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1.
Medicine (Baltimore) ; 100(12): e25110, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33761674

RESUMEN

ABSTRACT: Oral direct-acting antiviral (DAA) treatment leads to >95% sustained virological response (SVR) and could be clinically useful in regression of liver fibrosis in chronic hepatitis C virus (HCV) infection. We evaluated if ledipasvir/sofosbuvir or sofosbuvir + ribavirin is associated with regression of fibrosis in HCV patients who achieved SVR.In this prospective cohort study performed at 3 sites in Japan, patients with genotype 1 and genotype 2 were given standard treatment of ledipasvir 90 mg/sofosbuvir 400 mg and sofosbuvir 400 mg + 200-1000 mg/day ribavirin, respectively, for 12 weeks. Liver fibrosis was assessed using Mac-2-binding protein glycosylation isomer (M2BPGi) and other fibrosis markers (platelet count, Fib-4 index, liver stiffness measurement [LSM]) in patients who achieved SVR.A total of 98.1% of (n = 101/103) patients in genotype 1 cohort and 100% (n = 16/16) in the genotype 2 cohort achieved SVR12. Based on per-protocol analysis, M2BPGi levels showed a significant decrease (-2.2  cut-off index [COI], P < .0001) at week 48 after treatment initiation. Forty-three patients showed a significant decrease in Fib-4 index (-1.2, P < .0001), and 44 patients showed improvement in LSM (-5.9 kPa, P < .0001).Achievement of SVR after antiviral therapy was associated with fibrosis regression. M2BPGi correlated well with LSM at week 48 after treatment initiation, supporting the sustainable benefit of HCV therapy.


Asunto(s)
Bencimidazoles/administración & dosificación , Fluorenos/administración & dosificación , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Ribavirina/administración & dosificación , Sofosbuvir/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Combinada , Femenino , Hepatitis C Crónica/complicaciones , Humanos , Hígado/efectos de los fármacos , Hígado/virología , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Respuesta Virológica Sostenida , Resultado del Tratamiento
2.
Molecules ; 26(4)2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33671486

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is among the leading causes of end-stage liver disease. The impaired hepatic lipid metabolism in NAFLD is exhibited by dysregulated PPARα and SREBP-1c signaling pathways, which are central transcription factors associated with lipid degradation and de novo lipogenesis. Despite the growing prevalence of this disease, current pharmacological treatment options are unsatisfactory. Genistein, a soy isoflavone, has beneficial effects on lipid metabolism and may be a candidate for NAFLD treatment. In an in vitro model of hepatic steatosis, primary human hepatocytes (PHHs) were incubated with free fatty acids (FFAs) and different doses of genistein. Lipid accumulation and the cytotoxic effects of FFAs and genistein treatment were evaluated by colorimetric and enzymatic assays. Changes in lipid homeostasis were examined by RT-qPCR and Western blot analyses. PPARα protein expression was induced in steatotic PHHs, accompanied by an increase in CPT1L and ACSL1 mRNA. Genistein treatment increased PPARα protein expression only in control PHHs, while CPTL1 and ACSL1 were unchanged and PPARα mRNA was reduced. In steatotic PHHs, genistein reversed the increase in activated SREBP-1c protein. The model realistically reflected the molecular changes in hepatic steatosis. Genistein suppressed the activation of SREBP-1c in steatotic hepatocytes, but the genistein-mediated effects on PPARα were abolished by high hepatic lipid levels.


Asunto(s)
Hígado Graso/tratamiento farmacológico , Genisteína/farmacología , Hígado/efectos de los fármacos , Modelos Biológicos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Hígado Graso/metabolismo , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/antagonistas & inhibidores , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo
3.
Life Sci ; 274: 119344, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33716062

RESUMEN

AIMS: Amiodarone (AM) is a highly efficient drug for arrhythmias treatment, but its extra-cardiac adverse effects offset its therapeutic efficacy. Nanoparticles (NPs)-based delivery system could provide a strategy to allow sustained delivery of AM to the myocardium and reduction of adverse effects. The primary purpose was to develop AM-loaded NPs and explore their ameliorative effects versus off-target toxicities. MATERIALS AND METHODS: Polymeric NPs were prepared using poly lactic-co-glycolic acid and their physicochemical properties were characterized. Animal studies were conducted using a rat model to compare exposure to AM versus that of the AM-loaded NPs. Biochemical evaluation of liver enzymes, lipid profile, and thyroid hormones was achieved. Besides, histopathological changes in liver and lung were studied. KEY FINDINGS: Under optimal experimental conditions, the AM-loaded NPs had a size of 186.90 nm and a negative zeta potential (-14.67 mV). Biochemical evaluation of AM-treated animal group showed a significant increase in cholesterol, TG, LDL, T4, and TSH levels (ρ < 0.05). Remarkably, the AM-treated group exhibited a significant increase of liver enzymes (ρ < 0.05) coupled with an obvious change in liver architecture. The AM-loaded NPs displayed a reduction of liver damage and enzyme levels. Lung sections of the AM-treated group demonstrated thickening of interalveolar septa, mononuclear cellular infiltration with congested blood vessels, and heavy collagenous fibers deposition. Conversely, less cellular infiltration and septal thickening were observed in the animal lungs treated with the AM-loaded NPs-treated. SIGNIFICANCE: Our findings demonstrate the competence of the AM-loaded NPs to open several exciting avenues for evading the AM-induced off-target toxicities.


