Gut Microbiota Affects Mouse Pregnane X Receptor Agonist Pregnenolone 16α-Carbonitrile-Induced Hepatomegaly by Regulating Pregnane X Receptor and Yes-Associated Protein Activation.

Pregnane X receptor (PXR) is essential in the regulation of liver homeostasis, and the gut microbiota is closely linked to liver physiologic and pathologic status. We previously found that activation of PXR significantly promotes liver enlargement through interaction with yes-associated protein (YAP). However, whether gut microbiota contributes to PXR-induced hepatomegaly and the involved mechanisms remain unclear. In this study, C57BL/6 mice were administered the mouse-specific agonist pregnenolone 16α-carbonitrile (PCN) for 5 days. Depletion of gut microbiota was achieved using broad-spectrum antibiotics (ABX) and fecal microbiota transplantation (FMT) was performed to restore the gut microbia. The composition of gut microbiota was analyzed by 16S rRNA sequencing, while the expression of PXR, YAP, and their downstream target genes and proteins were assessed. The results indicated that PCN treatment altered the composition and abundance of specific bacterial taxa. Furthermore, depletion of gut microbiota using ABX significantly attenuated PCN-induced hepatomegaly. FMT experiments further demonstrated that the fecal microbiota from PCN-treated mice could induce liver enlargement. Mechanistic studies revealed that ABX treatment impeded the PXR and YAP activation induced by PCN, as evidenced by decreased expression of PXR, YAP, and their downstream targets. Moreover, alterations in PXR and YAP activation were likely contributing to hepatomegaly in recipient mice following FMT from PCN-treated mice. Collectively, the current study demonstrated that gut microbiota is involved in PCN-induced hepatomegaly via regulating PXR and YAP activation, providing potential novel insights into the involvement of gut microbiota in PXR-mediated hepatomegaly. SIGNIFICANCE STATEMENT: This work describes that the composition of gut microbiota is altered in mouse pregnane X receptor (PXR) agonist pregnenolone 16α-carbonitrile (PCN)-induced hepatomegaly. Treatment with an antibiotic cocktail depletes the intestinal microbiota, leading to the impairment of liver enlargement caused by PCN. Additionally, fecal microbiota transplantation from PCN-treated mice induces liver enlargement. Further study revealed that gut microbiota is involved in hepatomegaly via regulating PXR and yes-associated protein activation.

The reversal of PXR or PPARα activation-induced hepatomegaly.

The activation of pregnane X receptor (PXR) or peroxisome proliferator-activated receptor α (PPARα) can induce liver enlargement. Recently, we reported that PXR or PPARα activation-induced hepatomegaly depends on yes-associated protein (YAP) signaling and is characterized by hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. However, it remains unclear whether PXR or PPARα activation-induced hepatomegaly can be reversed after the withdrawal of their agonists. In this study, we investigated the regression of enlarged liver to normal size following the withdrawal of PCN or WY-14643 (typical agonists of mouse PXR or PPARα) in C57BL/6 mice. The immunohistochemistry analysis of CTNNB1 and KI67 showed a reversal of hepatocyte size and a decrease in hepatocyte proliferation after the withdrawal of agonists. In details, the expression of PXR or PPARα downstream proteins (CYP3A11, CYP2B10, ACOX1, and CYP4A) and the expression of proliferation-related proteins (CCNA1, CCND1, and PCNA) returned to the normal levels. Furthermore, YAP and its downstream proteins (CTGF, CYR61, and ANKRD1) also restored to the normal states, which was consistent with the change in liver size. These findings demonstrate the reversibility of PXR or PPARα activation-induced hepatomegaly and provide new data for the safety of PXR and PPARα as drug targets.

GenX analogs exposure induced greater hepatotoxicity than GenX mainly via activation of PPARα pathway while caused hepatomegaly in the absence of PPARα in female mice.

