Protective role of Nrf2 in zinc oxide nanoparticles-induced lung inflammation in female mice and sexual dimorphism in susceptibility.

BACKGROUND: Zinc oxide nanoparticles (ZnO-NPs) are currently employed in various products such as rubber, paint, and cosmetics. Our group reported recently that Nrf2 protein provides protection against pulmonary inflammation induced by ZnO-NPs in male mice. The current study investigated the effect of Nrf2 deletion on the lung inflammatory response in female mice exposed to ZnO-NPs. METHODS: An equal number of female Nrf2-/- mice and female Nrf2+/+ mice (24 each) were allocated into three equal groups, and each was exposed to ZnO-NPs at either 0, 10 or 30 µg ZnO-NPs/mouse through pharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) and lungs were examined 14 days later to determine the number of inflammatory cells, the protein level, and for scoring inflammation histopathologically. The mRNA levels of Nrf2-dependent antioxidant enzymes and proinflammatory cytokine in lung tissue were also measured. RESULTS: Exposure to ZnO-NPs increased all types of BALF cells and lung inflammation scores in both of female Nrf2-null (Nrf2-/-) and wild-type (Nrf2+/+) mice, and Nrf2 deletion enhanced ZnO-NPs-induced increase in the number of eosinophils in BALF. Exposure to ZnO-NPs dose-dependently increased the level of oxidized glutathione (GSSG), and mRNA levels of proinflammatory cytokines/chemokines; KC, MIP-2, IL-6, IL-1ß and MCP-1 only in wild-type mice. Nrf2 deletion decreased total glutathione levels and basal mRNA levels of SOD1 and NQO1, and increased the basal mRNA level of above proinflammatory cytokines/chemokines. Nrf2 deletion enhanced ZnO-NPs-induced downregulation of GcLc, GR and TGF-ß and upregulation of HO-1 and TNF-α. Taken together with our previous results in male mice, our results showed a lower susceptibility of females to lung tissue inflammation, relative to males, irrespective of Nrf2 deletion, and that enhancement of ZnO-NPs-induced upregulation of HO-1 and TNF-α and downregulation of GcLc, GR and TGF-ß by deletion of Nrf2 is specific to female mice. CONCLUSION: We conclude that Nrf2 provides protection in female mice against increase in BALF eosinophils, probably through down-regulation of proinflammatory cytokines/chemokines and upregulation of oxidative stress-related genes. The study also suggests lower susceptibility to lung tissue inflammation in female mice relative to their male counterparts and the synergistic effects of Nrf2 and exposure to ZnO-NPs on mRNA expression of GcLc, GR, HO-1, TGF-ß or TNF-α in female mice.

Role of Nrf2 in inflammatory response in lung of mice exposed to zinc oxide nanoparticles.

BACKGROUND: Zinc oxide nanoparticles (ZnO-NPs) are widely used in many industrial sectors and previous studies have reported that exposure of the lungs to ZnO-NPs induces both acute and/or chronic pulmonary inflammation, but the exact mechanism underlying such response remains elusive. This study investigated the role of nuclear factor-erythroid 2-related factor (Nrf2) in pulmonary inflammation induced by exposure to ZnO-NPs using Nrf2 null (Nrf2-/-) mice. METHODS: Twenty-four male Nrf2-/- mice and thirty male wild type C57BL/6 J mice were divided into three groups of eight and ten each respectively, and exposed once to ZnO-NPs at 0, 10, 30 µg/mouse by pharyngeal aspiration. At 14 days after the exposure to ZnO-NPs, bronchoalveolar lavage fluid (BALF) and lungs were collected to quantify protein level and the number of inflammatory cells. The mRNA levels of Nrf2-dependent antioxidant enzymes and inflammatory cytokines in lung tissue were measured. RESULTS: Exposure to ZnO-NPs dose-dependently increased the number of total cells, macrophages, lymphocytes and eosinophils in BALF both in Nrf2-/- mice and wild type mice, but the magnitude of increase was significantly higher in Nrf2-/- mice than wild type mice. The number of neutrophils in BALF increased in Nrf2-/- mice, being accompanied by marginal trend of increase in mRNA expression of MIP-2, neutrophil chemoattractant, but such changes were not observed in wild type mice. Exposure to ZnO-NPs did not dose-dependently increase mRNA level of Nrf2-dependent antioxidant enzymes both in Nrf2-/- mice and wild type mice. CONCLUSION: Pharyngeal aspiration of ZnO-NPs induced infiltration of inflammatory cells in the lung of mice, but minimally induced Nrf2-dependent antioxidant enzymes. The results suggest that Nrf2 play a role in negative regulation on ZnO-NP exposure-induced neutrophil migration, but does not demonstrate that the regulation is through suppression of oxidative stress.

Morbidity Profile of Cases Attended Oncology Center of Mansoura University (OCMU), Egypt: A Cross-Sectional Study.

