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Organotin compounds (OTCs) are a commercially important group of organometallic compounds of tin used globally as polyvinyl chloride stabilizers and marine antifouling biocides. Worldwide use of OTCs has resulted in their ubiquitous presence in ecosystems across all the continents. OTCs have metabolic and endocrine disrupting effects in marine and terrestrial organisms. Thus, harmful OTCs (tributyltin) have been banned by the International Convention on the Control of Harmful Antifouling Systems since 2008. However, continued manufacturing by non-member countries poses a substantial risk for animal and human health. In this study, structural binding of common commercial OTCs, tributyltin (TBT), dibutyltin (DBT), monobutyltin (MBT), triphenyltin (TPT), diphenyltin (DPT), monophenyltin (MPT), and azocyclotin (ACT) against sex-steroid nuclear receptors, androgen receptor (AR), and estrogen receptors (ERα, ERß) was performed using molecular docking and MD simulation. TBT, DBT, DPT, and MPT bound deep within the binding sites of AR, ERα, and Erß, showing good dock score, binding energy and dissociation constants that were comparable to bound native ligands, testosterone and estradiol. The stability of docking complex was shown by MD simulation of organotin/receptor complex with RMSD, RMSF, Rg, and SASA plots showing stable interaction, low deviation, and compactness of the complex. A high commonality (50-100%) of interacting residues of ERα and ERß for the docked ligands and bound native ligand (estradiol) indicated that the organotin compounds bound in the same binding site of the receptor as the native ligand. The results suggested that organotins may interfere with the natural steroid/receptor binding and perturb steroid signaling.
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Polycystic ovary syndrome (PCOS) is characterised by infertility, obesity, insulin resistance and clinical and/or biochemical signs of hyperandrogenism. Obesity is known to be correlated with PCOS causing ovulatory dysfunction and hormone imbalances. Moreover, fat mass and the obesity gene (FTO) were linked with obesity and PCOS. Therefore, it is of interest to determine the genotype and allele frequency for three FTO variants - rs17817449 (G/T), rs1421085 (C/T) and rs8050136 (A/C) -in western Saudi population. 95 PCOS patients and 94 controls were recruited for this study. The genetic variants were assayed using real-time polymerase chain reaction using TaqMan genotyping assays. The chi-squared test was applied to investigate the difference between single nucleotide polymorphisms on PCOS and control subjects, and binary logistic regression was used to determine the association of FTO variants with PCOS symptoms. Variants rs17817449 and rs1421085 were significantly linked with PCOS susceptibility in the study population. Rs17817449 and rs8050136 were significantly associated with hair loss in the PCOS group. Furthermore, rs1421085 and rs8050136 were associated with a high body mass index (BMI>30 kg/m2). Risk alleles in our population associated with hair loss and elevated BMI in women with PCOS were homozygous C for rs8050136. This data will help in defining the genetic predisposition of PCOS among women in western Saudi Arabia.
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Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine diseases affecting women of reproductive age. The pathogeny of PCOS is still not completely understood, but one contributing factor that has been proposed is anti-Müllerian hormone (AMH). There is currently no clear correlation between levels of AMH and incidence of PCOS in Saudi Arabian patients. The goal of this study was to determine the threshold of AMH and correlate it with PCOS clinical features to facilitate a proper diagnosis for PCOS. In this case-control study, we recruited 79 PCOS women and 69 normal ovulatory women; PCOS patients were diagnosed according to the Rotterdam criterion. On days 2-4 of the menstrual cycle, transvaginal/abdominal ultrasound was performed and serum levels of AMH, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured for all participants. The receiver operating characteristic curve (ROC) was used to determine the AMH diagnostic cut-off at 3.19 ng/mL, with 72% sensitivity and 70% specificity; AMH > 3.19 ng/mL was significantly correlated with PCOS. High AMH levels were correlated with age at menarche, polycystic ovarian morphology (PCOM), and oligo/amenorrhea. Serum AMH is a promising diagnostic marker of ovarian dysfunction in PCOS patients especially in cases in which the evaluation of PCOM was complicated.
