RESUMEN
BACKGROUND: Despite the national campaigns in 1997 to control Opisthorchis viverrini (OV), a significant risk factor for cholangiocarcinoma (CCA) was accounted for in the northeast of Thailand, which is also considered the highest-risk area for CCA as per the latest national-wide survey in 2019. Social innovations were employed to address OV and CCA issues in this area, but they have yet to be thoroughly investigated. Investigating social innovations in areas where issues can already be solved is a particular approach for expanding on a broad basis. OBJECTIVE: This study aimed to search for social innovations used to handle OV and CCA in northeast of Thailand. METHODS: Researchers coordinated with the Office of Disease Prevention and Control Region-10 (1 of 12 regional offices under the Department of Disease Control, Ministry of Public Health) to specify the model areas for taking OV and CCA. In addition, researchers cooperated with local coordination units for data collection. The data were coded and classified for content analysis, and triangulation was performed for comparative analysis. Finally, a meeting was conducted to summarize the social innovations discovered in each study site area. RESULTS: Our findings have been presented according to the epidemiologic triad: agent (risk factors), host (individuals/communities), and environment. The researchers and experts addressed and proposed social innovations for dealing with OV and CCA, such as the "3 Health" (Health Behaviours, Health Hygiene, and Environmental Health), in order to achieve a CCA-free society. CONCLUSIONS: This is the first study to highlight the significance of social innovations in managing OV and CCA. The findings will be utilized to further create strategies for addressing these public health issues in this and other regions in a sustainable and successful manner.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Opistorquiasis , Opisthorchis , Colangiocarcinoma/prevención & control , Colangiocarcinoma/parasitología , Colangiocarcinoma/epidemiología , Opistorquiasis/epidemiología , Opistorquiasis/prevención & control , Opistorquiasis/parasitología , Humanos , Tailandia/epidemiología , Animales , Opisthorchis/patogenicidad , Neoplasias de los Conductos Biliares/prevención & control , Neoplasias de los Conductos Biliares/epidemiología , Factores de RiesgoRESUMEN
Clonorchis sinensis, Opisthorchis viverrini and O. felineus are liver flukes of human and animal pathogens occurring across much of Europe and Asia. Nevertheless, they are often underestimated compared to other, better known neglected diseases in spite of the fact that many millions of people are infected and hundreds of millions are at risk. This is possibly because of the chronic nature of the infection and disease and that it takes several decades prior to a life-threatening pathology to develop. Several studies in the past decade have provided more information on the molecular biology of the liver flukes which clearly lead to better understanding of parasite biology, systematics and population genetics. Clonorchiasis and opisthorchiasis are characterized by a chronic infection that induces hepatobiliary inflammation, especially periductal fibrosis, which can be detected by ultrasonography. These chronic inflammations eventually lead to cholangiocarcinoma (CCA), a usually fatal bile duct cancer that develops in some infected individuals. In Thailand alone, opisthorchiasis-associated CCA kills up to 20,000 people every year and is therefore of substantial public health importance. Its socioeconomic impacts on impoverished families and communities are considerable. To reduce hepatobiliary morbidity and CCA, the primary intervention measures focus on control and elimination of the liver fluke. Accurate diagnosis of liver fluke infections in both human and other mammalian, snail and fish intermediate hosts is important for achieving these goals. While the short-term goal of liver fluke control can be achieved by praziquantel chemotherapy, a comprehensive health education package targeting school children is believed to be more beneficial for a long-term goal/solution. It is recommended that transdisciplinary research or multisectoral control approach including one health and/or eco health intervention strategy should be applied to combat the liver flukes and hence contribute to reduction of CCA in endemic areas.
Asunto(s)
Clonorquiasis , Clonorchis sinensis , Opistorquiasis , Opisthorchis , Animales , Humanos , Opisthorchis/patogenicidad , Opistorquiasis/epidemiología , Opistorquiasis/parasitología , Clonorquiasis/epidemiología , Clonorquiasis/parasitología , Clonorquiasis/prevención & control , Clonorquiasis/tratamiento farmacológico , Clonorchis sinensis/patogenicidad , Clonorchis sinensis/genética , Clonorchis sinensis/fisiología , Neoplasias de los Conductos Biliares/parasitología , Neoplasias de los Conductos Biliares/epidemiología , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/parasitología , Colangiocarcinoma/epidemiologíaRESUMEN