Asunto(s)
Amiodarona/química , Amiodarona/farmacología , Portadores de Fármacos/química , Hígado/patología , Nanopartículas/toxicidad , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Amiodarona/administración & dosificación , Animales , Antiarrítmicos/administración & dosificación , Antiarrítmicos/química , Antiarrítmicos/farmacología , Hígado/efectos de los fármacos , Masculino , Nanopartículas/administración & dosificación , Estudios Prospectivos , Ratas , Ratas Sprague-Dawley , Pruebas de Toxicidad
4.
Molecules ; 26(4)2021 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-33668635

RESUMEN

Launaea nudicaulis is used in folk medicine worldwide to treat several diseases. The present study aimed to assess the antidiabetic activity of L. nudicaulis ethanolic extract and its effect on diabetic complications in streptozotocin-induced hyperglycemic rats. The extract was orally administrated at 250 and 500 mg/kg/day for 5-weeks and compared to glibenclamide as a reference drug at a dose of 5 mg/kg/day. Administration of the extract exhibited a potential hypoglycemic effect manifested by a significant depletion of serum blood glucose concurrent with a significant elevation in serum insulin secretion. After 5-weeks, extract at 250 and 500 mg/kg/day decreased blood glucose levels by about 53.8 and 68.1%, respectively, compared to the initial values (p ≤ 0.05). The extract at the two dosages prevented weight loss of rats from the 2nd week till the end of the experiment, compared to diabetic control rats. The extract further exhibited marked improvement in diabetic complications including liver, kidney and testis performance, oxidative stress, and relative weight of vital organs, with respect to diabetic control. Histopathological examinations confirmed the previous biochemical analysis, where the extract showed a protective effect on the pancreas, liver, kidney, and testis that degenerated in diabetic control rats. To characterize extract composition, UPLC-ESI-qTOF-MS identified 85 chromatographic peaks belonging to flavonoids, phenolics, acyl glycerols, nitrogenous compounds, and fatty acids, with four novel phenolics reported. The potential anti-diabetic effect warrants its inclusion in further studies and or isolation of the main bioactive agent(s).


Asunto(s)
Asteraceae/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Etanol/química , Hipoglucemiantes/uso terapéutico , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Animales , Antioxidantes/metabolismo , Biomarcadores/sangre , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Hipoglucemiantes/farmacología , Insulina/sangre , Riñón/efectos de los fármacos , Riñón/fisiopatología , Lípidos/sangre , Hígado/efectos de los fármacos , Hígado/fisiopatología , Masculino , Malondialdehído/sangre , Metabolómica , Tamaño de los Órganos/efectos de los fármacos , Especificidad de Órganos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Ratas Wistar , Estreptozocina , Pruebas de Toxicidad Aguda
5.
Int J Nanomedicine ; 16: 2323-2335, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33776436

RESUMEN

Background: Colon cancer (CRC) was a malignant tumor and there were about 25% of patients with tumor metastasis at diagnosis stage. Chemotherapeutic agents for metastatic CRC patients were with great side effects and the clinical treatment results of advanced CRC were still not satisfactory. Human epidermal growth factor receptor 2 (HER2) is overexpressed in some CRC patients and is an effective target for CRC patient treatment. Anti-HER2 therapy had a beneficial role in the treatment of HER2-positive metastatic CRC with fewer side effects. CRC patients with BRAF mutations were resistant to HER2 antibodies treatment. Therefore, there was an urgent need to develop new therapeutic agents. Methods: HER2 targeted nanoparticles (TPLNP) drug delivery system loading triptolide (TPL) were prepared and identified. The effects of TPLNP and free TPL on cell viability, targeting and cell cycle progression on HT29 (BRAF mutation) with HER2 overexpression, were evaluated by Cell Counting Kit-8 (CCK8), Fluorescence Activating Cell Sorter (FACS) and immunofluorescence methods, respectively. The anti-tumor efficacies of TPLNP were evaluated in subcutaneous xenograft model of colon cancer and the survival rate, tumor volume, liver and kidney indexes of tumor-bearing mice were measured. Results: TPLNP was small in nanosize (73.4±5.2nm) with narrow size distribution (PDI=0.15±0.02) and favorable zeta potential (pH=9.6, zeta potential: -57.3±6.69mV; pH=7.0, zeta potential: -28.7±5.1mV; pH=5.6, zeta potential: -21.1±4.73mV). Comparing with free TPL treatment group, TPLNP developed stranger colon cancer-killing efficiency in a dose- and time-dependent manner detected with CCK8 method; achieved good in vitro colon cancer targeting detected with flow cytometry and immunofluorescence experiments; enhanced more HT29-HER2 apoptosis and induced more cell cycle arrested in G1-S phase detected with FACS in vitro. As for in vivo antitumor response, TPLNP remarkably inhibited the growth of colon cancer in the colon cancer xenograft model, significantly improved the survival rate and did not exhibit significant liver and kidney toxicity in contrast with free TPL in vivo. Conclusion: TPLNP was effectively against colon cancer with HER2 overexpression and BRAF mutation in pre-clinical models. In summary, the TPLNP appeared to be a promising treatment option for CRC in clinical application based on improved efficacy and the favorable safety profile.


