RESUMO
AIMS: Limonin is a tetracyclic triterpenoid isolated from citrus fruits. Here, the effects of limonin on cardiovascular abnormalities in nitric oxide-deficient rats induced by Nω-Nitrol-arginine methyl ester (L-NAME) were explored. MAIN METHODS: Male Sprague Dawley rats were given L-NAME (40 mg/kg, drinking water) for 3 weeks and then treated daily with polyethylene glycol (vehicle), limonin (50 or 100 mg/kg) or telmisartan (10 mg/kg) for two weeks. KEY FINDINGS: Limonin (100 mg/kg) markedly reduced L-NAME-induced hypertension, cardiovascular dysfunction and remodeling in rats (P < 0.05). Increases in systemic angiotensin-converting enzyme (ACE) activity and angiotensin II (Ang II) and a reduction in circulating ACE2 were restored in hypertensive rats treated with limonin (P < 0.05). Reductions in antioxidant enzymes and nitric oxide metabolites (NOx) and increases in oxidative stress components induced by L-NAME were relieved by limonin treatment (P < 0.05). Limonin suppressed the increased expression of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in cardiac tissue and circulating TNF-α in rats that received L-NAME (P < 0.05). Changes in Ang II receptor type I (AT1R), Mas receptor (MasR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) and NADPH oxidase subunit 2 (gp91phox) protein expression in cardiac and aortic tissue were normalized by limonin (P < 0.05). SIGNIFICANCE: In conclusion, limonin ameliorated L-NAME-induced hypertension, cardiovascular dysfunction and remodeling in rats. These effects were relevant to restorations of the renin-angiotensin system, oxidative stress and inflammation in NO-deficient rats. The molecular mechanisms are associated with the modulation of AT1R, MasR, NF-ĸB and gp91phox protein expression in cardiac and aortic tissue.
Assuntos
Hipertensão , Limoninas , Ratos , Masculino , Animais , Ratos Sprague-Dawley , NG-Nitroarginina Metil Éster/efeitos adversos , NF-kappa B/metabolismo , Pressão Sanguínea , Óxido Nítrico/metabolismo , Limoninas/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Hipertensão/metabolismoRESUMO
This study investigated the effects of nobiletin on cardiorenal changes and the underlying mechanisms involved in two-kidney, one-clip (2K-1C) hypertension. 2K-1C rats were treated with nobiletin (15 or 30 mg/kg/day) or losartan (10 mg/kg/day) for 4 weeks (n = 8/group). Nobiletin (30 mg/kg) reduced high levels of blood pressure and circulating angiotensin II and angiotensin-converting enzyme activity in 2K-1C rats. Left ventricular (LV) dysfunction and remodelling in 2K-1C rats were alleviated in the nobiletin-treated group (P < 0.05). Nobiletin reduced the upregulation of Ang II type I receptor (AT1R)/JAK (Janus kinase)/STAT (signal transducer and activator of transcription) protein expression in cardiac tissue of 2K-1C rats (P < 0.05). The reduction in kidney function, and accumulation of renal fibrosis in 2K-1C rats were alleviated by nobiletin (P < 0.05). Overexpression of AT1R and NADPH oxidase 4 (Nox4) protein in nonclipped kidney tissue was suppressed in the nobiletin-treated group (P < 0.05). The elevations in oxidative stress parameters and the reductions in antioxidant enzymes were attenuated in 2K-1C rats treated with nobiletin (P < 0.05). In summary, nobiletin had renin-angiotensin system inhibitory and antioxidant effects and attenuated LV dysfunction and remodelling via restoration of the AT1R/JAK/STAT pathway. Nobiletin also resolved renal damage that was related to modulation of the AT1R/Nox4 cascade in 2K-1C hypertension.
