RESUMEN

Attention deficit hyperactivity disorder (ADHD) manifests as poor attention, hyperactivity, as well as impulsive behaviors. Hesperetin (HSP) is a citrus flavanone with strong antioxidant and anti-inflammatory activities. The present study aimed to test hesperetin efficacy in alleviating experimental ADHD in mice and its influence on hippocampal neuron integrity and sirtuin 1 (SIRT1) signaling. An in silico study was performed to test the related proteins. Groups of mice were assigned as control, ADHD model, ADHD/HSP (25 mg/kg), and ADHD/HSP (50 mg/kg). ADHD was induced by feeding with monosodium glutamate (0.4 g/kg, for 8 weeks) and assessed by measuring the motor and attentive behaviors (open filed test, Y-maze test, and marble burying test), histopathological examination of the whole brain tissues, and estimation of inflammatory markers. The in-silico results indicated the putative effects of hesperetin on ADHD by allowing the integration and analysis of large-scale genomic, transcriptomic, and proteomic data. The in vivo results showed that ADHD model mice displayed motor hyperactivity and poor attention in the behavioral tasks and shrank neurons at various hippocampal regions. Further, there was a decline in the mRNA expression and protein levels for SIRT1, the erythroid 2-related factor-2 (Nrf2), kelch like ECH associated protein 1 (Keap1) and hemeoxygenase-1 (OH-1) proteins. Treatment with HSP normalized the motor and attentive behaviors, prevented hippocampal neuron shrinkage, and upregulated SIRT1/Nrf2/Keap1/OH-1 proteins. Taken together, HSP mainly acts by its antioxidant potential. However, therapeutic interventions with hesperetin or a hesperetin-rich diet can be suggested as a complementary treatment in ADHD patients but cannot be suggested as an ADHD treatment per se as it is a heterogeneous and complex disease.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad , Hesperidina , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2 , Transducción de Señal , Sirtuina 1 , Animales , Hesperidina/farmacología , Hesperidina/uso terapéutico , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Sirtuina 1/metabolismo , Sirtuina 1/genética , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Masculino , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Modelos Animales de Enfermedad , Antioxidantes/farmacología , Conducta Animal/efectos de los fármacos , Biología Computacional/métodos

RESUMEN

Rotenone is a pesticide that causes complex I inhibition and is widely known to induce motor disability and experimental Parkinson's disease (PD) in rodents. Evidence suggests a crucial role for sirtuin/nuclear factor-kappaB/nod-like receptor family, pyrin domain-containing 3 (SIRT1/NFκB/NLRP3) signaling and inflammation in PD and rotenone neurotoxicity. Hesperetin (C16H14O6) is a citrus flavonoid with documented anti-inflammatory activity. We investigated the value of hesperetin in delaying rotenone-induced PD in mice and the possible modulation of inflammatory burden. PD was induced in mice via rotenone injections. Groups were assigned as a vehicle, PD, or PD + hesperetin (50 or 100 mg/kg) and compared for the motor function, protein level (by ELISA), and gene expression (by real-time PCR) of the target proteins, histopathology, and immunohistochemistry for tyrosine hydroxylase enzyme. Hesperetin (50 or 100 mg/kg) alleviated the motor disability and the striatal dopamine level and decreased the expression of NLRP3 and NF-κB but increased SIRT1 expression (p < 0.05). Further, it enhanced the neural viability and significantly decreased neural degeneration in the substantia nigra, hippocampus, and cerebral cortex (p < 0.05). Taken together, we propose that hesperetin mediates its neuroprotective function via alleviating modulation of the SIRT1/NFκB/NLRP3 pathway. Therefore, hesperetin might delay the PD progression.

RESUMEN

Background: Quetiapine (QET) abuse has increased due to its anxiolytic and hedonic effects, necessitating protective adjunct treatments. Acacia saligna (A. saligna) flowers, used in traditional medicine, have potential health benefits. Aim: To investigate the protective role of A. saligna flower extract against QET-induced sexual toxicity, and to elucidate the possible underlying mechanisms through metabolomic and physiological studies. Methods: A. saligna extract was subjected to metabolite profiling via High-Resolution Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-ESI-qTOF-MS). Forty-eight adult male albino rats were assigned into six groups for 30 days. The intracavernosal pressure (ICP), semen, biochemical, hormonal, histological, genetic and Western blot (WB) analyses were determined. Results: A. saligna extract is rich in phenolic compounds, flavonoids, tannins, and unsaturated fatty acids. QET significantly decreased ICP and negatively affected semen parameters. A. saligna mitigated decreased sperm motility and ameliorated overexpressed proinflammatory genes in QET-55 group. A. saligna ameliorated the reduction of the antioxidant biomarkers, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), concurrent with downregulation of the nuclear factor kappa B (NF-κB) protein. A. saligna counteracted the disrupted testicular and prostatic structures revealed by histological examination. Conclusion: The extract from A. saligna, which contains a high concentration of antioxidants and anti-inflammatory chemicals, effectively mitigates sexual toxicity caused by QET. This study provided the first known explanation of the hypothesized processes behind the protective properties of A. saligna through biological, biochemical, and histological parameters. The results emphasize the potential of A. saligna as a safeguarding agent against drug-induced sexual toxicity.