Asunto(s)
Diterpenos/farmacología , Sistemas de Liberación de Medicamentos , Mutación/genética , Nanopartículas/química , Fenantrenos/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Receptor ErbB-2/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinogénesis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Diterpenos/toxicidad , Compuestos Epoxi/farmacología , Compuestos Epoxi/toxicidad , Femenino , Células HT29 , Humanos , Concentración 50 Inhibidora , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanomedicina , Fenantrenos/toxicidad , Transducción de Señal/efectos de los fármacos
6.
Aquat Toxicol ; 233: 105792, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33662877

RESUMEN

Although anticoagulant rodenticides (ARs) are effectively used for the control of invasive rodents, nontarget species are also frequently exposed to ARs and secondary poisonings occur widely. However, little data is available on the effects of ARs, especially on marine organisms. To evaluate the effects of ARs on marine wildlife, we chose green sea turtles (Chelonia mydas), which are one of the most common marine organisms around the Ogasawara islands, as our primary study species. The sensitivity of these turtles to ARs was assessed using both in vivo and in vitro approaches. We administered 4 mg/kg of warfarin sodium either orally or intravenously to juvenile green sea turtles. The turtles exhibited slow pharmacokinetics, and prolongation of prothrombin time (PT) was observed only with intravenous warfarin administration. We also conducted an in vitro investigation using liver microsomes from green sea turtles, and two other turtle species (softshell turtle and red-eared slider) and rats. The cytochrome P450 metabolic activity in the liver of green sea turtles was lower than in rats. Additionally, vitamin K epoxide reductase (VKOR), which is the target enzyme of ARs, was inhibited by warfarin in the turtles at lower concentration levels than in rats. These data indicate that turtles may be more sensitive to ARs than rats. We expect that these findings will be helpful for sea turtle conservation following accidental AR-broadcast incidents.


Asunto(s)
Anticoagulantes/toxicidad , Errores Innatos del Metabolismo/sangre , Rodenticidas/toxicidad , Tortugas/sangre , Contaminantes Químicos del Agua/toxicidad , Animales , Resistencia a Medicamentos , Islas , Hígado/efectos de los fármacos , Hígado/metabolismo , Tiempo de Protrombina , Ratas , Medición de Riesgo , Tortugas/metabolismo
7.
Aquat Toxicol ; 233: 105788, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33662878

RESUMEN

The gene expression response thought to underlie the negative apical effects resulting from estrogen exposure have been thoroughly described in fish. Although epigenetics are believed to play a critical role translating environmental exposures into the development of adverse apical effects, they remain poorly characterized in fish species. This study investigated alterations of DNA methylation of estrogen receptor alpha (esr1) in brain and liver tissues from 8 to 10 month old male fathead minnows (Pimephales promelas) after a 2d exposure to either 2.5 ng/L or 10 ng/L 17α-ethynylestradiol (EE2). Changes in the patterns of methylation were evaluated using targeted deep sequencing of bisulfite treated DNA in the 5' region of esr1. Methylation and gene expression were assessed at 2d of exposure and after a 7 and 14d depuration period. After 2d EE2 exposure, males exhibited significant demethylation in the 5' upstream region of esr1 in liver tissue, which was inversely correlated to gene expression. This methylation pattern reflected what was seen in females. No gene body methylation (GBM) was observed for liver of exposed males. Differential methylation was observed for a single upstream CpG site in the liver after the 14d depuration. A less pronounced methylation response was observed in the upstream region in brain tissue, however, several CpGs were necessarily excluded from the analysis. In contrast to the liver, a significant GBM response was observed across the entire gene body, which was sustained until at least 7d post-exposure. No differential expression was observed in the brain, limiting functional interpretation of methylation changes. The identification of EE2-dependent changes in methylation levels strongly suggests the importance of epigenetic mechanisms as a mediator of the organismal response to environmental exposures and the need for further characterization of the epigenome. Further, differential methylation following depuration indicates estrogenic effects persist well after the active exposure, which has implications for the risk posed by repeated exposures..


