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Anxiety Disorders and Posttraumatic Stress Disorders (PTSD) associated with type-1 diabetes mellitus (T1DM) are increasingly common comorbidities and the treatment is quite challenging. In that sense, evidence indicates that the anticonvulsant pregabalin is highly effective in treating severe cases of anxiety, as well as PTSD and diabetic neuropathic pain which is also very prevalent in T1DM. Herein, the short- and long-term effects of a single injection of pregabalin on the acquisition of a fear extinction memory and parameters of anxiety in induced-T1DM animals were investigated. For that, we used the contextual fear conditioning (CFC) and elevated plus maze paradigms, respectively. A putative antioxidant activity was also evaluated. Our findings demonstrated that induced-T1DM animals presented greater expression of fear memory, difficulty in extinguishing this fear memory, associated with a more pronounced anxiety-like response. Pregabalin was able to induce a short and long-lasting effect by facilitating the acquisition of the fear extinction memory and inducing a later anxiolytic-like effect. Also, the increased lipid peroxidation levels in the hippocampus and prefrontal cortex of induced-T1DM rats were reduced after pregabalin injection, while the decreased levels of reduced glutathione were increased in the hippocampus. Despite the need for more studies to understand the mechanism of action of pregabalin under these conditions, our data demonstrate for the first time that a single injection of pregabalin in a specific time window was able to improve behavioral parameters in addition to inducing neuroprotective effect. Thus, pregabalin has potential worth exploring for the treatment of PTSD and/or Anxiety associated with T1DM.
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Ansiolíticos , Diabetes Mellitus Tipo 1 , Animales , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Ansiedad/metabolismo , Extinción Psicológica/fisiología , Miedo , Pregabalina/farmacología , Pregabalina/uso terapéutico , RatasRESUMEN
Melanoma is a highly metastatic and rapidly progressing cancer, a leading cause of mortality among skin cancers. The melanoma microenvironment, formed from the activity of malignant cells on the extracellular matrix and the recruitment of immune cells, plays an active role in the development of drug resistance and tumor recurrence, which are clinical challenges in cancer treatment. These tumoral metabolic processes are affected by proteins, including Galectin-3 (Gal-3), which is extensively involved in cancer development. Previously, we characterized a partially methylated mannogalactan (MG-Pe) with antimelanoma activities. In vivo models of melanoma were used to observe MG-Pe effects in survival, spontaneous, and experimental metastases and in tissue oxidative stress. Analytical assays for the molecular interaction of MG-Pe and Gal-3 were performed using a quartz crystal microbalance, atomic force microscopy, and contact angle tensiometer. MG-Pe exhibits an additive effect when administered together with the chemotherapeutic agent dacarbazine, leading to increased survival of treated mice, metastases reduction, and the modulation of oxidative stress. MG-Pe binds to galectin-3. Furthermore, MG-Pe antitumor effects were substantially reduced in Gal-3/KO mice. Our results showed that the novel Gal-3 ligand, MG-Pe, has both antitumor and antimetastatic effects, alone or in combination with chemotherapy.
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Antineoplásicos , Galectina 3 , Melanoma , Neoplasias Cutáneas , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Dacarbazina/metabolismo , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Galectina 3/metabolismo , Galectina 3/farmacología , Galectina 3/uso terapéutico , Ligandos , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Ratones , Recurrencia Local de Neoplasia , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/fisiologíaRESUMEN