OBJECTIVES: In Egypt, the National Cancer Registry Program integrates hospital-based data from multiple Egyptian governorates to obtain representative rates. Unfortunately, Dakahlia (one of the largest Egyptian governorates) was not integrated in the National Cancer Registry Program. This research aimed to acquire malignancy rates from the Oncology Center of Mansoura University, which is one of the two oncology centers present in Dakalia Governorate in Egypt. METHODS: Electronic records of patients who attended the Oncology Center of Mansoura University during 2016 were accessed with permission. Analysis was performed to extract diagnostic categories (age, gender, and geographic distribution of cases). RESULTS: Most commonly diagnosed malignancies were breast cancer which represented about 10% of cases in the Oncology Center of Mansoura University during 2016. This was followed by leukemia (3.80%), lymphoma (3.59%), and liver cancer (3.44%). Diagnoses encountered included benign and malignant tumors as well as non-tumor diagnoses. The Mansoura district had the highest proportionate rate of breast cancer cases. Females in the age group ≥ 35 < 60 years had the highest incidence of malignancy cases across all diagnoses. CONCLUSION: The burden of breast cancer in Mansoura district is high. Risk factors need further evaluation with a recommendation to perform an environmental risk assessment.

HLA Class II-DRB1 Alleles with Hepatitis C Virus Infection Outcome in Egypt: A Multicentre Family-based Study.

INTRODUCTION AND AIM: Hepatitis C virus (HCV) infection is a global medical problem. HLA -DRB1 alleles have an important role in immune response against HCV. The aim of this study is to clarify the contribution of HLA -DRB1 alleles in HCV susceptibility in a multicentre family-based study. MATERIAL AND METHODS: A total of 162 Egyptian families were recruited in this study with a total of 951 individuals (255 with chronic hepatitis C (CHC), 588 persons in the control group(-ve household contact to HCV) and 108 persons who spontaneously cleared the virus (SVC). All subjects were genotyped for HLA -DRB1 alleles by SSP-PCR and sequence based typing (SBT) methods. RESULTS: The carriage of alleles 3:01:01 and 13:01:01 were highly significant in CHC when compared to that of control and SVC groups [OR of 3 family = 5.1289, PC (Bonferroni correction ) = 0.0002 and 5.9847, PC = 0.0001 and OR of 13 family = 4.6860, PC = 0.0002 and OR = 6.5987, PC = 0.0001 respectively]. While DRB1*040501, DRB1*040101, DRB1*7:01:01 and DRB1*110101 alleles were more frequent in SVC group than CHC patients (OR = 0.4052, PC = 0.03, OR: OR = 0.0916,PC = 0.0006, OR = 0.1833,PC = 0.0006 and OR = 0.4061, PC = 0.0001 respectively). CONCLUSIONS: It was concluded that among the Egyptian families, HLA-DRB1*030101, and DRB1*130101 alleles associated with the risk of progression to CHC infection, while DRB1*040101, DRB1*040501, DRB1*7:01:01and DRB1*110101 act as protective alleles against HCV infection.

Association of interferon gamma gene polymorphism and susceptibility to hepatitis C virus infection in Egyptian patients: A multicenter, family-based study.

BACKGROUND AND AIM: Polymorphisms in some genes may influence the persistence of hepatitis C virus (HCV) infection, clinical outcome, HCV replication, and liver damage. This study was conducted to investigate the role of the interferon gamma (IFN-γ) gene at (+874 T/A, -764 G/C, -179 C/A) single-nucleotide polymorphisms (SNPs) and its receptor (IFN-γR2) at (rs 2786067 A/C) SNP in the susceptibility of Egyptian families to HCV infection with high-resolution techniques. METHODS: In total, 517 Egyptian families, with 2246 subjects, were recruited to this study from the Upper and Lower Egypt governorates and were classified into three groups: 1034 patients with chronic hepatitis C virus, 108 subjects with spontaneous virus clearance (SVC), and 1104 subjects as a healthy control group. All subjects were genotyped for (+874 T/A, rs2430561, -764 G/C, rs2069707, -179 C/A, rs2069709, and rs 27860067, A/C) SNPs of the IFN-γ gene using the allelic discrimination real-time polymerase chain reaction technique and were confirmed using sequence-based typing. RESULTS: The carriage of T allele of (+874) IFN-γ is a risky allele and was significantly higher in chronic hepatitis C more than other two groups (odds ratio [OR]: 2.6646, P < 0.0002). On the other hand, the C allele of (-764, rs2069707) is a protective allele and was higher in SVC than the other two groups (OR: 0.2709, P < 0.0001). However, both (-179 C/A, rs 2069709) and (rs 27860067, A/C) SNPs are not polymorphic enough to be studied in the Egyptian population. CONCLUSIONS: HCV infection is associated with the T allele of (+874 rs2430561), while SVC of HCV is associated with the C allele of (-764, rs2069707) of the IFN-γ gene.