Cholangiocarcinoma (CCA) exhibits a heightened incidence in regions with a high prevalence of Opisthorchis viverrini infection, with previous studies suggesting an association with diabetes mellitus (DM). Our study aimed to investigate the spatial distribution of CCA in relation to O. viverrini infection and DM within high-risk populations in Northeast Thailand. Participants from 20 provinces underwent CCA screening through the Cholangiocarcinoma Screening and Care Program between 2013 and 2019. Health questionnaires collected data on O. viverrini infection and DM, while ultrasonography confirmed CCA diagnoses through histopathology. Multiple zero-inflated Poisson regression, accounting for covariates like age and gender, assessed associations of O. viverrini infection and DM with CCA. Bayesian spatial analysis methods explored spatial relationships. Among 263,588 participants, O. viverrini infection, DM, and CCA prevalence were 32.37%, 8.22%, and 0.36%, respectively. The raw standardized morbidity ratios for CCA was notably elevated in the Northeast's lower and upper regions. Coexistence of O. viverrini infection and DM correlated with CCA, particularly in males and those aged over 60 years, with a distribution along the Chi, Mun, and Songkhram Rivers. Our findings emphasize the association of the spatial distribution of O. viverrini infection and DM with high-risk CCA areas in Northeast Thailand. Thus, prioritizing CCA screening in regions with elevated O. viverrini infection and DM prevalence is recommended.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Opistorquiasis , Opisthorchis , Humanos , Colangiocarcinoma/epidemiología , Colangiocarcinoma/parasitología , Tailandia/epidemiología , Masculino , Opistorquiasis/complicaciones , Opistorquiasis/epidemiología , Opistorquiasis/parasitología , Femenino , Persona de Mediana Edad , Opisthorchis/patogenicidad , Animales , Neoplasias de los Conductos Biliares/epidemiología , Neoplasias de los Conductos Biliares/parasitología , Anciano , Prevalencia , Adulto , Análisis Espacial , Diabetes Mellitus/epidemiología , Teorema de Bayes , Factores de RiesgoRESUMEN
Although Opisthorchis viverrini (OV), lifestyle, and diet co-factors have a relatively high prevalence in the Greater Mekong Subregion (GMS) population, cumulative (0-74) incidence rates of cholangiocarcinoma (CCA) do not reach 5% in this region. Other co-factors must influence, but in this study, we only highlighted positive factors for guiding joint planning to address public health problems at the regional level. Therefore, we aimed to study prevalence and factors associated with CCA incidence focusing only on protective factors. A cross-sectional analytic study was carried out from June to October 2017. Participants with informed consent completed the questionnaires. Descriptive statistics were used to analyze general information. Primary variables were classified into high and low levels by mean. Logistic regression was employed to investigate the correlation between interesting variables and the overall risk level of CCA. The overall prevalence of CCA protective factors of the whole region was knowledge (61.39%), health beliefs (42.32%), prevention behavior (31.93%), and community participation (14.53%). When considering the proportions at a high level, they were 49.53%, 53.72%, 35.37%, and 49.67%, respectively. Significant factors associated with CCA prevention were females with secondary or vocational education, a high level of perceived seriousness and benefits, and community participation. These findings are likely to be helpful for both the public and administrators. First, it can be information for people to be aware of CCA risk. Second, policy-driven authorities at the local or regional level should apply the critical issues from this study for joint planning to sustainably solve regional public health problems.
Asunto(s)
Neoplasias de los Conductos Biliares/etiología , Neoplasias de los Conductos Biliares/prevención & control , Colangiocarcinoma/etiología , Colangiocarcinoma/prevención & control , Adulto , Animales , Conductos Biliares Intrahepáticos/parasitología , Colangiocarcinoma/parasitología , Participación de la Comunidad/estadística & datos numéricos , Estudios Transversales , Femenino , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Opistorquiasis/complicaciones , Opistorquiasis/parasitología , Opisthorchis/patogenicidad , Prevalencia , Factores Protectores , Salud Pública/estadística & datos numéricos , Factores de RiesgoRESUMEN
BACKGROUND: Liver fluke, Opisthorchis viverrini, is associated to cholangiocarcinoma which is found frequently in some areas of Southeast Asian countries particularly in Thailand, Lao People Republic Democratic, Cambodia. This study sought to investigate the effects of an O. viverrini and cholangiocarcinoma (OVCCA) web application to facilitate health literacy regarding O. viverrini in Northeast Thailand. METHODS: A randomized controlled trial study was performed among an intervention group (n=63) and a control group (n=63) during a one-year period from July 2019 to May 2020. The intervention group received the health literacy promotion program of O. viverrini information through the OVCCA web application for 6 weeks. The control group received an activity package from the public health department. The success of the program was evaluated at week 24 after the groups finished the last activity. ANCOVA, t-test and multiple logistic regression were used for data analysis for both groups. RESULTS: The scores for knowledge; ability to access, understand, appraise, and apply information; motivation for protection; and practice of O. viverrini prevention were significantly higher for the intervention group than for the control group. The results indicated that a health literacy promotion program through an OVCCA web application could be advantageous for preventing and controlling O. viverrini infection. CONCLUSION: This intervention may be used as a potential strategy and guideline for self-care and health promotion in other endemic areas.
