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1.
Int J Mol Sci ; 21(7)2020 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-32218158

RESUMEN

Radiation therapy is a standard treatment for patients with head and neck cancer. However, radiation exposure to the head and neck induces salivary gland (SG) dysfunction. Alpha lipoic acid (ALA) has been reported to reduce radiation-induced toxicity in normal tissues. In this study, we investigated the effect of ALA on radiation-induced SG dysfunction. Male Sprague-Dawley rats were assigned to the following treatment groups: control, ALA only (100 mg/kg, intraperitoneally), irradiation only, and ALA administration 24 h or 30 min prior to irradiation. The neck area, including SGs, was irradiated evenly at 2 Gy/min (total dose, 18 Gy) using a photon 6 MV linear accelerator. The rats were sacrificed at 2, 6, 8, and 12 weeks after irradiation. Radiation decreased SG weight, saliva secretion, AQP5 expression, parasympathetic innervation (GFRα2 and AchE expression), regeneration potentials (Shh and Ptch expression), salivary trophic factor levels (brain-derived neurotrophic factor and neurturin), and stem cell expression (Sca-1). These features were restored by treatment with ALA. This study demonstrated that ALA can rescue radiation-induced hyposalivation by preserving parasympathetic innervation and regenerative potentials.


Asunto(s)
Traumatismos Experimentales por Radiación/tratamiento farmacológico , Glándulas Salivales/efectos de los fármacos , Ácido Tióctico/farmacología , Animales , Peso Corporal/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Traumatismos Experimentales por Radiación/patología , Ratas Sprague-Dawley , Glándulas Salivales/patología
2.
Toxicol Lett ; 325: 43-50, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32092452

RESUMEN

As a consequence of the detoxification process, drugs and drug related metabolites can accumulate in the liver, resulting in drug induced liver injury (DILI), which is the major cause for dose limitation. Amitriptyline, a commonly used tricyclic anti-depressant, is known to cause DILI. The mechanism of Amitriptyline induced liver injury is not yet completely understood. However, as it undergoes extensive hepatic metabolism, unraveling the molecular changes in the liver upon Amitriptyline treatment can help understand Amitriptyline's mode of toxicity. In this study, Amitriptyline treated male rat liver tissue was analyzed using Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry Imaging (MALDI-MSI) to investigate the spatial abundances of Amitriptyline, lipids, and bile acids. The metabolism of Amitriptyline in liver tissue was successfully demonstrated, as the spatial distribution of Amitriptyline and its metabolites localize throughout treatment group liver samples. Several lipids appear upregulated, from which nine were identified as distinct phosphatidylcholine (PC) species. The detected bile acids were found to be lower in Amitriptyline treatment group. The combined results from histological findings, Oil Red O staining, and lipid zonation by MSI revealed lipid upregulation in the periportal area indicating drug induced macrovesicular steatosis (DIS).


Asunto(s)
Amitriptilina/toxicidad , Antidepresivos Tricíclicos/toxicidad , Ácidos y Sales Biliares/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hígado/química , Hígado/metabolismo , Hígado/patología , Masculino , Espectrometría de Masas , Tamaño de los Órganos/efectos de los fármacos , Fosfatidilcolinas/metabolismo , Ratas , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Regulación hacia Arriba/efectos de los fármacos
3.
PLoS One ; 15(1): e0228212, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31990961

RESUMEN

Acetyl-CoA carboxylase (ACC) catalyzes the rate-limiting step in de novo lipogenesis, which is increased in the livers of patients with nonalcoholic steatohepatitis. GS-0976 (firsocostat), an inhibitor of isoforms ACC1 and ACC2, reduced hepatic steatosis and serum fibrosis biomarkers such as tissue inhibitor of metalloproteinase 1 in patients with nonalcoholic steatohepatitis in a randomized controlled trial, although the impact of this improvement on fibrosis has not fully been evaluated in preclinical models. Here, we used Western diet-fed melanocortin 4 receptor-deficient mice that have similar phenotypes to nonalcoholic steatohepatitis patients including progressively developed hepatic steatosis as well as fibrosis. We evaluated the effects of ACC1/2 inhibition on hepatic fibrosis. After the confirmation of significant hepatic fibrosis with a 13-week pre-feeding, GS-0976 (4 and 16 mg/kg/day) treatment for 9 weeks lowered malonyl-CoA and triglyceride content in the liver and improved steatosis, histologically. Furthermore, GS-0976 reduced the histological area of hepatic fibrosis, hydroxyproline content, mRNA expression level of type I collagen in the liver, and plasma tissue metalloproteinase inhibitor 1, suggesting an improvement of hepatic fibrosis. The treatment with GS-0976 was also accompanied by reductions of plasma ALT and AST levels. These data demonstrate that improvement of hepatic lipid metabolism by ACC1/2 inhibition could be a new option to suppress fibrosis progression as well as to improve hepatic steatosis in nonalcoholic steatohepatitis.


Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Técnicas de Inactivación de Genes , Cirrosis Hepática/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Receptor de Melanocortina Tipo 4/deficiencia , Receptor de Melanocortina Tipo 4/genética , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/uso terapéutico , Isobutiratos/farmacología , Isobutiratos/uso terapéutico , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Tamaño de los Órganos/efectos de los fármacos , Oxazoles/farmacología , Oxazoles/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Triglicéridos/metabolismo
4.
Chemosphere ; 246: 125776, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-31918093

RESUMEN

The impairments of gestational cadmium (Cd) exposure on testicular development and male fertility in offspring have been reported. Here, we investigated the effect of paternal low-concentration cadmium exposure on testicular development and spermatogenesis in offspring. Five-week-old male mice were exposed to cadmium chloride (100 mg/L) in drinking water for 20 weeks. Results presented that Cd did not affect the testicular histology and sperm count in mice. After mating with untreated females, pregnant mice and pups were then evaluated. No significant difference in the rate for successful pregnancy and the body weight of pups was observed in Cd-exposed mice compared to the controls. Male offspring were given with a chow and high-fat diet from postnatal day (PND) 35 to PND70. Our data indicated that high-fat diet obviously decreased No. of sperm in epididymides of adult offspring due to paternal Cd exposure. Testicular histology revealed that the percentage of seminiferous tubules in stages IX-XII and the atypical residual bodies positive tubules in CdH (paternal cadmium exposure and pubertal high-fat diet) group were higher than these in CdC (paternal cadmium exposure and pubertal chow diet) group. Further analysis demonstrated that high-fat diet markedly accelerated testicular apoptosis, as determined by TUNEL assay and immunostaining for cleaved caspase-3, in male offspring due to paternal Cd exposure. Collectively, high-fat diet exacerbates the damage of testicular development and spermatogenesis in offspring due to paternal cadmium exposure.


Asunto(s)
Cadmio/toxicidad , Exposición Dietética , Contaminantes Ambientales/toxicidad , Espermatogénesis/efectos de los fármacos , Testículo/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Cloruro de Cadmio/toxicidad , Dieta , Femenino , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Túbulos Seminíferos , Espermatozoides/efectos de los fármacos
5.
Ecotoxicol Environ Saf ; 191: 110239, 2020 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-31991393

RESUMEN

In order to explore the mechanism of liver injury induced by florfenicol (FFC) in broilers, one hundred and twenty broilers were randomly divided into six groups, twenty broilers in each group. Except for control group, the other five groups were given different doses of FFC (0.15 g/L, 0.3 g/L, 0.6 g/L, 1.2 g/L and 1.8 g/L) in drinking water. After five days of continuous use, blood was collected from the subpterional vein and the chickens' liver were obtained. Chicken weight gain and liver indices were calculated; blood routine analysis was performed; the oxidative stress and apoptosis of hepatocytes was detected. The results showed that compared with the control group, except for 0.15 g/L FFC, the other doses of FFC significantly decreased the weight gain, white blood cell (WBC) and platelet (PLT) contents in blood, 0.3 g/mL FFC and 1.8 g/L FFC significantly reduced the content of hemoglobin (RGB) (P < 0.05); all doses of FFC significant decreased red blood cell (RBC) increased Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) contents in serum of chickens (P < 0.05), and significantly decreased the contents of albumin (ALB) and total protein (TP) in serum (P < 0.05), but had no significant effect on alkaline phosphatase (ALP) contents(P > 0.05). FFC significantly increased malondialdehyde (MDA) content in serum and liver tissues, but decreased glutathione (GSH), Superoxide dismutase (SOD) and catalase (CAT) content (P < 0.05), and significantly inhibited the mRNA transcription and protein expression of antioxidant proteins nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone-1 (NQO-1)(P < 0.05). FFC also inhibited the content and the transcription level of cytochrome P4501A1(CYP1A1) and CYP2H1 in liver (P < 0.05). At the same time, FFC significantly promoted the apoptotic rate of hepatocytes and the mRNA transcription and protein expression of caspase-3 and caspase-6 (P < 0.05). With the increase of FFC concentration, liver injury became more and more serious, which affected liver function in chickens by inhibiting enzyme activity in Nrf2-ARE pathway to increase oxidative stress and promoting apoptotic protein expression to accelerate hepatocyte apoptosis.


Asunto(s)
Antibacterianos/toxicidad , Apoptosis/efectos de los fármacos , Pollos/metabolismo , Hepatocitos/efectos de los fármacos , Hígado/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Tianfenicol/análogos & derivados , Animales , Antioxidantes/metabolismo , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Hepatocitos/metabolismo , Hepatocitos/patología , Hígado/metabolismo , Hígado/patología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Distribución Aleatoria , Transducción de Señal , Tianfenicol/toxicidad
6.
Food Chem Toxicol ; 135: 110873, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31600566

