RESUMO
PURPOSE: The COVID-19 pandemic might add to the stressors experienced by people living with rheumatic diseases. This study aimed to examine rheumatic patients' functional and psychosocial states during the pandemic and assess its impact on their quality of life. METHODS: Our time-series study included a patient-centered electronic survey, sampling adult rheumatic patients living in Saudi Arabia at different time points from March to August 2020. Patient-reported outcomes included physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles, and pain interference domains were measured using the Patient-Reported Outcomes Measurement Information System (PROMIS-29 Profile v2.1). RESULTS: A total of 1278 respondents were enrolled. Results showed significant variation in patients' experiences. Our analyses revealed that the physical well-being of rheumatic patients was significantly impacted, and such effect was persistent over time irrespective of public health measures to control the COVID-19 outbreak. CONCLUSION: Our findings consistently demonstrated the need for psychological and social consideration to improve rheumatic patients' quality of life. Nevertheless, there is still a lot to be learned about the extent of COVID-19 impact on rheumatic patients and the implications it has on long-term disease outcomes.
Assuntos
COVID-19 , Adulto , COVID-19/epidemiologia , Depressão/epidemiologia , Depressão/psicologia , Humanos , Pandemias , Qualidade de Vida/psicologia , Arábia Saudita/epidemiologiaRESUMO
The dysfunction of microtubules (α/ß-tubulin polymers) underlies a wide range of nervous system genetic abnormalities. Defects in TBCD, a tubulin-folding cofactor, cause diseases highlighted with early-onset encephalopathy with or without neurodegeneration, intellectual disability, seizures, microcephaly and tetraparaperesis. Utilizing various molecular methods, we describe nine patients from four unrelated families with two novel exon 18 variants in TBCD exhibiting the typical neurological phenotype of the disease. Interestingly, all the investigated patients had previously unreported hematological findings in the form of neutropenia and mild degree of anemia and thrombocytopenia. In addition to delineating the neurological phenotype in several patients with TBCD variants, our study stresses on the new association of neutropenia, in particular, with the disease.
Assuntos
Encefalopatias/sangue , Encefalopatias/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação de Sentido Incorreto , Adulto , Anemia/etiologia , Encefalopatias/complicações , Encefalopatias/diagnóstico por imagem , Criança , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Neutropenia/etiologia , Linhagem , Trombocitopenia/etiologia , Adulto JovemRESUMO
BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder, affecting millions of women worldwide. The role of genetic polymorphisms of the KISS1 gene on the development of PCOS is still obscure. This study was designed to investigate the probable influence of KISS1 gene polymorphisms on PCOS and its associated variables: BMI, waist-hip ratio, kisspeptin, LH, FSH, and LH-FSH ratio. METHODS: The study comprised 104 PCOS women and 109 controls, with age ranging from 19 to 36 years. BMI, waist-hip ratio, and circulating levels of kisspeptin, LH, and FSH were measured. DNA was extracted, and genotyping of the KISS1 gene was carried out by nucleotide sequencing. The PCOS-associated variables were analyzed in different genotypes of single nucleotide polymorphisms (SNPs) of the KISS1 gene. RESULTS: The values of waist-hip ratio (WHR), LH, and LH-FSH ratio were significantly higher in PCOS women than controls. BMI, kisspeptin, and FSH levels exhibited no significant difference between the groups. Six novel SNPs of KISS1 gene were identified. Three: rs372790354G > A, rs12998G > A, and rs35431622A > T were investigated. Among these SNPs, the genotype and allele frequencies of rs372790354 showed significant association with PCOS (GA: p = 0.018, AA: p = 0.022, mutant allele-A: p = 0.021) and the G allele was protective. The values of LH, kisspeptin, and WHR of PCOS women were significantly influenced (p < 0.05) by the AA genotype of rs372790354. The other two SNPs rs12998G > A and rs35431622A > T revealed no significant influence on PCOS and associated variables. Haplotypes were constructed, but there was no significant difference between the patients and controls. CONCLUSION: In conclusion, this is the first study, which reports a significant influence of KISS1 gene polymorphism (rs372790354G > A) on PCOS and its associated variables. However, more extensive research is necessary to confirm these findings.