Asunto(s)
Colangiocarcinoma/parasitología , Alfabetización en Salud/estadística & datos numéricos , Promoción de la Salud/métodos , Opisthorchis/patogenicidad , Programas Informáticos , Adolescente , Adulto , Anciano , Animales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Programas y Proyectos de Salud , Tailandia , Adulto JovenRESUMEN
BACKGROUND: The liver fluke, Opisthorchis felineus, is widely distributed throughout Europe and large parts of the Russian Federation. In Western Siberia, information about opisthorchiasis is lacking although infection may lead to severe liver and bile duct diseases. We aimed to assess the current prevalence of O. felineus infection along with associated risk factors and morbidity in rural Western Siberia. METHODS: We conducted a community-based, cross-sectional study in the rural Shegarskiy district, Tomsk Oblast, Russian Federation. All household members (≥ 7 years) present on the survey day were enrolled (n = 600). Two stool samples per person were examined for helminth eggs, using PARASEP (DiaSys Ltd, UK). The number of eggs per gram (EPG) of feces was recorded. Each study participant was interviewed to determine risk factors, using a pre-tested questionnaire. An abdominal ultrasonography examination of liver and bile ducts was performed with a mobile, high resolution ultrasound device. In total, 488 persons completed assessments (two stool samples, completed questionnaires); of those, 436 individuals had an ultrasonography (US) examination. RESULTS: We observed a prevalence of O. felineus infection of 60.2%. Significant risk factors for infection were the consumption of river fish (odds ratio from adjusted analysis [aOR] 2.4, 95% CI 1.52-3.95, p<0.001), particularly stock fish (OR from multivariable analysis [mOR] 3.2, 95% CI 2.63-3.80, p<0.001), smoked fish (mOR 1.5, 95% CI 1.24-1.72, p<0.001), frozen fish (mOR 1.6, 95% CI 1.29-2.02, p<0.001), and raw fish (mOR 1.4, 95% CI 1.05-1.84, p = 0.02); and fishing activities (mOR 1.2, 95% CI 1.03-1.43, p = 0.019). Women had a higher risk of infection than men. Infection was associated positively with age and negatively with socio-economic status. The respondents' general awareness of opisthorchiasis was quite high (93.2%), but their knowledge about infection transmission and prevention was insufficient. Children aged 7-18 years old had a lower level of awareness compared to adults. The abdominal ultrasonography results demonstrated a strong association between O. felineus infection and gallbladder stones (mOR 2.8, 95% CI 1.33-6.04, p = 0.007) and periductal fibrosis of intrahepatic bile ducts (mOR 1.9, 95% CI 1.08-3.46, p = 0.026). CONCLUSION: O. felineus infection is highly prevalent in rural regions of Western Siberia, and associated with severe hepatobiliary pathology. Identified risk factors will be used to develop a comprehensive targeted O. felineus infection control program.
Asunto(s)
Opistorquiasis/epidemiología , Opisthorchis/patogenicidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Neoplasias de los Conductos Biliares/parasitología , Conductos Biliares/parasitología , Niño , Estudios Transversales , Femenino , Peces/parasitología , Humanos , Hígado/parasitología , Masculino , Persona de Mediana Edad , Morbilidad , Análisis Multivariante , Opistorquiasis/complicaciones , Opistorquiasis/diagnóstico , Opistorquiasis/parasitología , Prevalencia , Factores de Riesgo , Población Rural , Siberia/epidemiología , Ultrasonografía , Adulto JovenRESUMEN
Crosstalk between malignant and neighboring cells contributes to tumor growth. In East Asia, infection with the liver fluke is a major risk factor for cholangiocarcinoma (CCA). The liver fluke Opisthorchis viverrini secretes a growth factor termed liver fluke granulin, a homologue of the human progranulin, which contributes significantly to biliary tract fibrosis and morbidity. Here, extracellular vesicle (EV)-mediated transfer of mRNAs from human cholangiocytes to naïve recipient cells was investigated following exposure to liver fluke granulin. To minimize the influence of endogenous progranulin, its cognate gene was inactivated using CRISPR/Cas9-based gene knock-out. Several progranulin-depleted cell lines, termed ΔhuPGRN-H69, were established. These lines exhibited >80% reductions in levels of specific transcript and progranulin, both in gene-edited cells and within EVs released by these cells. Profiles of extracellular vesicle RNAs (evRNA) from ΔhuPGRN-H69 for CCA-associated characteristics revealed a paucity of transcripts for estrogen- and Wnt-signaling pathways, peptidase inhibitors and tyrosine phosphatase related to cellular processes including oncogenic transformation. Several CCA-specific evRNAs including MAPK/AKT pathway members were induced by exposure to liver fluke granulin. By comparison, estrogen, Wnt/PI3K and TGF signaling and other CCA pathway mRNAs were upregulated in wild type H69 cells exposed to liver fluke granulin. Of these, CCA-associated evRNAs modified the CCA microenvironment in naïve cells co-cultured with EVs from ΔhuPGRN-H69 cells exposed to liver fluke granulin, and induced translation of MAPK phosphorylation related-protein in naïve recipient cells in comparison with control recipient cells. Exosome-mediated crosstalk in response to liver fluke granulin promoted a CCA-specific program through MAPK pathway which, in turn, established a CCA-conducive disposition.
Asunto(s)
Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Granulinas/metabolismo , Opisthorchis/metabolismo , Animales , Neoplasias de los Conductos Biliares/genética , Conductos Biliares/citología , Línea Celular , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Transformación Celular Neoplásica/patología , Colangiocarcinoma/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Vesículas Extracelulares/metabolismo , Regulación Neoplásica de la Expresión Génica , Granulinas/toxicidad , Mutación , Opisthorchis/patogenicidad , Progranulinas/genética , Progranulinas/metabolismo , Progranulinas/farmacología , ARN Mensajero/metabolismo , Microambiente TumoralRESUMEN
Millions of people are infected with the liver fluke, Opisthorchis viverrini (OV), but only ~25% of those infected develop liver disease and even fewer develop cholangiocarcinoma. The reasons for these differential outcomes following infection are unknown but it has been proposed that differential immune responses to the parasite may play a role. We therefore measured granulocyte (neutrophil) function in OV-infected individuals, with and without advanced periductal fibrosis, to determine if these cells have a "pro-inflammatory" phenotype that may contribute to liver disease post-infection. A case-controlled study (n = 54 in each cohort) from endemic OV-infected areas of northeastern Thailand measured neutrophil functions in whole blood from non-infected (healthy controls) and OV-infected individuals with and without APF. We measured reactive oxygen species production, phagocytosis, receptor expression and apoptosis. Secreted products from OV cultures (obtained after in vitro culture of parasites) stimulated reactive oxygen species production in non-infected healthy controls, but levels were two-fold greater after OV infection (P < 0.0001); neutrophil reactive oxygen species production in individuals with APF was double that observed in those without APF (P < 0.0001). OV-infected neutrophils had elevated CD11b expression and greater phagocytic capacity, which was even three-fold higher in those with advanced periductal fibrosis (P < 0.0001). This "activated" phenotype of circulating neutrophils was further confirmed by the observation that isolated neutrophils had delayed apoptosis ex vivo. We believe this is the first study to show that circulating blood neutrophil function is enhanced following OV infection and is more activated in those with advanced periductal fibrosis. We propose that this activated phenotype could contribute to the pathology of liver disease. These data support the hypothesis of an activated innate inflammatory phenotype following OV infection and provide the first evidence for involvement of neutrophils in disease pathology.