RESUMEN

In this study, the protective effects of Croton hookeri (CH) extract on renal injury were investigated in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single injection of STZ (45 mg/kg) to Sprague-Dawley rats. After 5 days, CH extract (200 mg/kg) was administered daily by oral gavage for 2 weeks. Administration of CH extracts significantly reduced blood glucose levels in STZ-induced diabetic rats. STZ-induced changes in total cholesterol, LDL, HDL, ALT, AST, BUN, and serum creatinine levels were significantly restored by treatment with CH extract. Abnormal levels of SOD, catalase, glutathione, and oxidized GSH (GSSG) in STZ-treated rats were also significantly recovered by CH extract treatment. CH extract markedly reduced the expression of collagen-1, fibronectin, and α-SMA in the kidney of STZ-induced diabetic rats. In particular, oxidative DNA damages, MDA, TGF-ß, IL-1ß, and IL-6 levels were significantly reduced in STZ-treated rats following treatment with CH extract, whereas IL-10 showed opposite trend. STZ-induced SIRT1, SIRT3 downregulation and cloudin-1 upregulation in the kidney were dramatically recovered by CH extract treatment. Our data suggest that CH extract protects against diabetic-induced nephropathy by inhibiting oxidative stress and inflammation. Therefore, it has potential as a food supplement to alleviate renal dysfunction caused by diabetes-induced nephropathy.


Asunto(s)
Croton/química , Nefropatías Diabéticas/prevención & control , Extractos Vegetales/farmacología , Animales , Biomarcadores/orina , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Citocinas/metabolismo , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/orina , Alimentos Funcionales , Productos Finales de Glicación Avanzada/metabolismo , Mediadores de Inflamación/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estreptozocina
7.
Life Sci ; 240: 117078, 2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31759041

RESUMEN

AIM: The cross regulation between neuroendocrine system, particularly Hypothalamus-Pituitary-Thyroid (HPT) axis and immune system during embryonic/early neonatal developmental stages shapes the functional attribute of immune response throughout the life. Thus, disruption of immune system was anticipated on exposure to thyroid disrupting pesticides (TDPs) mancozeb (MCZ) and fipronil (FPN) during critical windows of early postnatal days (PND) development. MAIN METHODS: Mice were exposed to MCZ and FPN as individual (0.5% LD 50 each) and as mixtures (0.25% and 0.5% LD 50 each) from PND 31 (initiation phase of immune response) till PND 60 (Maturation phase). Thyroxine (T4) supplementation was given from PND 51 to PND 60. Assessment was done at PND 61 as well as at PND 91 (adults). KEY FINDINGS: Plasma level of thyroid hormones (T3 and T4) was reduced but pituitary hormone (TSH) increased till adulthood on exposure to mixture pesticides but not on individual exposure. Mixture pesticides also increased body weight gain and reduced survival rate in adults. Exposure of individual pesticides exert immunotoxicity but more pronounced immune suppression was observed in mixture pesticides exposed group as reflected in reduced relative weight and cellularity in spleen and thymus, reduced in vitro mitogenic (Con A/LPS) response of splenocytes and thymocytes (reduced proliferative index and increased apoptotic/necrotic death). T4 supplementation ameliorated thyroid disruptive and immunotoxic effect of pesticides. SIGNIFICANCE: The additive/synergistic toxicity as well as hypothyroidism induced by mixture pesticides has produced pronounced immune suppression that reflected till adulthood. Supplementation of T4 prevented thyroid axis disruption mediated immunosuppression.


Asunto(s)
Disruptores Endocrinos/toxicidad , Fungicidas Industriales/toxicidad , Sistema Inmunológico/efectos de los fármacos , Insecticidas/toxicidad , Maneb/toxicidad , Plaguicidas/antagonistas & inhibidores , Plaguicidas/toxicidad , Pirazoles/toxicidad , Tiroxina/metabolismo , Tiroxina/uso terapéutico , Zineb/toxicidad , Animales , Peso Corporal , Femenino , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Bazo/citología , Bazo/efectos de los fármacos , Bazo/inmunología , Análisis de Supervivencia , Timo/citología , Timo/efectos de los fármacos , Timo/inmunología
8.
Food Chem Toxicol ; 135: 110914, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31672515

RESUMEN

The aim of the present study was to clarify whether oxidative stress and inflammatory responses are related to impaired insulin signaling and fat accumulation induced by the dietary fatty acids and fructose. C57BL/6 type 8 week-old male mice (n = 10/per group) were fed with standard chow or three isocaloric diets consisting fructose, monounsaturated fatty acids (MUFA), or saturated fatty acid (SFA) for 15 weeks. After the dietary manipulation, the mice were sacrificed, tissues and blood were collected. Consequently, body weight gains, liver weights, and plasma homeostasis model of assessment-insulin resistance (HOMA-IR) values in were at higher levels in SFA and fructose groups (p < 0.05). The plasma concentrations of the non-esterified fatty acids (NEFA), triglyceride (TG), and liver steatosis were found to be at higher levels in SFA and fructose groups (p < 0.05). Moreover, the expression levels of acetyl-CoA carboxylase-1 (ACC1), insulin receptor substrate-1 (IRS1), AMP-activated protein kinase (AMPK), and toll-like receptor-4 (TLR4) in the liver were affected by the intake of SFA and fructose. Furthermore, the plasma levels of C-reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP1) and the thiobarbituric acid reactive substances (TBARS) in the liver were elevated in SFA and fructose group (p < 0.05). The plasma level of anti-inflammatory cytokine interleukin-10 (IL -10) was found to be lower in the SFA group compared to the other groups (p < 0.05). In conclusion, the inflammation and oxidation are related with the fatty acid- and fructose-induced impaired insulin signaling and fat accumulation in liver. Hence, in order to decrease the oxidative stress and pro-inflammatory response, it is substantial to reduce the saturated fat and added sugar or to replace with the unsaturated fat and complex carbohydrates in diet.


