RESUMEN

BACKGROUND: Placental Derived Nucleoproteins (PDNs) is commonly associated with the process of angiogenesis, and doesn't affect the healthy vasculature. PDNs are clinically estimated for the treatment of cancer cases and severe hepatic injuries. Thus, the pathophysiological effects of PDNs targeting liver fibrosis is a concern. OBJECTIVES: To assess the molecular, histopathological, and chemical impact of PDNs on liver regeneration in Diethylnitrosamine (DEN)-induced mice liver fibrosis. METHODS: Normal untreated reference group of ten mice and two groups of induced liver cirrhosis using the recommended weekly dose of Diethylnitrosamine in total of eleven doses, initially 20 mg/kg body weight, and then 30 mg/kg in the third week, followed by 50 mg/kg for the last eight weeks, one of them combined treatment aligned with injection with total dose of extracted PDNs 25 mg/kg, in comparison to PDNs only treated group. An autopsy was performed after 22 weeks of the initial dose of DEN in each group. Molecular characterization of Alpha smooth muscle actin, TGFß and NF-κB biomarkers for liver then liver function panel were analyzed and finally hepatopathological changes were observed using H&E stain and Sirius red stain. RESULTS: Liver enzymes, total bilirubin and total proteins in tissue in PDNs-DEN treated models were controlled in the direction of normal group and 50 % reduction of fibrosis in comparing to DEN-treated models. The cellular arrangement of fibrosis in the DEN entire groups were differentiated with high significant impact on the survival of mice. Increased levels of the biochemical markers in liver homogenate, loss of tissue architecture, and proliferation were observed in induced groups and down regulation of alpha smooth muscle actin, TGFß and NF-κB. CONCLUSION: This finding demonstrates an improvement of Liver tissue induced fibrosis using DEN combined with PDNs. This strategy is to generate an animal model with a lower occurrence of fibrosis in a short time treatment regarding liver regeneration.

Asunto(s)

Dietilnitrosamina , Cirrosis Hepática , Regeneración Hepática , Placenta , Animales , Regeneración Hepática/efectos de los fármacos , Femenino , Ratones , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Embarazo , Dietilnitrosamina/toxicidad , Masculino , Placenta/efectos de los fármacos , Placenta/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Modelos Animales de Enfermedad , FN-kappa B/metabolismo , Actinas/metabolismo

RESUMEN

BACKGROUND: Myotonia Congenita (MC) is a rare disease classified into two major forms; Thomsen and Becker disease caused by mutations in the CLCN1 gene, which affects muscle excitability and encodes voltage-gated chloride channels (CLC-1). While, there are no data regarding the clinical and molecular characterization of myotonia in Egyptian patients. METHODS: Herein, we report seven Egyptian MC patients from six unrelated families. Following the clinical diagnosis, whole-exome sequencing (WES) was performed for genetic diagnosis. Various in silico prediction tools were utilized to interpret variant pathogenicity. The candidate variants were then validated using Sanger sequencing technique. RESULTS: In total, seven cases were recruited. The ages at the examination were ranged from eight months to nineteen years. Clinical manifestations included warm-up phenomenon, hand grip, and percussion myotonia. Electromyography was performed in all patients and revealed myotonic discharges. Molecular genetic analysis revealed five different variants. Of them, we identified two novel variants in the CLCN1 gene ( c.1583G > C; p.Gly528Ala and c.2203_2216del;p.Thr735ValfsTer57) and three known variants in the CLCN1 and SCN4A gene. According to in silico tools, the identified novel variants were predicted to have deleterious effects. CONCLUSIONS: As the first study to apply WES among Egyptian MC patients, our findings reported two novel heterozygous variants that expand the CLCN1 mutational spectrum for MC diagnosis. These results further confirm that genetic testing is essential for early diagnosis of MC, which affects follow-up treatment and prognostic assessment in clinical practice.