Asunto(s)
Fibrosis/parasitología , Neutrófilos/patología , Opistorquiasis , Opisthorchis/patogenicidad , Animales , Apoptosis , Neoplasias de los Conductos Biliares/parasitología , Conductos Biliares Intrahepáticos/patología , Estudios de Casos y Controles , Colangiocarcinoma/parasitología , Humanos , Inflamación , Hepatopatías/parasitología , Opistorquiasis/complicaciones , Opistorquiasis/inmunología , Opistorquiasis/parasitología , Fagocitosis , Especies Reactivas de Oxígeno/metabolismo , Estallido Respiratorio/inmunología , TailandiaRESUMEN
Infection with the liver fluke Opisthorchis viverrini is the major causative factor inducing cholangiocarcinoma in the Mekong region of Southeast Asia. Northeast Thailand has the highest incidence of this cancer worldwide leading to about 20,000 deaths every year. Infection with the liver fluke comes from eating raw or undercooked fish, a tradition in this area that can potentially be countered by education programs at school level. Here we develop a school-based health education model, based on protection motivation theory (PMT), including module design, learning materials, student activities, and capacity building amongst teachers. This education program was applied and tested in primary school to pupils (9-13 years) in Khon Kaen province, northeast Thailand. Using a randomized control trial, four schools served as intervention groups (n = 118 pupils) and another four acted as controls (n = 113 pupils). Based on PMT constructs, we found that the pupils in the intervention group had significantly greater knowledge and perceived the severity, vulnerability, response efficacy, and self-efficacy parameters concerning the dangers of eating raw fish and of developing cholangiocarcinoma than those in the control schools (p < 0.05). All of the PMT constructs measured were significantly intercorrelated with each other (p < 0.001). At the same time, some background knowledge, from community-based education programs, was present in the control schools. The result from this initial study suggests that PMT can be used to predict protective attitude as well as behavior changes in evaluating the consequence of school health intervention programs.
Asunto(s)
Neoplasias de los Conductos Biliares/parasitología , Colangiocarcinoma/parasitología , Educación en Salud/métodos , Opistorquiasis/prevención & control , Adolescente , Animales , Neoplasias de los Conductos Biliares/prevención & control , Niño , Colangiocarcinoma/prevención & control , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Incidencia , Masculino , Opisthorchis/patogenicidad , Prevalencia , Instituciones Académicas , Tailandia/epidemiologíaRESUMEN
Infections caused by Schistosoma haematobium and Opisthorchis viverrini are classified as carcinogenic. Although carcinogenesis might be a multifactorial process, it has been postulated that these helminth produce/excrete oxysterols and estrogen-like metabolites that might act as initiators of their infection-associated carcinogenesis. Current treatment and control of these infections rely on a single drug, praziquantel, that mainly targets the parasites and not the pathologies related to the infection including cancer. Thus, there is a need to search for novel therapeutic alternatives that might include combinations of drugs and drug repurposing. Based on these concepts, we propose a novel therapeutic strategy that combines drugs with molecule antioxidants. We evaluate the efficacy of a novel therapeutic strategy to prevent the formation of putative carcinogenic metabolites precursors and DNA adducts. Firstly, we used a methodology previously established to synthesize metabolites precursors and DNA adducts in the presence of CYP450. Then, we evaluated the inhibition of their formation induced by drugs and antioxidants alone or in combination. Drugs and resveratrol alone did not show a significant inhibitory effect while N-acetylcysteine inhibited the formation of most metabolite precursors and DNA adducts. Moreover, the combinations of classical drugs with antioxidants were more effective rather than compounds alone. This strategy might be a valuable tool to prevent the initiation of helminth infection-associated carcinogenesis.