Asunto(s)
Cyprinidae/metabolismo , Metilación de ADN/efectos de los fármacos , Receptor alfa de Estrógeno/genética , Etinilestradiol/toxicidad , Expresión Génica/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cyprinidae/genética , Estrógenos/metabolismo , Femenino , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Vitelogeninas/metabolismo
8.
Toxicol Lett ; 343: 1-10, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33571620

RESUMEN

AIMS: Both gefitinib and afatinib are epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in the treatment of non-small cell lung cancer (NSCLC). It has been reported that gefitinib and afatinib could cause hepatotoxicity during the clinic treatment, therefore it is critical to investigate their hepatotoxicity systematically. In this study, zebrafish (Danio rerio) were used as model animals to compare the hepatotoxicity and their toxic mechanism. MAIN METHODS: The zebrafish transgenic line [Tg (fabp10a: dsRed; ela3l:EGFP) was used in this study. After larvae developed at 3 days post fertilization (dpf), they were put into different concentrations of gefitinib and afatinib. At 6 dpf, the viability, liver area, fluorescence intensity, histopathology, apoptosis, transaminase reflecting liver function, the absorption of yolk sac, and the expression of relative genes were observed and analyzed respectively. KEY FINDINGS: Both gefitinib and afatinib could induce the larvae hepatotoxicity dose-dependently. Based on the liver morphology, histopathology, apoptosis and function assessments, gefitinib showed higher toxicity, causing more serious liver damage. Both gefitinib and afatinib caused abnormal expressions of genes related to endoplasmic reticulum stress (ERS) pathway and apoptosis. For example, jnk, perk, bip, chop, ire1, bid, caspase3 and caspase9 were up-regulated, while xbp1s, grp78, bcl-2/bax, and caspase8 were down-regulated. The hepatotoxicity difference of gefitinib and afatinib might be due to the different expression level of related genes.


Asunto(s)
Afatinib/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Embrión no Mamífero/efectos de los fármacos , Gefitinib/toxicidad , Hígado/efectos de los fármacos , Inhibidores de Proteínas Quinasas/toxicidad , Animales , Animales Modificados Genéticamente , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/patología , Pez Cebra/embriología
9.
Nat Commun ; 12(1): 1118, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602914

RESUMEN

Modern biomedical research and preclinical pharmaceutical development rely heavily on the phenotyping of small vertebrate models for various diseases prior to human testing. In this article, we demonstrate an acoustofluidic rotational tweezing platform that enables contactless, high-speed, 3D multispectral imaging and digital reconstruction of zebrafish larvae for quantitative phenotypic analysis. The acoustic-induced polarized vortex streaming achieves contactless and rapid (~1 s/rotation) rotation of zebrafish larvae. This enables multispectral imaging of the zebrafish body and internal organs from different viewing perspectives. Moreover, we develop a 3D reconstruction pipeline that yields accurate 3D models based on the multi-view images for quantitative evaluation of basic morphological characteristics and advanced combinations of metrics. With its contactless nature and advantages in speed and automation, our acoustofluidic rotational tweezing system has the potential to be a valuable asset in numerous fields, especially for developmental biology, small molecule screening in biochemistry, and pre-clinical drug development in pharmacology.


Asunto(s)
Acústica , Rotación , Pez Cebra/anatomía & histología , Animales , Etanol/farmacología , Imagenología Tridimensional , Larva/anatomía & histología , Larva/efectos de los fármacos , Hígado/anatomía & histología , Hígado/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Fenotipo , Transductores
10.
Int J Mol Sci ; 22(4)2021 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-33567653

RESUMEN

Zinc oxide (ZnO) particles have been used as dietary supplements because zinc is an essential trace element for humans. Along with the rapid development of nanotechnology, the use of ZnO nanoparticles (NPs) is increasing in the food industry, but their oral toxicity potential still remains to be answered. In this study, the effects of particle size and biological fate of ZnO on acute toxicity, toxicokinetics, and gene expression profiles in the livers were investigated after oral administration of ZnO NPs (N-ZnO), bulk-sized ZnO (B-ZnO) or Zn ions in rats. The plasma concentration-time profiles after a single-dose oral administration of ZnOs differed depending on particle/ionic forms and particle size, showing high absorption of Zn ions, followed by N-ZnO and B-ZnO, although in vivo solubility did not differ from particle size. No significant acute toxicity was found after oral administration of ZnOs for 14 days in rats. However, transcriptomic responses in the livers were differently affected, showing that metabolic process and metal biding were up-regulated by Zn ions and N-ZnO, respectively, which were not pronounced in the liver treated with B-ZnO. These findings will be useful to predict the potential oral toxicity of ZnO NPs and further mechanistic and long-term exposure studies are required to assume their safety.