Mitotane is the only adrenolytic drug approved by the Food and Drug Administration for treating adrenocortical carcinoma (ACC). This drug has cytotoxic effects on tumour tissues; it induces cell death and antisecretory effects on adrenal cells by inhibiting the synthesis of adrenocortical steroids, which are involved in the pathogenesis of ACC. However, high doses of mitotane are usually necessary to reach the therapeutic plasma concentration, which may result in several adverse effects. This suggests that important pharmacological processes, such as first pass metabolism, tissue accumulation and extensive time for drug elimination, are associated with mitotane administration. Few studies have reported the pharmacological aspects and therapeutic effects of mitotane. Therefore, the aim of this review was to summarize the chemistry, pharmacokinetics and pharmacodynamics, and therapeutic and toxic effects of mitotane. This review also discusses new perspectives of mitotane formulation that are currently under investigation. Understanding the pharmacological profile of mitotane can improve the monitoring and efficacy of this drug in ACC treatment and can provide useful information for the development of new drugs with specific action against ACC with fewer adverse effects.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Antineoplásicos , Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Humanos , Mitotano/uso terapéutico , EsteroidesRESUMEN
Diabetes mellitus is a metabolic disorder that can generate tissue damage through several pathways. Alteration and dysfunction of skeletal muscle are reported including respiratory muscles, which may compromise respiratory parameters in diabetic patients. We have aimed to evaluate the diaphragm muscle contractility, tissue remodeling, oxidative stress, and inflammatory parameters from 30 day streptozotocin-treated rats. The diaphragm contractility was assessed using isolated muscle, tissue remodeling using histology and zymography techniques, and tissue oxidative stress and inflammatory parameters by enzyme activity assay. Our data revealed in the diabetes mellitus group an increase in maximum tetanic force (4.82 ± 0.13 versus 4.24 ± 0.18 N/cm2 (p = 0.015)) and fatigue resistance (139.16 ± 10.78 versus 62.25 ± 4.45 s (p < 0.001)), reduction of 35.4% in muscle trophism (p < 0.001), increase of 32.6% of collagen deposition (p = 0.007), reduction of 21.3% in N-acetylglucosaminidase activity (p < 0.001), and increase of 246.7% of catalase activity (p = 0.002) without changes in reactive oxygen species (p = 0.518) and tissue lipid peroxidation (p = 0.664). All observed changes are attributed to the poor glycemic control (471.20 ± 16.91 versus 80.00 ± 3.42 mg/dL (p < 0.001)), which caused defective tissue regeneration and increased catalase activity as a compensatory mechanism.
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Antioxidantes/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Diafragma/fisiopatología , Contracción Muscular , Fatiga Muscular , Acetilglucosaminidasa/metabolismo , Animales , Diabetes Mellitus Experimental/metabolismo , Peroxidación de Lípido , Masculino , Estrés Oxidativo , Ratas , Ratas WistarRESUMEN
Salvia lachnostachys is an herbaceous plant with anti-inflammatory, analgesic and cytotoxic properties. This study investigated the antitumor effect of an ethanolic extract of Salvia lachnostachys leaves (EES) in a solid Ehrlich carcinoma model. Ehrlich cells were inoculated subcutaneously in the right pelvic member (2 × 106 cells) in female Swiss mice. The animals were treated with vehicle (10 mL kg-1, p.o.), EES (30 and 100 mg kg-1, p.o.), or methotrexate (2.5 mg kg-1, i.p.) for 21 days (early treatment) or 14 days (late treatment) after tumor inoculation, or 10 days before tumor inoculation and continued for 21 days after tumor inoculation (chemopreventive treatment). The acute toxicity test was performed according OECD guidelines Late treatment with EES had no antitumor effect. Early treatment with 100 mg kg-1 EES prevented tumor development, increased tumor necrosis factor-α (TNF-α) levels and decreased tumor superoxide dismutase (SOD) activity, interleukin-10 (IL-10) levels and Cyclin D1 expression, and tumor cell necrosis was observed. Chemopreventive treatment with EES for 10 and 31 days prevented tumor development in the same manner. EES treatment for 31 days decreased hepatic and tumor SOD activity, tumor IL-10 levels and Cyclin D1 expression, and increased tumor reduced glutathione, N-acetylglucosaminidase, reactive oxygen species, lipid peroxidation, TNF-α levels and Nrf2 expression. No toxicity was observed in the acute toxicity assay. In conclusion, EES had an antitumor effect by inhibiting Cyclin D1 expression and increasing inflammation with early and chemopreventive treatment. Modulation of the antioxidant system also contribute for the antitumor effects of EES.
