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BACKGROUND: The nutritional status and growth of children with Autism spectrum disorders (ASD) is influenced significantly by two factors; food selectivity behaviors due to their consumption of a limited variety of food and the high incidence of gastrointestinal (GIT) disorders. AIM: This study aimed to assess the nutritional adequacy and growth pattern of ASD children aged three to twelve years compared to their healthy developing peers. METHODS: A national comparative, facility-based cross-sectional study was conducted in eight Egyptian governorates on 285 Egyptian children diagnosed with ASD and 224 children who are their relatives as healthy developing peers. Anthropometric measurements were obtained, including weight, height, head circumference, and mid-upper arm circumference. Body Mass Index (BMI) was calculated and all numbers were plotted on WHO growth charts. Assessment of food preferences, and nutrient intake adequacy of children was done using the Food preference questionnaire, and the Dietary Reference Intakes (DRIs) of Egyptian children. RESULTS: Calorie-dense food and sugar intake were higher among ASD children than their healthy developing peers. ASD children omit some important protein sources such as dairy (COR = 5.2, 95% CI:2.7-9.9), meat, and poultry (COR = 2.7, 95% CI: 1.6-4.7), and a lower intake of fruits and vegetables than their healthy developing peers. For children with ASD in all age groups, a deficiency in the range of 50-60% was detected for vitamins (C, D, B6, thiamine, riboflavin, niacin) and minerals (iron). A deficiency in the range of 60-70% was detected for folate and calcium. A deficiency of vitamin C calcium and iron was also detected for both children with ASD and their healthy developing relatives aged 6 to 12 years. GIT disorders were common among ASD children compared to healthy developing peers (COR = 2.8 to 10.3). Children with ASD had four-fold higher odds of stunting (COR = 4.1, CI: 1.7-10.1), threefold higher odds of being overweight (COR = 3.3, CI: 1.48-7.32), and nearly eleven-fold higher odds of obesity (COR = 11.4, CI: 4.05-32.17) compared to their healthy developing peers. CONCLUSION: ASD children are prone to overweight and protein malnutrition. Their intake of fruits and vegetables is inadequate and hence their intake of vitamins and minerals is insufficient, contributing to stunting.
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Trastorno del Espectro Autista , Trastornos del Crecimiento , Obesidad Infantil , Humanos , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/etiología , Egipto/epidemiología , Masculino , Femenino , Estudios Transversales , Preescolar , Niño , Obesidad Infantil/epidemiología , Trastornos del Crecimiento/epidemiología , Trastornos del Crecimiento/etiología , Estado Nutricional , Estudios de Casos y Controles , Preferencias Alimentarias , Índice de Masa Corporal , DietaRESUMEN
Aberrant regulation of ß-catenin signaling is strongly linked with cancer proliferation, invasion, migration, and metastasis, thus, small molecules that can inhibit this pathway might have great clinical significance. Our molecular modeling studies suggest that ormeloxifene (ORM), a triphenylethylene molecule that docks with ß-catenin, and its brominated analogue (Br-ORM) bind more effectively with relatively less energy (-7.6 kcal/mol) to the active site of ß-catenin as compared to parent ORM. Herein, we report the synthesis and characterization of a Br-ORM by NMR and FTIR, as well as its anticancer activity in cervical cancer models. Br-ORM treatment effectively inhibited tumorigenic features (cell proliferation and colony-forming ability, etc.) and induced apoptotic death, as evident by pronounced PARP cleavage. Furthermore, Br-ORM treatment caused cell cycle arrest at the G1-S phase. Mechanistic investigation revealed that Br-ORM targets the key proteins involved in promoting epithelial-mesenchymal transition (EMT), as demonstrated by upregulation of E-cadherin and repression of N-cadherin, Vimentin, Snail, MMP-2, and MMP-9 expression. Br-ORM also represses the expression and nuclear subcellular localization of ß-catenin. Consequently, Br-ORM treatment effectively inhibited tumor growth in an orthotopic cervical cancer xenograft mouse model along with EMT associated changes as compared to vehicle control-treated mice. Altogether, experimental findings suggest that Br-ORM is a novel, promising ß-catenin inhibitor and therefore can be harnessed as a potent anticancer small molecule for cervical cancer treatment.