Asunto(s)
Hígado/patología , Nanopartículas del Metal/administración & dosificación , Nanopartículas del Metal/toxicidad , Transcriptoma/efectos de los fármacos , Óxido de Zinc/administración & dosificación , Óxido de Zinc/toxicidad , Administración Oral , Animales , Femenino , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratas , Ratas Sprague-Dawley , Toxicocinética
11.
Life Sci ; 270: 119146, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33545199

RESUMEN

Deferasirox (DFX) was formulated into oil-in-water microemulsions in the presence of pluronicto improve its oral bioavailability. The size of the DFX-loadedmicroemulsions system measured by dynamic light scattering (DLS) was about 9 nm. The anti-proliferative and anti-lipid peroxidation effects of DFX and DFX-loaded microemulsions were assessed on Human umbilical vein endothelial (HUVEC) cells. Our in vitro results showed that HUVEC cells are more susceptible to free DFX as compared to DFX-loaded microemulsions. Although both free and encapsulated DFX attenuated FeCl3-induced lipid peroxidation, after 6 and 12 h treatment, DFX-loaded microemulsions did not appear a better ameliorator than DFX. To compare the in vivo efficacy of free DFX and DFX-loaded microemulsions in iron- intoxicated rats, the animals were orally administered with 25 mg/kg DFX, or 25 mg/kg DFX microemulsions, respectively. In vivo gavage handling of free DFX significantly increased serum biochemical parameters. There was also a significant increase in lipid peroxidation in rats who received free DFX compared to those in the control rats. Treatment with DFX-loaded microemulsions restored the elevated levels of serum AST, ALT, and creatinine levels and also reduced liver MDA content. Histopathological analysis of renal and hepatic tissues was in line with the biochemical results. In conclusion, DFX-loaded microemulsions induce less toxicity than free DFX and appear a more desirable and safer drug carrier in combating the iron-overload complications. Theoretical simulations are performed to get better insight regarding interactions between DFX and surfactant F127.


Asunto(s)
Deferasirox/farmacología , Sistemas de Liberación de Medicamentos/métodos , Sobrecarga de Hierro/tratamiento farmacológico , Animales , Deferasirox/metabolismo , Emulsiones/farmacología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Hierro/análisis , Hierro/metabolismo , Hierro/toxicidad , Quelantes del Hierro/farmacología , Sobrecarga de Hierro/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Micelas , Ratas , Ratas Wistar
12.
Nucleic Acids Res ; 49(4): 1828-1839, 2021 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-33544849

RESUMEN

We recently showed that site-specific incorporation of 2'-modifications or neutral linkages in the oligo-deoxynucleotide gap region of toxic phosphorothioate (PS) gapmer ASOs can enhance therapeutic index and safety. In this manuscript, we determined if introducing substitution at the 5'-position of deoxynucleotide monomers in the gap can also enhance therapeutic index. Introducing R- or S-configured 5'-Me DNA at positions 3 and 4 in the oligodeoxynucleotide gap enhanced the therapeutic profile of the modified ASOs suggesting a different positional preference as compared to the 2'-OMe gap modification strategy. The generality of these observations was demonstrated by evaluating R-5'-Me and R-5'-Ethyl DNA modifications in multiple ASOs targeting HDAC2, FXI and Dynamin2 mRNA in the liver. The current work adds to a growing body of evidence that small structural changes can modulate the therapeutic properties of PS ASOs and ushers a new era of chemical optimization with a focus on enhancing the therapeutic profile as opposed to nuclease stability, RNA-affinity and pharmacokinetic properties. The 5'-methyl DNA modified ASOs exhibited excellent safety and antisense activity in mice highlighting the therapeutic potential of this class of nucleic acid analogs for next generation ASO designs.


Asunto(s)
ADN/química , Oligonucleótidos Antisentido/química , Animales , Glucosa/análogos & derivados , Glucosa/química , Células HeLa , Humanos , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Células 3T3 NIH , Oligonucleótidos Antisentido/uso terapéutico , Oligonucleótidos Antisentido/toxicidad , Compuestos Organofosforados/síntesis química , Ribonucleasa H
13.
Aquat Toxicol ; 233: 105771, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33578303