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Anticarcinógenos/farmacología , Antineoplásicos Fitogénicos/farmacología , Extractos Vegetales/farmacología , Salvia/química , Animales , Anticarcinógenos/química , Antineoplásicos Fitogénicos/química , Carcinoma de Ehrlich/genética , Carcinoma de Ehrlich/metabolismo , Quimioprevención , Cromatografía Líquida de Alta Presión , Ciclina D1/genética , Ciclina D1/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Ratones , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Hojas de la Planta/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
INTRODUCTION AND OBJECTIVES: Acute liver injury is a current health problem with few effective treatments. The present study investigated the hepatoprotective and curative potential of the glucagon-like peptide-1 analog liraglutide against carbon tetrachloride (CCl4)-induced hepatotoxicity. MATERIALS AND METHODS: Male Swiss mice were subjected to two protocols. The first protocol (Pretreatment) consisted of intraperitoneal (i.p.) treatment with liraglutide (0.057 and 0.118mgkg-1) or vehicle (distilled water) once daily for 7 days. On days 6 and 7, the animals were challenged with 2% CCl4 (5mgkg-1, i.p.). The second protocol (Late treatment) began with an injection of 5% CCl4 (5mgkg-1, i.p.) and subsequent treatment with liraglutide (0.057mgkg-1) or vehicle (distilled water) for 1 day. In both protocols, 24h after the last administration, blood and bile were collected from anesthetized animals, followed by euthanasia and liver collection. Plasma and bile underwent biochemical analyses, and histological, oxidative stress, and metabolic parameters were evaluated in the liver. RESULTS: Both liraglutide treatment protocols attenuated hepatotoxicity that was induced by CCl4, decreasing plasma levels of hepatic enzymes, stimulating the hepatic antioxidant system, and decreasing centrilobular necrosis, hepatic glycogen, and lipid accumulation. CCl4 tended to reduce bile lipid excretion, but liraglutide did not influence this parameter. CONCLUSIONS: The present results demonstrated the hepatoprotective and therapeutic effects of liraglutide, which may be attributable to a decrease in liver oxidative stress and the preservation of metabolism. Liraglutide may have potential as a complementary therapy for acute liver injury.
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Tetracloruro de Carbono/toxicidad , Incretinas/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Liraglutida/farmacología , Hígado/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Alanina Transaminasa/efectos de los fármacos , Alanina Transaminasa/metabolismo , Fosfatasa Alcalina/efectos de los fármacos , Fosfatasa Alcalina/metabolismo , Animales , Aspartato Aminotransferasas/efectos de los fármacos , Aspartato Aminotransferasas/metabolismo , Ácidos y Sales Biliares/metabolismo , Catalasa/efectos de los fármacos , Catalasa/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas , Glutatión Transferasa/efectos de los fármacos , Glutatión Transferasa/metabolismo , Glucógeno/metabolismo , Ácido Láctico/metabolismo , Hígado/metabolismo , Hígado/patología , Ratones , Ácido Pirúvico/metabolismo , Superóxido Dismutasa/efectos de los fármacos , Superóxido Dismutasa/metabolismoRESUMEN
The nonsteroidal anti-inflammatory drugs (NSAIDs) are amongst the most commonly detected classes of pharmaceuticals in freshwater environments, with paracetamol being the most abundant. The aim of this study was to evaluate the possible toxic effects of environmentally relevant concentrations (0.25, 2.5 and 25⯵g.L-1) of paracetamol in Rhamdia quelen fish exposed for 14 days using different biomarkers. The total count of leukocytes and thrombocytes was reduced at the highest concentration. In the gills, all concentrations of paracetamol reduced the glutathione S-transferase (GST) activity and the reduced glutathione (GSH) levels compared to the control group. The activity of catalase (CAT) was not altered and glutathione peroxidase (GPx) activity increased at the highest concentrations. The superoxide dismutase (SOD) activity decreased at 25⯵g.L-1 and the LPO levels increased at 2.5⯵g.L-1 when compared to the control group. The concentration of ROS was not different among the groups. In the posterior kidney the activities of GST (2.5⯵g.L-1), CAT (2.5⯵g.L-1 and at 25⯵g. L-1) and GPx and GSH levels increased at all concentrations when compared to the control group. The SOD activity and LPO levels did not change. Paracetamol caused genotoxicity in the blood and gills at concentrations of 2.5⯵g.L-1 and in the posterior kidney at 2.5 and 25⯵g.L-1. An osmoregulatory imbalance in plasma ions and a reduction in the carbonic anhydrase activity in the gills at 0.25⯵g.L-1 were observed. Histopathological alterations occurred in the gills of fish exposed to 25⯵g.L-1 and in the posterior kidney at 0.25 and 25⯵g.L-1 of paracetamol. The integrated biomarker index showed that the stress caused by the concentration of 25⯵g.L-1 was the highest one. These results demonstrated toxic effects of paracetamol on the gills and posterior kidneys of fish, compromising their physiological functions and evidencing the need for monitoring the residues of pharmaceuticals released into aquatic environment.