Assuntos
Kisspeptinas/genética , Síndrome do Ovário Policístico/genética , Adulto , Índice de Massa Corporal , Feminino , Hormônio Foliculoestimulante/metabolismo , Genótipo , Humanos , Kisspeptinas/metabolismo , Hormônio Luteinizante/metabolismo , Fenótipo , Síndrome do Ovário Policístico/metabolismo , Polimorfismo de Nucleotídeo Único , Arábia Saudita , Relação Cintura-Quadril , Adulto JovemRESUMO
BACKGROUND: Polycystic ovarian syndrome (PCOS) is of frequent occurrence in Saudi females and is often associated with obesity, insulin resistance, hypogonadotropic hypogonadism, and infertility. Since these features are also associated with leptin receptor (LEP-R) deficiency, several studies have attempted to link LEP-R gene polymorphisms to PCOS. METHODS: The purpose of this study is to assess the possible association of LEP-R gene polymorphism (rs1137101) with the main obesity-linked metabolic parameters in Saudi female patients affected by PCOS. A cohort of 122 Saudi female subjects, attending the outpatient's clinics at Makkah, Saudi Arabia and diagnosed with PCOS was investigated. Metabolic parameters in serum samples, including lipidogram, glucose, leptin, ghrelin and insulin and obesity markers (BMI, W/H ratio, HOMA) were assayed and compared with values from 130 healthy female volunteers (controls). The genotyping of rs1137101 polymorphism in the leptin receptor gene by amplification (PCR) followed by DNA sequencing, was conducted in both groups (PCOS and controls). RESULTS: Waist/hip ratio (W/H ratio), leptin serum levels and triglycerides appeared to be associated with PCOS but, aside from W/H ratio (AA s GG p = 0.009), this association also occurred for controls. No significant association in the leptin gene polymorphic locus rs1137101 with PCOS was seen in the results of the present study. In the control group, BMI, W/H ratio, leptin, Insulin, and HOMA-IR were significantly higher in the GG genotype compared to AA. CONCLUSION: Despite previous suggestion about a relationship between rs1137101, serum leptin levels, and PCOS, our studies do not show any statistical association and further investigations; possibly by also evaluating obese patients should be needed to elucidate this issue better.
Assuntos
Síndrome Metabólica/genética , Obesidade/genética , Síndrome do Ovário Policístico/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores para Leptina/genética , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Leptina/genética , Leptina/metabolismo , Arábia SauditaRESUMO
CONTEXT: Breast cancer is a leading cause of cancer fatalities among women worldwide. Of the more than 80% of patients who receive adjuvant chemotherapy, approximately 40% relapse. The majority of these patients die of disseminated metastatic disease, which emphasizes the need for new therapeutic strategies. OBJECTIVE: The study intended to investigate the anticancer effects of oleuropein (OL) and doxorubicin (DOX) individually and in combination on breast tumor xenografts and also to evaluate the molecular pathways involved. DESIGN: The research team designed in vivo (animal) and in vitro (cell culture) studies. SETTING: The study was performed in the College of Science of King Saud University in the University Center for Women Students (Riyadh, Saudi Arabia). ANIMALS: The study involved 40 female, nude mice (BALB/c OlaHsd-foxn1). INTERVENTION: The mice were injected subcutaneously with MDA-MB-231 human breast cancer cells. After the growth of tumors, the animals were randomly divided into 4 groups to receive intraperitoneal injections: (1) group 1 (control group)-dimethyl sulfoxide, (2) group 2 (intervention group)-50 mg/kg of OL, (3) group 3 (intervention group)-2.5 mg/kg of DOX, and (4) group 4 (intervention group)-1.5 mg/kg of DOX, immediately followed by 50 mg/kg of OL. The OL was extracted from Manzanillo olive trees (Olea europaea) grown in Tabouk, Saudi Arabia. OUTCOME MEASURES: The measures included the isolation and primary culture of the tumor xenografts, apoptosis analysis by annexin V, cellular lysate preparation, and immunoblotting. RESULTS: The volume of the tumor increased aggressively, reaching 173 mm3 in the control animals in a time-dependent manner. On the other hand, a sharp drop, to 48.7 mm3, in the volume of the tumor was observed with the 2 drugs combined, a more than 3-fold decrease. The effect was mediated through the induction of apoptosis via the mitochondrial pathway. The combined treatment downregulated the antiapoptosis and proproliferation protein, nuclear factor-kappa Β, and its main oncogenic target cyclin D1. Furthermore, it inhibited the expression of BCL-2 and survivin. This inhibition could explain the cooperative suppression of the proliferation of breast tumor xenografts and the induction of apoptosis by the combined effect of the compounds used. CONCLUSIONS: The key findings clearly indicate the synergistic efficacy of DOX with natural and nontoxic OL against breast tumor xenografts.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/uso terapêutico , Iridoides/uso terapêutico , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Glucosídeos Iridoides , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de NeoplasiaRESUMO