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BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder causing infertility in reproductive-age women. The cause of PCOS is not fully understood but it is thought to be influenced by environmental and genetic factors. Obesity is greatly related to PCOS and its reduction is one of the major aims in treating PCOS. Melanocortin 4 receptor (MC4R) gene polymorphisms were detected to be associated with different levels of obesity. Therefore, we aimed to determine the genotype and allele frequency of MC4R variants rs12970134 (A/G) and rs17782313 (C/T) in PCOS and investigate their association with PCOS and its clinical variables. METHODS: A case-control study was conducted on 189 women, consisting of 95 PCOS cases and 94 controls. Genotyping was performed by real-time polymerase chain reaction (PCR) using TaqMan™ Genotyping assays. Quantitative data were presented as (median ± interquartile range (IQR) whereas qualitative data were presented as frequencies. The chi-squared test was used to observe the difference between SNPs within the study groups (PCOS and control subjects). Multinomial logistic regression was used to test the risk of obesity and development of PCOS considering p < 0.05 is statistically significant. RESULTS: Rs12970134 and rs17782313 are significantly associated with body mass index (BMI, kg/m2, p < 0.0001) in PCOS women but not associated with PCOS itself. Risk alleles in our population are A in rs12970134 and C in rs17782313 that are associated with high BMI (> 30 kg/m2) in obese women with PCOS (OR = 1.348, p = 0.002 and OR = 1.364, p = 0.002 respectively) in the homozygous state. In addition, we found that the other genotypes for non-obese PCOS group, AG/GG for rs12970134 and CT/TT for rs17782313, are associated with hirsutism, loss of hair, hyperandrogenism and anti-Müllerian hormone in PCOS. CONCLUSIONS: These findings demonstrate that MC4R single nucleotide polymorphisms, rs12970134 and rs17782313, are correlated with elevated BMI in PCOS but are not causative factors for PCOS among women in the western region of Saudi Arabia. Moreover, the reverse genotypes are associated with major clinical variants in non-obese (< 30 kg/m2) PCOS patients may demonstrate a poor prognosis for this group.
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Predisposição Genética para Doença/genética , Variação Genética , Obesidade/genética , Síndrome do Ovário Policístico/genética , Receptor Tipo 4 de Melanocortina/genética , Adolescente , Adulto , Alelos , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Modelos Logísticos , Polimorfismo de Nucleotídeo Único , Arábia Saudita , Adulto JovemRESUMO
Background: Gut microbiota (GM) has recently been described as a functional reservoir of antimicrobial resistant genes (ARGs). However, the ARG-carrying bacterial species in the human gut has been poorly studied. This study, for the first time, is reporting bacterial communities' composition and antimicrobial resistome in the stool samples of pregnant and non-pregnant (NP) Saudi females. Methods: Gut bacterial community composition was analyzed by 16S amplicon sequencing and culturomics. High throughput MALDI-TOF technique was used for identification of the isolates from stool samples and evaluated for resistance against 13 antibiotics using the agar dilution method. Clinically important ARGs were PCR amplified from genomic DNA of the stool samples using gene-specific primers. Results: 16S amplicon sequencing revealed that GM of pregnant and NP women were predominantly comprised of phyla Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Bacterial diversity decreased in pregnant groups, whereas phylum Bacteroidetes declined significantly (p<0.05) in the first trimester. We noticed a relatively high abundance of butyrate-producing bacteria (eg, Faecalibacterium spp. and Eubacterium spp.) in the gut of pregnant women, whereas Prevotella copri was found at significantly (p<0.01) higher abundance in NP women. Moreover, about 14,694 isolates were identified and classified into 132 distinct species. The majority of the species belonged to phyla Firmicutes and Proteobacteria. About 8,125 isolates exhibited resistance against antibiotics. Out of 73 resistant-species, Enterococcus was the most diverse genus and Escherichia coli was the highly prevalent bacterium. The majority of the isolates were resistant to antibiotics; trimethoprim/sulfamethoxazole, cycloserine, and cefixime. ARGs encoding resistance against aminoglycoside, macrolide, quinolone, ß-lactam, and tetracycline antibiotics were predominantly found in genomic DNA of the stool samples. Conclusion: We conclude that pregnancy-associated GM modulations may help to sustain a healthy pregnancy, but a higher proportion of antibiotic resistance could be deleterious for both maternal and fetal health.