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Acetaminofén/toxicidad , Bagres/fisiología , Contaminantes Químicos del Agua/toxicidad , Animales , Antiinflamatorios no Esteroideos , Biomarcadores/metabolismo , Catalasa , Daño del ADN , Branquias/efectos de los fármacos , Glutatión/farmacología , Glutatión Peroxidasa , Glutatión TransferasaRESUMEN
The physiopathology of anxiety or depression related to diabetes is still poorly understood. The treatment with antidepressant drugs is a huge challenge due to theirs adherence low rate and many adverse effects. Thus, the seeking for a better treatment for these associated diseases is of utmost importance. Given that the oxidative stress in different tissues occurs in diabetes and anxiety or depression as well, the antioxidant gallic acid becomes an interesting compound to be investigated. Thus, the effects of long-term treatment with gallic acid (0, 10, 20 and 40 mg/kg; gavage) were evaluated in diabetic (DBT) animals submitted to the elevated plus-maze (EPM), the light-dark transition (LDT) tests and modified forced swim test (mFST). Also, indirect parameters of oxidative stress, lipid peroxidation (LPO) and reduced glutathione (GSH) levels were evaluated in the hippocampus (HIP) and prefrontal cortex (PFC). The results showed that DBT animals presented a decrease in the spent time in the open arms, in the end arm exploration and head dips when evaluated in the EPM test; moreover, a decrease in the spent time in the lit compartment of LDT test was observed, suggesting an anxiogenic-like behavior. During the mFST, an increase in the mean counts of immobility and a decrease in the mean counts of swimming and climbing were observed, indicating a depressive-like behavior. These aversive behaviors were more pronounced when compared to normoglycemic (NGL) animals and streptozotocin-treated animals that not become DBT. In addition, DBT rats showed an increase in the oxidative stress parameters in the HIP and PFC that was reversed by the gallic acid treatment (lowest dose - 10 mg/kg), i.e., the treatment decreased the elevated LPO levels and increased the reduced GSH in the HIP and PFC. Also, gallic acid treatment was able to produce an anxiolytic-like effect in the EPM and LDT tests, but not antidepressant-like effect in the FST. Taken together, the results suggest that the antioxidant/neuroprotective effect of gallic acid treatment in HIP and PFC of DBT animals may be essential to the anxiolytic-like effect.
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Ansiolíticos/farmacología , Antidepresivos/farmacología , Antioxidantes/farmacología , Ansiedad/tratamiento farmacológico , Depresión/tratamiento farmacológico , Diabetes Mellitus Experimental/psicología , Ácido Gálico/farmacología , Animales , Ansiolíticos/administración & dosificación , Antidepresivos/administración & dosificación , Antioxidantes/administración & dosificación , Ansiedad/etiología , Ansiedad/fisiopatología , Conducta Animal/efectos de los fármacos , Depresión/etiología , Depresión/fisiopatología , Diabetes Mellitus Experimental/inducido químicamente , Modelos Animales de Enfermedad , Fluoxetina/administración & dosificación , Fluoxetina/farmacología , Ácido Gálico/administración & dosificación , Glutatión/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hiperglucemia/tratamiento farmacológico , Peroxidación de Lípido/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , EstreptozocinaRESUMEN
Diabetes mellitus is a common metabolic disorder that is caused by a deficit in the production of (type 1) or response to (type 2) insulin. Diabetes mellitus is characterized by a state of chronic hyperglycemia and such symptoms as weight loss, thirst, polyuria, and blurred vision. These disturbances represent one of the major causes of morbidity and mortality nowadays, despite available treatments, such as insulin, insulin secretagogues, insulin sensitizers, and oral hypoglycemic agents. However, many efforts have been made to discover new drugs for diabetes treatment, including medicinal plant extracts. Silymarin is a powder extract of the seeds from Silybum marianum, a plant from the Asteraceae family. The major active ingredients include four isomers: silybin, isosilybin, silychristin, and silydianin. Silymarin is indicated for the treatment of hepatic disorders, such as cirrhosis, chronic hepatitis, and gallstones. Moreover, several studies of other pathologies, including diabetes, sepsis, osteoporosis, arthritis, hypercholesterolemia, cancer, viral infections, and Alzheimer's and Parkinson's diseases, have tested the effects of silymarin and reported promising results. This article reviews data from clinical, in vivo, and in vitro studies on the use of silymarin, with a focus on the complications of diabetes, including nephropathy, neuropathy, healing delays, oxidative stress, hepatotoxicity, and cardiomyopathy. Copyright © 2017 John Wiley & Sons, Ltd.