Assuntos
Hipertensão Renovascular , Hipertensão , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Pressão Sanguínea/fisiologia , Flavonas , Hipertensão Renovascular/metabolismo , Janus Quinases/metabolismo , Rim/metabolismo , Ratos , Fatores de Transcrição STAT/metabolismo , Transdução de SinaisRESUMO
Genistein is a bioflavonoid mainly found in soybean. This study evaluated the effect of genistein on vascular dysfunction and kidney damage in two-kidney, one-clipped (2K1C) hypertensive rats. Male Sprague-Dawley-2K1C hypertensive rats were treated with genistein (40 or 80 mg/kg) or losartan 10 mg/kg (n = 8/group). Genistein reduced blood pressure, attenuated the increase in sympathetic nerve-mediated contractile response and endothelial dysfunction in the mesenteric vascular beds and aorta of 2K1C rats. Increases in the intensity of tyrosine hydroxylase (TH) in the mesentery and plasma norepinephrine (NE) were alleviated in the genistein-treated group. Genistein also improved renal dysfunction, hypertrophy of the non-clipped kidney (NCK) and atrophy of the clipped kidney (CK) in 2K1C rats. Upregulation of angiotensin II receptor type I (AT1R), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit 4 (Nox4) and Bcl2-associated X protein (BAX) and downregulation of B-cell lymphoma 2 (Bcl2) protein found in CK were restored by genistein. It also suppressed the overexpression of AT1R, transforming growth factor beta I (TGF-ß1), smad2/3 and p-smad3 in NCK. Genistein reduced serum angiotensin converting enzyme (ACE) activity and plasma angiotensin II (Ang II) in 2K1C rats. Low levels of catalase activity as well as high levels of superoxide generation and malondialdehyde (MDA) in 2K1C rats were restored by genistein treatment. In conclusion, genistein suppressed renin-angiotensin system-mediated sympathetic activation and oxidative stress in 2K1C rats. It alleviated renal atrophy in CK via modulation of AT1R/NADPH oxidase/Bcl-2/BAX pathways and hypertrophy in NCK via AT1R/TGF-ß1/smad-dependent signalling pathways.
Assuntos
Genisteína/farmacologia , Hipertensão Renovascular/metabolismo , Rim/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Rim/patologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The effects of a Cratoxylum formosum (Jack) Dyer ssp. (CF) extract on testicular damage were assessed in hypertensive rats. Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME; 40 mg kg-1 day-1 ) was administered for 5 weeks to induce hypertension in male Sprague-Dawley rats, and treated with CF extract (100, 300 or 500 mg kg-1 day-1 ) or sildenafil (5 mg kg-1 day-1 ) during the final 2 weeks (n = 8/group). Biochemical components of the CF extract were identified and mainly contained phenolic compounds. The CF extract significantly reduced systolic blood pressure and alleviated impaired sperm quality and seminiferous tubular morphology in hypertensive rats. CF extract restored reduced serum testosterone and protein expression of steroidogenic acute regulatory protein (StAR), nuclear factor erythroid-related factor 2 (Nrf2), and haem oxygenase 1 (HO-1) in L-NAME rats. Hypertensive rats presented decreased antioxidant enzyme activities, and increased testicular and plasma malondialdehyde (MDA) levels and superoxide production, all of which were normalised by CF extract. Furthermore, endothelial nitric oxide synthase (eNOS) expression in testicular tissue and plasma nitrate/nitrite levels were restored in hypertensive rats administered CF extract. Conclusion: CF extract alleviated testicular damage in hypertensive rats. Potential molecular mechanisms may involve suppression of oxidative stress and restoration of StAR, Nrf2, HO-1 and eNOS expression in hypertensive rats.