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In recent years, genetic studies have yielded great progress in elucidating causes of male infertility. This investigation aims to identify frequent genetic abnormalities, that is, sex chromosome aneuploidies and Y-chromosome microdeletions among infertile men in Western Saudi Arabia. From a population of infertile patients, 88 male patients with either azoospermia or severe oligozoospermia (sperm concentration <5 million/ml) were selected. In addition to a thorough clinical workup, karyotypes and Y-chromosomal microdeletions were investigated. Among those 88 infertile patients, we detected six patients with Klinefelter syndrome, two with 47 XYY syndrome and two with Y-chromosome microdeletions AZFb,c. While the prevalence of sex chromosome aneuploidies was in the range of globally investigated populations, the microdeletions appeared to be less frequent in Western Saudi Arabia compared to other regions of the world. All genetically abnormal cases showed sperm concentration <1 million/ml, and hence, this appears to be the threshold for warranting genetic investigations in Western Saudi Arabia. Since Klinefelter and 47 XYY syndromes were only discovered late in life, upon an infertility investigation, sex chromosome aneuploidies due to their many-fold comorbidities require earlier medical attention. A neonatal screening programme is suggested for detection of these aneuploidies in Saudi Arabia for the general health benefit of these patients.
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Aneuploidia , Infertilidade Masculina/epidemiologia , Síndrome de Klinefelter/epidemiologia , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/epidemiologia , Adulto , Deleção Cromossômica , Cromossomos Humanos Y/genética , Testes Genéticos/métodos , Necessidades e Demandas de Serviços de Saúde , Humanos , Incidência , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/genética , Cariotipagem , Síndrome de Klinefelter/diagnóstico , Síndrome de Klinefelter/genética , Masculino , Programas de Rastreamento/métodos , Programas de Rastreamento/organização & administração , Pessoa de Meia-Idade , Estudos Prospectivos , Arábia Saudita/epidemiologia , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/diagnóstico , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Contagem de EspermatozoidesRESUMO
The PI3K/AKT/mTOR pathway is one of the most commonly disrupted signaling pathways that plays a role in the development and pathogenicity of multiple cancers. Therefore, the critical proteins of this pathway have been targeted for anticancer therapy. The scientific community has increasingly been realizing the anti-cancer therapeutic potential of naphthoquinone analogs. These compounds constitute a major class of diverse sets of plant metabolites, which include various natural products and synthetic compounds with proven anticancer activity. The current study involved structural computational biology approaches to explore compounds from a diverse pool of naphthoquinone analogs that can inhibit key cancer-signaling proteins phosphoinositide 3-kinase (PI3K), protein kinase B, PKB (AKT), and mammalian target of rapamycin (mTOR). The novel compound identified commonly among the top 10 dock score lists of PI3K, AKT, and mTOR was selected for further study and proposed as a potential inhibitor of the 3 cancer-signaling proteins and an anticancer agent. Further, to check the docking accuracy and potential of the compound, post docking analyses, namely, binding comparison with the native ligand, the role of the interacting residue role in binding, predicted binding energy and dissociation constant calculations, etc., were performed. All these measures showed good-quality binding, and thus provide weight to our prediction of the novel compound as a pan PI3K/AKT/mTOR inhibitor and an anticancer agent. Finally, to compare the binding and similarity in the active sites of the 3 protein kinases, a ligand-based active site alignment was performed and analyzed. Thus, the study proposed a novel naphthoquinone analog as a potential anticancer drug, and provided comparative structural insight into its binding to the 3 protein kinases.