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Complicaciones de la Diabetes/tratamiento farmacológico , Silimarina/farmacología , Silimarina/uso terapéutico , Animales , Diabetes Mellitus/tratamiento farmacológico , Humanos , Cirrosis Hepática/tratamiento farmacológico , Hepatopatías/tratamiento farmacológico , Enfermedades Metabólicas/tratamiento farmacológico , Silybum marianum/química , Estrés Oxidativo/efectos de los fármacos , Semillas/químicaRESUMEN
Alcoholic liver diseases have complex and multiple pathogenic mechanisms but still no effective treatment. Steatosis or alcoholic fatty liver disease (AFLD) has a widespread incidence and is the first step in the progression to more severe stages of alcoholic liver disease, with concomitant increases in morbidity and mortality rates. The ways in which this progression occurs and why some individuals are susceptible are still unanswered scientific questions. Research with animal models and clinical evidence have shown that it is a multifactorial disease that involves interactions between lipid metabolism, inflammation, the immune response and oxidative stress. Each of these pathways provides a better understanding of the pathogenesis of AFLD and contributes to the development of therapeutic strategies. This review emphasizes the importance of research on alcoholic steatosis based on incidence data, key pathogenic mechanisms and therapeutic interventions, and discusses perspectives on the progression of this disease.
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It has been established that bile salts play a role in the regulation of hepatic lipid metabolism. Accordingly, overt signs of steatosis have been observed in mice with reduced bile salt synthesis. The aim of this study was to identify the mechanism of hepatic steatosis in mice with bile salt deficiency due to a liver specific disruption of cytochrome P450 reductase. In this study mice lacking hepatic cytochrome P450 reductase (Hrn) or wild type (WT) mice were fed a diet supplemented with or without either 0.1% cholic acid (CA) or 0.025% obeticholic acid, a specific FXR-agonist. Feeding a CA-supplemented diet resulted in a significant decrease of plasma ALT in Hrn mice. Histologically, hepatic steatosis ameliorated after CA feeding and this was confirmed by reduced hepatic triglyceride content (115.5±7.3mg/g liver and 47.9±4.6mg/g liver in control- and CA-fed Hrn mice, respectively). The target genes of FXR-signaling were restored to normal levels in Hrn mice when fed cholic acid. VLDL secretion in both control and CA-fed Hrn mice was reduced by 25% compared to that in WT mice. In order to gain insight in the mechanism behind these bile salt effects, the FXR agonist also was administered for 3weeks. This resulted in a similar decrease in liver triglycerides, indicating that the effect seen in bile salt fed Hrn animals is FXR dependent. In conclusion, steatosis in Hrn mice is ameliorated when mice are fed bile salts. This effect is FXR dependent. Triglyceride accumulation in Hrn liver may partly involve impaired VLDL secretion.
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Ácidos y Sales Biliares/metabolismo , Hígado Graso/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Animales , VLDL-Colesterol/metabolismo , Ácidos Cólicos/farmacología , Modelos Animales de Enfermedad , Expresión Génica , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Depuradores de Clase B/metabolismoRESUMEN
UNLABELLED: The difference in bile salt (BS) composition between rodents and humans is mainly caused by formation of muricholate in rodents as well as by efficient rehydroxylation of deoxycholic acid. The aim of this study was to characterize bile formation in a mouse model (Hrn mice) with hepatic disruption of the cytochrome p450 (CYP) oxidoreductase gene, encoding the single electron donor for all CYPs. Bile formation was studied after acute BS infusion or after feeding a BS-supplemented diet for 3 weeks. Fecal BS excretion in Hrn mice was severely reduced to 7.6% ± 1.8% of wild-type (WT), confirming strong reduction of (CYP-mediated) BS synthesis. Hrn bile contained 48% ± 18% dihydroxy BS, whereas WT bile contained only 5% ± 1% dihydroxy BS. Upon tauroursodeoxycholate infusion, biliary BS output was equal in WT versus Hrn, indicating that canalicular secretion capacity was normal. In contrast, taurodeoxycholic acid (TDC) infusion led to markedly impaired bile flow and BS output, suggesting onset of cholestasis. Feeding a cholate-supplemented diet (0.1%) resulted in a completely restored bile salt pool in Hrn mice, with 50% ± 9% TDC and 42% ± 10% taurocholic acid in bile, as opposed to 2% ± 1% and 80% ± 3% in WT mice, respectively. Under these conditions, biliary cholesterol secretion was strongly increased in Hrn mice, whereas serum alanine aminotransferase levels were decreased. CONCLUSION: Hrn mice have strongly impaired bile salt synthesis and (re)hydroxylation capacity and are more susceptible to acute TDC-induced cholestasis. In this mouse model, a more-human BS pool can be instilled by BS feeding, without hepatic damage, which makes Hrn mice an attractive model to study the effects of human BS.