BACKGROUND: Kisspeptin is involved in female reproduction. This study was designed to i- estimate kisspeptin levels in women with polycystic ovary syndrome (PCOS), in comparison with controls, ii- study the correlations between kisspeptin and PCOS-related reproductive hormones, and iii- investigate the relation between KISS1 gene polymorphisms and hormone levels in women suffering from PCOS. METHODS: The investigation was a clinically designed study on 28 women with PCOS, and 30 normal, healthy women with no signs of PCOS as controls. Blood samples were collected between day 3 and day 6 of the menstrual cycle in both groups at 8:00 a.m., and circulating levels of LH, FSH and kisspeptin were estimated. DNA was extracted from whole blood and all coding exons of KISS1 gene were sequenced. RESULTS: Women with PCOS had higher LH levels and BMI compared to controls. Plasma kisspeptin levels were positively correlated with LH levels. There was no statistically significant difference between the groups in terms of kisspeptin and FSH levels. The SNP rs4889 C/G, a non-synonymous SNP, was investigated in the PCOS group. The frequency of GG genotype was significantly higher in the PCOS compared to the controls. These patients were more obese, had higher kisspeptin and FSH levels. CONCLUSION: The results of the study show that the genetic variation of KISS1 gene may be a factor contributing to PCOS development. The association between the gene and the gene variation and PCOS need further validation in large-scaled and functional studies.
Assuntos
Índice de Massa Corporal , Hormônio Foliculoestimulante/sangue , Kisspeptinas/genética , Hormônio Luteinizante/sangue , Síndrome do Ovário Policístico/genética , Polimorfismo Genético , Adulto , Feminino , Humanos , Obesidade/complicações , Obesidade/epidemiologia , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/epidemiologia , Arábia Saudita/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Polycystic ovary syndrome (PCOS) is considered as one of the most frequently encountered hormonal pathologies in women during their reproductive years. Leptin and ghrelin, peptide hormones with adipostatic and orexigenic effect, respectively, seem to be involved in the metabolic changes that occur in PCOS. The aim of this study was to determine serum ghrelin and leptin levels in obese and lean Saudi women with PCOS and to investigate their relationship to the metabolic profiles in these women. METHODS: This study was conducted as a prospective, observational, cross-sectional, case-control study, at the Department of Obstetrics and Gynecology, Al-Noor Hospital, Makkah, Kingdom of Saudi Arabia. The study population included 252 women [130 women with PCOS (diagnosed according to the Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus, 2003) and 122 normo-ovulatory women as matched controls] attending the outpatient Gynecology Clinic. Demographic details were recorded, blood was extracted following overnight fast and serum was used for the determination of serum ghrelin and leptin levels and other hormonal and biochemical parameters including total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, glucose, and insulin. Insulin resistance and sensitivity were calculated as HOMA-IR and HOMA-S. RESULTS: No significant differences in ghrelin (P = 0.1830) and leptin (P = 0.8329) levels were detected between the PCOS and control groups. However, ghrelin levels were significantly lower; and leptin levels were significantly higher in obese PCOS patients in comparison with lean patients (P = 0.0001 for both). In the PCOS group, there were significant correlations between ghrelin and leptin levels with Body Mass Index (BMI), waist-hip ratio, total cholesterol, triglycerides, HDL, LDL and insulin levels. Multiple regression analysis demonstrated that insulin was the main determinant for ghrelin (R2 = 0.316) and leptin (R2 = 0.352) levels (P = 0.0001 for both). CONCLUSIONS: Although serum ghrelin and leptin levels were found to be normal in women with PCOS; yet, there is a relationship, possibly linked to obesity, hyperinsulinemia and insulin resistance between these levels and metabolic profile of Saudi PCOS.