RESUMEN

INTRODUCTION: Although fluoroquinolones are used to treat methicillin-resistant Staphylococcus aureus (MRSA)-induced infections, acquisition of antibiotic resistance by bacteria has impaired their clinical relevance. We aimed to evaluate the frequency of norA, norB, and norC efflux pump genes-mediating fluoroquinolones resistance and measure their expression levels in MRSA isolates. METHODOLOGY: 126 S. aureus isolates were collected from different clinical samples of adult hospitalized patients and identified by conventional microbiological methods. MRSA was diagnosed by cefoxitin disc diffusion method and minimum inhibitory concentration (MIC) of ciprofloxacin by broth microdilution method. The expression levels of efflux pump genes were measured by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: 80 (63.5%) MRSA isolates were identified and showed high level of resistance to erythromycin (80%), gentamicin (75%), clindamycin (65%) and ciprofloxacin (60 %). norA, norB and norC were detected in 75%, 35% and 55% of the MRSA isolates respectively. norC was the most commonly overexpressed gene measured by qRT-PCR, occurring in 40% of MRSA isolates, followed by norA (35%) and norB (30%). The expression of these genes was significantly higher in ciprofloxacin-resistant than quantitative real-time PCR ciprofloxacin-sensitive MRSA isolates. CONCLUSIONS: This study showed high prevalence and overexpression of efflux pump genes among MRSA isolates which indicates the significant role of these genes in the development of multidrug resistance against antibiotics including fluoroquinolones.

Asunto(s)

Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Humanos , Fluoroquinolonas/farmacología , Staphylococcus aureus , Infecciones Estafilocócicas/microbiología , Proteínas Bacterianas/genética , Ciprofloxacina/farmacología , Antibacterianos/farmacología , Pruebas de Sensibilidad Microbiana

RESUMEN

BACKGROUND: Variation in host immune responses to SARS-CoV-2 is regulated by multiple genes involved in innate viral response and cytokine storm emergence like IL-10 and TNFa gene polymorphisms. We hypothesize that IL-10; -592 C > A and - 1082 A > G and TNFa-308 G > A are associated with the risk of SARS-COV2 infections and clinical outcome. METHODS: Genotyping, laboratory and radiological investigations were done to 110 COVID-19 patients and 110 healthy subjects, in Ismailia, Egypt. RESULTS: A significant association between the - 592 A allele, A containing genotypes under all models (p < 0.0001), and TNFa A allele with risk to infection was observed but not with the G allele of the - 1082. The - 592 /-1082 CG and the - 592 /-1082/ -308 CGG haplotypes showed higher odds in COVID-19 patients. Severe lung affection was negatively associated with - 592, while positive association was observed with - 1082. Higher D-dimer levels were strongly associated with the - 1082 GG genotype. Survival outcomes were strongly associated with the GA genotype of TNFa. -308 as well as AGG and AAA haplotypes. CONCLUSION: IL-10 and TNFa polymorphisms should be considered for clinical and epidemiological evaluation of COVID-19 patients.

Asunto(s)

COVID-19 , Interleucina-10 , Humanos , COVID-19/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Interleucina-10/genética , Polimorfismo de Nucleótido Simple , ARN Viral , SARS-CoV-2/genética , Factor de Necrosis Tumoral alfa/genética