Assuntos
Clusiaceae , Hipertensão , Animais , Pressão Sanguínea , Clusiaceae/metabolismo , Hipertensão/tratamento farmacológico , Masculino , NG-Nitroarginina Metil Éster , Óxido Nítrico , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: This study aimed to explore whether VDR polymorphisms (Fok1, Apa1 and Taq1) are associated to the cervical cancer in Thai population. MATERIALS AND METHODS: Subjects of 204 cervical cancer patient and 204 age-matched healthy control were enrolled in the case-control study. VDR polymorphisms were detected by using real-time PCR. Haplotype analysis of three loci was applied to the obtained genotypes. RESULTS: Significantly increased risk for cervical cancer was observed in carriers of TT genotype (p = 0.0388) and T allele (p = 0.0357) of Fok1 and TC genotype (p = 0.0001), CC genotype (p = 0.0160) and the C allele of Taq1 (p = 0.0001). Haplotype analyses revealed a significant correlation between C-T-C, T-G-C and T-T-C haplotypes and elevated risk for cervical cancer (OR = 2.06; 95%CI = 1.06-4.00; p = 0.0313, OR = 2.15; 95%CI = 1.22-3.80; p = 0.0078 and OR = 2.81; 95%CI = 1.53-5.16; p = 0.0006, respectively). Furthermore, haplotype carrying C allele of Taq1 (C-G-C + C-T-C + T-G-C + T-T-C) significantly increased cervical cancer risk with OR of 1.92 (95%CI = 1.32-2.79, p = 0.0006). CONCLUSION: Our finding revealed an association between VDR polymorphisms and cervical cancer risk. Taq1 C allele might be a molecular marker for cervical cancer development.
.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/epidemiologia , Polimorfismo Genético , Receptores de Calcitriol/genética , Neoplasias do Colo do Útero/epidemiologia , Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Genótipo , Humanos , Prognóstico , Receptores de Calcitriol/sangue , Fatores de Risco , Tailândia/epidemiologia , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologiaRESUMO
Tangeretin is a polymethoxyflavone concentrated in citrus peels and has several biological activities. This study examined whether tangeretin improved reproductive dysfunction in Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Male Sprague-Dawley rats received L-NAME to induce hypertension and reproductive dysfunction for 5 w and were treated with tangeretin (15 or 30 mg/kg) or sildenafil citrate (10 mg/kg) for the final two weeks. Mean arterial pressure (MAP), intracavernosal pressure (ICP) response to cavernous nerve stimulation, endothelial nitric oxide synthase (eNOS), Angiotensin II receptor type 1 (AT1R) and gp91phox protein expressions and malondialdehyde (MDA) level in penile tissues were measured. Sperm concentrations and motility, seminiferous tubule morphology, serum testosterone, testicular eNOS and steroidogenic acute regulatory protein (StAR) expression were evaluated. Aortic superoxide generation, plasma and testicular MDA and plasma nitrate/nitrite levels were determined. Tangeretin reduced blood pressure and increased the maximum ICP/MAP associated with suppression of AT1R/gp91phox and upregulation of eNOS expression in hypertensive rats (P < 0.05). Furthermore, improvement of sperm quality relevant to increased testicular eNOS and StAR expression was found in tangeretin treated rats (P < 0.05). Changes in seminiferous tubule morphology in hypertensive rats were recovered by tangeretin (P < 0.05). It increased testosterone levels and reduced oxidative stress biomarkers and raised plasma nitrate/nitrite levels in L-NAME rats (P < 0.05). In conclusion, tangeretin improved maximum ICP/MAP and testicular dysfunction and morphology in rats treated with L-NAME. The molecular mechanisms are mediated by modulations of penile eNOS and AT1R/gp91phox expressions and testicular eNOS and StAR expression.