Asunto(s)
Ácidos Grasos Monoinsaturados/efectos adversos , Hígado Graso/metabolismo , Fructosa/efectos adversos , Inflamación/metabolismo , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Citocinas/metabolismo , Dieta , Hígado Graso/inducido químicamente , Inflamación/inducido químicamente , Resistencia a la Insulina/fisiología , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Tamaño de los Órganos/efectos de los fármacos
9.
Food Chem Toxicol ; 135: 110896, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31654707

RESUMEN

Metal oxide nanoparticles (NP) are increasingly used in the food and agriculture industries, making human consumption nearly unavoidable. The goal of this study was to use the Gallus gallus (broiler chicken) intra-amniotic administration of physiologically relevant concentrations of TiO2, SiO2, and ZnO to better understand the effects of NP exposure on gut health and function. Immediately after hatch, blood, cecum, and small intestine were collected for assessment of iron (Fe)-metabolism, zinc (Zn)-metabolism, brush border membrane (BBM) functional, and pro-inflammatory related proteins gene expression; blood Fe and Zn levels; cecum weight; and the relative abundance of intestinal microflora. NP type, dose, and the presence or absence of minerals was shown to result in altered mineral transporter, BBM functional, and pro-inflammatory gene expression. Metal oxide NP also altered the abundance of intestinal bacterial populations. Overall, the data suggest that the in vivo results align with in vitro studies, and that NP have the potential to negatively affect intestinal functionality and health.


Asunto(s)
Microbioma Gastrointestinal/efectos de los fármacos , Nanopartículas del Metal/toxicidad , Microvellosidades/efectos de los fármacos , Dióxido de Silicio/toxicidad , Titanio/toxicidad , Óxido de Zinc/toxicidad , Amnios , Animales , Ciego/efectos de los fármacos , Ciego/microbiología , Pollos , Inyecciones , Nanopartículas del Metal/administración & dosificación , Tamaño de los Órganos/efectos de los fármacos , Dióxido de Silicio/administración & dosificación , Titanio/administración & dosificación , Óxido de Zinc/administración & dosificación
10.
Food Chem Toxicol ; 135: 110930, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31678261

RESUMEN

Cigarette smoke (CS) is a risk factor for the development of nonalcoholic fatty liver disease. However, the role of mainstream CS (MSCS) in the pathogenesis of nonalcoholic steatohepatitis (NASH) remains unclear. During the first (early exposure) or last (late exposure) three weeks of methionine-choline deficient with high fat diet feeding (6 weeks), each diet group was exposed to MSCS (300 or 600 µg/L). Hepatic or serum biochemical analysis showed that MSCS differentially modulated hepatic injury in NASH milieu, depending on exposure time points. Consistently, NASH-related hepatocellular apoptosis and fibrosis were increased in the early exposure group, but decreased in the late exposure group, except for steatosis. Ex vivo experiments showed that CS extract differentially regulated inflammatory responses in co-cultured hepatocytes and macrophages isolated from steatohepatitic livers after 10 days or 3 weeks of diet feeding. Furthermore, CS differentially up- and down-regulated the expression levels of M1/M2 polarization markers and peroxisome proliferator-activated receptor-gamma (PPARγ) in livers (29% and 38%, respectively) or co-cultured macrophages (2 and 2.5 fold, respectively). Collectively, our findings indicate that opposite effects of MSCS on NASH progression are mediated by differential modulation of PPARγ and its-associated M1/M2 polarization in hepatic macrophages, depending on exposure time points.


Asunto(s)
Fumar Cigarrillos/efectos adversos , Inflamación/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Animales , Peso Corporal/efectos de los fármacos , Deficiencia de Colina , Citocinas/metabolismo , Dieta Alta en Grasa , Progresión de la Enfermedad , Inflamación/patología , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática/patología , Cirrosis Hepática/fisiopatología , Macrófagos/efectos de los fármacos , Masculino , Metionina/deficiencia , Ratones Endogámicos C57BL , Monocitos/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/patología , Tamaño de los Órganos/efectos de los fármacos , PPAR gamma/metabolismo , Factores de Tiempo
11.
Food Chem Toxicol ; 135: 110927, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31678484

RESUMEN

The present study was conducted to examine the influence of dietary canola oil (CAN) and partially-hydrogenated soybean oil (HSO) compared to soybean oil (SOY, control) on the morphology and function of testes using miniature pigs as the test subject. Male miniature pigs were fed a diet containing 10%SOY, 9%CAN+1%SOY, or 9%HSO+1%SOY for 18 months. The scheduled autopsies revealed no abnormalities in histopathological examination of the major organs, except the testes. Atrophy of the seminiferous tubules and hyperplasia in the Leydig cells were found in the SOY and CAN groups. DNA microarray analysis indicated downregulation in the CAN and the HSO groups of genes encoding for gonadotropins in the pituitary gland and of enzymes and proteins involved in steroid hormone metabolism in the testes, compared to the SOY group. Plasma levels of sex hormones in the CAN and HSO groups tended to be higher and testosterone and dihydrotestosteorne in the HSO group were significantly higher than in the SOY group. These results demonstrate that testes are morphologically and functionally affected by the dietary oils, while the plasma steroid hormone levels do not necessarily reflect the gene expression, probably owing to feedback regulation via the gonadal hormones in the hypothalamus-pituitary-gonadal axis.


