RESUMO
Aristolochic acid I (AAI) is a well-known nephrotoxic carcinogen, which is currently reported to be also associated with hepatocellular carcinoma (HCC). Whether AAI is a direct hepatocarcinogen remains controversial. In this study we investigated the association between AAI exposure and HCC in adult rats using a sensitive rat liver bioassay with several cofactors. Formation of glutathione S-transferase placental form-positive (GST-P+) foci was used as the marker for preneoplastic lesions/clonal expansion. We first conducted a medium-term (8 weeks) study to investigate whether AAI had any tumor-initiating or -promoting activity. Then a long-term (52 weeks) study was conducted to determine whether AAI can directly induce HCC. We showed that oral administration of single dose of AAI (20, 50, or 100 mg/kg) in combination with partial hepatectomy (PH) to stimulate liver proliferation did not induce typical GST-P+ foci in liver. In the 8-week study, only high dose of AAI (10 mg · kg-1 · d-1, 5 days a week for 6 weeks) in combination with PH significantly increased the number and area of GST-P+ foci initiated by diethylnitrosamine (DEN) in liver. Similarly, only high dose of AAI (10 mg· kg-1· d-1, 5 days a week for 52 weeks) in combination with PH significantly increased the number and area of hepatic GST-P+ foci in the 52-week study. No any nodules or HCC were observed in liver of any AAI-treated groups. In contrast, long-term administration of AAI (0.1, 1, 10 mg· kg-1· d-1) time- and dose-dependently caused death due to the occurrence of cancers in the forestomach, intestine, and/or kidney. Besides, AAI-DNA adducts accumulated in the forestomach, kidney, and liver in a time- and dose-dependent manner. Taken together, AAI promotes clonal expansion only in the high-dose group but did not induce any nodules or HCC in liver of adult rats till their deaths caused by cancers developed in the forestomach, intestine, and/or kidney. Findings from our animal studies will pave the way for further large-scale epidemiological investigation of the associations between AA and HCC.
Assuntos
Ácidos Aristolóquicos/toxicidade , Carcinógenos/toxicidade , Carcinoma Hepatocelular/etiologia , Hepatócitos/metabolismo , Neoplasias Hepáticas/etiologia , Mutagênicos/toxicidade , Animais , Carcinogênese/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Adutos de DNA/efeitos dos fármacos , Glutationa S-Transferase pi/metabolismo , Neoplasias Intestinais/induzido quimicamente , Intestinos/patologia , Rim/patologia , Neoplasias Renais/induzido quimicamente , Fígado/metabolismo , Fígado/patologia , Masculino , Ratos Sprague-Dawley , Estômago/patologia , Neoplasias Gástricas/induzido quimicamenteRESUMO
OBJECTIVE: To study the expression of interferon-λ1 (IFN-λ1) in respiratory epithelial cells in children with human rhinovirus (HRV) infection. METHODS: Sputum samples and nasopharyngeal swabs were collected from the children who were hospitalized due to acute respiratory infection from February to October, 2017. Bacterial culture was performed, and nucleic acid test was performed for 11 respiratory pathogens. A total of 90 children with positive HRV alone were enrolled as the HRV infection group, and 95 children with positive respiratory syncytial virus (RSV) alone were enrolled as the RSV infection group. A total of 50 healthy children who underwent outpatient physical examination during the same period of time and had negative results for all pathogen tests were enrolled as the healthy control group. Nasopharyngeal swabs were collected from all groups, and quantitative real-time PCR was used to measure viral load and the mRNA expression of IFN-λ1. RESULTS: In the HRV infection group, there was no significant difference in the mRNA expression of IFN-λ1 between boys and girls and across all age groups (P>0.05). In the HRV infection group, there was no correlation between the mRNA expression of IFN-λ1 and HRV load (P>0.05). The mRNA expression of IFN-λ1 in the HRV infection group was significantly higher than that in the healthy control group (P<0.05), but significantly lower than that in the RSV infection group (P<0.05). CONCLUSIONS: HRV can induce the expression of IFN-λ1 in respiratory epithelial cells, suggesting that IFN-λ1 may play an important role in anti-HRV infection in children.
Assuntos
Infecções por Picornaviridae , Infecções Respiratórias , Antivirais , Criança , Células Epiteliais , Feminino , Humanos , Interferons , Masculino , RhinovirusRESUMO
Aristolochic acid I (AAI) derived from a natural herbal alkaloid is a nephrotoxicant. AAI-induced acute kidney injury (AKI), a devastating clinical disease associated with high mortality rates, is difficult for early diagnosis. To address this issue, we identified and validated early-detection biomarkers for AAI-induced acute kidney injury via profiling microRNA expression in rats. Global miRNA expression profile analysis found that 21 miRNAs were significantly dysregulated in kidney of rats treated by 40 mg/kg AAI on day 2, day 4, or day 6, among which 5 miRNAs were upregulated at all three time points. Quantitative RT-PCR confirmed that miR-21-3p on day 4 and day 6 was obviously upregulated in kidney of rats treated by 40 mg/kg AAI. Further examination found that miR-21-3p was increased in plasma early on day 2 in 10 mg/kg AAI-treated rats, but not in non-target organs. Importantly, the elevation of plasma miR-21-3p preceded the increase in blood urea nitrogen and creatinine, and the presence of renal tubular injury, characterized by differential increase before and after the presence of renal tubular lesions. Our findings thus show that miRNA expression is upregulated in kidney and plasma of AKI rat induced by AAI, and plasma miR-21-3p may be served as a new potential biomarker for early diagnosing AAI-induced acute kidney injury in rats, and possibly in humans.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Ácidos Aristolóquicos/efeitos adversos , MicroRNAs/sangue , Injúria Renal Aguda/sangue , Injúria Renal Aguda/genética , Animais , Biomarcadores/sangue , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Masculino , MicroRNAs/genética , Análise de Componente Principal , Ratos Wistar , Reprodutibilidade dos Testes , Testes de Toxicidade Aguda/métodosRESUMO
Many Aristolochia species herbal drugs, used for diseases treatment since antiquity, contain active component aristolochic acid mixture, which consists of aristolochic acid I and II. However, it remains unclear whether aristolochic acid I is gastrotoxic, though evidence has shown that aristolochic acid mixture is nephrotoxic, carcinogenic, and genotoxic. The present study aimed to investigate the gastrotoxicity in rats treated with aristolochic acid I alone. Four groups of rats were orally administrated with vehicle (1% NaHCO3), or 30mg, 60mg, and 90mg/kg/day of aristolochic acid I for twelve days. The results showed that aristolochic acid I can induce obvious body weight loss, forestomach injury characterized by necrosis, ulcer, hyperkeratosis, and hyperplasia of epithelial cells. The severity of these forestomach lesions was presented in a dose-dependent mode. Meanwhile, only non-specific, slight renal tubule degeneration, and occasionally single necrotic epithelial cell were found in aristolochic acid I-treated rats' kidney. These resulst indicated aristolochic acid I had obvious gastrotoxicity, and such aristolochic acid I-induced forestomach toxicity probably presented much prior to kidney injury. Such irritation lesions may play a partial role in gastric cancer development of rats induced by aristolochic acid. Therefore, these results expanded our understanding on the digestive system toxicity of aristolochic acid I.