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1.
Sci Total Environ ; 720: 137528, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32143041

RESUMO

Aristolochic acids (AAs) are persistent soil pollutants in the agricultural fields of the Balkan Peninsula that are endemic for Aristolochia clematitis L. This class of carcinogenic and nephrotoxic phytotoxins is taken up by crops through root absorption and contaminates staple foods across the peninsula. Human exposure to AAs via dietary intake has recently been recognized as a cause of Balkan endemic nephropathy. For the sake of public health, human exposure to AAs from all sources should be minimized in a timely manner. However, currently, there is no available remediation method to remove AAs from soil. In this study, we developed the first soil remediation method for AAs using Fenton's reagent (FR), a combination of ferrous ion and hydrogen peroxide, and optimized factors, including pH, temperature, time, and dose of FR, to achieve the best degradation performance. The maximum AA degradation efficiency was found to be >97% in soil with 500 µg kg-1 of AAs. We anticipate that this developed method, mediated via Fenton reaction, will be useful to effectively eliminate AAs from the Balkan farmlands.


Assuntos
Solo , Aristolochia , Ácidos Aristolóquicos , Nefropatia dos Bálcãs , Península Balcânica , Humanos , Peróxido de Hidrogênio
2.
Environ Sci Technol ; 54(3): 1554-1561, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31884786

RESUMO

Aristolochic acids (AAs) have been known as potent nephrotoxins since the use of AA-containing herbal medicines was linked with a series of sporadic renal fibrotic nephropathy cases, and yet an estimated 100 million people worldwide are still at risk today because of continued use of similar medicines. However, a similar nephropathic condition is endemic in the rural Balkan regions (e.g., Serbian farming villages) and AAs were again found to be the causative agents. In the case of this Balkan endemic nephropathy, AAs were found to have originated from a widespread local weed Aristolochia clematitis L. In this study, we tested the hypothesis that AAs released from decomposition of A. clematitis were also being leached into groundwater, thus polluting the drinking water of local residents. We initiated the study by developing a dispersive solid-phase extraction-based sample preparation method for water samples suspected of AA contamination. The validated method was then coupled with a liquid chromatography-tandem mass spectrometric method to measure AAs in groundwater samples collected from Serbia. Our study revealed for the first time that groundwater in Serbia is extensively contaminated with AA-I, at ng/L levels. Results also showed that AAs are long-lived water contaminants, with no observable concentration changes over a 2-month period of sample storage.


Assuntos
Ácidos Aristolóquicos , Nefropatia dos Bálcãs , Água Subterrânea , Península Balcânica , Humanos , Sérvia
3.
BMC Cancer ; 19(1): 950, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615453

RESUMO

BACKGROUND: Strong associations exist between Balkan endemic nephropathy (BEN) and upper urothelial carcinomas (UUCs). However, the common etiology between the two remains unclear and there are no studies to date that visualize UUC risks in Croatia. In Croatia, 14 villages in the southwestern part of Brod-Posavina County are considered endemic for BEN. The aim of this ecological study is to map cancer risks and describe the case distribution of UUCs in Croatia at the county level during 2001-2011. METHODS: A total of 608 incident cases from the Croatian National Cancer Registry were identified. Indirect standardization was employed to compute standardized incidence ratios (SIRs). RESULTS: Counties with SIRs greater than 1 were concentrated around the agricultural region of Slavonia and the coastal region of Dalmatia. However, only Brod-Posavina County and Vukovar-Srijem County had a statistically significant risk of UUC development, where there were 390 and 210% more UUC cases observed than expected, respectively. Only unique to Brod-Posavina County, females were at higher risk (SIR 4.96; 95% CI 3.59-6.34) of developing UUCs than males (SIR 3.03; 95% CI 2.04-4.01) when compared to their Croatian counterparts. Although Brod-Posavina County only made up 3.7% of the total Croatian population (as of 2011), it had the highest frequency of incident UUC cases after the capital City of Zagreb. No elevated cancer risks were noted in the City of Zagreb, even after stratifying by sex. CONCLUSION: Our findings suggest that Brod-Posavina County had the highest cancer risk for UUCs, especially among females, when compared to Croatia as a whole during 2001-2011. Given that a majority of BEN patients develop associated UUCs, concurrent screening programs for UUCs and BEN should be considered not only in endemic areas of BEN but also the surrounding rural areas and amongst at-risk groups such as those undergoing hemodialysis, who frequently develop UUCs, to help clarify BEN-UUC associations by identifying common risk factors while standardizing disease estimates across endemic regions for BEN.