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Ácidos y Sales Biliares/metabolismo , Sistema Enzimático del Citocromo P-450/deficiencia , Hepatopatías/metabolismo , Hepatopatías/patología , Animales , Colesterol/metabolismo , Modelos Animales de Enfermedad , Hidroxilación , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hepatopatías/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oxidorreductasas/deficiencia , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Fosfolípidos/metabolismo , Ácido Taurocólico/farmacologíaRESUMEN
Protectin DX (PDX), a specialized pro-resolving lipid mediator, presents potential therapeutic applications across various medical conditions due to its anti-inflammatory and antioxidant properties. Since type-1 diabetes mellitus (T1DM) is a disease with an inflammatory and oxidative profile, exploring the use of PDX in addressing T1DM and its associated comorbidities, including diabetic neuropathic pain, depression, and anxiety becomes urgent. Thus, in the current study, after 2 weeks of T1DM induction with streptozotocin (60 mg/kg) in Wistar rats, PDX (1, 3, and 10 ng/animal; i.p. injection of 200 µl/animal) was administered specifically on days 14, 15, 18, 21, 24, and 27 after T1DM induction. We investigated the PDX's effectiveness in alleviating neuropathic pain (mechanical allodynia; experiment 1), anxiety-like and depressive-like behaviors (experiment 2). Also, we studied whether the PDX treatment would induce antioxidant effects in the blood plasma, hippocampus, and prefrontal cortex (experiment 3), brain areas involved in the modulation of emotions. For evaluating mechanical allodynia, animals were repeatedly submitted to the Von Frey test; while for studying anxiety-like responses, animals were submitted to the elevated plus maze (day 26) and open field (day 28) tests. To analyze depressive-like behaviors, the animals were tested in the modified forced swimming test (day 28) immediately after the open field test. Our data demonstrated that PDX consistently increased the mechanical threshold throughout the study at the two highest doses, indicative of antinociceptive effect. Concerning depressive-like and anxiety-like behavior, all PDX doses effectively prevented these behaviors when compared to vehicle-treated T1DM rats. The PDX treatment significantly protected against the increased oxidative stress parameters in blood plasma and in hippocampus and prefrontal cortex. Interestingly, treated animals presented improvement on diabetes-related parameters by promoting weight gain and reducing hyperglycemia in T1DM rats. These findings suggest that PDX improved diabetic neuropathic pain, and induced antidepressant-like and anxiolytic-like effects, in addition to improving parameters related to the diabetic condition. It is worth noting that PDX also presented a protective action demonstrated by its antioxidant effects. To conclude, our findings suggest PDX treatment may be a promising candidate for improving the diabetic condition per se along with highly disabling comorbidities such as diabetic neuropathic pain and emotional disturbances associated with T1DM.
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Ansiedad , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Ácidos Docosahexaenoicos , Ratas Wistar , Animales , Masculino , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/psicología , Ratas , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/psicología , Ácidos Docosahexaenoicos/farmacología , Ácidos Docosahexaenoicos/uso terapéutico , Ansiedad/tratamiento farmacológico , Ansiedad/etiología , Depresión/tratamiento farmacológico , Depresión/etiología , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Corteza Prefrontal/efectos de los fármacos , Neuropatías Diabéticas/tratamiento farmacológicoRESUMEN
Breast cancer is a high-magnitude public health problem, continually challenging physicians and scientists worldwide in the field of drug therapy. 4-nitrochalcone (4NC) is a phenolic compound that has promising antitumor activity in vitro, but its application in breast cancer treatment is still poorly explored. This study aimed to evaluate the action of 4NC in vitro and in vivo breast cancer models. The cytotoxic potential of 4NC was tested towards MCF-7 and MDA-MD-231 breast cancer cells, with a lower impact in the non-tumor lineage HB4a. For in vivo studies, solid Ehrlich carcinoma (SEC) was used, a syngeneic mouse model with non-nuclear estrogen and progesterone positivity, characterized by immunohistochemistry. Daily oral administration of 4NC (25 mg kg-1) for 21 days led to a consistent reduction in tumor growth compared to the vehicle group. No signs of toxicity evaluated by hematological, biochemical, histological, and oxidative stress parameters were observed in mice, and the DL50 was >2000 mg kg-1. The effectors Raptor and S6K1 showed decreased activation, with a consequent reduction in protein synthesis; concomitantly, there was an increase in LC3-II levels, but the protective autophagic response was not completed, with the maintenance of p62 levels and cell death. These results open new possibilities for the use of 4NC as a tumor cell metabolism modulating agent.