Assuntos
Disfunção Erétil/tratamento farmacológico , Flavonas/uso terapêutico , Hipertensão/tratamento farmacológico , Animais , Aorta Torácica/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Disfunção Erétil/induzido quimicamente , Disfunção Erétil/metabolismo , Disfunção Erétil/fisiopatologia , Flavonas/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Malondialdeído/sangue , Malondialdeído/metabolismo , NADPH Oxidase 2/metabolismo , NG-Nitroarginina Metil Éster , Óxido Nítrico/sangue , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Pênis/efeitos dos fármacos , Pênis/metabolismo , Pênis/fisiologia , Fosfoproteínas/metabolismo , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Motilidade dos Espermatozoides/efeitos dos fármacos , Superóxidos/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismoRESUMO
BACKGROUND: CYP1A1 is an enzyme in phase I of the cytochrome P450 (CYP) superfamily, and plays a key role in detoxification of carcinogens. Host genetic predisposition in the CYP1A1 may be associated with an increased susceptibility to cervical cancer.The study aimed to evaluate four common polymorphisms of the CYP1A1 and cervical cancer susceptibility among Northeast Thai women. METHODS: A case-control study was conducted involving 204 patients with squamous cell cervical cancer (SCCA) and 204 age-matched healthy controls. DNA was extracted from peripheral blood leucocytes. CYP1A1 m1, m3, and m4 genotypes were detected using PCR-RFLP, whereas the CYP1A1 m2 genotype was investigated using real-time PCR. Haplotype analysis was performed using PHASE algorithm version 2.1.1. RESULTS: CYP1A1 m3 was monomorphic. Association between the common CYP1A1 polymorphisms, m1 and m2, and cervical cancer risk was not observed (p>0.05), nor was any association found between the m1-m2-m4 haplotype and cervical cancer risk (p>0.05). Interestingly, the CA genotype of CYP1A1 m4 was observed in 30.88% of the cervical cancer patients but was absent in healthy controls. CONCLUSION: Our results demonstrated a possible involvement of the CYP1A1 m4 polymorphism but no other common polymorphisms (viz., m1, m2, and m3) in the risk for cervical cancer.This finding may be useful when screening for risk of cervical cancer among Northeast Thai women.
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Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Citocromo P-450 CYP1A1/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de RiscoRESUMO
Objective: We aimed to investigate any association between a genetic polymorphism of the detoxification GSTP1 gene and risk of cervical cancer in northeastern Thailand. Materials and Methods: Genotyping of GSTP1 was performed for 198 squamous cell cervical cancer (SCCA) patients and 198 age-matched healthy controls with the PCR-RFLP method. Results: The respective frequencies of the G allele were 0.33 and 0.26 in the controls and cases, the difference being significant (OR = 0.69 [95% CI: 0.50-0.95, p=0.0192]). Among women infected with high-risk types of HPV, being a heterozygous carrier was associated with a reduced risk of cervical cancer (adjusted OR = 0.32 [95% CI: 0.12-0.91, p=0.031]). Similarly, a decreased risk was observed in heterozygous women with a non-smoking partner (adjusted OR = 0.27 [95% CI: 0.09-0.83, p=0.023]). Conclusions: GSTP1 polymorphism could influence susceptibility to cervical cancer among northeast Thai women; either as a independent factor or in combination with high-risk HPV infection. Dual-testing of HPV and the GSTP1 might prove an effective screening tool for cervical cancer.
Assuntos
Biomarcadores Tumorais/genética , Glutationa S-Transferase pi/genética , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Polimorfismo Genético , Neoplasias do Colo do Útero/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/virologia , Prognóstico , Fatores de Risco , Tailândia/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/virologiaRESUMO
Objective: The aim of this study was to investigate the association between genotype and haplotype of MDR1 (C1236T, G2677T/A and C3435T) and the risk for cervical cancer in Northeastern Thai women. Methods: An age-matched case-control study involving squamous cell cervical cancer (SCCA) patients (n=204) and healthy controls (n=204) was enrolled for MDR1 genotyping by real-time PCR method. Results: The genotype distribution of MDR1 in both patients and controls was not significantly different (p>0.05). The haplotype analysis showed that T-T-T was the most common haplotype in this population. Significantly increased risk of cervical cancer was observed in carriers of T-T-C and C-G-T haplotypes with ORs of 1.86 (95%CI=1.02-3.39, p=0.0416) and 2.00 (95%CI=1.18-3.40, p=0.0140), respectively. Analysis of 2677-3435 haplotype showed increased risk for cervical cancer in G-T (OR=1.55; 95% CI=1.12-2.13, p=0.0432) and T-C (OR=1.91; 95%CI=1.05-3.47, p=0.0325). Conclusion: The results provide evidence that haplotype of MDR1 may be an important risk factor for cervical cancer development in Northeastern Thai women.