Assuntos
Nefropatia dos Bálcãs/epidemiologia , Carcinoma de Células Renais/epidemiologia , Neoplasias Renais/epidemiologia , Sistema de Registros , Neoplasias Ureterais/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Croácia/epidemiologia , Doenças Endêmicas , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Risco , Fatores Sexuais , Urotélio , Adulto Jovem
4.
Chem Biodivers ; 16(11): e1900406, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31568671

RESUMO

An understanding of the fate of organic compounds originating from plants in soil is crucial for determining their persistence and concentrations in the environment. Aristolochic acids are believed to be the causal agents that induce Balkan endemic nephropathy by food contamination through soil adsorption of humic acids, major components of soil. Aristolochic acids are active chemicals in Aristolochia plant species found in endemic villages. In this article, molecular structure interactions between 18 structures of aristolochic acids with an inserted humic acid structure were studied. These structures were optimized in vacuo and by periodic box simulation with water solvate using the computational molecular mechanics MM+ method with HyperChem software. The QSPR models were used for correlation of the relationship between the hydrophobicity values of 18 AA structures coupled with a HA structure by MM+ and QSAR+ properties. Computational hydrophobicity values were considered dependent variables and were related to the structural features obtained by molecular and quantum mechanics calculations by multiple linear regression approaches. The obtained model was validated, and the results indicated differing hydrophobicity between the MM+ and QSAR+ properties.


Assuntos
Ácidos Aristolóquicos/química , Nefropatia dos Bálcãs/induzido quimicamente , Contaminação de Alimentos/análise , Substâncias Húmicas/análise , Simulação de Dinâmica Molecular , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade
5.
Medicina (Kaunas) ; 55(8)2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31382611

RESUMO

Background: Experimental data show that superoxide dismutase 2 (SOD2) is involved in ochratoxin (OTA)-induced nephrotoxicity, whereas clinical data indicate the role of SOD2 rs4880 or glutathione peroxidase 1 (GPX1) rs1050450 polymorphisms in end-stage renal disease and urothelial carcinoma risk, known to be the major complications of Balkan endemic nephropathy (BEN). Therefore, we hypothesized that SOD2 and GPX1 gene polymorphisms would influence the risk of BEN and its associated tumors. Materials and Methods: The study was conducted in 207 BEN patients and 86 controls from endemic areas. Results: Individuals with both copies of variant SOD2 allele, known for lower mitochondrial antioxidant protection, are at a significantly higher BEN risk (OR = 2.6, p = 0.021). No association was observed between GPX1 gene polymorphism and BEN risk. Combining SOD2 and GPX1 genotypes did not alter the risk of BEN development. Regarding the risk of urothelial tumors in BEN patients, none of the polymorphisms studied was significantly associated with the risk of these tumors. Conclusions: Polymorphism in SOD2 rs4880 gene affects the risk of BEN development. Hence, SOD2 genotyping could, together with a panel of other enzymes, be used as a biomarker of susceptibility in BEN areas.


Assuntos
Nefropatia dos Bálcãs/genética , Glutationa Peroxidase/genética , Polimorfismo Genético/genética , Superóxido Dismutase/genética , Idoso , Idoso de 80 Anos ou mais , Nefropatia dos Bálcãs/epidemiologia , Nefropatia dos Bálcãs/fisiopatologia , Biomarcadores/análise , Biomarcadores/sangue , Bósnia e Herzegóvina/epidemiologia , Feminino , Glutationa Peroxidase/sangue , Humanos , Masculino , Sérvia/epidemiologia , Superóxido Dismutase/sangue
6.
Medicina (Kaunas) ; 55(5)2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31108979

RESUMO

Background: A previous study indicated that Balkan endemic nephropathy (BEN) patients in the early stage of the disease had significantly higher creatinine clearance (Ccr) than healthy persons. The aim of the study was to assess whether tubular creatinine secretion affects Ccr in early stages of BEN and to check the applicability of serum creatinine-based glomerular filtration rate (GFR) equations in these patients. Methods: The study involved 21 BEN patients with estimated GFR (eGFR) above 60 mL/min/1.73 m2, excluding any conditions that could affect GFR or tubular creatinine secretion, and 15 healthy controls. In all participants Ccr with and without cimetidine and iohexol clearance (mGFR) were measured and eGFR calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease Study (MDRD) equations. Glomerular hyperfiltration cutoff (GFR-HF) was calculated. Results: There was no significant difference between the groups in Ccr before and after cimetidine or for eGFR, but mGFR was significantly higher in BEN patients than in controls (122.02 ± 28.03 mL/min/1.73 m2 vs. 101.15 ± 27.32 mL/min/1.73 m2; p = 0.032). Cimetidine administration reduced Ccr by 10% in both groups. The ratio of Ccr to mGFR was significantly above one in seven BEN patients and five controls and their mGFR values were similar. Seven other patients and eight controls had this ratio equal to one, while values below one were recorded for seven more patients and two controls. mGFR of all these 14 patients was significantly higher than that of healthy controls (129.88 ± 27.52 mL/min/1.73 m2 vs. 107.43 ± 19.51 mL/min/1.73 m2; p = 0.009). Mean GFR-HF was significantly higher than mGFR in controls, but these two values were similar in BEN patients. eGFR underestimated mGFR in both BEN patients and controls. Conclusion: The ratio of Ccr to mGFR and mGFR to GFR-HF indicated that elevated mGFR in early stages of BEN could be explained by increased glomerular filtration, but tubular creatinine secretion augmented Ccr in a smaller proportion of patients, who did not differ from healthy subjects.