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Antineoplásicos , Chalconas , Neoplasias , Animales , Ratones , Humanos , Preparaciones Farmacéuticas , Chalconas/farmacología , Chalconas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Muerte Celular , Autofagia , Línea Celular Tumoral , Células MCF-7 , ApoptosisRESUMEN
This study investigated the antitumoral, anti-inflammatory and oxidative effects of polysaccharides from tucum (Bactris setosa, TUC) using the Ehrlich carcinoma as a tumor model. Additionally, the glycogen content, cytochrome P levels, and gluconeogenesis from lactate were assessed in the liver of healthy animals. Tumor-bearing female mice were orally treated with 50 and 100 mg.kg-1 of TUC or vehicle, once a day, or with 1.5 mg.kg-1 methotrexate via i.p., every 3 days, along 21 days. Both doses of TUC reduced the tumor weight and volume. In the tumor tissue, it decreased GSH and IL-1ß levels, and increased LPO, NAG, NO and TNF-α levels. The tumor histology showed necrosis and leukocytes infiltration. The metabolic effects of TUC were investigated by measurement of total cytochrome P (CYP) and glycogen in tumor-bearing mice, and by ex vivo liver perfusion on non-bearing tumor male mice, using lactate as gluconeogenic precursor. Metabolically, the hepatic glucose and pyruvate productions, oxygen uptake, and the total CYP concentration were not modified by TUC. Thus, tucum-do-cerrado polysaccharides have antitumor effects through the modulation of oxidative stress and inflammation, without impairing glucose production from lactate in the liver, the main organ responsible for the metabolism of organic and xenobiotic compounds.
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Diabetes mellitus (DM) complications are a burden to health care systems due to the associated consequences of poor glycemic control and the side effects of insulin therapy. Recently. adjuvant therapies, such as vanadium compounds, have gained attention due to their potential to improve glucose homeostasis in patients with diabetes. In order to determine the anti-diabetic and antioxidant effects of the oxidovanadium(IV) complex (Et3NH)2[{VO(OH}2)(ox)2(µ-ox)] or Vox2), rats with streptozotocin (STZ)-induced diabetes were treated with 30 and 100 mg/kg of Vox2, orally administered for 12 days. Vox2 at 100 mg/kg in association with insulin caused a 3.4 times decrease in blood glucose in STZ rats (424 mg/dL), reaching concentrations similar to those in the normoglycemic animals (126 mg/dL). Compared to insulin alone, the association with Vox2 caused an additional decrease in blood glucose of 39% and 65% at 30 and 100 mg/kg, respectively, and an increased pancreatic GSH levels 2.5 times. Vox2 alone did not cause gastrointestinal discomfort, diarrhea, and hepatic or renal toxicity and was not associated with changes in blood glucose level, lipid profile, or kidney or liver function. Our results highlight the potential of Vox2 in association with insulin in treating diabetes.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already infected more than 272 million people, resulting in 5.3 million deaths worldwide from COVID-19. Breast tumors are considered the world's most commonly diagnosed cancer. Both breast cancer and COVID-19 share common pathogenic features, represented by inflammatory mediators and the potential of SARS-CoV-2 replication in metastatic cancer cells. This may intensify viral load in patients, thereby triggering severe COVID-19 complications. Thus, cancer patients have a high risk of developing severe COVID-19 with SARS-CoV-2 infection and a higher rate of complications and death than non-cancer patients. The present review discusses common mechanisms between COVID-19 and breast cancer and the particular susceptibility to COVID-19 in breast cancer patients. We describe the effects of chemotherapeutic agents that are used against this cancer, which should be considered from the perspective of susceptibility to SARS-CoV-2 infection and risk of developing severe events. We also present potential drug interactions between chemotherapies that are used to treat breast cancer and drugs that are applied for COVID-19. The drugs that are identified as having the most interactions are doxorubicin and azithromycin. Both drugs can interact with each other and with other drugs, which likely requires additional drug monitoring and changes in drug dosage and timing of administration. Further clinical and observational studies involving breast cancer patients who acquire COVID-19 are needed to define the best therapeutic approach when considering the course of both diseases.