Assuntos
Grelina/sangue , Leptina/sangue , Metabolômica , Obesidade/sangue , Síndrome do Ovário Policístico/sangue , Magreza/sangue , Adulto , Estudos de Casos e Controles , Feminino , Homeostase , Humanos , Resistência à Insulina , Arábia SauditaRESUMO
BACKGROUND: In some populations, obesity and body weight related disorders show a correlation with polymorphisms in three subtypes of beta-adrenoceptor (ß1, ß2, and ß3) [ADRB1, ADRB2 and ADRB3] genes. We scanned for the polymorphism of Arg389Gly (rs1801253) in ADRB1 and Trp64Arg (rs4994) in ADRB3 genes in Saudi population to determine association, if any, of these polymorphisms with obesity and related disorders. METHODS: We studied 329 non-related adults (33.1% men and 66.9% women), aged 18-36 years. Anthropometric measurements were recorded, and Body mass index (BMI) and waist/hip ratio were calculated; leptin, insulin, lipidogram, and glucose concentrations were determined. ADRB1 and ADRB3 polymorphisms (Arg389Gly and Trp64Arg, respectively) were screened by DNA sequencing. The subjects were divided into three groups according to BMI: normal weight (BMI < 25 kg/m2), overweight (BMI ≥25.1-29.9 kg/m2) subjects, and obese (≥30 kg/m2). RESULTS: In the age-matched groups of the normal weight, overweight and obese male and female subjects, all anthropometric parameters were found to be significantly higher, and in the obese group, all biochemical parameters were significantly elevated compared to the normal weight controls. The allelic frequency of Gly389 ADRB1 did not differ amongst the three groups, whereas the frequency of Arg64 of ADRB3 gene was significantly higher in the overweight and obese subjects, compared with the normal weight subjects. In addition, subjects carrying Arg64 allele regardless of their BMI had a greater waist and hip circumference, W/H ratio, plasma cholesterol, triglyceride, LDL, leptin, insulin, and glucose level compared to those with the wild-type Trp allele. CONCLUSION: The results of this study have shown a significant association between the Trp64Arg polymorphism in ADRB3 gene and the development of overweight and obesity in Saudi populations. It also has an influence on the levels of lipid, insulin, leptin, and glucose, whereas, Arg389Gly polymorphism in ADRB1 is not associated with overweight, obesity or dyslipidaemias in Saudis.
Assuntos
Dislipidemias/genética , Polimorfismo Genético/genética , Receptores Adrenérgicos beta 3/genética , Adolescente , Adulto , Peso Corporal/genética , Peso Corporal/fisiologia , Feminino , Genótipo , Humanos , Masculino , Receptores Adrenérgicos beta 1/genética , Adulto JovemRESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Therefore, novel molecules and therapeutic options are urgently needed for this category of patients. Recently, we have identified PAC as a curcumin analogue with potent anti-cancer features. METHODS: HPLC was used to evaluate the stability of PAC and curcumin in PBS and also in circulating blood. Cytotoxicity/apoptosis was assessed in different breast cancer cell lines using propidium iodide/annexinV associated with flow cytometry. Furthermore, immunoblotting analysis determined the effects of PAC on different oncogenic proteins and pathways. Additionally, the real time xCELLigence RTCA technology was applied to investigate the effect of PAC on the cellular proliferation, migration and invasion capacities. RESULTS: PAC is more stable than curcumin in PBS and in circulating blood. Furthermore, we have shown differential sensitivity of estrogen receptor-alfa positive (ERα(+)) and estrogen receptor alfa negative (ERα(-)) breast cancer cells to PAC, which down-regulated ERα in both cell types. This led to complete disappearance of ERα in ERα(-) cells, which express very low level of this receptor. Interestingly, specific down-regulation of ERα in receptor positive cells increased the apoptotic response of these cells to PAC, confirming that ERα inhibits PAC-dependent induction of apoptosis, which could be mediated through ERα down-regulation. Additionally, PAC inhibited the proliferation and suppressed the epithelial-to-mesenchymal transition process in breast cancer cells, with higher efficiency on the TNBC subtype. This effect was also observed in vivo on tumor xenografts. Additionally, PAC suppressed the expression/secretion of 2 important cytokines IL-6 and MCP-1, and consequently inhibited the paracrine procarcinogenic effects of breast cancer cells on breast stromal fibroblasts. CONCLUSION: These results indicate that PAC could be considered as important candidate for future therapeutic options against the devastating TNBC subtype.