Despite their use as substitutes for perfluorooctanoic acid, the potential toxicities of hexafluoropropylene oxide dimer acid (HFPO-DA, commercial name: GenX) and its analogs (PFDMOHxA, PFDMO2HpA, and PFDMO2OA) remain poorly understood. To assess the hepatotoxicity of these chemicals on females, each chemical was orally administered to female C57BL/6 mice at the dosage of 0.5 mg/kg/d for 28 d. The contribution of peroxisome proliferator-activated receptors (PPARα and γ) and other nuclear receptors involving in these toxic effects of GenX and its analogs were identified by employing two PPAR knockout mice (PPARα-/- and PPARγΔHep) in this study. Results showed that the hepatotoxicity of these chemicals increased in the order of GenX < PFDMOHxA < PFDMO2HpA < PFDMO2OA. The increases of relative liver weight and liver injury markers were significantly much lower in PPARα-/- mice than in PPARα+/+ mice after GenX analog exposure, while no significant differences were observed between PPARγΔHep and its corresponding wildtype groups (PPARγF/F mice), indicating that GenX analog induce hepatotoxicity mainly via PPARα instead of PPARγ. The PPARα-dependent complement pathways were inhibited in PFDMO2HpA and PFDMO2OA exposed PPARα+/+ mice, which might be responsible for the observed liver inflammation. In PPARα-/- mice, hepatomegaly and increased liver lipid content were observed in PFDMO2HpA and PFDMO2OA treated groups. The activated pregnane X receptor (PXR) and constitutive activated receptor (CAR) pathways in the liver of PPARα-/- mice, which were highlighted by bioinformatics analysis, provided a reasonable explanation for hepatomegaly in the absence of PPARα. Our results indicate that GenX analogs could induce more serious hepatotoxicity than GenX whether there is a PPARα receptor or not. These chemicals, especially PFDMO2HpA and PFDMO2OA, may not be appropriate PFOA alternatives.

Sindrome de Atra / Atra syndrome

La leucemia promielocítica aguda (APL) es el subtipo de leucemia mieloide aguda de mejor pronóstico en niños. Su incidencia es menor a 10%. Desde el punto de vista citogenético se observa una translocación t (15;17). En la terapéutica la incorporación del ácido transretinoico ha logrado altas tasas de remisión completa debido a la rápida desaparición de la coagulopatía y, en consecuencia, disminución de la tasa de recaídas, en comparación con el tratamiento de monoterapia. En general es un fármaco bien tolerado pero puede tener reacciones adversas; el más grave es el síndrome de ácido transretinoico (ATRA), potencialmente mortal. Las manifestaciones clínicas son: fiebre, ganancia de peso, infiltrados pulmonares, síndrome de dificultad respiratoria, derrame pleural o pericárdico, hipotensión, insuficiencia hepática y renal. El tratamiento es con suspensión del ácido transretinoico, medidas de apoyo y altas dosis de esteroides. Se presenta un caso clínico del hospital del Niño DIF con APL y Síndrome de ATRA.

The leukemia promyelocytic acute (APL) is the subtype of leukemia myeloid acute of better prognosis in children. Its incidence is less than 10%. From the point of view cytogenetic is observed a translocation t (15; 17). The addition of the acid transretinoico has achieved high rates of complete remission because of the rapid disappearance of the coagulopathy and, consequently, decrease in the rate of relapses, compared with monotherapy treatment. In general it is a well-tolerated drug but can have adverse reactions; the most serious is transretinoico acid (ATRA), potentially fatal syndrome. The manifestations are: fever, weight gain, pulmonary infiltrates, syndrome of shortness of breath, hypotension, pleural effusion or pericardial, hepatic and renal insufficiency. The treatment is with suspension of the acid transretinoico, measures of support and high doses of steroids. It presents a case clinical of the Hospital del Niño DIF with APL and syndrome of ATRA.