Asunto(s)

Canales de Cloruro , Secuenciación del Exoma , Mutación , Miotonía Congénita , Humanos , Miotonía Congénita/genética , Miotonía Congénita/diagnóstico , Secuenciación del Exoma/métodos , Canales de Cloruro/genética , Femenino , Masculino , Egipto , Niño , Adolescente , Mutación/genética , Preescolar , Adulto Joven , Lactante , Canal de Sodio Activado por Voltaje NAV1.4/genética , Adulto , Linaje , Electromiografía

RESUMEN

BACKGROUND: Breast cancer (BC) is one of the most prevalent cancers that contribute to mortality among women worldwide. Despite contradictory findings, considerable evidence suggests that single nucleotide polymorphisms (SNPs) in the FSCN1 and HOTAIR genes may have a causative impact on the development of BC. This case-control study was conducted to evaluate the association of genotype frequency in FSCN1 rs852479, rs1640233, and HOTAIR rs920778 with susceptibility and prognosis of BC, as well as the impact of clinical stages and hormonal features. METHODS AND RESULTS: FSCN1 (rs852479, rs1640233) and HOTAIR (rs920778) were genotyped using TaqMan real-time PCR assay in 200 BC patients and 200 cancer-free controls, all representing Egyptian women. Genotypic analyses in association with clinicopathological factors and disease risk were assessed. As a result, a significant association with BC risk was observed for CC genotype frequency of FSCN1 rs852479 A > C (OR = 0.395, 95% CI 0.204-0.76, p-value = 0.005). However, no significant correlation was detected between the FSCN1 rs1640233 C > T and HOTAIR rs920778 C > T polymorphic variants and susceptibility to BC. Interestingly, CC genotype of FSCN1 rs1640233 was more likely to progress tumor size and lymph node invasion in BC cases (p-value = 0.04 and 0.02, respectively). Moreover, it was revealed that there was a non-significant correlation between the haplotype distributions of FSCN1 rs852479 and rs1640233 and the probability of BC. CONCLUSIONS: Based on the sample size and genetic characteristics of the subjects involved in the present study, our findings indicated that FSCN1 rs852479 may contribute to BC susceptibility in a sample of the Egyptian population.

Asunto(s)

Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/genética , Proteínas Portadoras , Estudios de Casos y Controles , Egipto , Genotipo , Proteínas de Microfilamentos , Polimorfismo de Nucleótido Simple/genética

RESUMEN

Background: Therapeutic microRNAs (miRNAs) delivery holds a lot of promise for treating human malignancies. So, this study was carried out to examine the potential of miR-122 mimic and/or miR-221 inhibitor as an innovative therapeutic strategy for HCC in an animal model. Methodology: Mice were categorized into five groups comprising: (1) a normal control group, (2) an HCC group subjected to diethylnitrosamine (DEN) injection for 12 weeks, (3) a miR-122 mimic-treated HCC group, (4) a miR-221 inhibitor-treated HCC group, and (5) a miR-122 mimic/miR-221 inhibitor-treated HCC group. After 16 weeks, all animals were sacrificed and underwent biochemical, miRNAs and genes expression, histopathological, and immunohistochemical examinations. Results: The miR-122 mimic/miR-221 inhibitor combination dramatically reduced the levels of pro-inflammatory, liver cancer, angiogenesis, and cell proliferation markers when compared to either treatment alone. It also down-regulated the expression of cyclin D1, TGF-ß, and ß-catenin genes, which are involved in promoting cell cycle progression and cancer cell proliferation. Furthermore, it caused the resolution of nearly all the histological malignant features as well as the reduction of malignant cellular markers, including α-smooth muscle actin, arginase-1, and tropomyosin-1. Conclusions: The co-treatment with miR-122 mimic and miR-221 inhibitor amplifies the benefits of either treatment on HCC through targeting the SENP1 and ARF4 genes, respectively. This combination can inhibit cancer cell proliferation and angiogenesis while inducing tumor apoptosis and necrosis. This study demonstrates the therapeutic potential of reversing a dysregulated miRNAs expression pattern in HCC. As a result, future research should concentrate on turning miRNA understanding into therapeutic applications.