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BACKGROUND: Nanotechnology exploits materials and devices with a functional organization that has been engineered at the nanometre scale. The application of nanotechnology in neuroscience involves specific interactions with neurons and glial cells. This property is used for delivering drugs and other small molecules (such as genes, oligonucleotides and contrasting agents) across the blood brain barrier (BBB), an important requirement for delivering the drug successfully to the brain. OBJECTIVE: Nanotechnology based approaches (NBA) favours transcytosis-mediated delivery of nanoparticles to the brain by crossing the BBB. The last five years have witnessed the successful applications of NBA to treat neurological disorders. It is expected that the development of novel NBA will result in important insights on the brain mechanisms, and eventually provide better medical care to patients suffering from neurological disorders. CONCLUSION: This review introduces the emerging work in this area and summarizes the successful NBA used in recent past for treating various neurological disorders ike Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, meningitis and glioblastoma.
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Nanopartículas/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Animais , Encéfalo/metabolismo , Humanos , Nanotecnologia , TranscitoseRESUMO
OBJECTIVES: Tocompare maternal and neonatal complications in twin and triplet gestations at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Methods: Retrospective medical records of 165 women with 144 twin and 21 triplet pregnancies from 2004 to 2011 were analyzed. Comparisons were carried out for maternal complications, gestational age at birth, neonatal birth weight, and neonatal intensive care admission. Results: Most common complications were preterm birth (49%), gestational diabetes mellitus (13.3%), and premature rupture of membrane (4.8%). All triplet pregnancies and 42% twin pregnancies terminated in preterm birth. Gestational length was longer (p less than 0.001) in twin births (36.0 ± 3.05 weeks) than for triplet births (32 ± 3.81 weeks). Rates for in vitro fertilization, ovulation induction, and cesareans were higher in women with triplets than in those with twins. Neonatal intensive care unit (NICU) admission was higher (p less than 0.001) for triplets (76.2%) than for twins (23.6%). The mean weight of twins was 2333.83 ± 558.69 grams and triplets was 1553.41 ± 569.73 grams. Hyaline membrane disease, neonatal jaundice, and neonatal sepsis were most common neonatal complications. Conclusion: Neonates from triplet pregnancies were preterm, had low birth weight and needed more often NICU admission in comparison to those from twin pregnancies.
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Resultado da Gravidez , Gravidez de Trigêmeos , Gravidez de Gêmeos , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Estudos RetrospectivosRESUMO
Environmental contamination has been one of the major drawbacks of the industrial revolution. Several man-made chemicals are constantly released into the environment during the manufacturing process and by leaching from the industrial products. As a result, human and animal populations are exposed to these synthetic chemicals on a regular basis. Many of these chemicals have adverse effects on the physiological functions, particularly on the hormone systems in human and animals and are called endocrine disrupting chemicals (EDCs). Bisphenol A (BPA), 4-tert-octylphenol (OP), and 4-nonylphenol (NP) are three high volume production EDCs that are widely used for industrial purposes and are present ubiquitously in the environment. Bisphenol A is metabolized in the human body to a more potent compound (MBP: 4-Methyl-2, 4-bis (4-hydroxyphenyl) pent-1-ene). Epidemiological and experimental studies have shown the three EDCs to be associated with adverse effects on reproductive system in human and animals. Sex hormone-binding globulin (SHBG) is a circulatory protein that binds sex steroids and is a potential target for endocrine disruptors in the human body. The current study was done in order to understand the binding mechanism of OP, BPA, NP, and MBP with human SHBG using in silico approaches. All four compounds showed high binding affinity with SHBG, however, the binding affinity values were higher (more negative) for MBP and NP than for OP and BPA. The four ligands interacted with 19-23 residues of SHBG and a consistent overlapping of the interacting residues for the four ligands with the residues for the natural ligand, dihydrotestosterone (DHT; 82-91% commonality) was shown. The overlapping SHBG interacting residues among DHT and the four endocrine disruptors suggested that these compounds have potential for interference and disruption in the steroid binding function.