Assuntos
Nefropatia dos Bálcãs/fisiopatologia , Taxa de Filtração Glomerular/fisiologia , Idoso , Nefropatia dos Bálcãs/complicações , Índice de Massa Corporal , Distribuição de Qui-Quadrado , Creatinina/análise , Creatinina/urina , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-Idade , Estatísticas não Paramétricas
7.
Semin Nephrol ; 39(3): 284-296, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31054628

RESUMO

Balkan endemic nephropathy is a chronic tubulointerstitial disease with insidious onset, slowly progressing to end-stage renal disease and frequently associated with urothelial carcinoma of the upper urinary tract (UTUC). It was described in South-East Europe at the Balkan peninsula in rural areas around tributaries of the Danube River. After decades of intensive investigation, the causative factor was identified as the environmental phytotoxin aristolochic acid (AA) contained in Aristolochia clematitis, a common plant growing in wheat fields that was ingested through home-baked bread. AA initially was involved in the outbreak of cases of rapidly progressive renal fibrosis reported in Belgium after intake of root extracts of Aristolochia fangchi imported from China. A high prevalence of UTUC was found in these patients. The common molecular link between Balkan and Belgian nephropathy cases was the detection of aristolactam-DNA adducts in renal tissue and UTUC. These adducts are not only biomarkers of prior exposure to AA, but they also trigger urothelial malignancy by inducing specific mutations (A:T to T:A transversion) in critical genes of carcinogenesis, including the tumor-suppressor TP53. Such mutational signatures are found in other cases worldwide, particularly in Taiwan, highlighting the general public health issue of AA exposure by traditional phytotherapies.


Assuntos
Ácidos Aristolóquicos/toxicidade , Nefropatia dos Bálcãs/induzido quimicamente , Carcinoma de Células de Transição/induzido quimicamente , Exposição Ambiental/efeitos adversos , Neoplasias Renais/induzido quimicamente , Neoplasias Ureterais/induzido quimicamente , Animais , Aristolochia , Nefropatia dos Bálcãs/diagnóstico , Nefropatia dos Bálcãs/patologia , Nefropatia dos Bálcãs/terapia , Carcinógenos/toxicidade , Adutos de DNA , Humanos , Programas de Rastreamento
8.
Curr Opin Nephrol Hypertens ; 28(1): 87-96, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30451737

RESUMO

PURPOSE OF REVIEW: Chronic kidney disease (CKD) can cluster in geographic locations or in people of particular genetic ancestries. We explore APOL1 nephropathy and Balkan nephropathy as examples of CKD clustering that illustrate genetics and environment conspiring to cause high rates of kidney disease. Unexplained hotspots of kidney disease in Asia and Central America are then considered from the perspective of potential gene × environment interactions. RECENT FINDINGS: We report on evidence supporting both genes and environment in these CKD hotspots. Differing genetic susceptibility between populations and within populations may explain why causal environmental risk factors have been so hard to identify conclusively. Similarly, one cannot explain why these epidemics of kidney disease are happening now without invoking environmental changes. SUMMARY: Approaches to these CKD hotspots are of necessity becoming more holistic. Genetic studies may help us identify the environmental triggers by teaching us about disease biology and may empower environmental risk factor studies by allowing for stratification of study participants by genetic susceptibility.