RESUMEN

BACKGROUND: Toxic cardiomyopathies were a potentially fatal adverse effect of anthracycline therapy. AIM: This study was conducted to demonstrate the pathogenetic, morphologic, and toxicologic effects of doxorubicin on the heart and to investigate how the MAPK /TNF-α pathway can be modulated to improve doxorubicin-Induced cardiac lesions using bone marrow-derived mesenchymal stem cells (BM-MSCs) and olive leaf extract (OLE). METHODS: During the study, 40 adult male rats were used. Ten were used to donate MSCs, and the other 30 were split into 5 equal groups: Group I was the negative control, Group II obtained oral OLE, Group III obtained an intraperitoneal cumulative dose of DOX (12 mg/kg) in 6 equal doses of 2 mg/kg every 48 h for 12 days, Group IV obtained intraperitoneal DOX and oral OLE at the same time, and Group V obtained intraperitoneal DOX and BM-MSCs through the tail vein at the same time for 12 days. Four weeks after their last dose of DOX, the rats were euthanized. By checking the bioinformatic databases, a molecularly targeted path was selected. Then the histological, immunohistochemistry, and gene expression of ERK, JNK, NF-κB, IL-6, and TNF-α were done. RESULTS: Myocardial immunohistochemistry revealed severe fibrosis, cell degeneration, increased vimentin, and decreased CD-31 expression in the DOX-treated group, along with a marked shift in morphometric measurements, a disordered ultrastructure, and overexpression of inflammatory genes (ERK, NF-κB, IL-6, and TNF-α), oxidative stress markers, and cardiac biomarkers. Both groups IV and V displayed reduced cardiac fibrosis or inflammation, restoration of the microstructure and ultrastructure of the myocardium, downregulation of inflammatory genes, markers of oxidative stress, and cardiac biomarkers, a notable decline in vimentin, and an uptick in CD-31 expression. In contrast to group IV, group V showed a considerable beneficial effect. CONCLUSION: Both OLE and BM-MSCs showed an ameliorating effect in rat models of DOX-induced cardiotoxicity, with BM-MSCs showing a greater influence than OLE.

Asunto(s)

Cardiotoxicidad , Células Madre Mesenquimatosas , Ratas , Masculino , Animales , Cardiotoxicidad/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Vimentina/metabolismo , FN-kappa B/metabolismo , Interleucina-6/metabolismo , Doxorrubicina/toxicidad , Estrés Oxidativo , Células Madre Mesenquimatosas/metabolismo , Biomarcadores/metabolismo , Apoptosis

RESUMEN

Urokinase receptors regulate the interplay between inflammation, immunity, and blood clotting. The soluble urokinase plasminogen activator system is an immunologic regulator affecting endothelial function and its related receptor; the soluble urokinase plasminogen activator receptor (suPAR) has been reported to impact kidney injury. This work aims to measure serum levels of suPAR in COVID-19 patients and correlate the measurements with variable clinicolaboratory parameters and patient outcomes. In this prospective cohort study, 150 COVID-19 patients and 50 controls were included. The circulating suPAR levels were quantified by Enzyme-linked immunosorbent assay (ELISA). Routine COVID-19 laboratory assessments, including CBC, CRP, LDH, serum creatinine, and estimated glomerular filtration rates, were performed. The need for oxygen therapy, CO-RAD score, and survival rates was assessed. Bioinformatic analysis and molecular docking were run to explore the urokinase receptor structure/function and to characterize molecules as potential anti-suPAR therapeutic targets, respectively. We found higher circulating suPAR levels in COVID-19 patients vs. controls (p < 0.001). Circulating suPAR levels positively correlated with COVID-19 severity, the need for O2 therapy, the total leukocytes count, and the neutrophils to lymphocyte ratio, while they were negatively correlated with the O2 saturation level, albumin, blood calcium, lymphocytic count, and GFR. In addition, the suPAR levels were associated with poor prognostic outcomes such as a high incidence of acute kidney injury (AKI) and mortality rate. Kaplan-Meier curves showed a lower survival rate with higher suPAR levels. The logistic regression analysis confirmed the significant association of suPAR levels with the occurrence of AKI related to COVID-19 and with increased mortality probability within three months of COVID-19 follow-up. Some compounds that can act similarly to uPAR were discovered and tested by molecular docking to identify the possible ligand-protein interactions. In conclusion, higher circulating suPAR levels were associated with COVID-19 severity and could be considered a putative predictor of AKI development and mortality.

Asunto(s)

Lesión Renal Aguda , COVID-19 , Humanos , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Estudios Prospectivos , Activador de Plasminógeno de Tipo Uroquinasa , Simulación del Acoplamiento Molecular , COVID-19/complicaciones , Lesión Renal Aguda/etiología , Biomarcadores