Asunto(s)
Antioxidantes/farmacología , Neoplasias/tratamiento farmacológico , Opistorquiasis/tratamiento farmacológico , Esquistosomiasis Urinaria/tratamiento farmacológico , Acetilcisteína/química , Animales , Carcinogénesis/efectos de los fármacos , Carcinogénesis/patología , Carcinógenos/química , Aductos de ADN/efectos de los fármacos , Combinación de Medicamentos , Humanos , Metaboloma/efectos de los fármacos , Metaboloma/genética , Neoplasias/metabolismo , Neoplasias/parasitología , Opistorquiasis/complicaciones , Opistorquiasis/metabolismo , Opistorquiasis/parasitología , Opisthorchis/efectos de los fármacos , Opisthorchis/patogenicidad , Praziquantel/farmacología , Resveratrol/farmacología , Schistosoma haematobium/efectos de los fármacos , Schistosoma haematobium/patogenicidad , Esquistosomiasis Urinaria/complicaciones , Esquistosomiasis Urinaria/metabolismo , Esquistosomiasis Urinaria/parasitologíaRESUMEN
In contrast to northern and northeastern Thailand, central Thailand was believed not to be endemic for Opisthorchis viverrini (OV). Fieldwork conducted in a rural area of central Thailand revealed that the prevalence and incidence were relatively high compared with regional average data. We hypothesized that the behavioural-psycho-social background of the study population might play an important role in the high burden of the infection. As a result, a qualitative study was conducted to highlight potential social determinants of the infection dynamics to gain greater understanding of the risk behaviours and their contexts. A qualitative study using focus group discussion and in-depth interviews was conducted in Na-ngam Village, Chachoengsao Province from 2012-14. Framework analysis was used to explore associations between infection and thematic content. Social influence showed a strong impact on infection dynamics of OV infection. Our results revealed that Koi pla (chopped raw fish salad) remains a popular dish in the community, as the dish itself represents northeastern culture. The cultural norm had been transferred from ancestors to their descendants. Some elders complained that discontinuing the consumption of Koi pla went against old traditions with respect to cultural norms and socialization. In contrast, modern education teaches about hygiene including OV infection risks, and accordingly teenagers and young adults were reported to modify their lifestyles including their eating habits. Children are a potential key to pass knowledge to their parents and school-based education programs can serve as a practical hub for knowledge dissemination. However, health education alone might not lead to behavioural change in other age groups. Therefore, more efforts are needed to support the transformation.
Asunto(s)
Peces/parasitología , Enfermedades Transmitidas por los Alimentos/epidemiología , Opistorquiasis/parasitología , Opistorquiasis/transmisión , Opisthorchis/patogenicidad , Alimentos Crudos/parasitología , Alimentos Marinos/parasitología , Adolescente , Adulto , Anciano , Animales , Niño , Susceptibilidad a Enfermedades , Conducta Alimentaria , Femenino , Enfermedades Transmitidas por los Alimentos/parasitología , Humanos , Incidencia , Persona de Mediana Edad , Opistorquiasis/epidemiología , Factores de Riesgo , Medio Social , Encuestas y Cuestionarios , Tailandia/epidemiología , Adulto JovenRESUMEN
Infection with the food-borne liver fluke Opisthorchis viverrini is the principal risk factor (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2012) for cholangiocarcinoma (CCA) in the Lower Mekong River Basin countries including Thailand, Lao PDR, Vietnam and Cambodia. We exploited this link to explore the role of the secreted growth factor termed liver fluke granulin (Ov-GRN-1) in pre-malignant lesions by undertaking programmed CRISPR/Cas9 knockout of the Ov-GRN-1 gene from the liver fluke genome. Deep sequencing of amplicon libraries from genomic DNA of gene-edited parasites revealed Cas9-catalyzed mutations within Ov-GRN-1. Gene editing resulted in rapid depletion of Ov-GRN-1 transcripts and the encoded Ov-GRN-1 protein. Gene-edited parasites colonized the biliary tract of hamsters and developed into adult flukes, but the infection resulted in reduced pathology as evidenced by attenuated biliary hyperplasia and fibrosis. Not only does this report pioneer programmed gene-editing in parasitic flatworms, but also the striking, clinically-relevant pathophysiological phenotype confirms the role for Ov-GRN-1 in virulence morbidity during opisthorchiasis.
Asunto(s)
Conductos Biliares Intrahepáticos/patología , Conductos Biliares Intrahepáticos/parasitología , Técnicas de Inactivación de Genes , Granulinas/genética , Mutación/genética , Opisthorchis/patogenicidad , Animales , Sistemas CRISPR-Cas/genética , Carcinogénesis/patología , Línea Celular , Proliferación Celular , Enfermedad Crónica , Cricetinae , Fibrosis , Edición Génica , Regulación de la Expresión Génica , Genoma , Granulinas/metabolismo , Humanos , Hiperplasia , Opistorquiasis/genética , Opistorquiasis/parasitología , Opistorquiasis/patología , Cicatrización de HeridasRESUMEN
Modulation or prevention of protein changes during the cholangiocarcinoma (CCA) process induced by Opisthorchis viverrini (Ov) infection may become a key strategy for prevention and treatment of CCA. Monitoring of such changes could lead to discovery of protein targets for CCA treatment. Curcumin exerts anti-inflammatory and anti-CCA activities partly through its protein-modulatory ability. To support the potential use of curcumin and to discover novel target molecules for CCA treatment, we used a quantitative proteomic approach to investigate the effects of curcumin on protein changes in an Ov-induced CCA-harboring hamster model. Isobaric labelling and tandem mass spectrometry were used to compare the protein expression profiles of liver tissues from CCA hamsters with or without curcumin dietary supplementation. Among the dysregulated proteins, five were upregulated in liver tissues of CCA hamsters but markedly downregulated in the CCA hamsters supplemented with curcumin: S100A6, lumican, plastin-2, 14-3-3 zeta/delta and vimentin. Western blot and immunohistochemical analyses also showed similar expression patterns of these proteins in liver tissues of hamsters in the CCA and CCA + curcumin groups. Proteins such as clusterin and S100A10, involved in the NF-κB signaling pathway, an important signaling cascade involved in CCA genesis, were also upregulated in CCA hamsters and were then suppressed by curcumin treatment. Taken together, our results demonstrate the important changes in the proteome during the genesis of O. viverrini-induced CCA and provide an insight into the possible protein targets for prevention and treatment of this cancer.
