Intriguing hepatoprotective effects of sucrose on hepatocellular carcinoma pathogenesis.

Chronic liver disease is closely linked to dietary intake factors, such as high consumption of simple carbohydrates including sucrose. In this study, the influence of sucrose on the development of hepatocellular carcinoma (HCC), the most common primary liver malignancy, was explored. Using the hepatocarcinogen diethylnitrosamine (DEN) to induce HCC in the rat, we co-administered sucrose with DEN. The co-administration significantly modified body, liver and pancreas weight, as well as, serum fatty acids and triglycerides. DEN caused liver structural alteration, fibrosis, and tumor formation; surprisingly, co-administration with sucrose restored hepatic lipids, improved liver architecture, and reduced fibrosis and tumor development. Sucrose intake negatively regulated tumor markers and cell proliferation, and reduced the expression of genes associated with lipid metabolism and oxidative stress response. These findings highlight a hepatoprotective effect of sucrose during DEN-induced hepatocarcinogenesis, underlining an intriguing role of high sucrose consumption during HCC development and providing new insights as well as possible pathways of cellular protection under sucrose intake on hepatocarcinogenesis.

Identification of ABCC3 and its isoforms as potential biomarker in hepatocellular carcinoma.

Liver diseases preceding the occurrence of hepatocellular carcinoma (HCC) play a crucial role in the progression and establishment of HCC, a malignancy ranked as the third deadliest cancer worldwide. Late diagnosis, alongside ineffective treatment, leads patients to a poor survival rate. This scenario argues for seeking novel alternatives for detecting liver alterations preceding the early occurrence of HCC. Experimental studies have reported that ABCC3 protein increases within HCC tumors but not in adjacent tissue. Therefore, we analyzed ABCC3 expression in public databases and investigated the presence of ABCC3 and its isoforms in plasma, urine and its release in extracellular vesicles (EVs) cargo from patients bearing cirrhosis and HCC. The UALCAN and GEPIA databases were used to analyze the expression of ABCC3 in HCC. The results were validated in a case-control study including 41 individuals bearing cirrhosis and HCC, and the levels of ABCC3 in plasma and urine samples, as well as EVs, were analyzed by ELISA and western blot. Our data showed that ABCC3 expression was higher in HCC tissues than in normal tissues and correlated with HCC grade and stage. ABCC3 protein levels were highly increased in both plasma and urine and correlated with liver disease progression and severity. The isoforms MRP3A and MRP3B of ABCC3 were significantly increased in both EVs and plasma/urine of patients bearing HCC. ABCC3 expression gradually increases in HCC tissues, and its protein levels are increased in both plasma and urine of patients with cirrhosis and HCC. MRP3A and MRP3B isoforms have the potential to be prognostic biomarkers of HCC.

[Risk factors for metabolic dysfunction-associated fatty liver disease in the Hispanic-Mexican population.] / Factores de riesgo de la enfermedad hepática grasa asociada a disfunción metabólica en población hispano-mexicana.

OBJECTIVE: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a poor attended disease, which has gained attention due the elevated number of cases in countries as Mexico, where the incidence is the number 4th globally. MAFLD develops in obese or overweighted individuals and is characterized by triglycerides accumulation in the liver, this condition can develop to hepatocellular carcinoma. It has been observed that MAFLD depends on the genetics and lifestyle. Due to the high prevalence of this disease among Hispanic population, we focused on this study in the characteristics and prevalence of MAFLD in Mexican patients. METHODS: In this study were included 572 overweighted and obese patients, who underwent a screening analysis using the fatty liver index (IHG), clinical parameters were analysed, demographic and comorbidities. Frequency of variables were obtained, and the data were analysed by Chi-square test or Fisher test, odd ratio (OR) and binary logistic regression. RESULTS: A MALFD prevalence of 37% were obtained, where the history of familiar obesity, paracetamol usage, carbohydrate and fat intake are shown to be risk factors. It was found that high blood pressure, central obesity and hypertriglyceridemia were also associated to the MAFLD development. On the other hand, physical exercise was a protector factor. CONCLUSIONS: Our results show the necessity to study the MAFLD causalities in Mexican patients, focused on the paracetamol intake.