Assuntos
Antineoplásicos/administração & dosagem , Compostos de Benzilideno/administração & dosagem , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Piperidonas/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Compostos de Benzilideno/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Curcumina/administração & dosagem , Curcumina/análogos & derivados , Curcumina/farmacologia , Estabilidade de Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-6/metabolismo , Camundongos , Piperidonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
One of the common causes of iron overload is excessive iron intake in cases of iron-poor anemia, where iron saccharate complex (ISC) is routinely used to optimize erythropoiesis. However, non-standardized ISC administration could entail the risk of iron overload. To induce iron overload, Wistar rats were intraperitoneally injected with subacute (0.2 mg kg⻹) and subchronic (0.1 mg kg⻹) overdoses of ISC for 2 and 4 weeks, respectively. Iron status was displayed by an increase in transferrin saturation (up to 332%) and serum and liver iron burden (up to 19.3 µmol L⻹ and 13.2 µmol g⻹ wet tissue, respectively) together with a drop in total and unsaturated iron binding capacities "TIBC, UIBC" as surrogate markers of transferrin activity. Iron-induced leukocytosis (up to 140%), along with the decline in serum transferrin markers (up to 43%), respectively, mark positive and negative acute phase reactions. Chemical stress was demonstrated by a significant rise (p > 0.05) in indices of the hemogram (erythrocytes, hemoglobin, hematocrit, leukocytes) and stress metabolites [corticosterone (CORT) and lactate]. Yet, potential causes of the unexpected decline in serum activities of ALT, AST and LDH (p > 0.05) might include decreased hepatocellular enzyme production and/or inhibition or reduction of the enzyme activities. The current findings highlight the toxic role of elevated serum and liver iron in initiating erythropoiesis and acute phase reactions, modifying iron status and animal organ function, changing energy metabolism and bringing about accelerated glycolysis and impaired lactate clearance supposedly by decreasing anaerobic threshold and causing premature entering to the anaerobic system.
Assuntos
Sobrecarga de Ferro/metabolismo , Fígado/metabolismo , Reação de Fase Aguda , Animais , Eritropoese , Ferro/administração & dosagem , Ratos , Ratos Wistar , Transferrina/metabolismoRESUMO
DEAF1 encodes a transcriptional binding factor and is a regulator of serotonin receptor 1A. Its protein has a significant expression in the neurons of different brain regions and is involved in early embryonic development. In addition, its role in neural tube development is evident from the knockout mouse as many homozygotes have exencephaly. Heterozygous mutations of this gene have been linked to intellectual disability in addition to the gene's involvement in major depression, suicidal tendencies, and panic disorder. In this clinical report, we describe two children from a consanguineous family with intellectual disability, microcephaly, and hypotonia. The brain MRI of both patients showed bilateral and symmetrical white matter abnormalities, and one of the patients had a seizure disorder. Using whole exome sequencing combined with homozygosity mapping, a homozygous p.R226W (c.676C>T) mutation in DEAF1 was found in both patients. Furthermore, sequencing analysis confirmed complete segregation in tested family members and absence of the mutation in control cohort (n = 650). The mutation is located in a highly conserved structural domain that mediates DNA binding and therefore regulates transcriptional activity of its target molecules. This study indicates, for the first time to our knowledge, a hereditary role of DEAF1 in white matter abnormalities, microcephaly and syndromic intellectual disability.
Assuntos
Deficiência Intelectual/genética , Leucoencefalopatias/genética , Microcefalia/genética , Proteínas Nucleares/genética , Substância Branca/anormalidades , Sequência de Bases , Pré-Escolar , Proteínas de Ligação a DNA , Epilepsia/genética , Exoma/genética , Humanos , Masculino , Mutação , Tubo Neural/embriologia , Receptores de Serotonina , Análise de Sequência de DNA , Fatores de TranscriçãoRESUMO
Humans are frequently exposed to aluminum from various food additives, therapeutic treatments and the environment, and it can be potentially toxic. This study is aimed to elucidate the protective effects of propolis against aluminum chloride (AlCl3 )-induced histopathological and immunohistochemical changes in kidney tissues of rats. Sixty Wistar Albino male rats (average weight 250-300 g) were divided into three equal groups. The first served as a negative control. The second received AlCl3 (34 mg/kg bw, 1/ 25 LD 50). The third were administered AlCl3 (34 mg/kg bw, 1/ 25 LD 50) plus propolis (50 mg/kg bw). Doses were given once daily via a gavage for 8 weeks every day. The results showed that shrunken glomeruli, intraglomerular congestion, loss of apical microvilli, degeneration of mitochondria and widened rough endoplasmic reticulum were also observed in the Proximal Convoluted Tubules of these animals. Treatment with propolis ameliorated the harmful effects of AlCl3 ; this was also proved histopathologically by the noticeable improvement in the renal tissues. There were also significant variations in the expressed of ki-67 and p53 proteins. It can be concluded that propolis may be promising as a natural therapeutic agent in AlCl3 -induced renal toxicity and oxidative stress in rat kidneys.