Asunto(s)
Neoplasias de los Conductos Biliares/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Curcumina/administración & dosificación , Proteómica , Proteínas 14-3-3/genética , Animales , Neoplasias de los Conductos Biliares/complicaciones , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/prevención & control , Quimioprevención , Colangiocarcinoma/complicaciones , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Cricetinae , Modelos Animales de Enfermedad , Fasciola hepatica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hígado/efectos de los fármacos , Hígado/patología , Lumican/genética , Glicoproteínas de Membrana/genética , Proteínas de Microfilamentos/genética , Opistorquiasis/complicaciones , Opistorquiasis/tratamiento farmacológico , Opistorquiasis/genética , Opistorquiasis/patología , Opisthorchis/patogenicidad , Proteína A6 de Unión a Calcio de la Familia S100/genética , Vimentina/genéticaRESUMEN
The secreted growth factor granulin (GRN) is upregulated during diverse epithelial cancers. GRN stimulates cell growth and development while inhibiting apoptosis. Orthologues of vertebrate granulins evolved in other animals including the liver fluke Opisthorchis viverrini. Curiously, liver fluke granulin, termed Ov-GRN-1 promotes cholangiocarcinogenesis during chronic opisthorchiasis but, by contrast, limited information is available concerning mammalian GRN during liver fluke infection-induced cholangiocarcinoma (CCA). Here we investigated the expression of mammalian granulin in the O. viverrini-associated a hamster model of opisthorchiasis and liver fluke infection-induced CCA. Male Syrian golden hamsters were assigned to one of four treatment groups, each group included 30 hamsters: 1) normal (control), 2) infected with O. viverrini (OV); 3) exposed to N-dimethylnitrosamine in drinking water (DMN); and 4) infected with O. viverrini and exposed to DMN (OVDMN). Immunohistochemistry using an anti-granulin specific probe for mammalian granulin was undertaken to monitor expression and location in hepatobiliary tissues of the hamsters. In parallel, cognate studies of transcription of mRNA and protein. Histopathological examination revealed development of proliferative lesions from the onset and eruption of CCA onwards, an outcome that was most prominent in the OVDMN hamsters. Proliferating cell nuclear antigen (PCNA) index rose continuously from initiation of infection and increased with lesion progression in OV, DMN and markedly in OVDMN hamsters. Expression of GRN in biliary was elevated in biliary epithelial cells in CCA lesions in hamsters in the DMN and OVDMN groups. Expression of GRN as assayed by western blot and RT-PCR reflected the same trend as seen with PCNA. Together the histopathogical and molecular assay based findings revealed marked expression of granulin during cholangiocarcinoma in these hamsters, and highlighted the prospect that granulin represents a potential prognostic marker for cholangiocarcinoma.
Asunto(s)
Neoplasias de los Conductos Biliares/metabolismo , Carcinogénesis/metabolismo , Colangiocarcinoma/metabolismo , Granulinas/metabolismo , Opistorquiasis/metabolismo , Opisthorchis/patogenicidad , Animales , Neoplasias de los Conductos Biliares/patología , Carcinogénesis/patología , Proliferación Celular/fisiología , Colangiocarcinoma/patología , Cricetinae , Células Epiteliales/patología , Células Epiteliales/virología , Fasciola hepatica/metabolismo , Fasciola hepatica/patogenicidad , Inmunohistoquímica/métodos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Opistorquiasis/parasitología , Antígeno Nuclear de Célula en Proliferación/metabolismoRESUMEN
BACKGROUND: Chronic inflammation and repeated infection with Opisthorchis viverrini (O. viverrini) induces intrahepatic cholangiocarcinoma (ICC). Inflammatory cytokines such as interleukin (IL) and tumor necrosis factor (TNF) are substances in the immune system that promote inflammation and causes disease to progress. Genes that help express proinflammatory cytokines can affect an individual's susceptibility to disease, especially in cancer-related chronic inflammation. This study aimed to investigate risk factors for ICC with a focus on opisthorchiasis and polymorphisms of proinflammatory cytokines (IL-1ß and TNF-α). METHODS: This study was a nested case-control study within a cohort study. 219 subjects who developed a primary ICC were identified and matched with two non-cancer controls from the same cohort based on sex and age at recruitment (±3 years). An O. viverrini-IgG antibody was assessed using enzyme linked immunosorbent assay. IL-1ß and TNF-α polymorphisms were analyzed using a polymerase chain reaction with high resolution melting analysis. Associations between variables and ICC were assessed using conditional logistic regression. RESULTS: Subjects with a high infection intensity had higher risk of ICC than those who had a low level (OR = 2.1; 95% CI: 1.2-3.9). Subjects with all genotypes of TNF-α (GG, GA, AA) and high infection intensity were significantly related to an increased risk of ICC (p < 0.05). CONCLUSIONS: Polymorphisms of IL-1ß and TNF-α are not a risk of ICC, but an individual with O. viverrini infection has an effect on all genotypes of the TNF-α gene that might promote ICC. Primary prevention of ICC in high-risk areas is based on efforts to reduce O. viverrini infection.