OBJETIVO: La enfermedad hepática grasa asociada a disfunción metabólica (MAFLD) es una enfermedad poco considerada, que ha recibido atención debido al número de casos en países como México, donde ocupa el 4º lugar mundial de incidencia. La MAFLD se desarrolla en personas con sobrepeso u obesidad y se caracteriza por la acumulación de triglicéridos en el hígado, donde puede evolucionar hacia carcinoma hepatocelular. Se ha observado que la MAFLD depende de la genética y del estilo de vida. Tomando en cuenta la alta prevalencia de MAFLD en la población hispana, nos enfocamos en este trabajo en estudiar la prevalencia y características relacionadas con esta enfermedad en pacientes mexicanos. METODOS: En este estudio se incluyeron 572 pacientes con sobrepeso u obesidad, a los cuales se les realizó un análisis de cribado mediante el índice de hígado graso (IHG), se analizaron parámetros clínicos, demográficos y comorbilidades. Se obtuvieron frecuencias de las variables y se analizaron los datos mediante chi cuadrado o exacta de Fisher, razón de momios (OR) y regresión logística binaria. RESULTADOS: Se obtuvo una prevalencia del 37% de MAFLD, donde la historia familiar de obesidad, el uso de paracetamol, así como el consumo de carbohidratos y grasas fueron factores de riesgo para su desarrollo. Se encontró que la hipertensión arterial, la obesidad visceral y la hipertrigliceridemia también estaban asociados al desarrollo de la MAFLD. Por otro lado, el ejercicio fue un factor protector. CONCLUSIONES: Nuestros resultados ponen de manifiesto la necesidad de realizar estudios relacionados con las causalidades de la MAFLD en los pacientes mexicanos, principalmente en el uso del paracetamol.

Efficacy of nutrition therapy with food rich in methionine for treating nonalcoholic fatty liver / Eficacia de la terapia nutricional con alimentos ricos en metionina para el tratamiento de hígado graso no alcohólico

Non-Alcoholic Fatty Liver disease (NAFLD) can lead to Non Alcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. The treatment for NAFLD involves modification of caloric intake and physical activity. NAFLD has a pro-oxidant nature; therefore, it is logical to suppose that the antioxidant methionine can be used as a treatment for this disease. Aim. This study aimed to evaluate the effect of high-methionine dietary therapy on patients with NAFLD. Materials and methods. A randomized clinical study was conducted over three months. In this study, 121 NAFLD patients participated, and the age of the participants was ≥ 20 years (experimental group included 56 and control group 65), all of whom were randomized and matched by sex, recluted from the ISSSTE hospital in Xalapa, Mexico. The patients were instructed to consume food to cover the recommended methionine daily doses, and the daily amount consumed was calculated. Methionine effect was measured as NAFLD regression and quality of life improvement. Results. Nutritional therapy induced NAFLD regression and diminished central fat accumulation, blood pressure, and the fatty liver index. Some parameters, such as liver enzymes, did not changed. The quality of life of patients improved after treatment. Conclusions. In this study, we show a hepatoprotective effect induced only in three months of chances in the diet, thus, a longer diet may generate more relevant benefits in the resistant parameters of our study(AU)

La enfermedad del hígado graso no alcohólico (NAFLD) puede conducir a la esteatohepatitis no alcohólica (NASH), la cirrosis y el cáncer de hígado. El tratamiento para NAFLD es la modificación de la ingesta calórica y la actividad física. Debido a que NAFLD tiene una naturaleza pro-oxidante; es lógico suponer que el antioxidante metionina puede utilizarse en el tratamiento de esta enfermedad. Objetivo. el presente trabajo evaluó el papel de la terapia nutricional con alimentos ricos en metioninaen pacientes con NAFLD. Materiales y Métodos. Se realizó un ensayo clínico aleatorizado durante tres meses. Participaron en el estudio 121 pacientes con NAFLD con edad ≥ 20 años (56 en el grupo experimental y 65 en el control), todos aleatorizados y pareados por sexo, reclutados de la Clínica Hospital ISSTE en la ciudad de Xalapa, México, en el año 2015. Se instruyó a los pacientes en consumir los alimentos hasta completar la dosis diaria recomendada de metioninay se calculó la cantidad diaria consumida. Su efecto se midió como la regresión de NAFLD y la mejora de la calidad de vida. Resultados. La terapia nutricional retrocedió NAFLD; disminuyó la acumulación de grasa central, la presión arterial y el índice de hígado graso. Algunos parámetros, como las enzimas de la función hepática, no se modificaron con el tratamiento. Otro parámetro fue la mejora de la calidad de vida de los pacientes tratados. Conclusiones. En este trabajo mostramos un impacto hepatoprotector producido con tan solo tres meses de cambios en la dieta, por lo que una dieta más prolongada podría generar beneficios aún más significativos en los parámetros resistentes en nuestro protocolo(AU)