Asunto(s)
Aceite de Brassica napus/toxicidad , Aceite de Soja/toxicidad , Testículo/efectos de los fármacos , Congéneres de la Testosterona/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Dieta , Regulación hacia Abajo/genética , Expresión Génica/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Porcinos , Porcinos Enanos , Testículo/metabolismo
12.
Toxicol Lett ; 319: 1-10, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31689472

RESUMEN

Chlorocholine chloride (CCC), a plant growth retardant, may act as an endocrine disruptor. Our previous study showed that pubertal CCC exposure in rats might decrease testosterone (T) synthesis. This study observed the changes in pubertal development and reproduction of male rats exposed to CCC and its underlying mechanisms. Rats were exposed to CCC (0, 75, 137.5 and 200 mg/kg bw/day) from postnatal day 23 to 60. The results showed that CCC treatment delayed the onset of puberty and reduced the relative organ weight of prostate. Seminiferous tubules with deciduous spermatogenic cells were observed in the 200 mg/kg bw/day group. Sexual behavior was inhibited in the 137.5 and 200 mg/kg bw/day groups. Sperm motility, litter size and normalized anogenital distance (AGD) of male pups were decreased in the 137.5 and 200 mg/kg bw/day groups. Serum kisspeptin level and serum and testicular levels of T were reduced in all CCC treated groups. Crucial hormones in hypothalamic-pituitary-testicular (HPT) axis were reduced subsequently after CCC treatment. Collectively, our results demonstrated that CCC might disturb HPT axis through suppressing the secretion of kisspeptin and subsequently lead to delayed puberty onset and impaired reproductive functions.


Asunto(s)
Clormequat/toxicidad , Reproducción/efectos de los fármacos , Maduración Sexual/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Genitales/anatomía & histología , Genitales/efectos de los fármacos , Genitales/crecimiento & desarrollo , Hormonas Esteroides Gonadales/sangre , Kisspeptinas/metabolismo , Tamaño de la Camada/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Próstata/efectos de los fármacos , Próstata/crecimiento & desarrollo , Ratas , Ratas Sprague-Dawley , Túbulos Seminíferos/efectos de los fármacos , Conducta Sexual Animal/efectos de los fármacos , Motilidad Espermática/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Testosterona/sangre
13.
Food Chem Toxicol ; 135: 111051, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31837348

RESUMEN

Excessive reactive oxygen radicals (ROS) produced by ionizing radiation (IR) can cause human body to serious oxidative damage, leading to oxidation-reduction (REDOX) system imbalance and immune system damage. Here, the radioprotection of EGCG was studied through a model of oxidative damage in 60Coγ radiation mice. Firstly, the weights and the main organs indexes of mice, including the liver index, spleen index and pancreas index, indicated preliminarily the safety and protection of EGCG. Then, the radioprotection of EGCG based on immune-regulation on radiation mice was further investigated. Results suggested that EGCG could prevent significantly the immune system damage caused by 60Coγ via increasing the immune organ index, inducing the transformation of spleen cells into T- and B-lymphocytes, and enhancing the macrophage phagocytosis, compared with model group. In addition, EGCG could also protect spleens of radiation mice from 60Coγ-induced the imbalance of REDOX system by enhancing the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), increasing the level of glutathione (GSH), suppressing lipid peroxidation (Malondialdehyde, MDA). The antioxidant enzymes activities of serum and livers were also increased markedly. Taken together, our results indicated that EGCG possessed the excellent potential to serve as a natural radioprotector against IR-induced damage.


Asunto(s)
Antioxidantes/metabolismo , Catequina/análogos & derivados , Radioisótopos de Cobalto/toxicidad , Traumatismos Experimentales por Radiación/prevención & control , Protectores contra Radiación/farmacología , Animales , Peso Corporal/efectos de los fármacos , Catequina/farmacología , Masculino , Ratones , Monocitos/inmunología , Monocitos/efectos de la radiación , Tamaño de los Órganos/efectos de los fármacos , Oxidación-Reducción , Traumatismos Experimentales por Radiación/inmunología , Traumatismos Experimentales por Radiación/metabolismo , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/efectos de la radiación
14.
Toxicol Lett ; 318: 30-43, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31647946