RESUMEN

Present study aims to investigate interaction of molecular chaperons (heat shock protein 70, heat shock protein 90) with transcriptional factors (nuclear factor kappa B/nuclear factor E2-related factor 2/Kelch-like ECH-associated protein 1) to evaluate their role during metal induced stress in fish hepatocytes. Adult Puntius ticto were exposed to lead nitrate at 0 mg/l (control), 1/50th (0.04 mg/l) and 1/20th (0.12 mg/l) of LC50 for 30 days and sacrificed to collect liver tissues. Activity of selected liver enzymes, antioxidants and metallothionein were analyzed. Levels of heat shock protein 70, heat shock protein 90, nuclear factor kappa B, nuclear factor E2-related factor 2 and Kelch-like ECH-associated protein 1 were also measured. Liver enzymes showed a significant increase (p < 0.05) in both Pb exposed groups indicating that the liver might be at risk of damage. Increased level of lipid peroxidation due to metal stress was marked by significant increase (p < 0.05) in malondialdehyde level in fish exposed to the higher Pb concentration compared to control (+ 13.7 %). Significant increase (p < 0.05) in gluthathione reductase (+ 35 %, + 39.2 %), glutathione s-transferase (+ 22.4 %, + 50.4 %) activities and decrease in reduced glutathione level (- 6.75 %, - 12.25 %) in fish exposed to both lower and higher Pb concentration compared to control also indicated metal induced oxidative damage in fish liver. Super oxide dismutase and catalase activities increased significantly (p < 0.05) during exposure to lower Pb concentration, while decreased significantly (p < 0.05) during exposure to higher Pb concentration compared to those in control. Significant (P < 0.05) increase (+ 52.63 %, + 89.47 %) in metallothionein in Pb exposed groups confirmed its role in detoxification process of the metal. Heat shock protein 70 and heat shock protein 90 expression levels increased significantly (p < 0.05) during metal exposure indicating their role as modulator of stress-induced antioxidant protein remodelling. A positive correlation between nuclear factor kappa B/nuclear factor E2-related factor 2/Kelch-like ECH-associated protein 1 with gluthathione regulatory enzymes (gluthathione reductase and glutathione s-transferase) was noted. Current study effectively illuminates the critical role of different factors (heat shock proteins/nuclear factor kappa B/nuclear factor E2-related factor 2/Kelch-like ECH-associated protein 1) to influence the expression and synthesis of antioxidants and other functional enzymes in lead-exposed fish liver.


Asunto(s)
Antioxidantes/metabolismo , Cyprinidae/metabolismo , Proteínas de Choque Térmico/metabolismo , Plomo/toxicidad , Hígado/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Contaminantes Químicos del Agua/toxicidad , Animales , Peroxidación de Lípido/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Nitratos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal
14.
Ecotoxicol Environ Saf ; 212: 111989, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33524913

RESUMEN

Drinking water exposure to microcystin-leucine-arginine (MC-LR), the most widely occurring cyanotoxins, poses a highly potential risk for human health. However, the health risk of MC-LR exposure at current guideline value in drinking water has not yet entirely evaluated. In the current study, we used 1H NMR-based metabolomics combined with targeted metabolic profiling by GC/LC-MS to explore the toxic effects of MC-LR exposure at environmentally relevant concentrations via drinking water in rats. The results revealed that multiple biological consequences of MC-LR exposure on host metabolism in rats. Both relatively low and high doses of MC-LR used here induced hepatic lipogenesis and inflammation. While only relatively high dose MC-LR (10 µg/L) in drinking water caused more metabolic disorders including inhibition of gluconeogenesis and promotion of ß-oxidation of fatty acid. Although the dose of 1.0 µg/L MC-LR is extremely low for rats, alterations of metabolic profiles were unexpectedly found in rat liver and serum, alarming potential health risk of MC-LR at the WHO guideline level.


Asunto(s)
Agua Potable/química , Microcistinas/toxicidad , Animales , Cromatografía Liquida , Agua Potable/análisis , Hígado/efectos de los fármacos , Masculino , Metaboloma , Metabolómica , Ratas
15.
Drug Deliv ; 28(1): 325-342, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33517789

RESUMEN

The aim of the present study was to investigate the pharmacological mechanism of matrine in treatment of COVID-19 combined with liver injury. Potential targets related to matrine, COVID-19 and liver injury were identified from several databases. We constructed PPI network and screened the core targets according to the degree value. Then, GO and KEGG enrichment were carried out. Molecular docking technology was used to verify the affinity between matrine and the crystal structure of core target protein. Finally, real-time RT-PCR was used to detect the effects of matrine on hub gene expression in liver tissue of liver injury mice and lung tissue of lung injury mice to further confirm the results of network pharmacological analysis. The results show that six core targets including AKT1, TP53, TNF, IL6, BCL2L1 and ATM were identified. The potential therapeutic mechanism of matrine on COVID-19 combined with liver injury is closely related to regulate antiviral process, improve immune system and regulate the level of inflammatory factors. Molecular docking showed that matrine could spontaneously bind to the receptor protein and had strong binding force. Real-time RT-PCR demonstrated that matrine could significantly reduce the expression of AKT1, TP53, TNF, IL6 and ATM in mice with liver injury or lung injury (P < 0.05), and increase the expression of BCL2L1 to a certain extent (P > 0.05). Our results indicate that matrine can achieve simultaneous intervention of COVID-19 combined with liver injury by multi-dimensional pharmacological mechanism.