Asunto(s)
Colangiocarcinoma/genética , Interleucina-1beta/genética , Opistorquiasis/genética , Factor de Necrosis Tumoral alfa/genética , Adulto , Anciano , Animales , Colangiocarcinoma/complicaciones , Colangiocarcinoma/parasitología , Colangiocarcinoma/patología , Citocinas/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Opistorquiasis/complicaciones , Opistorquiasis/parasitología , Opistorquiasis/patología , Opisthorchis/genética , Opisthorchis/patogenicidad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , TailandiaRESUMEN
We adapt a population-based model of Opisthorchis viverrini transmission dynamics to determine the effectiveness of three different interventions. The model includes the definitive hosts, humans; the reservoir hosts, dogs and cats; and the intermediate hosts, snails and fish. We consider the interventions: education campaigns to reduce the consumption of raw or undercooked fish, improved sanitation and treatment through mass drug administration. We fit model parameters to a data set from two islands in southern Lao PDR. We calculate the control reproduction number, simulate different scenarios and optimise the interventions with optimal control. We look at the potential of the interventions to eliminate transmission within 20 years. The model shows that education and improved sanitation need a very high coverage to fulfil the goal of elimination, whereas annual drug distribution at medium coverage is sufficient. The best solution is a combination of drug distribution at a medium level of coverage and as high as possible coverage of education and improved sanitation.
Asunto(s)
Opistorquiasis/prevención & control , Animales , Antiplatelmínticos/administración & dosificación , Número Básico de Reproducción , Gatos , Simulación por Computador , Reservorios de Enfermedades/parasitología , Perros , Peces/parasitología , Educación en Salud , Humanos , Laos , Conceptos Matemáticos , Modelos Biológicos , Opistorquiasis/tratamiento farmacológico , Opistorquiasis/transmisión , Opisthorchis/efectos de los fármacos , Opisthorchis/patogenicidad , Saneamiento , Caracoles/parasitologíaRESUMEN
BACKGROUND/AIM: Early detection of disease is a pivotal factor for determining prognosis and clinical outcome of patients with cancer. As cholangiocarcinoma (CCA) is currently difficult to detect and most cases of such cancer present with late-stage disease at the time of initial diagnosis, we employed proteomic analysis of the bile to identify potential candidate biomarkers for Opisthorchis viverrini (OV)-associated CCA. MATERIALS AND METHODS: Proteins in pooled bile samples from patients with CCA and OV infection, with CCA without OV infection, with OV infection but no CCA, and with neither OV infection nor CCA were separated by 15% sodium dodecyl sulfate-polyacrylamide gel electrophoresis, in-gel trypsin digestion and analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: According to our analysis, three proteins, namely aristaless-like homeobox1 isoform X1 (ALX1), major histocompatibility complex polypeptide-related sequence A (MICA), and uncharacterized protein C14orf105 isoform X12 were found to be potential markers for OV infection, as they were predominantly found in all OV-infected groups. Although these proteins were detected in both OV-infected patients with and without CCA, their abundance was 2.90-, 7.06-and 3.65-fold higher, respectively, in those with CCA. In patients with CCA, potential novel biomarkers wre immunoglobulin heavy chain, translocated in liposarcoma (TLS), visual system homeobox 2 (VSX2) and an unnamed protein product. CONCLUSION: We provided novel information regarding potential biomarkers for OV infection and CCA. These two protein profiles could benefit diagnosis as well as monitoring of CCA.
Asunto(s)
Colangiocarcinoma/genética , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de Homeodominio/genética , Opistorquiasis/genética , Animales , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Biomarcadores de Tumor/genética , Colangiocarcinoma/complicaciones , Colangiocarcinoma/parasitología , Colangiocarcinoma/patología , Cromatografía Liquida , Detección Precoz del Cáncer , Femenino , Humanos , Masculino , Opistorquiasis/complicaciones , Opistorquiasis/parasitología , Opistorquiasis/patología , Opisthorchis/aislamiento & purificación , Opisthorchis/patogenicidad , Mapas de Interacción de Proteínas/genética , Proteómica/métodosRESUMEN
Intestinal parasitic infection rate among school-aged children in Thailand has been decreasing. However, certain intestinal parasites remain problematic in some regions. This cross-sectional study was conducted between February and September 2016 in three suburban government primary schools (KK, BR, and HK), Saraburi, Thailand. Stool was collected from 263 asymptomatic subjects (4-15 years old), using simple direct smear, formalin-ether concentration, Boeck and Drbohlav's Locke-Egg-Serum (LES) medium culture, and agar plate culture. A self-administered questionnaire was used to collect data about lifestyle and socioeconomic status. The overall rate of intestinal parasites was 22.1% (15.6% single infection and 6.5% multiple infections). The helminths involving the digestive system found were Strongyloides stercoralis (1.5%) and Opisthorchis viverrini (0.4%). For protozoan infection, the major cause was Blastocystis hominis (17.5%). The other protozoa included Endolimax nana (4.6%), Entamoeba coli (3.4%), Entamoeba histolytica/Entamoeba dispar (1.1%), and Giardia intestinalis (0.8%). The sensitivity for the detection of B. hominis increased with the LES culture technique. The infection rate of each organism was not significantly different among the three schools except for B. hominis which showed the highest prevalence in the HK school (P = 0.001). This was correlated with the questionnaire results in which the HK school showed the highest risk of drinking contaminated water (P = 0.004). The present study emphasized the persistent problems of protozoan infections among suburban school-aged children. Lifestyle was still an important factor for intestinal parasitic infections among suburban school-aged Thai children in this study. Health education as well as routine surveillance was necessary to control the infections.