RESUMO
Risks with GSTM1 genotypes and potential roles of smoking in the susceptibility to oral squamous cell carcinoma (OSCC) were studied in Northeastern Thailand. Study subjects were 79 histologically-confirmed OSCC cases (31 men, 48 women) and 79 age- and sex-matched healthy controls ranging in age from 25 to 84 years. GSTM1 genotyping was achieved by two independent PCR assays. The GSTM1 null allele and the homozygous genotype did not increase risk of OSCC vs the wild type allele and the remaining genotypes. When the focus was on the smoking habit, male subjects who smoked ≥10 or ≥35 years were at significantly increased risk for OSCC with adjusted ORs of 4.88 [95%CI, 1.41-16.87, p=0.012] or 4.94 [95%CI, 1.62-15.12, p=0.005], respectively. A higher risk for OSCC was found for smoking amount; those who smoked >5 or >10 pack-years were at a higher risk with adjusted OR of 4.46 [95%CI; 1.45-13.74, p=0.009] or 3.89 [95%CI; 1.34-11.28, p=0.012], respectively. There are certain smoking patterns that give greater risks and thus both smoking duration and pack-years should be taken into consideration in tobacco related cancer prevention.
Assuntos
Biomarcadores Tumorais/genética , Glutationa Transferase/genética , Neoplasias Bucais/etiologia , Polimorfismo Genético/genética , Fumar/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Seguimentos , Predisposição Genética para Doença , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Prognóstico , Fatores de RiscoRESUMO
The potential association between the GSTM1 deletion polymorphism and risk of cervical cancer was investigated in Northeastern Thailand. DNA was extracted from buffy coat specimens of 198 patients with squamous cell carcinoma of the cervix and 198 age-matched healthy controls. Genotyping of the GSTM1 was conducted by using two PCR methods, a short- and a long-PCR. Distribution of the GSTM1 genotypes in between the cases and the controls was not significantly different (p>0.5 by χ2 test). The results suggest that the GSTM1 deletion polymorphism is not a risk factor for squamous cell carcinoma of the cervix in the northeast Thai women.
Assuntos
Carcinoma de Células Escamosas/genética , Predisposição Genética para Doença/genética , Glutationa Transferase/genética , Polimorfismo Genético/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Deleção de Sequência/genética , TailândiaRESUMO
Human papillomavirus (HPV) genotype 52 is commonly found in Asian cases of cervical cancer but is rare elsewhere. Analysis of 611 isolates collected worldwide revealed a remarkable geographical distribution, with lineage B predominating in Asia (89.0% vs 0%-5.5%; P(corrected) < .001), whereas lineage A predominated in Africa, the Americas, and Europe. We propose that the name "Asian lineage" be used to denote lineage B, to signify this feature. Preliminary analysis suggested a higher disease risk for lineage B, although ethnogeographical confounders could not be excluded. Further studies are warranted to verify whether the reported high attribution of disease to HPV52 in Asia is due to the high prevalence of lineage B.
Assuntos
Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Topografia Médica , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Saúde Global , Humanos , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Filogeografia , Prevalência , Medição de Risco , Adulto JovemRESUMO
Human papillomavirus (HPV) is a major cause of cervical cancer. More than 100 HPV genotypes have been identified; however the distribution varies geographically and according to ethnicity. The purpose of this study was to investigate the prevalence and distribution of HPV subtypes among Northeast Thai women. Subjects included 198 cases of SCCA and 198 age-matched, healthy controls. HPV-DNA was amplified by PCR using the consensus primers GP5+/6+ system followed by reverse line blot hybridization genotyping. The prevalence of high-risk HPV infection was 21 (10.1%) and 152 (76.8%) in the controls and in the cases, respectively. High-risk HPV significantly increased the risk for cervical cancer with an OR of 42.4 (95%CI: 22.4-81.4, p<0.001) and an adjusted OR of 40.7-fold (95%CI: 21.5-76.8, p <0.001). HPV-16 was the most prevalent HPV type in the SCCA (56.2%) followed by HPV-58 (17.8%) and HPV-18 (13.6%); whereas HPV-58 (46.4%) was a prominent genotype in the controls followed by HPV-16 (39.3%) and unidentified HPV types (25.0%). These findings indicate that HPV infection remains a critical risk factor for SCCA; particularly, HPV-16, HPV-58 and HPV-18. In order to eradicate cervical cancer, sustained health education, promoted use of prophylactics and a HPV-58 vaccine should be introduced in this region.