Assuntos
Compostos de Alumínio/antagonistas & inibidores , Cloretos/antagonistas & inibidores , Rim/efeitos dos fármacos , Própole/administração & dosagem , Cloreto de Alumínio , Compostos de Alumínio/toxicidade , Animais , Cloretos/toxicidade , Relação Dose-Resposta a Droga , Humanos , Rim/ultraestrutura , Masculino , Microscopia Eletrônica de Transmissão , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Decorin (DCN), a member of the small leucine-rich proteoglycan gene family, is secreted from stromal fibroblasts with non-cell-autonomous anti-breast-cancer effects. Therefore, in the present study, we sought to elucidate the function of decorin in breast stromal fibroblasts (BSFs). We first showed DCN downregulation in active cancer-associated fibroblasts (CAFs) compared to their adjacent tumor counterpart fibroblasts at both the mRNA and protein levels. Interestingly, breast cancer cells and the recombinant IL-6 protein, both known to activate fibroblasts in vitro, downregulated DCN in BSFs. Moreover, specific DCN knockdown in breast fibroblasts modulated the expression/secretion of several CAF biomarkers and cancer-promoting proteins (α-SMA, FAP- α, SDF-1 and IL-6) and enhanced the invasion/proliferation abilities of these cells through activation of the STAT3/AUF1 signaling. Furthermore, DCN-deficient fibroblasts promoted the epithelial-to-mesenchymal transition and stemness processes in BC cells in a paracrine manner, which increased their resistance to cisplatin. These DCN-deficient fibroblasts also enhanced angiogenesis and orthotopic tumor growth in mice in a paracrine manner. On the other hand, ectopic expression of DCN in CAFs suppressed their active features and their paracrine pro-carcinogenic effects. Together, the present findings indicate that endogenous DCN suppresses the pro-carcinogenic and pro-metastatic effects of breast stromal fibroblasts.
Assuntos
Neoplasias da Mama , Fibroblastos Associados a Câncer , Decorina , Regulação para Baixo , Interleucina-6 , Fator de Transcrição STAT3 , Transdução de Sinais , Decorina/metabolismo , Decorina/genética , Humanos , Fator de Transcrição STAT3/metabolismo , Feminino , Interleucina-6/metabolismo , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Camundongos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Regulação para Baixo/genética , Ribonucleoproteína Nuclear Heterogênea D0/metabolismo , Fibroblastos/metabolismo , Células Estromais/metabolismo , Linhagem Celular Tumoral , Carcinogênese/patologia , Carcinogênese/genética , Carcinogênese/metabolismo , Proliferação de Células , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Mama/patologia , Mama/metabolismoRESUMO
Exposure to arsenic via drinking water is considered as a worldwide problem. Studies have shown that arsenic exposure during pregnancy affects embryogenesis and offspring development in rats and mice. Zinc as a micronutrient regulates many physiological functions, including an antioxidative role under various toxic conditions. However, studies on the perinatal protective effect of zinc on offspring need further attention. The present study was designed to evaluate the potential protective role of zinc in mitigating the adverse effects in the offspring of arsenic exposure during pregnancy. The arsenic (40mg/kg body weight) and zinc (4% w/v) doses formed the only drinking fluid source for the experimental groups of dams during the perinatal period of the experiment. The early development of sensory motor coordination reflexes together with morphological development in the male pups was measured during the weaning period. In adolescence, the offspring were tested for their motor behavior. The enzyme γ-glutamyl transferase (γ-GT) and the oxidative stress indices like reduced glutathione (GSH) and lipid peroxidation (TBARS) were also estimated in the serum of the young adult male mice. Perinatal arsenic exposure caused depletion in body weight gain, delay in morphological development and retardation in the development of all sensory motor reflexes of the pups. In young adults, significant decrease in motor behavior with significant decrease in GSH level in the serum was observed. On the other hand, γ-GT and TBARS were significantly increased in the serum due to arsenic treatment. However, animals exposed to arsenic in the presence of zinc showed a remarkable ameliorating effect of zinc on all observed teratological and biochemical arsenic toxicity in male offspring. It was observed that zinc has an antioxidative role in the perinatal toxicity of arsenic. It is concluded from the present study that zinc consumed during the perinatal period of pregnancy can ameliorate the possible toxicities of arsenic exposure in the offspring by acting as an ameliorative supplement.