RESUMEN

Heat shock proteins (HSPs) are cytoprotective against stressful conditions, as in the case of cancer cell metabolism. Scientists proposed that HSP70 might be implicated in increased cancer cell survival. This study aimed to investigate the HSP70 (HSPA4) gene expression signature in patients with renal cell carcinoma (RCC) in correlation to cancer subtype, stage, grade, and recurrence, combining both clinicopathological and in silico analysis approaches. One hundred and thirty archived formalin-fixed paraffin-embedded samples, including 65 RCC tissue specimens and their paired non-cancerous tissues, were included in the study. Total RNA was extracted from each sample and analyzed using TaqMan quantitative Real-Time Polymerase Chain Reaction. Correlation and validation to the available clinicopathological data and results were executed. Upregulated HSP70 (HSPA4) gene expression was evident in RCC compared to non-cancer tissues in the studied cohort and was validated by in silico analysis. Furthermore, HSP70 expression levels showed significant positive correlations with cancer size, grade, and capsule infiltration, as well as recurrence in RCC patients. The expression levels negatively correlated with the overall survival (r = -0.87, p < 0.001). Kaplan-Meier curves showed lower survival rates in high HSP70 expressor group compared to the low expressors. In conclusion, the HSP70 expression levels are associated with poor RCC prognosis in terms of advanced grade, capsule infiltration, recurrence, and short survival.

Asunto(s)

Carcinoma de Células Renales , Proteínas HSP70 de Choque Térmico , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Proteínas HSP70 de Choque Térmico/genética , Neoplasias Renales/genética , Pronóstico

RESUMEN

BACKGROUND: Hepatic and renal damage is a cisplatin (Cis)-induced deleterious effect that is a major limiting factor in clinical chemotherapy. OBJECTIVES: The current study was designed to investigate the influence of pretreatment with olive leaf extract (OLE), bone-marrow-derived mesenchymal stem cells (BM-MSC), and their conditioned media (CM-MSC) against genotoxicity, nephrotoxicity, hepatotoxicity, and immunotoxicity induced by cisplatin in rats. METHODS: The rats were randomly divided into six groups (six rats each) as follows: Control; OLE group, treated with OLE; Cis group, treated with a single intraperitoneal dose of Cis (7 mg/kg bw); Cis + OLE group, treated with OLE and cisplatin; Cis + CM-MSC group, treated with BM-MSC conditioned media and Cis; and Cis + MSC group, treated with BM-MSC in addition to Cis. RESULTS: Cis resulted in a significant deterioration in hepatic and renal functions and histological structures. Furthermore, it increased inflammatory markers (TNF-α, IL-6, and IL-1ß) and malondialdehyde (MDA) levels and decreased glutathione (GSH) content, total antioxidant capacity (TAC), catalase (CAT), and superoxide dismutase (SOD) activity in hepatic and renal tissues. Furthermore, apoptosis was evident in rat tissues. A significant increase in serum 8-hydroxy-2-deoxyguanosine (8-OH-dG), nitric oxide (NO) and lactate dehydrogenase (LDH), and a decrease in lysozyme activity were detected in Cis-treated rats. OLE, CM-MSC, and BM-MSC have significantly ameliorated Cis-induced deterioration in hepatic and renal structure and function and improved oxidative stress and inflammatory markers, with preference to BM-MSC. Moreover, apoptosis was significantly inhibited, evident from the decreased expression of Bax and caspase-3 genes and upregulation of Bcl-2 proteins in protective groups as compared to Cis group. CONCLUSIONS: These findings indicate that BM-MSC, CM-MSC, and OLE have beneficial effects in ameliorating cisplatin-induced oxidative stress, inflammation, and apoptosis in the hepatotoxicity, nephrotoxicity, immunotoxicity, and genotoxicity in a rat model.

RESUMEN

Background: Methotrexate (MTX) is one of the most common medications used for rheumatoid arthritis (RA) treatment. Single-nucleotide polymorphisms (SNPs) could potentially predict variability in therapeutic outcomes. Aim: This study aims to assess the impact of SNPs in genes encoding for the MTX pathway for predicting clinical and therapeutic responses to MTX in a cohort of Egyptian patients with RA. Subjects and Methods: Data from 107 Egyptian RA patients (aged 44.4 ± 11.4 years) treated with MTX monotherapy, for a duration of 3.7 ± 3.3 years, were collected. Genotypes of 10 SNPs from four different genes were analyzed using the allelic discrimination PCR technique. Results: The ATIC rs3821353 G/T (p = 0.034) and the C/T and C/C of SLC19A1 rs7279445 (p = 0.0018) were associated with a non-response to MTX, while DHFR rs10072026 C/T and C/C were associated with a good response (p < 0.001). Carriers of the ATIC rs382135 3 G (p = 0.001) and ATIC rs4673990 G (p < 0.001) alleles were more likely to develop RA, while the SLC19A1 rs11702425 T (p < 0.001) and GGH rs12681874 T (p = 0.003) allele carriers were more likely to be protected against RA. Carriers of the ATIC rs4673990 A/G genotype (p < 0.001) were at risk of developing RA, while carriers of the following genotypes were mostly protected against RA: ATIC rs3821353 T/T (p < 0.001), ATIC rs3821353 G/G (p = 0.004), SLC19A1 rs11702425 T/T (p = 0.001), SLC19A1 rs11702425 C/T (p = 0.003), GGH rs12681874 C/T (p = 0.004) and GGH rs12681874 T/T (0.002). Conclusion: The genotyping of genes involved in the MTX pathway may be helpful to predict which RA patients will/will not benefit from MTX, and thus, may help to apply a personalized medicine approach in RA.