Efecto hepatoprotector del extracto hidroetanólico atomizado del maíz morado (Zea mays L) en lesiones hepáticas inducidas en ratas / Hepatoprotective effect of atomized hydroethanolic extract from Andean purple corn (Zea mays L) in induced hepatic injury in rats

Evaluar el efecto hepatoprotector del extracto hidroetanólico atomizado de Zea mays variedad morado sobre lesiones hepáticas inducidas en ratas. Diseño: Experimental. Institución: Laboratorio de Farmacología Experimental, Facultad de Medicina Humana, Universidad Nacional Mayor de San Marcos, Lima, Perú. Material biológico: Extracto hidroetanólico atomizado de maíz morado (EAM). Intervenciones: Se formó seis grupos de ratas machos (n=10, por cada grupo), se les administró fenobarbital a concentración de 0,5 g/L en agua potable ad líbitum por 15 días; posteriormente se administró tetracloruro de carbono (CCl4) a una dosis de 0,2 mL/kg, por vía oral. El diseño experimental fue el siguiente: G1: suero fisiológico (SSF); G2: CCl4 0,2 mL/kg (T); G3: T+ silimarina 25 mg/kg; G4: T + EAM 500 mg/kg; G5: T + EAM 1 000 mg/kg; G6: T + EAM 2 000 mg/kg. Principales medidas de resultados: Perfil hepático, especies reactivas al ácido tiobarbitúrico (TBARS) en suero, índice hepático, observación histológica. Resultados: Se observó aumento significativo (p<0,05) en la actividad de alanina amino transferasa (ALT) entre el grupo G2 y los grupos G3 y G4 (p<0,001). Hubo disminución significativa (p<0,05) de fosfatasa alcalina (FAL) en el grupo G2 con respecto G1. El nivel de TBARS fue menor en el grupo que recibió 1 000 mg/kg de EAM con respecto al control. Las actividades de HDL-C y triglicéridos no mostraron diferencias significativas. Se ha observado la reducción de 60 por ciento de la lesión hepática, evidenciado con menor daño del hepatocito al estudio histológico. Conclusiones: El extracto hidroetanólico atomizado de maíz morado a la dosis de 1 000 mg/kg disminuyó las lesiones hepáticas inducidas en ratas...

To evaluate the hepatoprotector effect of hydroalcoholic extract atomized of Zea mays against hepatic injuries induced in rats. Design: Experimental. Institution: Laboratory of Experimental Pharmacology, Faculty of Human Medicine, Universidad Nacional Mayor de San Marcos, Lima, Peru. Biological material: Hydroethanolic extract atomized of purple corn (EAM). Interventions: To six groups of male rats (n = 10, for each group) phenobarbital 0.5 g/L in drinkable water ad libitum was administered for 15 days, followed by carbon tetrachloride 0.2 mL/kg p.o. The experimental design was a follow: G1: normal; G2: CCl4 0.2 mL/kg (T); G3:T+ silimarina 25 mg/kg; G4: T+ EAM 500 mg/kg; G5: T + EAM 1 000 mg/kg; G6 T + EAM 2 000 mg/kg. Main outcome measures: Hepatic profile, reactive species to thiobarbituric acid (TBARS), liver index, and histological observation. Results: Significant increase (p<0.05) in ALT activity was observed between group G2 in comparison to groups G3 and G4 (p<0.001). There was significant decrease (p<0.05) of alkaline phosphatase (AP) in group G2 with respect to G1. TBARS level was less in the group that received 1 000 mg/kg of EAM regarding to control. HDL-C and triglycerides activities did not show significant differences. Reduction in 60 per cent of hepatic injury was observed, evidencing less damage of the hepatocyte by histological study. Conclusions: The purple corn atomized hydroethanolic extract at 1 000 mg/kg dose decreased induced hepatic injuries in rats...

Two-year follow-up of hycanthone-treated schistosomiasis mansoni patients in St. Lucia

Of 433 schistosomiasis mansoni patients in St. Lucia who were treated with hycanthone ( 3mg/kg of body weight), 190 were seen 2 years after treatment and 143 of these had attended all follow-up examinations at 6 weeks, 6 months, 1 year, and 2 years. Viable eggs were not detected in 86 percent at 1 year nor in 76 percent at 2 years. The reinfection rate, as judged by a significant increase in egg excretion, was 15 percent and was related to the geographic area to which the patient returned. Extremely high total reduction in egg excreation (98 percent) was achieved through 1 year, and even with reinfections this fell only to 87 percent at 2 years. Liver and spleen enlargement was related to intensity of infection and responded to treatment in 92 percent and 83 percent of instances, respectively. Among patients with hepatosplenomegaly, those 15 years or older showed less clinical response than younger patients but were too few for statistical comparison. (AU)