Acetaminophen-Induced Liver Damage in Hepatic Steatosis.

One of the most used painkillers is acetaminophen (APAP), which is safe at the right dose. However, several studies have described populations susceptible to APAP-induced liver damage, mainly in livers with steatosis. Thus, clinicians should consider the presence of obesity and other chronic liver diseases like nonalcoholic fatty liver disease (NAFLD) when indicating treatment with APAP. Liver damage from this drug is generated through its metabolite N-acetyl-p-benzoquinone imine, which is detoxified with glutathione (GSH). Prior depletion of GSH in steatotic hepatocytes plays a key role in APAP-induced hepatotoxicity in people with obesity and NAFLD. The knowledge about the damage to the liver or APAP in susceptible people like the obese and those with NAFLD is of great relevance for the sanitary sector because it would imply strategies of different therapeutic approach in such patients. This paper reviews the role of APAP in liver damage in the presence of obesity, NAFLD, and nonalcoholic steatohepatitis.

The transmembrane transporter ABCC3 participates in liver cancer progression and is a potential biomarker.

The poor prognosis, few available treatment options, and multidrug resistance present in hepatocellular carcinoma are major problems, and new early biomarkers are needed to reduce the liver cancer death rate. ATP-binding cassette sub-family C member 3 (Abcc3) is overexpressed in different cancers and is associated with multidrug resistance and a carcinogenic stem cell phenotype. We present evidence for the first time that ABCC3 is a potential sanguine biomarker and anticancer target in hepatocellular carcinoma. Abcc3 mRNA expression was elevated in liver nodules and tumors in rat hepatocarcinogenesis model. Accordingly, the ABCC3 protein was preferentially overexpressed within the nodules and tumors during hepatocellular carcinoma progression and was secreted into the bloodstream of rat hepatocarcinogenesis model. The ABCC3 protein was expressed in human hepatoma cells and, importantly, was also present in HepG2- and Huh7-conditioned media. Furthermore, ABCC3 was overexpressed in human hepatocellular carcinoma. This report is the first to describe liver overexpression of Abcc3 during the cancer initiation, promotion, and progression periods in rat hepatocarcinogenesis model and in human hepatocellular carcinoma.

4EBP1 Is Dephosphorylated by Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) requires protein biosynthesis machinery to generate progeny. There is evidence that RSV might alter some translation components since stress granules are formed in their host cells. Consistent with these observations, we found that RSV induces dephosphorylation of 4EBP1 (eIF4E-binding protein), an important cellular translation factor. Our results show no correlation between the 4EBP1 dephosphorylation time and the decrease in the global rate of protein synthesis. Interestingly, treatment with rapamycin stimulates virus generation. The results suggest that RSV is a virus that still contains unknown mechanisms involved in the translation of their mRNAs through the alteration or modification of some translation factors, such as 4EBP1, possibly to favor its replicative cycle.

Viral coinfection in acute respiratory infection in Mexican children treated by the emergency service: A cross-sectional study.