RESUMEN

In Egypt, antibiotic sensitivity analysis for Helicobacter pylori is not routinely performed. We aimed to identify the clarithromycin and metronidazole resistance directly from gastric biopsies for better guide treatment regimens. This cross-sectional descriptive study included 75 adult dyspeptic patients referred to the upper endoscopy unit in Suez Canal University Hospital, Ismailia, Egypt. Gastric biopsies were taken for rapid urease test (RUT) and cultured on brucella agar with antibiotic supplements. Genomic DNA was extracted directly from the specimen, and PCR was performed for direct detection of H. pylori. Also, to explore clarithromycin and metronidazole resistance, mutations in the 23S rRNA gene and the rdxA gene were investigated. We found that 60 samples were positive to RUT (80%), and only 4 samples were positive by culture. UreC gene was detected in 45 specimens. Meanwhile, 26 isolates were contained mutations at positions 2142 and 2143. Amplification of the metronidazole rdx gene was performed by conventional PCR. Out of 45 isolates, DNA sequence analysis of PCR product showed the wild type (ACA) in 9 isolates, while the mutant type (ATA) was detected in 28 isolates. We found a significant proportion of clarithromycin and metronidazole resistance among H. pylori infected patients in our region.

Asunto(s)

Infecciones por Helicobacter , Helicobacter pylori , Adulto , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Claritromicina/farmacología , Estudios Transversales , Farmacorresistencia Bacteriana/genética , Helicobacter pylori/genética , Humanos , Metronidazol/farmacología , Pruebas de Sensibilidad Microbiana

RESUMEN

BACKGROUND: Vitiligo is an acquired cutaneous depigmenting disease caused by a T helper (Th) 1-cytotoxic T cells driven autoimmune attack against melanocytes, in which Th17 is also involved. Interleukin (IL)-38 belongs to the IL-1 family of cytokines and suppresses Th1 and Th17 activation. IL-38 protein and mRNA levels have been found to be elevated in various autoimmune disorders and correlated with disease severity and activity, including psoriasis, systemic sclerosis, rheumatoid arthritis, and atopic dermatitis. No previous studies have been performed to investigate the expression of IL-38 in patients with vitiligo. AIM: To evaluate IL-38 serum level in patients with vitiligo compared to healthy controls (Hcs) and examine the association between IL-38 level and severity and activity of vitiligo. PATIENTS AND METHODS: The study comprised 21 patients with vitiligo and 21 Hcs. Vitiligo severity and activity were evaluated via Vitiligo Extent Score (VES) and Vitiligo Disease Activity (VIDA) Score, respectively. IL-38 serum level was evaluated by enzyme-linked immunosorbent assay. RESULTS: Vitiligo patients had significantly higher serum level of IL-38 than Hcs (p < 0.001). This level was significantly higher among patients with signs of vitiligo activity (p = 0.048), correlated positively with VES (p < 0.001), and correlated negatively with the age of patients (p = 0.001) and the age of disease onset (p = 0.022). CONCLUSION: IL-38 serum level was higher in patients with vitiligo than in Hcs and was related to vitiligo severity and signs of activity.

Asunto(s)

Interleucinas , Vitíligo , Humanos , Interleucinas/sangre , Índice de Severidad de la Enfermedad , Células TH1 , Células Th17