Assuntos
Intoxicação por Arsênico/congênito , Arsênio/toxicidade , Feto/anormalidades , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Zinco/fisiologia , Animais , Antioxidantes/administração & dosagem , Feminino , Glutationa/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Exposição Materna , Camundongos , Gravidez , gama-Glutamiltransferase/sangueRESUMO
BACKGROUND: The purpose of this study was to appraise the possible adverse effects of quercetin against the aromatase inhibitor letrozole-induced developmental toxicity potential in male Wistar rats. METHODS: Control male albino rats were received vehicles used for flavonoids and vehicle used for letrozole. The rats in the first experimental group received letrozole at 0.04 mg/kg body weight (bwt) for 3 months. The second experimental group was treated with the flavonoid quercetin by gavage at a dose of 50 mg/kg bwt for 10 consecutive days after letrozole administration. RESULTS: Major treatment-related effects of letrozole included a dose-dependent increase in hormone levels and lipid peroxidation following exposure to 0. 04 mg/kg letrozole; and severe abnormalities with severe cellular deformation and disorganization in both spermatogenic and interstitial cells. The seminiferous tubules of the testes of the animals given quercetin and letrozole exhibited a rather normal appearance and the measured hormone levels were restored to nearly the normal levels. CONCLUSION: Exposure doses of letrozole that are equal to the daily recommended human dose has toxic effects on the spermatogenic lineage in rats, while simultaneous treatment of quercetin and letrozole could prevent the deleterious effects on testicular tissue caused by letrozole administration.
Assuntos
Inibidores da Aromatase/toxicidade , Nitrilas/toxicidade , Substâncias Protetoras/farmacologia , Quercetina/farmacologia , Testículo/efeitos dos fármacos , Triazóis/toxicidade , Animais , Biomarcadores/sangue , Citoproteção , Relação Dose-Resposta a Droga , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Letrozol , Hormônio Luteinizante/sangue , Masculino , Ratos , Ratos Wistar , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/ultraestrutura , Espermatozoides/efeitos dos fármacos , Espermatozoides/ultraestrutura , Testículo/metabolismo , Testículo/ultraestrutura , Testosterona/sangue , Fatores de TempoRESUMO
Phytotherapy has a promising future in the management of diabetes, considered to be less toxic and free from side effects as compared to the use of synthetic drugs. The aim of the present study was to assess the antidiabetic possible of orally administered aqueous extracts of Murraya koenigii (ML) and Olea europaea (OL) leaves (100 and 200 mg/kg doses), in streptozotocin (70 mg/kg) induced diabetic rats. Metformin was used as a standard drug. Blood glucose, cholesterol, triglycerides, creatinine levels and body weight were estimated. ML and OL administration showed significant decrease (p>0.05) in cholesterol, triglyceride, and serum glucose levels (range 55.6%-64.6%) compared to the metformin (62.7%); however, there was no significant effect on body weight and serum creatinine. Our results suggest that both the ML and OL possess a potent antihyperglycemic and hypolipidemic effect, which may be due to the presence of antioxidants such as carbazole alkaloids and polyphenols.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Murraya/química , Olea/química , Extratos Vegetais/farmacologia , Administração Oral , Animais , Biomarcadores/metabolismo , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Creatinina/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/isolamento & purificação , Hipolipemiantes/farmacologia , Masculino , Metformina/farmacologia , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Folhas de Planta , Plantas Medicinais , Ratos , Ratos Wistar , Estreptozocina , Triglicerídeos/sangueRESUMO
OBJECTIVES: To determine the prevalence of selected single nucleotide polymorphisms (rs1080985, rs28624811, rs1065852, rs28371725, and rs1135840) in cytochrome P450 2D6 (CYP2D6) gene among Saudi systemic lupus erythematosus (SLE) patients and to investigate the association between the genetic variants and clinical features of SLE. METHODS: This cross-sectional study was carried out on adult Saudi patients at King Khalid University Hospital, Riyadh, Saudi Arabia. Patients with confirmed SLE based on the 2012 Systemic Lupus International Collaborating Clinics classification criteria were included in the study. Peripheral blood was collected for genomic deoxyribonucleic acid extraction and TaqMan® technologies were used for target genotyping. For statistical analysis, differences in genotype frequencies were determined using the Chi-square test, and the association between the variant genotypes and SLE features was evaluated using logistical regression models. RESULTS: There were 107 participants included in this study. Overall, the most predominant (23.4%) recessive genotype was AA in rs28624811, and the least prevalent (1.9%) recessive genotype was TT in rs28371725. Moreover, the variant rs1080985 genotypes (GC or CC) were significantly associated with the presence of serositis manifestation (OR=3.15, p=0.03), even after adjusting for age and gender. However, the dominant rs28624811 genotype (GG) was associated with renal involvement (OR=2.56, p=0.03). CONCLUSION: Systemic lupus erythematosus patients carrying CYP2D6 variants might be considered at risk for certain manifestations of SLE. Further studies are needed to investigate the implication of these genetic variations in clinical outcomes and drug response.