Asunto(s)
Alcaloides/farmacología , /epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Simulación del Acoplamiento Molecular/métodos , Quinolizinas/farmacología , Alcaloides/administración & dosificación , Animales , Antivirales/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Relación Dosis-Respuesta a Droga , Humanos , Lipopolisacáridos/farmacología , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Quinolizinas/administración & dosificación , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/efectos de los fármacos
16.
Nat Commun ; 12(1): 1041, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589633

RESUMEN

Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.


Asunto(s)
Regulación del Apetito/fisiología , Ejercicio Físico/fisiología , Conducta Alimentaria/fisiología , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor 15 de Diferenciación de Crecimiento/genética , Resistencia Física/fisiología , Adulto , Animales , Creatina Quinasa/sangre , Creatina Quinasa/genética , Regulación de la Expresión Génica , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/deficiencia , Factor 15 de Diferenciación de Crecimiento/sangre , Factor 15 de Diferenciación de Crecimiento/metabolismo , Humanos , Interleucina-10/sangre , Interleucina-10/genética , Interleucina-6/administración & dosificación , Leptina/sangre , Leptina/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Motivación/fisiología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Condicionamiento Físico Animal , Factores de Tiempo
17.
Ecotoxicol Environ Saf ; 213: 111987, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33582408

RESUMEN

Protective effects of estrogen (E2) on traumatic brain injury (TBI) have been determined. In this study, the hepatoprotective effects of E2 after TBI through its receptors and oxidative stress regulation have been evaluated. Diffuse TBI induced by the Marmarou method in male rats. G15, PHTPP, MPP, and ICI182-780 as selective antagonists of E2 were injected before TBI. The results indicated that TBI induces a significant increase in liver enzymes [Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Glutamyl transferase (GGT)], and oxidants levels [Malondialdehyde (MDA), Nitric oxide (NO)] and decreases in antioxidant biomarkers [Glutathione peroxidase (GPx) and Superoxide dismutase (SOD)] in the brain and liver, and plasma. We also found that E2 significantly preserved levels of these biomarkers and enzymatic activity. All antagonists inhibited the effects of E2 on increasing SOD and GPx. Also, the effects of E2 on brain MDA levels were inhibited by all antagonists, but in the liver, only ICI + G15 + E2 + TBI group was affected. The impacts of E2 on brain and liver and plasma NO levels were inhibited by all antagonists. The current findings demonstrated that E2 probably improved liver injury after TBI by modulating oxidative stress. Also, both classic (ERß, ERα) and non-classic [G protein-coupled estrogen receptor (GPER)] receptors are affected in the protective effects of E2.


Asunto(s)
Estradiol/farmacología , Sustancias Protectoras/farmacología , Alanina Transaminasa/metabolismo , Animales , Antioxidantes/metabolismo , Aspartato Aminotransferasas/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Estradiol/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Estrógenos/metabolismo , Glutatión Peroxidasa/metabolismo , Hígado/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Receptores Estrogénicos/metabolismo , Superóxido Dismutasa/metabolismo
18.
Life Sci ; 271: 119220, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33592199

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is a disorder of excessive fat accumulation in the liver, known as steatosis, without alcohol overconsumption. NAFLD can either manifest as simple steatosis or steatohepatitis, known as non-alcoholic steatohepatitis (NASH), which is accompanied by inflammation and possibly fibrosis. Furthermore, NASH might progress to hepatocellular carcinoma. NAFLD and NASH prevalence is in a continuous state of growth, and by 2018, NAFLD became a devastating metabolic disease with a global pandemic prevalence. The pathophysiology of NAFLD and NASH is not fully elucidated, but is known to involve the complex interplay between different metabolic, environmental, and genetic factors. In addition, unhealthy dietary habits and pre-existing metabolic disturbances together with other risk factors predispose NAFLD development and progression from simple steatosis to steatohepatitis, and eventually to fibrosis. Despite their growing worldwide prevalence, to date, there is no FDA-approved treatment for NAFLD and NASH. Several off-label medications are used to target disease risk factors such as obesity and insulin resistance, and some medications are used for their hepatoprotective effects. Unfortunately, currently used medications are not sufficiently effective, and research is ongoing to investigate the beneficial effects of different drugs and phytochemicals in NASH. In this review article, we outline the different risk factors and pathophysiological mechanisms involved in NAFLD, diagnostic procedures, and currently used management techniques.