RESUMEN

Lead (Pb), a widespread heavy metal, may induce serious diseases, particularly male reproductive injury. However, the mechanisms by which Pb induces testicular injury remain unclear. In this paper, we established a mouse model of Pb-induced testicular injury via an intraperitoneal injection of lead chloride at a concentration of 1.5 mg/kg body weight. We confirmed that Pb could induce a series of injuries, including a low litter size, smaller testes, more weak offspring, direct injury, and aberrant spermiogenesis. Our study demonstrated that Pb could inhibit lysine acetylation (Kac) and succinylation (Ksuc) via western blot (WB) and immunofluorescence (IF) analyses. We subsequently separated different germ cells that contained Pre-meiotic spermatogonia (SPG), meiotic spermatocyte (SPC), and round spermatid (RS) into the Pb-treated and control groups and verified that Pb inhibited Kac in SPC, RS, and particularly, during meiosis. Furthermore, our results regarding the inhibition of pyruvate kinase and mitochondrial electron transport chain complex I and II in the Pb-treated groups suggested that Pb may restrain key enzymes to block the TCA cycle and that the low TCA cycle activity could reduce the contents of two important metabolites, acetyl-CoA and succinyl-CoA, to inhibit Kac and Ksuc. Moreover, we examined the influences of the inhibition of Kac and Ksuc on spermiogenesis, which indicated that decreased Kac and Ksuc could impede the replacement of transition proteins in elongating sperm and disorder the distribution of germ cells in the seminiferous tubule. Our research provides novel insights into the mechanisms of Pb reproductive toxicity with respect to lysine acetylation and succinylation.


Asunto(s)
Plomo/toxicidad , Lisina/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Testículo/efectos de los fármacos , Acetilación , Animales , Metabolismo Energético/efectos de los fármacos , Tamaño de la Camada/efectos de los fármacos , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Espermatozoides/metabolismo , Espermatozoides/patología , Testículo/metabolismo , Testículo/patología
15.
Toxicol Lett ; 318: 99-103, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31669098

RESUMEN

Fluorination preventing metabolic hydroxylation of 17ß-estradiol (E2) was applied to investigate the mechanisms underlying estrogen-induced carcinogenesis. Either 2-fluoro-17ß-estradiol (2-FE2) or 4-fluoro-17ß-estradiol (4-FE2) was administered subcutaneously for 52 weeks to August Copenhagen Irish (ACI) rats, the preferred animal model for human breast cancer. 4-FE2 induced frequent mammary tumors whereas 2-FE2 did not. The cumulative incidence of mammary tumors in rats treated with 4-FE2 was comparable to that observed with E2. The carcinogenic results were supported by histological examination of mammary glands of fluorinated estrogen-treated ACI rats. To evaluate the estrogenic potential of the fluorinated estrogens, 2-FE2 or 4-FE2 was administrated subcutaneously to ovariectomized rats. Both 4-FE2 and 2-FE2 showed high uterotrophic potency. Our results indicate that estrogenic potential may not be the sole factor driving mammary tumorigenesis. Since fluorination inhibits metabolic hydroxylation of E2 at the substituted position, the carcinogenic effect may occur through the metabolic activation of 2-hydroxylated E2, in combination with the compound's estrogenic potency.


Asunto(s)
Neoplasias de la Mama/inducido químicamente , Transformación Celular Neoplásica/inducido químicamente , Estradiol/análogos & derivados , Animales , Neoplasias de la Mama/patología , Transformación Celular Neoplásica/patología , Estradiol/toxicidad , Femenino , Tamaño de los Órganos/efectos de los fármacos , Ratas Endogámicas ACI , Medición de Riesgo , Útero/efectos de los fármacos , Útero/patología
16.
BMC Complement Altern Med ; 19(1): 367, 2019 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-31830971

RESUMEN

BACKGROUND: ChondroT, a new herbal medication, consists of Angelica grosseserrata Maxim., Lonicera japonica Thunb., Angelica gigas Nakai, Clematis terniflora var. manshurica (Rupr.) Ohwi, and Phellodendron amurense Rupr. (6:4:4:4:3). Our previous studies have shown that ChondroT exhibits significant anti-arthritic and anti-inflammatory effects. In this study, we aimed to assess the toxicological safety assessment of ChondroT. METHODS: This study was designed to assess the safety of ChondroT after repeated oral administration. Male and female Sprague-Dawley rats were treated with ChondroT at oral doses of 0, 500, 1000, and 2000 mg/kg for 13 weeks. Mortality, clinical signs, body weight changes, food consumption, ophthalmological findings, urinalysis, hematological and blood-chemical parameters, necropsy findings, organ weights, and histological markers were recorded throughout the study period. Rats were also monitored for an additional 4 weeks to determine the recovery time. RESULTS: No death occurred and no significant changes in food consumption, ophthalmologic findings, and urinalysis were found. Although there were alterations in clinical signs, body weights, hematological parameters, blood-chemical parameters, necropsy findings, organ weights, and histological markers, they were not considered to be toxicologically significant. CONCLUSIONS: The results suggest that the no-observed adverse effects level (NOAEL) was 2000 mg/kg/day for the test substance. ChondroT, a new complex herbal medication composed of five plants, can therefore be used safely at the NOAEL.