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Neoplasias de la Mama , COVID-19 , Humanos , Femenino , SARS-CoV-2 , Neoplasias de la Mama/tratamiento farmacológicoRESUMEN
Background and Objective: Breast cancer is the most prevalent cancer worldwide, responsible for a large number of deaths, especially among women. Therapeutic options for breast cancer include surgery, radiotherapy, chemotherapy, hormone therapy, and immunotherapy, but further studies of the pathogenesis of this disease and new treatments are still needed. In vitro and in vivo cancer models are important research tools. Murine Ehrlich tumors are one of these models, especially for hormone-positive breast cancer. The present narrative review discusses characteristics of the Ehrlich tumor model, laboratory manipulations of Ehrlich cells (ECs), and applications in pharmacological, pathological, and translational studies. Methods: This review was based on scientific articles, books, and theses on Ehrlich tumors. We searched the PubMed, SciELO, Google Scholar, Google, and Clarivate databases. Key Content and Findings: Hormone-positive ECs produce solid Ehrlich carcinoma (SEC) and ascitic Ehrlich carcinoma (AEC), with different features and applications. The presence of SEC or AEC induces systemic and immunological alterations that are similar to cancer in humans, what makes this model applicable to different studies in the cancer field. Conclusions: Ehrlich tumors are a relevant tool for improving our understanding of the pathogenesis of breast cancer and investigating the tumor microenvironment, side effects of therapies, and new treatment options. Despite some limitations, such as the absence of an invasive phenotype to produce metastasis, both SEC and AEC are relevant in preclinical and translational studies of breast cancer.
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The soluble fraction of polysaccharides from cabernet franc red wine (SFP) previously showed antitumoral effects by modulating the immune system. The present study tested the hypothesis that the SFP can regulate CYPs in vitro in HepG2 cells and in vivo in Walker-256 tumor-bearing rats. The SFP was used in the following protocols: (i) solid tumor, (ii) liquid tumor, and (iii) chemopreventive solid tumor. The SFP reduced solid tumor growth in both solid tumor protocols but did not inhibit liquid tumor development. The SFP reduced total CYP levels in the solid and liquid tumor protocols and reduced the gene expression of Cyp1a1 and Cyp2e1 in rats and CYP1A2 in HepG2 cells. An increase of N-acetylglucosaminidase activity was observed in all SFP-treated rats, and TNF-α levels increased in the solid tumor protocol in the vehicle, SFP, and vincristine (positive control) groups. The chemopreventive solid tumor protocol did not modify CYP levels in the liver or intestine or N-acetylglucosaminidase and myeloperoxidase activity in the liver. The in vitro digestion and nuclear magnetic resonance analyses suggested that SFP was minimally modified in the gastrointestinal system. In conclusion, SFP inhibited CYPs both in vivo and in vitro, likely as a result of its immunoinflammatory actions.
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Vino , Ratas , Animales , Acetilglucosaminidasa , Sistema Enzimático del Citocromo P-450/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Polisacáridos/farmacologíaRESUMEN
Background: Dulaglutide emerged as a promising therapeutic option for diabetes mellitus Type 2 (DM2). Aims: Owing to epigenetic similarities between the pathophysiology of DM2 and breast cancer (BC), we investigated the antitumor effect of dulaglutide. Materials & methods: To investigate the effect of dulaglutide, we analyzed the expression of methylated gene promoter regions in BC (ESR1, CDH1 and ADAM33). Results: Dulaglutide increased the expression of ESR1, CDH1 and ADAM33 up to fourfold in the MDA-MB-231 lineage by demethylating the gene promoter regions. This effect was translated to in vivo antitumoral activity and revealed significant tumor inhibition by combining the half-dose of methotrexate with dulaglutide. Conclusion: This therapy may mitigate the severe side effects commonly associated with chemotherapy.