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There is increasing evidence suggesting the role of microbiome alterations in relation to pancreatic adenocarcinoma and tumor immune functionality. However, molecular mechanisms of the interplay between microbiome signatures and/or their metabolites in pancreatic tumor immunosurveillance are not well understood. We have identified that a probiotic strain (Lactobacillus casei) derived siderophore (ferrichrome) efficiently reprograms tumor-associated macrophages (TAMs) and increases CD8 + T cell infiltration into tumors that paralleled a marked reduction in tumor burden in a syngeneic mouse model of pancreatic cancer. Interestingly, this altered immune response improved anti-PD-L1 therapy that suggests promise of a novel combination (ferrichrome and immune checkpoint inhibitors) therapy for pancreatic cancer treatment. Mechanistically, ferrichrome induced TAMs polarization via activation of the TLR4 pathway that represses the expression of iron export protein ferroportin (FPN1) in macrophages. This study describes a novel probiotic based molecular mechanism that can effectively induce anti-tumor immunosurveillance and improve immune checkpoint inhibitors therapy response in pancreatic cancer.
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Adenocarcinoma , Neoplasias Pancreáticas , Probióticos , Ratones , Animales , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma/metabolismo , Sideróforos , Microambiente Tumoral , Ferricromo/uso terapéutico , Monitorización Inmunológica , Inhibidores de Puntos de Control Inmunológico , Probióticos/farmacología , Neoplasias PancreáticasRESUMEN
BACKGROUND: Protein kinase D1 (PKD1) is a serine-threonine kinase that regulates various functions within the cell. Herein, we report the significance of PKD1 expression in glucose metabolism resulting in pancreatic cancer (PanCa) progression and chemo-resistance. METHODS: PKD1 expression in PanCa was investigated by using immunohistochemistry. Functional and metabolic assays were utilised to analyse the effect of PKD1 expression/knockdown on associated cellular/molecular changes. RESULTS: PKD1 expression was detected in human pancreatic intraepithelial neoplasia lesions (MCS = 12.9; P < 0.0001) and pancreatic ductal adenocarcinoma samples (MCS = 15, P < 0.0001) as compared with faint or no expression in normal pancreatic tissues (MCS = 1.54; P < 0.0001). Our results determine that PKD1 enhances glucose metabolism in PanCa cells, by triggering enhanced tumorigenesis and chemo-resistance. We demonstrate that mTORC1 activation by PKD1 regulates metabolic alterations in PanCa cells. siRNA knockdown of Raptor or treatment with rapamycin inhibited PKD1-accelerated lactate production as well as glucose consumption in cells, which confirms the association of mTORC1 with PKD1-induced metabolic alterations. CONCLUSION: This study suggests a novel role of PKD1 as a key modulator of the glucose metabolism in PanCa cells accelerating tumorigenesis and chemo-resistance. The remodelling of PKD1-dysregulated glucose metabolism can be achieved by regulation of mTORC1 for development of novel therapeutic strategies.