Assuntos
Carcinoma de Células Escamosas/virologia , DNA Viral/genética , Papillomaviridae/genética , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Colo do Útero/metabolismo , Colo do Útero/patologia , Feminino , Seguimentos , Genótipo , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Infecções por Papillomavirus/diagnóstico , Reação em Cadeia da Polimerase , Prevalência , Prognóstico , Fatores de Risco , Tailândia/epidemiologia , Neoplasias do Colo do Útero/patologia , Esfregaço VaginalRESUMO
Human papillomavirus (HPV) 58 accounts for a notable proportion of cervical cancers in East Asia and parts of Latin America, but it is uncommon elsewhere. The reason for such ethnogeographical predilection is unknown. In our study, nucleotide sequences of E6 and E7 genes of 401 HPV58 isolates collected from 15 countries/cities across four continents were examined. Phylogenetic relationship, geographical distribution and risk association of nucleotide sequence variations were analyzed. We found that the E6 genes of HPV58 variants were more conserved than E7. Thus, E6 is a more appropriate target for type-specific detection, whereas E7 is more appropriate for strain differentiation. The frequency of sequence variation varied geographically. Africa had significantly more isolates with E6-367A (D86E) but significantly less isolates with E6-203G, -245G, -367C (prototype-like) than other regions (p ≤ 0.003). E7-632T, -760A (T20I, G63S) was more frequently found in Asia, and E7-793G (T74A) was more frequent in Africa (p < 0.001). Variants with T20I and G63S substitutions at E7 conferred a significantly higher risk for cervical intraepithelial neoplasia grade III and invasive cervical cancer compared to other HPV58 variants (odds ratio = 4.44, p = 0.007). In conclusion, T20I and/or G63S substitution(s) at E7 of HPV58 is/are associated with a higher risk for cervical neoplasia. These substitutions are more commonly found in Asia and the Americas, which may account for the higher disease attribution of HPV58 in these areas.
Assuntos
Biomarcadores Tumorais/genética , Proteínas do Capsídeo/genética , Variação Genética/genética , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/genética , Displasia do Colo do Útero/genética , Neoplasias do Colo do Útero/genética , Colo do Útero/metabolismo , DNA de Neoplasias/genética , Feminino , Seguimentos , Geografia , Humanos , Agências Internacionais , Papillomaviridae/genética , Infecções por Papillomavirus/virologia , Filogenia , Reação em Cadeia da Polimerase , Prognóstico , Medição de Risco , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/virologiaRESUMO
Cervical cancer is a serious public health problem in Thailand. We investigated possible risk factors for cervical cancer including HPV infection, p53 polymorphism, smoking and reproductive history among women in Northeast Thailand using a case control study with 177 cases and age-matched controls. Among the HPV carriers, a significantly increased risk for cervical cancer with an OR of 36.97 (p<0.001) and an adjusted OR of 38.07 (p<0.001) were observed. Early age at first sexual exposure, and multiple sexual partners increased the risk of cervical cancer with ORs ranging between 1.73-2.78 (p<0.05). The interval between menarche and first sexual intercourse<6 years resulted in a significant increase in the risk for cervical cancer with ORs ranging between 3.32-4.09 and the respective adjusted OR range for the 4-5 and 2-3 year-old groups were 4.09 and 2.92. A higher risk was observed among subjects whose partner had smoking habits, whether currently or formerly; with respective ORs of 3.36 (p<0.001) and 2.17 (p<0.05); and respective adjusted ORs of 2.90 (p<0.05) and 3.55 (p<0.05). Other smoking characteristics of the partners including smoking duration≥20 years, number of cigarettes smokes≥20 pack-years and exposure time of the subject to passive smoking≥5 hrs per day were found to be statistically significant risks for cervical cancer with adjusted ORs of 3.75, 4.04 and 11.8, respectively. Our data suggest that the risk of cervical cancer in Thai women is substantially associated with smoking characteristics of the partner(s), the interval between menarche and first sexual intercourse as well as some other aspects of sexual behavior.