BACKGROUND: Acute respiratory infections (ARIs) cause illness. Children under five years of age are highly vulnerable to these infections. Viral coinfection or multiple viral infection is a variable that can have a significant impact on the evolution of these diseases. METHODS: This cross-sectional study was carried out in Mexican children (under five years of age) who had an ARI and who were treated by an emergency service in a hospital in Guadalajara, Jalisco, Mexico. The viral etiology, as well as the presence of multiple viral infections, was determined. A structured questionnaire was used to obtain demographic and clinical information. Odds ratio (OR) was calculated, and univariate and multivariate analyses using logistic regression were performed. RESULTS: In the study population, metapneumovirus (hMPV) was the most frequent virus (22%), followed by adenovirus (hAD) (16%), respiratory syncytial virus (RSV) (14%), rhinovirus (hRV) (12%), bocavirus (hBoV) (9%), influenza virus (IF) (7%), and parainfluenza (PIF) (4%). The frequency of viral coinfections was 31.62%, and multiple logistic regression analysis revealed that hMPV, RSV, PIF, and hBoV were independently associated with multiple viral infection. No difference was found in the clinical manifestation of children with simple and multiple infections. Simple hMPV infection was associated with patients who presented with severe ARI. Using a multivariate analysis, we found that overcrowding is associated with coinfection when the viral etiology was hRV (OR = 2.56, 95% confidence interval (CI) 1.07 to 6.13), IF (OR = 2.56, 95% CI 1.07 to 6.13), PIF (OR = 2.96, 95% CI 1.15 to 7.65), hAD (OR = 2.56, 95% CI 1.07 to 6.13), and hBoV (OR = 2.9, 95% CI 1.14 to 7.34). CONCLUSIONS: Viral coinfections are frequent in children requiring treatment by an emergency service. However, the severity of ARI is similar to that of children with a simple infection. The hMPV is common and may confer a significant disease burden in the Mexican population. Finally, overcrowding is a housing characteristic that favors the development of coinfections.

eIF4E as a control target for viruses.

Translation is a complex process involving diverse cellular proteins, including the translation initiation factor eIF4E, which has been shown to be a protein that is a point for translational regulation. Viruses require components from the host cell to complete their replication cycles. Various studies show how eIF4E and its regulatory cellular proteins are manipulated during viral infections. Interestingly, viral action mechanisms in eIF4E are diverse and have an impact not only on viral protein synthesis, but also on other aspects that are important for the replication cycle, such as the proliferation of infected cells and stimulation of viral reactivation. This review shows how some viruses use eIF4E and its regulatory proteins for their own benefit in order to spread themselves.

Increased expression of prostaglandin reductase 1 in hepatocellular carcinomas from clinical cases and experimental tumors in rats.

To identify novel tumor-associated proteins, we analyzed the protein expression patterns from experimental hepatocellular carcinoma (HCC) that were induced using hepatocarcinogenesis models in rats. Rats were subjected to two previously described protocols of hepatocarcinogenesis using diethylnitrosamine as a carcinogen: the alternative Solt-Farber (aS&F) protocol, which induces HCC within 9 months, and Schiffer's model, which induces cirrhosis and multifocal HCC within 18 weeks. The patterns of protein expression from tumors and normal liver tissue were examined by SDS-PAGE and the bands identified at 33-34 kDa were analyzed by mass spectrometry. The prostaglandin reductase 1 (PTGR1) showed the highest number of peptides, with a confidence of level >99%. The increased expression of PTGR1 in tumors was confirmed in these two models by Western blotting and by increase in alkenal/one oxidoreductase activity (25-fold higher than normal liver). In addition, the gene expression level of Ptgr1, as measured by qRT-PCR, was increased during cancer development in a time-dependent manner (200-fold higher than normal liver). Furthermore, PTGR1 was detected in the cytoplasm of neoplastic cells in rat tumors and in 12 human HCC cases by immunohistochemistry. These analyses were performed by comparing the expression of PTGR1 to that of two well-known markers of hepatocarcinoma, Glutathione S-transferase pi 1 (GSTP1) in rats and glypican-3 in humans. The increased expression and activity of PTGR1 in liver carcinogenesis encourage further research aimed at understanding the metabolic role of PTGR1 in HCC and its potential application for human cancer diagnosis and treatment.

Occult HBV infection: a faceless enemy in liver cancer development.