Asunto(s)
Extractos Vegetales/toxicidad , Pruebas de Toxicidad Subcrónica , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Femenino , Masculino , Tamaño de los Órganos/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Próstata/efectos de los fármacos , Próstata/patología , Ratas , Ratas Sprague-Dawley , Glándula Submandibular/efectos de los fármacos , Glándula Submandibular/patología , Testículo/efectos de los fármacos , Testículo/patología
17.
BMC Gastroenterol ; 19(1): 228, 2019 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-31883514

RESUMEN

BACKGROUND: Compounds in clinical development for nonalcoholic steatohepatitis (NASH) improve liver histopathology in diet-induced obese mouse models of biopsy-confirmed NASH. Since the biopsy section used for histopathological evaluation represents only < 1% of the whole mouse liver, we evaluated how well biopsy-based quantitative image analyses correlate to stereology-based whole-liver quantitative changes upon drug treatment. METHODS: Male leptin-deficient Lepob/Lepob mice were fed the Amylin liver NASH (AMLN) diet for 16 weeks before stratification into treatment groups using a biopsy-based evaluation of type I collagen αI (col1a1) levels. Mice were treated for 8 weeks with either vehicle (PO, QD), liraglutide (0.4 mg/kg, SC, QD), elafibranor (30 mg/kg, PO, QD) or INT-767 (10 mg/kg, PO, QD). Terminal quantitative histological assessment of liver lipid (hematoxylin-eosin staining), inflammation (galectin-3 immunohistochemistry (IHC); gal-3), and fibrosis (col1a1 IHC) was performed on terminal liver biopsies and compared with stereologically sampled serial sections spanning the medial, left and right lateral lobe of the liver. RESULTS: The distribution of liver lipid and fibrosis was markedly consistent across lobes, whereas inflammation showed some variability. While INT-767 and liraglutide significantly reduced total liver weight by 20 and 48%, respectively, elafibranor tended to exacerbate hepatomegaly in Lepob/Lepob-NASH mice. All three compounds markedly reduced biopsy-based relative liver lipid content. Elafibranor and INT-767 significantly reduced biopsy-based relative gal-3 levels (P < 0.001), whereas INT-767 and liraglutide tended to reduce relative col1a1 levels. When changes in liver weight was accounted for, both INT-767 and liraglutide significantly reduced biopsy-based total col1a1 content. Although minor differences in absolute and relative liver lipid, inflammation and fibrosis levels were observed across lobes, the interpretation of drug-induced effects were consistent with biopsy-based conclusions. Notably, the incorporation of changes in total liver mass revealed that liraglutide's efficacy reached statistical significances for all analyzed parameters. CONCLUSIONS: In conclusion, in-depth analyses of liver homogeneity demonstrated that drug-induced improvement in liver biopsy-assessed histopathology is representative for overall liver effects assessed using stereology. Importantly, these findings reveal how changes in whole-liver mass should be considered to provide a deeper understanding of apparent drug treatment efficacy in preclinical NASH studies.


Asunto(s)
Hígado/efectos de los fármacos , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/complicaciones , Animales , Ácidos y Sales Biliares/uso terapéutico , Biopsia , Peso Corporal/efectos de los fármacos , Chalconas/uso terapéutico , Colágeno Tipo I/análisis , Dieta Alta en Grasa , Galectina 3/análisis , Polipéptido Amiloide de los Islotes Pancreáticos/administración & dosificación , Leptina/deficiencia , Lípidos/análisis , Liraglutida/uso terapéutico , Hígado/química , Cirrosis Hepática/patología , Masculino , Ratones , Ratones Obesos , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Tamaño de los Órganos/efectos de los fármacos , PPAR alfa/agonistas , PPAR delta/agonistas , Propionatos/uso terapéutico , Reproducibilidad de los Resultados
18.
Biomed Res Int ; 2019: 8428304, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31886260

RESUMEN

Ayurvedic and traditional medical practitioners of Sri Lanka use the decoction of the immature inflorescence of Cocos nucifera L. (IC) variety aurantiaca for the treatment of menorrhagia. The progestogenic effect of the ethyl acetate soluble proanthocyanidins (EASPA) of the IC in female rats at a dose of 3.5 mg/kg body weight has been reported. Acute and subacute toxicity studies of EASPA of the IC carried out using female Wistar rats according to Organization for Economic Co-operation and Development (OECD) guidelines 423 and 407, respectively, are reported herein. In the acute toxicity study, a single dose of EASPA (2000 mg/kg body weight) was orally administered to rats, which were monitored for 14 days. In the subacute toxicity study, rats were orally administered with EASPA daily for 28 days at doses of 1.75, 3.5, 7, and 14 mg/kg body weight. No rat in either the acute or subacute toxicity study exhibited mortality or clinical signs of toxicity. Further, these rats did not show any significant change in their mean body weight, food, and water intake, haematological and biochemical parameters as well as in the results of their histopathological examinations compared to those of control group rats. According to results of the acute toxicity, the LD50 of EASPA is estimated to be greater than 2000 mg/kg body weight. Considering the results of the subacute toxicity study, the oral administration of EASPA daily for 28 days was well tolerated up to the dose, 14 mg/kg by rats. These results will be useful in the development of a novel therapeutic agent from EASPA of the IC for the treatment of menorrhagia, which incapacitates a considerable proportion of women worldwide.