Assuntos
Carcinoma de Células Escamosas/etiologia , Comportamento Sexual/psicologia , Fumar/psicologia , Neoplasias do Colo do Útero/etiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/psicologia , Estudos de Casos e Controles , DNA/análise , DNA/genética , Feminino , Humanos , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , História Reprodutiva , Fatores de Risco , Tailândia , Neoplasias do Colo do Útero/psicologiaRESUMO
To identify risk factors other than high risk human papillomavirus infection for the development of cervical cancer, functional polymorphisms of DNA repair genes, XRCC1 Arg399Gln and Arg194Trp and XRCC3 Thr241Met, were studied among Northeastern Thai women. Cases (n=111) were defined as squamous cell cervical cancer and controls (n=118) were recruited from healthy women without cervical abnormalities. The XRCC1 194Trp/Trp genotype significantly increased the risk for cervical cancer (OR=5.52; 95%CI=1.14-26.64; p=0.03). Among the HPV infection negative group, significantly higher risks for cervical cancer were visualized for XRCC1 399Arg/Gln (adjusted OR=3.69; 95%CI=1.04-13.06; p=0.04) and XRCC1 194Arg/Trp (adjusted OR=4.13; 95%CI=1.13-15.12; p=0.03). This study indicates that variant types of DNA repair genes play partial roles in modifying individual susceptibility to cervical cancer. Since cervical cancer is a multi-factorial disease, the contribution of DNA repair enzymes to the development of cervical cancer, if it exists may be concealed by HPV infection.
Assuntos
Reparo do DNA , Proteínas de Ligação a DNA/genética , Neoplasias de Células Escamosas/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Códon , Feminino , Frequência do Gene/genética , Loci Gênicos , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/complicações , Polimorfismo Genético , Fatores de Risco , Tailândia , Neoplasias do Colo do Útero/virologia , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
BACKGROUND: Human papillomavirus type 58 (HPV-58) accounts for a much higher proportion of cervical cancers in East Asia than other types. A classification system of HPV-58, which is essential for molecular epidemiological study, is lacking. METHODS AND RESULTS: This study analyzed the sequences of 401 isolates collected from 15 countries and cities. The 268 unique concatenated E6-E7-E2-E5-L1-LCR sequences that comprised 57% of the whole HPV-58 genome showed 4 distinct clusters. L1 and LCR produced tree topologies that best resembled the concatenated sequences and thus are the most appropriate surrogate regions for lineage classification. Moreover, short fragments from L1 (nucleotides 6014-6539) and LCR (nucleotides 7257-7429 and 7540-52) were found to contain sequence signatures informative for lineage identification. Lineage A was the most prevalent lineage across all regions. Lineage C was more frequent in Africa than elsewhere, whereas lineage D was more prevalent in Africa than in Asia. Among lineage A variants, sublineage A2 dominated in Africa, the Americas, and Europe, but not in Asia. Sublineage A1, which represents the prototype that originated from a patient with cancer, was rare worldwide except in Asia. CONCLUSIONS: HPV-58 can be classified into 4 lineages that show some degree of ethnogeographic predilection in distribution. The evolutionary, epidemiological, and pathological characteristics of these lineages warrant further study.