RESUMEN

In colon cancer, wingless (Wnt)/ß-catenin signaling is frequently upregulated; however, the creation of a molecular therapeutic agent targeting this pathway is still under investigation. This research aimed to study how nitazoxanide can affect Wnt/ß-catenin signaling in colon cancer cells (HCT-116) and a mouse colon cancer model. Our study included 2 experiments; the first was to test the cytotoxic activity of nitazoxanide in an in vitro study on a colon cancer cell line (HCT-116) versus normal colon cells (FHC) and to highlight the proapoptotic effect by MTT assay, flow cytometry and real-time polymerase chain reaction (RT-PCR). The second experiment tested the in vivo cytotoxic effect of nitazoxanide against 1,2-dimethylhydrazine (DMH) prompted cancer in mice. Mice were grouped as saline, DMH control and DMH + nitazoxanide [100 or 200 mg per kg]. Colon levels of Wnt and ß-catenin proteins were assessed by Western blotting while proliferation was measured via immunostaining for proliferating cell nuclear antigen (PCNA). Treating HCT-116 cells with nitazoxanide (inhibitory concentration 50 (IC50) = 11.07 µM) revealed that it has a more cytotoxic effect when compared to 5-flurouracil (IC50 = 11.36 µM). Moreover, it showed relatively high IC50 value (non-cytotoxic) against the normal colon cells. Nitazoxanide induced apoptosis by 15.86-fold compared to control and arrested the cell cycle. Furthermore, nitazoxanide upregulated proapoptotic proteins (P53 and BAX) and caspases but downregulated BCL-2. Nitazoxanide downregulated Wnt/ß-catenin/glycogen synthase kinase-3ß (GSK-3ß) signaling and PCNA staining in the current mouse model. Hence, our findings highlighted the cytotoxic effect of nitazoxanide and pointed out the effect on Wnt/ß-catenin/GSK-3ß signaling.

Asunto(s)

Antiparasitarios/farmacología , Neoplasias del Colon/tratamiento farmacológico , Nitrocompuestos/farmacología , Tiazoles/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Antiparasitarios/química , Apoptosis/efectos de los fármacos , Apoptosis/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células HCT116 , Humanos , Masculino , Ratones , Simulación del Acoplamiento Molecular , Nitrocompuestos/química , Antígeno Nuclear de Célula en Proliferación/inmunología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Tiazoles/química , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/metabolismo

RESUMEN

Cisplatin is an important antineoplastic drug used in multiple chemotherapeutic regimens but unfortunately causes serious toxic effects as ovarian and uterine toxicity. This study aimed to investigate the potential protective effect of resveratrol (RSV) against cisplatin-induced ovarian and uterine toxicity in female rats. Thirty-two female Wistar rats were divided randomly into four groups (n = 8 in each). Control group received oral normal saline for 28 days; RSV group received RSV (10 mg/kg; daily) via oral gavage; CIS group received a single dose of CIS (7 mg/kg; i.p.) on the 21st day; (CIS + RSV) group received both RSV and CIS by the same schedules and doses of RSV and CIS groups, respectively. Results demonstrated a significant decrease in MDA level and a significant increase in both glutathione content and activity of the antioxidant enzymes GPx, SOD, and CAT in the tissues of the ovary and uterus of CIS + RSV group in comparison to that of CIS group (P<0.05), also there are significantly decreased tissue levels of the proinflammatory cytokines and enzymes (NF-κB, IL-1ß, IL-6, TNF-α, COX-2, and iNOS), increased estradiol, progesterone, prolactin and decreased FSH serum levels in CIS + RSV group compared to CIS group (P < 0.05). Moreover, there is downregulation of tissues Cleaved Caspase-3, NF-κB and Cox-2 proteins as shown in Western blot analysis, also apoptosis was significantly inhibited, evidenced by downregulation of Bax and upregulation of Bcl-2 proteins, and the ovarian and uterine histological architecture and integrity were maintained in CIS + RSV group compared to CIS group. In conclusion, these findings indicate that RSV has beneficial effects in ameliorating cisplatin-induced oxidative stress, inflammation, and apoptosis in the ovarian and uterine tissues of female rats.

Asunto(s)

Apoptosis/efectos de los fármacos , Cisplatino/efectos adversos , Inflamación/patología , Ovario/patología , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Resveratrol/farmacología , Útero/patología , Animales , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Catalasa/metabolismo , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Malondialdehído/metabolismo , Modelos Biológicos , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ovario/efectos de los fármacos , Progesterona/sangre , Prolactina/sangre , Carbonilación Proteica/efectos de los fármacos , Ratas Wistar , Superóxido Dismutasa/metabolismo , Proteína X Asociada a bcl-2/metabolismo