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Compostos Benzidrílicos/farmacologia , Disruptores Endócrinos/farmacologia , Poluentes Ambientais/farmacologia , Simulação de Acoplamento Molecular , Fenóis/farmacologia , Globulina de Ligação a Hormônio Sexual/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Di-Hidrotestosterona/metabolismo , Estrogênios/farmacologia , Humanos , Ligantes , Globulina de Ligação a Hormônio Sexual/metabolismoRESUMO
BACKGROUND: Preterm birth (PTB), birth at <37 weeks of gestation, is a significant global public health problem. World-wide, about 15 million babies are born preterm each year resulting in more than a million deaths of children. Preterm neonates are more prone to problems and need intensive care hospitalization. Health issues may persist through early adulthood and even be carried on to the next generation. Majority (70 %) of PTBs are spontaneous with about a half without any apparent cause and the other half associated with a number of risk factors. Genetic factors are one of the significant risks for PTB. The focus of this review is on single nucleotide gene polymorphisms (SNPs) that are reported to be associated with PTB. RESULTS: A comprehensive evaluation of studies on SNPs known to confer potential risk of PTB was done by performing a targeted PubMed search for the years 2007-2015 and systematically reviewing all relevant studies. Evaluation of 92 studies identified 119 candidate genes with SNPs that had potential association with PTB. The genes were associated with functions of a wide spectrum of tissue and cell types such as endocrine, tissue remodeling, vascular, metabolic, and immune and inflammatory systems. CONCLUSIONS: A number of potential functional candidate gene variants have been reported that predispose women for PTB. Understanding the complex genomic landscape of PTB needs high-throughput genome sequencing methods such as whole-exome sequencing and whole-genome sequencing approaches that will significantly enhance the understanding of PTB. Identification of high risk women, avoidance of possible risk factors, and provision of personalized health care are important to manage PTB.
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Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/genética , Adulto , Suscetibilidade a Doenças , Feminino , Saúde Global , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido , Morbidade , Gravidez , Fatores de RiscoRESUMO
Exposure to toxic industrial chemicals that have capacity to disrupt the endocrine system, also known as endocrine disrupting chemicals (EDCs), has been increasingly associated with reproductive problems in human population. Bisphenol A (BPA; 4,4'-(propane-2,2-diyl)diphenol) and 4-tert-octylphenol (OP; 4-(1,1,3,3-tetramethylbutyl)phenol) are among the most common environmental contaminants possessing endocrine disruption properties and are present in plastics, epoxy resins, detergents and other commercial products of common personal and industrial use. A metabolite of BPA, 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) is about 1000 times more biologically active compared to BPA. Epidemiological, clinical, and experimental studies have shown association of BPA and OP with adverse effects on male and female reproductive system in human and animals. The endocrine disruption activity can occur through multiple pathways including binding to steroid receptors. Androgen receptor (AR) and progesterone receptor (PR) are critical for reproductive tract growth and function. Structural binding characterization of BPA, MBP, and OP with AR and PR using molecular docking simulation approaches revealed novel interactions of BPA with PR, and MBP and OP with AR and PR. For BPA, MBP, and OP, five AR interacting residues Leu-701, Leu-704, Asn-705, Met-742, and Phe-764 overlapped with those of native AR ligand testosterone, and four PR interacting residues Leu-715, Leu-718, Met-756, and Met-759 overlapped with those of PR co-complex ligand, norethindrone. For both the receptors the binding strength of MBP was maximum among the three compounds. Thus, these compounds have the potential to block or interfere in the binding of the endogenous native AR and PR ligands and, hence, resulting in dysfunction. The knowledge of the key interactions and the important amino-acid residues also allows better prediction of potential of xenobiotic molecules for disrupting AR- and PR-mediated pathways, thus, helping in design of less potent alternatives for commercial use.