Assuntos
Insuficiência Renal Crônica/etiologia , Apolipoproteína L1/genética , Nefropatia dos Bálcãs/etiologia , Meio Ambiente , Predisposição Genética para Doença , Humanos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/genética , Fatores de Risco
9.
Medicina (Kaunas) ; 54(1)2018 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30344235

RESUMO

Aims: The aim of this study was to compare the risk factors and prevalence of vascular calcification (VC) in pre-dialysis and hemodialysis (HD) patients with Balkan endemic nephropathy (BEN) or other kidney diseases (non-BEN). Materials and Methods: The study involved 115 patients, 32 pre-dialysis and 83 HD patients, separated into groups of BEN and non-BEN patients. In addition to interviews, objective examinations and laboratory analyses, VC was assessed using Adragao score. Results: Patients with BEN were significantly older in both groups, while pre-dialysis BEN patients had significantly lower systolic blood pressure, serum cholesterol and phosphorus levels, but higher urinary excretion of phosphorus than non-BEN patients. These differences were lost in HD groups. In pre-dialysis patients, prevalence of VC was lower in BEN than in non-BEN group and mean VC score differed significantly between them (2.8 (1.7) vs. 4.6 (1.8); p = 0.009). No significant difference in VC score was found between BEN and non-BEN patients on HD. Multivariate analysis showed that in pre-dialysis patients VC score >4 was associated with lower iPTH and higher serum cholesterol level, but in the HD group with higher serum triglyceride level and longer HD vintage. Conclusions: Lower prevalence of risk factors for VC in the BEN than non-BEN patients was found in pre-dialysis but not in HD group and this was reflected in the prevalence and severity of VC in the groups. Prevalence of VC and mean VC score were significantly lower in pre-dialysis BEN than in non-BEN patients but not for those on HD.


Assuntos
Nefropatia dos Bálcãs/terapia , Nefropatias/terapia , Diálise Renal/efeitos adversos , Calcificação Vascular/epidemiologia , Idoso , Nefropatia dos Bálcãs/sangue , Nefropatia dos Bálcãs/complicações , Pressão Sanguínea , Colesterol/sangue , Feminino , Humanos , Nefropatias/sangue , Nefropatias/complicações , Masculino , Análise Multivariada , Fósforo/sangue , Fósforo/urina , Prevalência , Fatores de Risco , Calcificação Vascular/etiologia
10.
Chem Res Toxicol ; 31(11): 1109-1110, 2018 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-30346143

RESUMO

Aristolochic acid released from decaying Aristolochia clematitis weed is contaminating soil and food crops in Eastern Europe and is one of the major causes to Balkan endemic nephropathy. Measures should be taken to prevent people from being exposed to these highly potent phytotoxins. Research needs to develop remediation methods.


Assuntos
Aristolochia/química , Ácidos Aristolóquicos/toxicidade , Nefropatia dos Bálcãs/etiologia , Poluentes do Solo/química , Aristolochia/crescimento & desenvolvimento , Aristolochia/metabolismo , Produtos Agrícolas/efeitos dos fármacos , Produtos Agrícolas/crescimento & desenvolvimento , Produtos Agrícolas/metabolismo , Humanos , Poluentes do Solo/toxicidade , Poluentes da Água/química , Poluentes da Água/toxicidade
11.
Crit Rev Toxicol ; 48(7): 575-595, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30277423

RESUMO

Scientific databases were searched for terms applicable to karyomegaly in renal tubules of laboratory animals used in preclinical safety evaluation studies, and in humans. Renal tubule karyomegaly was more frequently reported in the rat in response to chemical exposure compared to other laboratory animal species. Renal tubule karyomegaly also occurred in the mouse in response to chemical insult, but much less commonly than in the rat. This nuclear lesion was recorded infrequently for hamster, dog, guinea pig, rabbit, pig, and non-human primate. Most instances of renal karyomegaly reported in humans represented cases of the genetic syndrome, karyomegalic interstitial nephritis, known to be caused by a mutation in the FAN1 gene. Human reports of karyomegaly in the kidney associated with chemical exposure are rare, and linked mainly to chemotherapeutic or antiviral therapies. The rat appears to be highly predisposed to developing karyomegaly as a renal response on exposure to diverse chemical agents, but karyomegaly in the rat is not consistently associated with renal tubule tumor development. Because of this inconsistency, renal tubule karyomegaly is an inaccurate predictor of renal tubule neoplasia, and there is no evidence that karyomegalic cells are involved in tumor development as a form of preneoplasia. A chemically induced karyomegalic response in the rat does not necessarily predict a similar alteration in human kidneys. Because modest nuclear enlargement of kidney tubule cells can occur as physiological or functional responses, it is recommended that the threshold for diagnosing renal tubule karyomegaly in animal studies should be accepted as at least four times normal nuclear size or larger.Abbreviations: BEN: Balkan Endemic Nephropathy; DMN: dimethylnitrosamine; GLP: Good Laboratory Practice; KIN: karyomegalic interstitial nephritis; LAL: lysinoalanine; MeCCNU: 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea; NTP: National Toxicology Program; OSOM: outer stripe of outer medulla; OTA: ochratoxin A; RTT: renal tubule tumor.