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Carcinoma in Situ/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Neoplasias Pancreáticas/metabolismo , Pancreatitis Crónica/metabolismo , Proteína Quinasa C/metabolismo , Carcinogénesis/genética , Carcinoma in Situ/patología , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Resistencia a Antineoplásicos/genética , Técnicas de Silenciamiento del Gen , Glucosa/metabolismo , Humanos , Inmunohistoquímica , Neoplasias Pancreáticas/patología , Pancreatitis Crónica/patología , Proteína Quinasa C/genética , Transducción de Señal/genética , TransfecciónRESUMEN
BACKGROUND: Cervical cancer (CxCa) ranks as the fourth most prevalent women-related cancer worldwide. Therefore, there is a crucial need to develop newer treatment modalities. Ormeloxifene (ORM) is a non-steroidal, selective estrogen receptor modulator (SERM) that is used as an oral contraceptive in humans. Recent investigations suggest that ORM exhibits potent anti-cancer activity against various types of cancers. Nanoparticulates offer targeted delivery of anti-cancer drugs with minimal toxicity and promise newer approaches for cancer diagnosis and treatment. Therefore, the nanotherapy approach is superior compared to traditional chemotherapy, which is not site-specific and is often associated with various side effects. METHODS: Pursuing this novel nanotherapy approach, our lab has recently developed ORM-loaded poly [lactic-co-glycolic acid] (PLGA), an FDA-approved biodegradable polymer, nanoparticles to achieve targeted drug delivery and improved bioavailability. Our optimized PLGA-ORM nanoformulation showed improved internalization in both dose- and energy-dependent manners, through endocytosis-mediated pathways in both Caski and SiHa cell lines. Additionally, we employed MTS and colony forming assays to determine the short- and long-term effects of PLGA-ORM on these cells. RESULTS: Our results showed that this formulation demonstrated improved inhibition of cellular proliferation and clonogenic potential compared to free ORM. Furthermore, the PLGA-ORM nanoformulation exhibited superior anti-tumor activities in an orthotopic cervical cancer mouse model than free ORM. CONCLUSION: Collectively, our findings suggest that our novel nanoformulation has great potential for repurposing the drug and becoming a novel modality for CxCa management.
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Benzopiranos/uso terapéutico , Nanopartículas/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Animales , Benzopiranos/farmacología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Clonales , Modelos Animales de Enfermedad , Endocitosis/efectos de los fármacos , Eritrocitos/metabolismo , Femenino , Hemólisis/efectos de los fármacos , Humanos , Ensayo de Materiales , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Desnudos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Suero/química , Neoplasias del Cuello Uterino/patologíaRESUMEN
Pancreatic cancer (PanCa) is a major cause of cancer-related death due to limited therapeutic options. As pancreatic tumors are highly desmoplastic, they prevent appropriate uptake of therapeutic payloads. Thus, our objective is to develop a next-generation nanoparticle system for treating PanCa. We generated a multi-layered Pluronic F127 and polyvinyl alcohol stabilized and poly-L-lysine coated paclitaxel loaded poly(lactic-co-glycolic acid) nanoparticle formulation (PPNPs). This formulation exhibited optimal size (~160 nm) and negative Zeta potential (-6.02 mV), efficient lipid raft mediated internalization, pronounced inhibition in growth and metastasis in vitro, and in chemo-naïve and chemo-exposed orthotopic xenograft mouse models. Additionally, PPNPs altered nanomechanical properties of PanCa cells as suggested by the increased elastic modulus in nanoindentation analyses. Immunohistochemistry of orthotopic tumors demonstrated decreased expression of tumorigenic and metastasis associated proteins (ki67, vimentin and slug) in PPNPs treated mice. These results suggest that PPNPs represent a viable and robust platform for (PanCa).
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Nanopartículas/química , Paclitaxel/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Endocitosis , Humanos , Microdominios de Membrana/metabolismo , Ratones Desnudos , Invasividad Neoplásica , Metástasis de la Neoplasia , Paclitaxel/farmacología , Neoplasias Pancreáticas/patología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Obesity is a common disorder that has a significant impact on human health as it may lead to many serious diseases and sometimes morbidity. Previous genome-wide association studies (GWAS) confirmed that there is a relationship between some variants in the first intron of the fat mass and obesity associated (FTO) gene and obesity in adults and children in different ethnic groups. In our study, the association of the FTO rs9939609 and rs17817449 variants with obesity was investigated in Egyptian children and adolescents. We examined rs9939609 and rs17817449 polymorphisms in 100 control and 100 obese cases, we used the restriction fragment length polymorphism (RFLP) technique to genotype the samples. The current study showed that there were no significant differences (P > 0.05) between the cases and controls in both variants of rs17817449 and rs9939609 polymorphisms. However, there were significant correlations between rs17817449 and cholesterol and between rs9939609 and LDL. In Current Study although the two variants (rs9939609 and rs17817449) didn't show an association with obesity, but there was a correlation between the lipid profile and these two variants.