RESUMEN

BACKGROUND: Alopecia areata is a common non-scarring hair loss disorder. It has been generally recognised as a loss of immune privilege leading to an autoimmune attack upon anagen hair follicles. Survivin is one of the apoptosis inhibitor proteins, responsible for apoptosis suppression and cell cycle regulation. Survivin expression has been demonstrated in the matrix and outer root sheath keratinocytes of anagen hair follicles. Survivin overexpression was shown in several autoimmune diseases, and it was postulated that it contributes to the survival of self-reactive T and B cells. P53 is a tumour suppressor gene that was suggested to repress autoimmunity via induction of T regulatory cells. Survivin gene expression is transcriptionally suppressed by wild-type p53. AIM: The aim of this study was to investigate survivin and p53 genes expression in alopecia areata patients. METHODS: The mRNA tissue expression of survivin and p53 was measured by quantitative real-time polymerase chain reaction in lesional and non-lesional punch scalp biopsies of 25 alopecia areata patients and 25 healthy subjects. RESULTS: The study showed higher mRNA expression of survivin in lesional biopsies compared to non-lesional (P < 0.001) and control biopsies (P = 0.001). In non-lesional biopsies, the expression was significantly lower than in control biopsies (P < 0.001). The expression of p53 was lower in both lesional and non-lesional biopsies relative to control biopsies. However, the difference was only significant in non-lesional biopsies (P = 0.017). CONCLUSION: Our results suggested that survivin and p53 genes expression was altered in patients with alopecia areata.

Asunto(s)

Alopecia Areata/genética , Genes p53 , Survivin/metabolismo , Adolescente , Adulto , Biopsia con Aguja , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Cuero Cabelludo/metabolismo , Cuero Cabelludo/patología , Survivin/genética , Adulto Joven

RESUMEN

Rotenone is an insecticide that generates oxidative stress in the CNS and induces locomotor dysfunction and neurodegeneration in rodents. Biochanin A [BioA] is an isoflavone with antioxidant and anti-inflammatory actions. The antioxidant and the modulatory action of BioA on PI3K/Akt/mTOR signaling and autophagy were tested in rotenone-Parkinsonian mice. Mice were allocated into; Group I: oil control group, Group II: rotenone group [1-mg/kg/48h, subcutaneously], group III: rotenone and BioA [10-mg/kg]. Rotenone injection resulted in locomotor disturbances in mice, degeneration in dopaminergic neurons [tyrosine hydroxylase-immunoreactive cells], low striatal dopamine, increased malondialdehyde and decreased level of glutathione. Neuroinflammation was evidenced by upregulation of astrocytes [glia fibrillary acidic protein, GFAP] and elevated levels of cytokines. The phosphorylation of PI3K/Akt/mTOR and the autophagy-related protein, beclin-1, were decreased significantly as indicated by Western blot analysis. BioA treatment enhanced locomotor activity and afforded nigral neuroprotection. The mechanism by which BioA produced this effect includes increased antioxidant defenses, lessened proinflammatory cytokines, increased phosphorylation of PI3K/Akt/mTOR proteins and upregulated beclin-1. Importantly, BioA suppressed the striatal astrocyte marker [GFAP]. Overall, the currents study highlighted that BioA activates PI3K/Akt/mTOR signaling and enhances beclin-1 leading to neuroprotection for nigral dopaminergic neurons.

Asunto(s)

Genisteína/farmacología , Insecticidas/toxicidad , Fármacos Neuroprotectores/farmacología , Rotenona/toxicidad , Animales , Autofagia/efectos de los fármacos , Beclina-1/metabolismo , Citocinas/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Glutatión/metabolismo , Masculino , Ratones , Síndromes de Neurotoxicidad/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo

RESUMEN

PURPOSE: Putative roles of long non-coding RNAs (lncRNAs) as indicators for diabetic retinopathy (DR) and associated complications are beginning to emerge. We aimed to evaluate a panel of circulating hyperglycemia-related lncRNAs: RNCR2, NEAT2, CDKN2B-AS1, and PVT1 in type 2 diabetes patients with/without DR and to correlate their levels with the clinical characteristics and response to aflibercept intravitreal injection in terms of visual acuity (VA) improvement, central macular thickness (CMT) decline, and macular edema resolution after 4 weeks of the initial injection. METHODS: Pre-treatment plasma relative expression levels of the specified lncRNAs were quantified in 130 consecutive patients with diabetes (75 and 55 with/without DR, respectively) and 108 controls using quantitative real-time PCR. RESULTS: One month after aflibercept injection, significant reductions in CMT and VA were observed in DR cohorts. The four lncRNAs were over-expressed in DM compared with those in controls. However, downregulated baseline plasma levels of RNCR2 and NEAT2 were observed in glycemic-controlled DR patients. None of the lncRNAs showed a correlation with the severity of retinopathy or drug response. CONCLUSION: Though circulating levels of the analyzed lncRNAs did not show an association with DR progression or aflibercept therapy response, the expression pattern demonstrated good diagnostic performance in differentiating DM from controls and DR.