Assuntos
Nefropatia dos Bálcãs/patologia , Núcleo Celular/patologia , Túbulos Renais/patologia , Animais , Nefropatia dos Bálcãs/epidemiologia , Estudos de Avaliação como Assunto , Humanos , Mamíferos , Medição de Risco
12.
Food Chem ; 264: 270-276, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-29853376

RESUMO

Emerging evidence suggests that aristolochic acids (AA) produced naturally by a common weed Aristolochia clematitis in the cultivation fields is contaminating the food products in Balkan Peninsula and acting as the etiological agent in the development of Balkan endemic nephropathy. In this study, we investigated the combined use of natural anti-oxidative "food additives" and different cooking methods to find a solution for the widespread contamination of AA in food products. The results indicated that the addition of healthy dietary supplements (such as cysteine, glutathione, ascorbic acid, citric acid and magnesium) during cooking, is a highly efficient method in lowering the concentration of AA in the final food products. Because previous observation indicated one of the toxicological mechanisms by which AA exert its toxicity is to induce oxidative stress in internal organs, it is anticipated that these added anti-oxidants will also help to attenuate the nephrotoxicity of AA.


Assuntos
Antioxidantes/química , Ácidos Aristolóquicos/química , Culinária/métodos , Aditivos Alimentares/química , Contaminação de Alimentos , Aristolochia , Ácidos Aristolóquicos/toxicidade , Ácido Ascórbico/química , Nefropatia dos Bálcãs/etiologia , Carcinógenos/química , Ácido Cítrico/química , Cisteína/química , Suplementos Nutricionais , Farinha , Glutationa/química , Humanos , Magnésio/química
13.
Int Urol Nephrol ; 50(7): 1301-1309, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29779117

RESUMO

PURPOSE: In the early 1970s, a number of authors described the development of Balkan endemic nephropathy (BEN) in immigrants in endemic regions. The aim of this study was to examine whether immigrants in endemic regions are suffering from BEN today. METHODS: The study involved 193 residents of two endemic regions divided into three groups: two groups of native residents-(1) members of BEN families, (2) members of non-BEN families, and (3) immigrants, who had moved from non-affected settlements to the endemic regions of Kolubara (38 years ago) or Semberia (20 years ago). All persons were subjected to an interview, objective examination, kidney ultrasound, and laboratory analysis to detect the presence of BEN consensus diagnostic criteria. RESULTS: The number of immigrants with BEN biomarkers outside cutoff values was significantly lower than for BEN family members. Five BEN family members met diagnostic criteria for BEN and four for suspected BEN. Although five non-BEN family members had different combinations of BEN biomarkers, all of them had diseases other than BEN in which these biomarkers also occurred. None of the immigrants met the criteria for BEN. Nevertheless, one descendant of an immigrant, a 78-year-old male, whose mother was from a non-BEN family in the Kolubara district, exhibited all the criteria for BEN: alpha1-microglobulinuria, chronic renal failure, and anemia. CONCLUSION: While 30 years ago, BEN was reported equally among immigrants and natives, currently it is diagnosed in some BEN family members in the eighth decade of life, but extremely rarely in immigrants also in old age.


Assuntos
Nefropatia dos Bálcãs/diagnóstico , Nefropatia dos Bálcãs/epidemiologia , Emigrantes e Imigrantes/estatística & dados numéricos , Falência Renal Crônica/epidemiologia , Grupos Populacionais/estatística & dados numéricos , Adulto , Distribuição por Idade , Idoso , Península Balcânica/epidemiologia , Progressão da Doença , Doenças Endêmicas , Feminino , Humanos , Incidência , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Medição de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Análise de Sobrevida
14.
Environ Geochem Health ; 40(4): 1437-1448, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29288399

RESUMO

Aristolochic acids (AAs) are carcinogenic and nephrotoxic plant alkaloids present in Aristolochia species, used in traditional medicine. Recent biomolecular and environmental studies have incriminated these toxins as an etiological agent in Balkan endemic nephropathy (BEN), a severe kidney disease occurring in the Balkan Peninsula. The questions on how the susceptible populations are exposed to these toxins have not yet been clearly answered. Exposure to AAs through the food chain, and environmental pollution (soil/dust), could provide an explanation for the presence of BEN in the countries where no folkloric use of the plant has been documented (Bulgaria, Croatia). Additional exposure pathways are likely to occur, and we have shown previously that AAs can contaminate crop plants through absorption from soil, under controlled laboratory environment. Here, we attempt to provide additional support to this potential exposure pathway, by revealing the presence of AAI in soil and soil organic matter samples collected from BEN and non-BEN areas. The samples were processed in order to be analyzed by high-pressure liquid chromatography, and ion trap mass spectrometry. Our results showed the presence of AAI in small concentrations, both in BEN and non-BEN soils, especially where Aristolochia plants and seeds were present.