Asunto(s)
Hígado/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/terapia , Curcumina/farmacología , Curcumina/uso terapéutico , Humanos , Resistencia a la Insulina/fisiología , Hígado/efectos de los fármacos , Trasplante de Hígado/métodos , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/fisiopatología , Síndrome Metabólico/terapia , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Obesidad/diagnóstico , Obesidad/fisiopatología , Obesidad/terapia , Preparaciones de Plantas/farmacología , Preparaciones de Plantas/uso terapéutico , Resveratrol/farmacología , Resveratrol/uso terapéutico , Factores de Riesgo
19.
Life Sci ; 271: 119237, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33600859

RESUMEN

AIMS: Echinacoside (ECH) is a natural compound extracted from the stem of the Cistanche deserticola plant, has significant biological properties, including antioxidant, anti-inflammatory, neuroprotective, anti-tumor, hepatoprotective, and immunomodulatory properties. In this study, we aimed to explore the protection effects and mechanisms of ECH on diabetic liver injury in db/db mice. MAIN METHODS: Overall, 6-week-old db/db mice (n = 20) were randomly allocated to 2 groups: diabetic model group (db/db group, intragastric administration of normal saline, n = 10) and ECH-treated group (db/db + ECH group, n = 10). Additionally, the normal control group comprised 6-week-old db/m mice (db/m group, normal saline intragastric administration, n = 10). ECH was administered once a day for 10 weeks. Weight and fasting blood glucose (FBG) were measured biweekly. HE staining and Oil O staining were used to evaluate liver tissue pathological changes and lipid accumulation respectively. Immunofluorescence staining, Western blot and RT-PCR analysis were used to detect the expression of components of the AMPK/SIRT1 signaling axis. KEY FINDINGS: The results showed that the administration of echinacoside for 10 weeks could significantly improve liver injury and insulin resistance in db/db mice (p < 0.01). Also, echinacoside treatment helped to reduce blood lipids and blood glucose (p < 0.01). Moreover, ECH actived AMPK/SIRT1 signaling, upregulated peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), proliferator-activated receptor-α (PPARα), carnitine palmitoyl transferase-1A (CPT1A) in db/db mice (p < 0.01). SIGNIFICANCE: The effect of ECH may be elicited by the activation of the liver AMPK/SIRT1 pathway and its downstream factors to improve adiposity, insulin resistance, and dyslipidemia.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glicósidos/uso terapéutico , Hígado/metabolismo , Proteínas Quinasas/metabolismo , Sirtuina 1/metabolismo , Animales , Glicósidos/farmacología , Hígado/efectos de los fármacos , Masculino , Ratones , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
20.
Arch Virol ; 166(4): 1071-1081, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33533976

RESUMEN

Elimination of hepatitis C virus (HCV) may fail, leading to a non-response outcome because of inappropriate testing for viral RNA in peripheral blood mononuclear cells (PBMCs). Sequelae of HCV genotype 4 therapy with sofosbuvir and daclatasvir ± ribavirin were assessed in our study at the 12th week after end of treatment (EOT) by screening for viral genomic RNA in serum and PBMCs with correlation to hepatic parenchymal changes. We recruited 102 out of 2165 patients who had received sofosbuvir/daclatasvir, either alone (n = 1573) or together with ribavirin (n = 592). Subjects were classified into three groups based on testing by single-step reverse transcription PCR: group I, HCV negative in both serum and PBMCs (n = 25); group II, HCV positive in PBMCs only (n = 52); and group III, HCV positive in both serum and PBMCs (n = 25). Groups I and II (n = 77) were selected out of 2102 (every 27th subject), while group III (n = 25) were selected from every second or third serologic relapse (n = 63). The pre-sampling population (n = 2165) showed sustained virologic response (SVR) in 33.21%; serologic relapse in 2.91%; HCV RNA only in PBMCs (66.79%) compared to serologic relapses and potential cure (P < 0.0001); higher serologic (38 out of 63, P = 0.03210) and cellular (36 out of 52, P = 0.0002) relapses in dual therapy than in triple therapy. The post-sampling population (n = 102) showed more HCV relapses in dual (50 out of 60) than in triple (27 out of 42) therapy (P = 0.0351); increased HCV antisense RNA strand in relapses compared to positive-sense strands alone (P < 0.001); and significant SVR events in undetectable (15 out of 31) compared to early (10 out of 55, P = 0.0058) and cirrhotic liver tissue changes (0 out of 16, P = 0.0006). In summary, HCV treatment with sofosbuvir/daclatasvir is followed by higher rates of serologic and intracellular viral RNA relapse than treatment with sofosbuvir/daclatasvir plus ribavirin. Cellular and serum viral RNA relapses are accompanied by HCV-induced hepatic pathology. An increased SVR with no detectable liver tissue changes was observed after triple therapy due to elimination of HCV RNA from PBMCs.


Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , ARN Viral/efectos de los fármacos , Ribavirina/uso terapéutico , Adulto , Carbamatos/uso terapéutico , Quimioterapia Combinada , Femenino , Hepacivirus/genética , Hepatitis C Crónica/patología , Hepatitis C Crónica/virología , Humanos , Imidazoles/uso terapéutico , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/virología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Persona de Mediana Edad , Tejido Parenquimatoso/efectos de los fármacos , Tejido Parenquimatoso/patología , Pirrolidinas/uso terapéutico , ARN Viral/análisis , Prevención Secundaria , Sofosbuvir/uso terapéutico , Resultado del Tratamiento , Valina/análogos & derivados , Valina/uso terapéutico
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