Assuntos
Alphapapillomavirus/classificação , Alphapapillomavirus/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , África/epidemiologia , América/epidemiologia , Ásia/epidemiologia , Sequência de Bases , Colo do Útero/patologia , Colo do Útero/virologia , Distribuição de Qui-Quadrado , Europa (Continente)/epidemiologia , Feminino , Humanos , Dados de Sequência Molecular , Filogenia , Filogeografia , Alinhamento de Sequência , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/virologiaRESUMO
Epstein-Barr virus (EBV) is ubiquitous in the human population and seroepidemiological studies have revealed that more than 90% of adults are infected with the virus in Thailand. It has been suggested that latent membrane protein 1 (LMP1) variants may differ in their tumorigenicity and geographical localization. The distribution of LMP1 variants of EBV in the Thai population was studied. A total of 259 LMP1 sequences from ten Thai ethnic groups (Lahu, Lisu, Shan, Red Karen, White Karen, Hmong, Akha, Mlabri, Moken and Urak Lawoi) were studied using direct PCR sequencing. Nucleotide sequences corresponding to the C terminus of the LMP1, including previously published sequences from central and southern Thais, were used in the phylogenetic analysis. Five strains--the B95-8 prototype, China 1, China 2, Mediterranean (Med) and SEA 2--were identified in ethnic groups in Thailand. The major strain and the distribution pattern differed by group and location. When the ethnic groups were classified by linguistic group, the prevalence of the SEA 2 strain was significantly different between Austro-Thais and other linguistic groups (P=0.0001), whereas, among Tibeto-Burman linguistic groups, the prevalence of the Med strain was different between matrilocal and patrilocal groups (P=0.0245). The distribution of LMP1 strains in ethnic minorities in Thailand is associated with ethnogeographical factors and the social/marriage system. This study thus provides evidence for the importance of interactions between populations in virus diversity.
Assuntos
Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/classificação , Herpesvirus Humano 4/genética , Polimorfismo Genético , Proteínas da Matriz Viral/genética , Adulto , Análise por Conglomerados , DNA Viral/química , DNA Viral/genética , Etnicidade , Geografia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Epidemiologia Molecular , Dados de Sequência Molecular , Filogenia , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Homologia de Sequência , Tailândia/epidemiologiaRESUMO
To evaluate the relationships between genetic polymorphisms of the GSTs (GSTM1 and GSTT1) and cervical cancer, the null genotype of each gene was studied in squamous cell cervical cancer (SCCA) patients (n=90) and controls (n=94) in Northeast Thailand. The prevalence of the GSTM1-null genotype in the controls and SCCA patients was 59.6% and 60.0%, respectively, whereas those of the GSTT1-null genotype in the control and SCCA patients was 40.4% and 46.7%, respectively. Neither of the GST-null genotypes increased the risk for SCCA (p>0.05); however, the combination of the GSTM-1 and GSTT1-null genotypes showed a non-significant trend for an increased risk for developing cervical cancer with an adjusted OR of 2.7 (95%CI=0.8-9.0, p=0.10). Genetic polymorphisms of GSTM1 and GSTT1 were not significant risk factors for cervical cancer in either tobacco-smokers or non-smokers. A different contribution of the GST genotype to cancer risk may be attributed to a different, as yet undefined, property of the enzymes.
Assuntos
Carcinoma de Células Escamosas/genética , Glutationa Transferase/genética , Polimorfismo Genético/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Fumar , Tailândia , Neoplasias do Colo do Útero/patologiaRESUMO
Hair morphology is one of the most differentiated traits among human populations. A previous study has shown that a nonsynonymous single nucleotide polymorphism (SNP) in the EDAR gene, EDAR 1540T/C, is strongly associated with hair thickness in Asian populations. However, the contributions of other genes remain to be elucidated. In this study, 12 SNPs on 10 hair formation-related genes with high differentiation between Asian and other populations were examined to further identify genes associated with hair morphology. A multiple regression analysis adjusted for age, sex, population and the effect of EDAR 1540T/C revealed an SNP in intron 9 of FGFR2, rs4752566, to be significantly associated with hair thickness (cross-sectional area; P-value=0.0052, small diameter; P-value=0.029 and large diameter; P-value=0.0015). In the genomic region containing the FGFR2 gene, rs4752566 was not in strong linkage disequilibrium (LD) with the surrounding SNPs, indicating that the significant association of rs4752566 with the hair thickness is not due to LD with polymorphisms of the other genes. The rs4752566-T allele of FGFR2, associated with thicker hair, was also shown to be associated with higher mRNA level of FGFR2 (P-value=0.0270). These results suggest that the FGFR2 polymorphism affects the variation in hair thickness in Asia through alteration in the expression level of FGFR2.