Assuntos
Ácidos Aristolóquicos/toxicidade , Nefropatia dos Bálcãs/induzido quimicamente , Exposição Ambiental , Substâncias Húmicas , Poluentes do Solo/toxicidade , Ácidos Aristolóquicos/análise , Cromatografia Líquida de Alta Pressão , Produtos Agrícolas , Humanos , Espectrometria de Massas , Estações do Ano , Poluentes do Solo/análise , Espectrofotometria Ultravioleta
15.
Int J Mol Sci ; 18(10)2017 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-29036902

RESUMO

Aristolochic acid (AA) is a plant alkaloid that causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases frequently associated with upper urothelial cancer (UUC). This review summarizes the significance of AA-derived DNA adducts in the aetiology of UUC leading to specific A:T to T:A transversion mutations (mutational signature) in AAN/BEN-associated tumours, which are otherwise rare in individuals with UCC not exposed to AA. Therefore, such DNA damage produced by AA-DNA adducts is one rare example of the direct association of exposure and cancer development (UUC) in humans, confirming that the covalent binding of carcinogens to DNA is causally related to tumourigenesis. Although aristolochic acid I (AAI), the major component of the natural plant extract AA, might directly cause interstitial nephropathy, enzymatic activation of AAI to reactive intermediates capable of binding to DNA is a necessary step leading to the formation of AA-DNA adducts and subsequently AA-induced malignant transformation. Therefore, AA-DNA adducts can not only be utilized as biomarkers for the assessment of AA exposure and markers of AA-induced UUC, but also be used for the mechanistic evaluation of its enzymatic activation and detoxification. Differences in AA metabolism might be one of the reasons for an individual's susceptibility in the multi-step process of AA carcinogenesis and studying associations between activities and/or polymorphisms of the enzymes metabolising AA is an important determinant to identify individuals having a high risk of developing AA-mediated UUC.


Assuntos
Ácidos Aristolóquicos/metabolismo , Biomarcadores , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Adutos de DNA/metabolismo , Neoplasias Urológicas/etiologia , Neoplasias Urológicas/metabolismo , Animais , Ácidos Aristolóquicos/química , Nefropatia dos Bálcãs/etiologia , Nefropatia dos Bálcãs/metabolismo , Carcinógenos/química , Carcinógenos/metabolismo , Suscetibilidade a Doenças , Humanos , Neoplasias Urológicas/patologia
16.
Int J Mol Sci ; 18(2)2017 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-28146082

RESUMO

The term "aristolochic acid nephropathy" (AAN) is used to include any form of toxic interstitial nephropathy that is caused either by ingestion of plants containing aristolochic acids (AA) as part of traditional phytotherapies (formerly known as "Chinese herbs nephropathy"), or by the environmental contaminants in food (Balkan endemic nephropathy). It is frequently associated with urothelial malignancies. Although products containing AA have been banned in most of countries, AAN cases remain regularly reported all over the world. Moreover, AAN incidence is probably highly underestimated given the presence of AA in traditional herbal remedies worldwide and the weak awareness of the disease. During these two past decades, animal models for AAN have been developed to investigate underlying molecular and cellular mechanisms involved in AAN pathogenesis. Indeed, a more-in-depth understanding of these processes is essential to develop therapeutic strategies aimed to reduce the global and underestimated burden of this disease. In this regard, our purpose was to build a broad overview of what is currently known about AAN. To achieve this goal, we aimed to summarize the latest data available about underlying pathophysiological mechanisms leading to AAN development with a particular emphasis on the imbalance between vasoactive factors as well as a focus on the vascular events often not considered in AAN.


Assuntos
Ácidos Aristolóquicos/efeitos adversos , Medicamentos de Ervas Chinesas/efeitos adversos , Nefrite Intersticial/etiologia , Animais , Ácidos Aristolóquicos/química , Ácidos Aristolóquicos/metabolismo , Nefropatia dos Bálcãs/diagnóstico , Nefropatia dos Bálcãs/epidemiologia , Nefropatia dos Bálcãs/etiologia , Biópsia , Transformação Celular Neoplásica/induzido quimicamente , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Fibrose , Humanos , Neoplasias Renais/etiologia , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/epidemiologia , Estresse Oxidativo
17.
Med Arch ; 71(6): 430-433, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29416205