Asunto(s)

Retinopatía Diabética/sangre , ARN Largo no Codificante/sangre , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/genética , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica , Humanos , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , ARN/genética , ARN Largo no Codificante/genética , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Retina/patología , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Agudeza Visual

RESUMEN

PURPOSE: Catheter-related bloodstream infections (CRBSIs) are among the most common hospital-acquired infections. We aimed to survey methicillin resistance, biofilm production and susceptibility to vancomycin, linezolid and other antibiotics for staphylococci isolated from CRBSIs. METHODOLOGY: Fifty-eight isolates [20 S. aureus and 38 coagulase-negative staphylococci (CoNS; 20 Staphylococcusepidermidis, nine Staphylococcushaemolyticus, three Staphylococcusschleiferi, two Staphylococcuswarneri and four Staphylococcuslugdunensis)] were tested for methicillin resistance by cefoxitin disk diffusion and detection of the mecA gene by PCR; biofilm-forming ability using Congo red agar and tissue culture plate methods; susceptibility to ciprofloxacin, clindamycin, cotrimoxazole, erythromycin, gentamicin, linezolid, rifampicin and tetracycline; and MIC determination for vancomycin.Results/Key findings. Cefoxitin resistance was detected among 40 % (8/20) S. aureus isolates, 70 % (14/20) S. epidermidis isolates and 16.7 % (3/18) of other CoNS, although the mecA gene was detected in 45 % (9/20) S. aureus isolates, 35 % (7/20) S. epidermidis isolates and 16.7 % (3/18) of other CoNS. Biofilm-forming ability ranged from 45 to 75 %. Methicillin-resistant S. aureus and other CoNS were considered to be more virulent than methicillin-resistant S. epidermidis due to the higher biofilm forming abilities of the former. All tested isolates exhibited 100 % sensitivity to vancomycin and linezolid, irrespective of their methicillin resistance or biofilm-forming ability. Rifampicin showed overall sensitivity of 75.9 %. Varying degrees of multi-resistance were found for the other antibiotics. CONCLUSION: Vancomycin, linezolid and rifampicin could be used effectively against methicillin-resistant staphylococci isolated from CRBSIs.

Asunto(s)

Antibacterianos/farmacología , Infecciones Relacionadas con Catéteres/microbiología , Linezolid/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Infecciones Estafilocócicas/microbiología , Vancomicina/farmacología , Bacteriemia/etiología , Bacteriemia/microbiología , Proteínas Bacterianas/genética , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Catéteres/microbiología , Farmacorresistencia Bacteriana , Egipto/epidemiología , Humanos , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Staphylococcus aureus Resistente a Meticilina/fisiología , Pruebas de Sensibilidad Microbiana , Proteínas de Unión a las Penicilinas/genética , Reacción en Cadena de la Polimerasa , Rifampin/farmacología , Infecciones Estafilocócicas/epidemiología , Staphylococcus/clasificación , Staphylococcus/efectos de los fármacos , Staphylococcus/aislamiento & purificación , Staphylococcus aureus/efectos de los fármacos , Centros de Atención Terciaria

RESUMEN

Stem cell transcriptional signature activation is an essential event in the development of cancer. This study aimed to investigate the differential expression profile of three pluripotency-associated genes (OCT4, NANOG, and SOX2), G-protein-coupled chemokine receptor 4 (CXCR4) and the ligand (CXCL2), and alpha feto-protein (AFP) in hepatogenic differentiated stem cells and in sera of hepatitis C virus (HCV) and HCV-induced hepatocellular carcinoma (HCC) patients. Mesenchymal stem cells derived from umbilical cord blood were differentiated using hepatogenic differentiation media. Serum specimens were collected from 96 patients (32 cirrhotic HCV, 32 early HCC, and 32 late HCC) and 96 controls. Real-time quantitative reverse transcription polymerase chain reaction was performed for relative quantification of the 6 target genes using LIVAC method. In silico network analysis was also executed to explore the pluripotency and tumorigenic regulatory circuits in liver cancer. The expression levels of all genes declined gradually during the stages of stem cell differentiation. On univariate and multivariate analyses, NANOG, CXCR4 and AFP were significantly up-regulated in HCC patients with late clinical stage. In contrast, SOX2 and CXCL2 were markedly over-expressed in cirrhotic patients and could be used for clear demarcation between cirrhotic and HCC patients in our cases. In conclusion, our data highlight the potential role of SOX2 stem cell marker and CXCL2 chemokine in liver cell degeneration and fibrogenesis in HCV-induced hepatic cirrhosis in our sample of the Egyptian population. In addition, the significant association of NANOG and CXCR4 high-expression with late HCC, could contribute to the acquisition of stem cell-like properties in hepatic cancer and dissemination in late stages, respectively. Taken together, our results could have a potential application in HCC prognosis and treatment.