The hepatitis B virus (HBV) represents a worldwide public health problem; the virus is present in one third of the global population. However, this rate may in fact be higher due to occult hepatitis B virus infection (OBI). This condition is characterized by the presence of the viral genome in the liver of individuals sero-negative for the virus surface antigen (HBsAg). The causes of the absence of HBsAg in serum are unknown, however, mutations have been identified that produce variants not recognized by current immunoassays. Epigenetic and immunological host mechanisms also appear to be involved in HBsAg suppression. Current evidence suggests that OBI maintains its carcinogenic potential, favoring the progression of fibrosis and cirrhosis of the liver. In common with open HBV infection, OBI can contribute to the establishment of hepatocellular carcinoma. Epidemiological data regarding the global prevalence of OBI vary due to the use of detection methods of different sensitivity and specificity. In Latin America, which is considered an area of low prevalence for HBV, diagnostic screening methods using gene amplification tests for confirmation of OBI are not conducted. This prevents determination of the actual prevalence of OBI, highlighting the need for the implementation of cutting edge technology in epidemiological surveillance systems.

Clinical characteristics and genetic variability of human rhinovirus in Mexico.

Human rhinovirus (HRV) is a leading cause of acute respiratory infection (ARI) in young children and infants worldwide and has a high impact on morbidity and mortality in this population. Initially, HRV was classified into two species: HRV-A and HRV-B. Recently, a species called HRV-C and possibly another species, HRV-D, were identified. In Mexico, there is little information about the role of HRV as a cause of ARI, and the presence and importance of species such as HRV-C are not known. The aim of this study was to determine the clinical characteristics and genetic variability of HRV in Mexican children. Genetic characterization was carried out by phylogenetic analysis of the 5'-nontranslated region (5'-NTR) of the HRV genome. The results show that the newly identified HRV-C is circulating in Mexican children more frequently than HRV-B but not as frequently as HRV-A, which was the most frequent species. Most of the cases of the three species of HRV were in children under 2 years of age, and all species were associated with very mild and moderate ARI.

Celecoxib activates Stat5 and restores or increases the expression of growth hormone-regulated genes in hepatocarcinogenesis.

We have previously evaluated the chemopreventive effect of celecoxib on preneoplastic lesions in rat liver. However, though the effects of celecoxib have been tested in a variety of carcinomas, there has not been a study on the modulation of gene expression in response to this drug. Here, we evaluated the effect of celecoxib on the gene expression profile associated with hepatocarcinogenesis. Male Sprague-Dawley rats underwent the modified resistant hepatocyte model and were fed a diet containing 1500 ppm of celecoxib. Gene expression profiles were evaluated using DNA microarrays and further validations were performed using quantitative PCR, western blotting and immunohistochemical staining. Celecoxib modulated the expression of 46 genes, and those regulated by growth hormone were selected for further analysis. Celecoxib significantly upregulated the expression of the Cyp2b1/2, Cyp3a1, and alpha2-urinary globulin (alpha2uG) genes and restored the expression of Cyp2b3 to normal. The protein expression of Cyp2b1/2 was increased, but the expressions of Cyp3a1 and alpha2uG were only restored to normal levels. The increased Cyp2b1/2 expression in response to celecoxib was mainly confined to preneoplastic lesions. A search for the upstream mediator of these genetic alterations found that carcinogenesis inactivated by 87% the signal transducer and activator of transcription 5 (Stat5), a transcription factor that is activated by growth hormone signaling, but celecoxib treatment restored its activation. In conclusion, these results suggest that celecoxib exerts anticancer effects on altered hepatic cells by restoring mRNA and the protein expression levels of specific genes, in part through the reactivation of Stat5.

Inhibition of reactive oxygen species and pre-neoplastic lesions by quercetin through an antioxidant defense mechanism.

There is a correlation between oxidative stress generated by diethylnitrosamine (DEN) metabolism and liver cancer development. Quercetin is a flavonoid with anti-carcinogenic and antioxidant properties. This study demonstrates the mechanism of action for the chemopreventive effect of quercetin. A 10 mg/kg dose of quercetin produced drastic effect, when it is administrated 2 h before DEN; at 24 days post-DEN, a 70.3% and 66.2% decrease in total area and number of preneoplastic lesions were observed, respectively. At 12 h post-DEN, quercetin inhibited levels of lipid peroxidation by 40%. Quercetin increased the levels of both GSH and of total glutathione, it increased the GSH/GSSG index and it caused a rapid and simultaneous elevation in the activities of superoxide dismutase, glutathione peroxidase and catalase. In conclusion, the quercetin mechanism of action is due to promote the enzymatic and non-enzymatic antioxidant defense system during the initiation of hepatocarcinogenesis.