RESUMO

Objectives: Endemic nephropathy (EN) is a chronic tubulointerstitial renal disease associated with increased incidence of upper urinary tract urothelial cancer (UTUC) occurring predominantly in geographically limited areas in villages along big Danube river. Based on results obtained by the research it is confirmed that aristolochic acid is causative agent of endemic nephropathy (EN). Aim: The aim of this study was to determine characteristics of UTUC in two endemic areas and analyze trends in 5-year period. Methods: This study included all patients with UTUC with or without synchronous/metachronous urothelial cancer in urinary bladder, from Croatian and Bosnian EN and non-EN regions. We analyzed archival data bases from all patients with UTUC who were admitted and operated in Department for surgery and urology, General Hospital Josip Bencevic Slavonski Brod in the time period between 2005 and 2010. Analyzed groups of patients were divided and compared as EN group (that includes patients from Croatian and Bosnian EN region) and non-EN group (that includes patients from Croatian and Bosnian non-EN region). All surgical specimens were processed according to standardized pathological procedures. Results: Comparing patients basic characteristics from Croatian and Bosnian EN region there was no significant difference in gender (females were more frequently affected in both EN regions, p=0.99) or age (p=0.43) of patients. We found higher blood levels of urea and creatinine in group of patients from Croatian EN region when compared with group of patients from Bosnian EN region but the difference was not statistically significant (p=0.79 and p=0.44, respectively). In patients from Croatian EN group Hemoglobin levels were significantly lower than levels from Bosnian EN region patients, p=0.0049. In group of patients from Bosnian EN region ureteral tumors were more frequently observed than in Croatian group of patients, when compared with renal pelvis tumors but the difference was not statistically significant (p=0.258). Conclusion: Our data showed some differences in tumor localization between to investigated, relatively nearly situated, EN regions in Croatia and Bosnia. Statistically significant difference in hemoglobin levels between Croatian and Bosnian EN regions that should be further analyzed to give some reasonable explanation.


Assuntos
Nefropatia dos Bálcãs/sangue , Nefropatia dos Bálcãs/epidemiologia , Carcinoma de Células de Transição/epidemiologia , Hemoglobinas/metabolismo , Neoplasias Renais/epidemiologia , Neoplasias Ureterais/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Nefropatia dos Bálcãs/complicações , Bósnia e Herzegóvina/epidemiologia , Carcinoma de Células de Transição/patologia , Creatinina/sangue , Croácia/epidemiologia , Feminino , Humanos , Neoplasias Renais/patologia , Pelve Renal , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia , Fatores Sexuais , Ureia/sangue , Neoplasias Ureterais/patologia
18.
Chem Biol Interact ; 261: 63-79, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-27871899

RESUMO

The spreading of mycotoxic nephropathy in animals/humans was studied. The possible etiological causes provoking this nephropathy were carefully reviewed and analyzed. The natural content of the most frequent nephrotoxic mycotoxins in target feedstuffs/foods were investigated, in addition to their significance for development of renal damages in endemic areas. An estimation of the level of exposure of humans to the nephrotoxic mycotoxin, ochratoxin A (OTA), is made. The possible synergism or additive effects between some target mycotoxins in the development of nephropathy is also covered. The significance of joint mycotoxin interaction and masked mycotoxins, in addition to some newly isolated fungal toxic agents in the complicated etiology of mycotoxic nephropathy ranged in Balkan countries is discussed. The importance of some target fungal species which can induce kidney damages was evaluated. The morphological/ultrastructural, functional and toxicological similarities between human and animal nephropathy are studied. The possible hazard of low content of combinations of some target mycotoxins in food or feedstuff ingested by pigs, chickens or humans under natural conditions is evaluated and a risk assessment was made. Some different but more effective manners of prophylaxis and/or prevention against OTA contamination of feedstuffs/foods are suggested. A survey was made in regard to the best possible ways of veterinary hygiene control of OTA-exposed animals at slaughter time for preventing the entrance of OTA in commercial feedstuffs/food channels with a view to reduce the possible health hazard for humans. The economic efficacy and applicability of such preventive measures is additionally discussed and some practical suggestions are made.