Asunto(s)
Acetatos/química , Cocos/química , Inflorescencia/química , Proantocianidinas/toxicidad , Pruebas de Toxicidad Aguda , Animales , Peso Corporal/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Femenino , Tamaño de los Órganos/efectos de los fármacos , Proantocianidinas/aislamiento & purificación , Ratas Wistar
19.
Curr Med Sci ; 39(6): 1003-1008, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31845234

RESUMEN

Human beings are increasingly exposed to phthalates, which are a group of chemicals used to make plastics more flexible and harder to break, and simultaneously ingesting abundant food emulsifiers via daily diet. The purpose of this study was to investigate the effect of the food emulsifier glycerin monostearate (GMS) on male reproductive toxicity caused by di(2-ethylhexyl) phthalate (DEHP, one of the phthalates) and explore the underlying mechanism. Thirty male Sprague-Dawley rats were randomly divided into control group, DEHP group and DEHP+GMS group. Rats in the DEHP group and DEHP+GMS group were orally administered with 200 mg/kg/d DEHP with or without 20 mg/kg/d GMS. After 30 days of continuous intervention, it was found that the serum testosterone level was significantly lowered in DEHP group and DEHP+GMS group than that in control group (P<0.01). The serum testosterone level and the relative testis weight were significantly decreased in the DEHP+GMS group as compared with those in the DEHP group and control group (P<0.05). More spermatids were observed to be shed off in DEHP+GMS group than in DEHP group. The expression levels of cell cycle checkpoint kinase 1 (Chk1), cell division cycle gene 2 (Cdc2), and cyclin-dependent kinase 2 (CDK2) were down-regulated in DEHP group, and this tendency was more significant in DEHP+GMS group (P<0.05 or P<0.01). There was no significant difference in the P-glycoprotein (P-gp) expression between DEHP group and control group. However, P-gp was markedly down-regulated in DEHP+GMS group (P<0.01). The results indicated that the food emulsifier GMS aggravated the toxicity of DEHP on male reproduction by inhibiting the cell cycle of testicular cells and the expression of P-gp in testis tissues.


Asunto(s)
Dietilhexil Ftalato/toxicidad , Emulsionantes/toxicidad , Glicerol/toxicidad , Reproducción/efectos de los fármacos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Administración Oral , Animales , Proteína Quinasa CDC2/metabolismo , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Quinasa 2 Dependiente de la Ciclina/metabolismo , Dietilhexil Ftalato/administración & dosificación , Regulación hacia Abajo , Emulsionantes/administración & dosificación , Glicerol/administración & dosificación , Masculino , Tamaño de los Órganos/efectos de los fármacos , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Testículo/efectos de los fármacos , Testosterona/sangre
20.
BMC Complement Altern Med ; 19(1): 333, 2019 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-31771569

RESUMEN

BACKGROUND: Monotropein, astragalin, and spiraeoside (MAS) are active compounds extracted from medicinal herbs; monotropein from Morinda officinalis How (Rubiaceae), astragalin (kaempferol 3-O-glucoside) from Cuscuta chinensis Lamark (Convolvulaceae) and spiraeoside from the outer scales of Allium cepa L. (Liliceae) in a ratio of 6.69:0.41:3.61. Monotropein, astragalin, and spiraeoside are well-known antioxidants, anti-inflammatory, and antinociceptive agents. The current investigation aims to study the molecular mechanism of varicocele-induced male infertility and the underlying pharmacological mechanisms of MAS. METHODS: Four groups were included: control (CTR), MAS 200 group (MAS 200 mg/kg), varicocele group (VC), and VC + MAS 200 group (MAS 200 mg/kg). Sprague-Dawley (SD) rats were treated with 200 mg/kg MAS or vehicle once daily for 28 days. The possible signaling mechanism and effects of MAS were measured via histological staining, immunohistochemistry, western blot, and biochemical assays. RESULTS: Parameters such as sperm motility and count, Johnsen's scores, spermatogenic cell density, serum testosterone, testicular superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and expression of the steroidogenic acute regulatory protein (StAR) improved significantly in the VC + MAS 200 group compared with the VC group. MAS treatment of varicocele-induced group significantly decreased the levels of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as testicular interleukin-6 (IL6), tumor necrosis factor-α (TNF-α), ROS/RNS, and malondialdehyde (MDA). It also decreased the apoptotic index and reduced the expression of endoplasmic reticulum (ER) protein levels (Grp78, p-IRE1α, and p-JNK) and apoptotic markers such as cleaved caspase-3 and Bax/Bcl2 ratio. CONCLUSION: This study suggests that the crosstalk between oxidative stress, ER stress, and mitochondrial pathway mediates varicocele-induced testicular germ cell apoptosis. MAS promotes spermatogenesis in varicocele-induced SD rat, probably by decreasing cytokines (IL-6, TNF-α) levels, regulating abnormal sex hormones, and decreasing oxidative stress, ER stress, and apoptosis.


Asunto(s)
Iridoides/farmacología , Quempferoles/farmacología , Estrés Oxidativo/efectos de los fármacos , Quercetina/análogos & derivados , Varicocele/metabolismo , Animales , Antioxidantes/farmacología , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Masculino , Mitocondrias/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Quercetina/farmacología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Testículo/química , Testículo/efectos de los fármacos , Testículo/patología , Varicocele/patología
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