuntos
Ciclosporina/farmacocinética , Portadores de Fármacos/farmacocinética , Composição de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Imunossupressores/farmacocinética , Ciclosporina/química , Portadores de Fármacos/química , Imunossupressores/química , Lipossomos
20.
Neuroscience ; 390: 160-173, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30125687

RESUMO

MiR-335-3p, a neuron-enriched microRNA, has been reported to be involved in aging and age-related neurological diseases. However, the role of miR-335-3p in cholesterol metabolism of astrocytes, and whether it affects neuronal functions, particularly during aging process, largely remains unknown. In this study, we uncover that miR-335-3p is significantly increased in aged cultured astrocytes and aged hippocampal brains, accompanied by decreased cellular cholesterol and diminished expression of HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) and 3-hydroxy-3-methylglutaryl-CoA synthase-1 (HMGCS1), both step-limiting enzymes in cholesterol synthesis pathway. We also demonstrate that miR-335-3p suppresses HMGCS1 post-transcriptionally by directly binding to its 3'UTR, and HMGCR through binding mediated by SFRS2. More importantly, aged mice with miR-335-3p deficiency in hippocampal brains exhibit improved learning and memory, accompanied by enhanced levels of postsynaptic density protein 95 (PSD95). We further reveal that the level change of PSD95 is resulted from altered cholesterol metabolism. Our findings provide a novel insight into the regulatory role of miR-335-3p in cholesterol metabolism in astrocytes, and consequently cognitive functions during aging.

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