Assuntos
Nefropatia dos Bálcãs/epidemiologia , Doenças Endêmicas , Micotoxinas/toxicidade , Medição de Risco , Animais , Península Balcânica , Humanos , Modelos Biológicos
19.
Arch Toxicol ; 90(11): 2595-2615, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27538407

RESUMO

Balkan endemic nephropathy (BEN) is a unique, chronic renal disease frequently associated with upper urothelial cancer (UUC). It only affects residents of specific farming villages located along tributaries of the Danube River in Bosnia-Herzegovina, Croatia, Macedonia, Serbia, Bulgaria, and Romania where it is estimated that ~100,000 individuals are at risk of BEN, while ~25,000 have the disease. This review summarises current findings on the aetiology of BEN. Over the last 50 years, several hypotheses on the cause of BEN have been formulated, including mycotoxins, heavy metals, viruses, and trace-element insufficiencies. However, recent molecular epidemiological studies provide a strong case that chronic dietary exposure to aristolochic acid (AA) a principal component of Aristolochia clematitis which grows as a weed in the wheat fields of the endemic regions is the cause of BEN and associated UUC. One of the still enigmatic features of BEN that need to be resolved is why the prevalence of BEN is only 3-7 %. This suggests that individual genetic susceptibilities to AA exist in humans. In fact dietary ingestion of AA along with individual genetic susceptibility provides a scenario that plausibly can explain all the peculiarities of BEN such as geographical distribution and high risk of urothelial cancer. For the countries harbouring BEN implementing public health measures to avoid AA exposure is of the utmost importance because this seems to be the best way to eradicate this once mysterious disease to which the residents of BEN villages have been completely and utterly at mercy for so long.


Assuntos
Ácidos Aristolóquicos/toxicidade , Nefropatia dos Bálcãs/induzido quimicamente , Carcinógenos Ambientais/toxicidade , Doenças Endêmicas , Medicina Baseada em Evidências , Contaminação de Alimentos , Rim/efeitos dos fármacos , Animais , Aristolochia/química , Aristolochia/crescimento & desenvolvimento , Aristolochia/toxicidade , Ácidos Aristolóquicos/análise , Nefropatia dos Bálcãs/epidemiologia , Nefropatia dos Bálcãs/fisiopatologia , Nefropatia dos Bálcãs/prevenção & controle , Carcinógenos Ambientais/análise , Fatores de Confusão Epidemiológicos , Produtos Agrícolas/crescimento & desenvolvimento , Dieta/efeitos adversos , Resistência a Medicamentos , Europa Oriental/epidemiologia , Farinha/efeitos adversos , Farinha/análise , Contaminação de Alimentos/prevenção & controle , Humanos , Rim/fisiopatologia , Plantas Daninhas/química , Plantas Daninhas/crescimento & desenvolvimento , Plantas Daninhas/toxicidade , Prevalência , Risco , Sementes/crescimento & desenvolvimento , Triticum/crescimento & desenvolvimento , Neoplasias Urológicas/induzido quimicamente , Neoplasias Urológicas/epidemiologia , Neoplasias Urológicas/fisiopatologia , Neoplasias Urológicas/prevenção & controle
20.
Tohoku J Exp Med ; 240(1): 25-30, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27568660

RESUMO

Balkan endemic nephropathy (BEN) is a chronic familial form of interstitial nephritis that might eventually lead to end stage renal disease. This nephropathy affects individuals living along of the Danube River and its tributaries in Serbia, Bosnia, Croatia, Bulgaria and Romania. The increased incidence of urinary tract tumors in the BEN areas is well described, but its specific genetic predisposition is still unclear. Certain nephrocarcinogenic compounds, including those associated with BEN, are metabolized by glutathione S-transferase (GST) superfamily of phase II detoxication enzymes. Importantly, the GST-mediated detoxification may result in formation of more toxic compounds. We examined the association of common GST polymorphisms and bladder cancer (BC) risk in individuals from BEN areas in Serbia. A hospital-based case-control study included 201 BC cases (67 from BEN region) and 122 controls. Each polymorphism was identified by a PCR-based method. Individuals from BEN region with low-expression GSTA1 genotype (AB+BB) exhibited a 2.6-fold higher BC risk compared to those with GSTA1 (AA) genotype who were from non-BEN region (OR = 2.60, p = 0.015). In contrast, carriers of GSTM1-active genotype from BEN region had a 2.9-fold increased BC risk compared to those with GSTM1-active genotype from non-BEN region (OR = 2.90, p = 0.010). Likewise, carriers with GSTT1-active genotype from BEN region exhibited 2.1-fold higher BC risk compared to those from non-BEN region with GSTT1-active genotype (OR = 2.10, p = 0.027). Thus, common polymorphisms in GSTA1, GSTM1 and GSTT1 are associated with susceptibility to BC in individuals from BEN areas of Serbia.


Assuntos
Nefropatia dos Bálcãs/genética , Predisposição Genética para Doença , Glutationa Transferase/genética , Polimorfismo Genético , Neoplasias da Bexiga Urinária/enzimologia , Neoplasias da Bexiga Urinária/genética , Estudos de Casos e Controles , Demografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sérvia
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