Assuntos
Citocromo P-450 CYP2D6 , Lúpus Eritematoso Sistêmico , Adulto , Humanos , Estudos de Casos e Controles , Estudos Transversais , Citocromo P-450 CYP2D6/genética , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Arábia Saudita/epidemiologiaRESUMO
Compound heterozygous mutations in SHQ1 have been associated with a rare and severe neurological disorder characterized by global developmental delay (GDD), cerebellar degeneration coupled with seizures, and early-onset dystonia. Currently, only five affected individuals have been documented in the literature. Here, we report three children from two unrelated families harboring a homozygous variant in the gene but with a milder phenotype than previously described. The patients had GDD and seizures. Magnetic resonance imaging analyses revealed diffuse white matter hypomyelination. Sanger sequencing confirmed the whole-exome sequencing results and revealed full segregation of the missense variant (SHQ1:c.833 T > C; p.I278T) in both families. We performed a comprehensive in silico analysis using different prediction classifiers and structural modeling of the variant. Our findings demonstrate that this novel homozygous variant in SHQ1 is likely to be pathogenic and leads to the clinical features observed in our patients.
RESUMO
OBJECTIVES: To determine the allelic frequencies and effects of genotypic variations in cytokine gene polymorphisms in a Saudi Arabian population. METHODS: This cross-sectional study involved 41 patients with Primary Sjögren's syndrome (pSS) and 71 healthy controls between October 2018 and May 2019. Single nucleotide polymorphisms genotyping was performed using the SEQUENOM MassARRAY® System, targeting nine polymorphisms in different cytokine genes. Chi-square tests were used to compare the patients and controls. RESULTS: The interleukin-1 beta (IL-1ß) rs1143627 CT (control, 52.7%; patients, 21.2%) and TT + CT (p= 0.003; p=0.033) genotypes were less frequent in patients with pSS than in healthy controls. The C allele in rs10488631 in the interferon regulatory factor 5 (IRF5) gene and the A allele in rs12583006 in the B-cell activating factor (BAFF) gene were associated with an increased risk of pSS development in the patient group. CONCLUSION: The CT genotype at -31 (rs1143627) in the IL-1ß gene was not associated with a high risk of pSS development in the Saudi population, in contrast to what has been verified in other ethnicities. However, the C allele in rs10488631 in IRF-5 and the A allele in rs12583006 in BAFF were associated.
Assuntos
Polimorfismo de Nucleotídeo Único , Síndrome de Sjogren , Humanos , Estudos Transversais , Arábia Saudita , Síndrome de Sjogren/genética , Citocinas/genéticaRESUMO
Rheumatoid arthritis (RA) is a complex, multifactorial disorder with an autoimmune etiology. RA is highly heritable and is associated with both human leucocyte antigen (HLA) and non-HLA genes. We investigated the associations of 33 single nucleotide polymorphisms (SNPs) with RA in the Saudi population. METHODS: This study included 105 patients with RA and an equal number of age- and sex-matched controls. The patients with RA attended outpatient clinics at King Khalid University Hospital in Riyadh, Saudi Arabia. Blood samples were collected, and DNA was extracted using Qiagen kits. Primers were designed for the 33 selected SNPs using the MassEXTEND primers program, and samples were genotyped on the Sequenom MassARRAY iPLEX platform. The allele frequencies and genotypes were determined for each SNP, and the results obtained for the patients were compared to those for the controls. RESULTS: The allele and genotype frequencies of six SNPs were significantly associated with RA: rs1188934, rs10919563, rs3087243, rs1980422, rs10499194, and rs629326. The minor alleles of rs1188934, rs10919563, rs10499194, and rs629326 were protective, with odds ratios of 0.542, 0.597, 0.589, and 0.625, and p-values of 0.002, 0.023, 0.013 and 0.036, respectively. In addition, the heterozygote frequencies of two SNPs (rs6859219 and rs11586238) were significantly higher in the controls than in the patients. CONCLUSIONS: There is considerable heterogeneity in the genetics of RA in different populations, and the SNPs that are associated with RA in some populations are not in others. We studied 33 SNPs and only eight were associated with RA. The remaining SNPs showed no allelic or genotypic associations with RA.