Asunto(s)
Amebiasis/epidemiología , Infecciones por Blastocystis/epidemiología , Entamebiasis/epidemiología , Opistorquiasis/epidemiología , Estrongiloidiasis/epidemiología , Adolescente , Amebiasis/diagnóstico , Amebiasis/parasitología , Animales , Infecciones por Blastocystis/diagnóstico , Infecciones por Blastocystis/parasitología , Blastocystis hominis/aislamiento & purificación , Blastocystis hominis/patogenicidad , Niño , Preescolar , Estudios Transversales , Endolimax/aislamiento & purificación , Endolimax/patogenicidad , Entamoeba/aislamiento & purificación , Entamoeba/patogenicidad , Entamebiasis/diagnóstico , Entamebiasis/parasitología , Heces/parasitología , Femenino , Humanos , Masculino , Opistorquiasis/diagnóstico , Opistorquiasis/parasitología , Opisthorchis/aislamiento & purificación , Opisthorchis/patogenicidad , Clase Social , Strongyloides stercoralis/aislamiento & purificación , Strongyloides stercoralis/patogenicidad , Estrongiloidiasis/diagnóstico , Estrongiloidiasis/parasitología , Encuestas y Cuestionarios , Tailandia/epidemiologíaRESUMEN
BACKGROUND: The combination of Opisthorchis viverrini (OV) infection and chemical carcinogen induces cholangiocarcinoma (CCA) in hamsters via inflammation-mediated mechanisms. Thus, suppression of inflammatory cells at the initial stages of CCA development would be of benefit. We aimed to investigate whether IL-17-producing CD4+ T cells (Th17) and CD4+ Foxp3+ T cells (Treg) are involved in the early stages of CCA genesis and can be targeted for suppression by melatonin. METHODS: Inflammation, an initial stage of CCA development, was induced in hamsters by a combination of O. viverrini infection and N-nitrosodimethylamine (NDMA) administration. Melatonin (50mg/kg) was additionally administered to one group for the 30days of the experiment. Liver tissue-resident T cells were investigated using immunostaining, western blotting, and real-time PCR. RESULTS: OV+NDMA-induced CCA tissues showed significantly higher numbers of inflammatory cells, especially eosinophils, bile duct proliferation and IL-17+ cell infiltration compared to normal livers. Expression of Foxp3 was localized in the bile duct epithelial cells, and especially in the bile duct hyperplasia. Accumulation of CD4+ and IL-17+ cells and intense staining of the Foxp3+ marker were consistent with their protein levels. Infiltration of IL-17+ inflammatory cells and Foxp3+ cells, as well as increases in their transcription expression levels, were significantly lower in the melatonin-treated group. In contrast, increased CD4+ cell infiltration and TNF-α expression were also observed through melatonin treatment. CONCLUSION: Melatonin exerts an immunomodulatory effect, suppressing eosinophils and Th17 cells and expression of Foxp3, but enhancing CD4+ cells and TNF-α. This suggests that melatonin may be used for CCA chemoprevention.
Asunto(s)
Anticarcinógenos/farmacología , Neoplasias de los Conductos Biliares/prevención & control , Colangiocarcinoma/prevención & control , Dimetilnitrosamina , Eosinófilos/efectos de los fármacos , Inmunosupresores/farmacología , Hígado/efectos de los fármacos , Melatonina/farmacología , Opistorquiasis/tratamiento farmacológico , Opisthorchis/inmunología , Células Th17/efectos de los fármacos , Animales , Neoplasias de los Conductos Biliares/inducido químicamente , Neoplasias de los Conductos Biliares/inmunología , Neoplasias de los Conductos Biliares/parasitología , Colangiocarcinoma/inducido químicamente , Colangiocarcinoma/inmunología , Cricetinae , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Eosinófilos/inmunología , Eosinófilos/metabolismo , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Mediadores de Inflamación/metabolismo , Hígado/inmunología , Hígado/metabolismo , Hígado/parasitología , Opistorquiasis/inmunología , Opistorquiasis/parasitología , Opisthorchis/patogenicidad , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/parasitología , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/parasitologíaRESUMEN
Parasitic infection remains as a persistent public health problem and can be carcinogenic. Three helminth parasites, namely, Clonorchis sinensis (liver fluke) and Opisthorchis viverrini as well as Schistosoma haematobium (blood fluke), are classified as Group 1 carcinogens by the World Health Organization's International Agency for Research on Cancer (IARC Infection with liver flukes (Opisthorchis viverrini, Opisthorchis felineus and Clonorchis sinensis), World Health Organization, International Agency for Research on Cancer, 2011). Infection by these parasites is frequently asymptomatic and is thus rarely diagnosed at early exposure. Persistent infection can cause severe cancer complications. Until now, the cellular and molecular mechanisms linking fluke infections to cancer formation have yet to be defined, although many studies have focused on these mechanisms in recent years, and numerous findings were made in various aspects of parasite-associated cancers. Herein, we only introduce the fluke-induced cholangiocarcinoma (CCA) and bladder carcinoma and mainly focus on key findings in the last 5 years.