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1.
Biomolecules ; 10(9)2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32825327

RESUMO

There is a growing consensus that the antioxidant and anti-inflammatory properties of melatonin are of great importance in preserving the body functions and homeostasis, with great impact in the peripartum period and adult life. Melatonin promotes adaptation through allostasis and stands out as an endogenous, dietary, and therapeutic molecule with important health benefits. The anti-inflammatory and antioxidant effects of melatonin are intertwined and are exerted throughout pregnancy and later during development and aging. Melatonin supplementation during pregnancy can reduce ischemia-induced oxidative damage in the fetal brain, increase offspring survival in inflammatory states, and reduce blood pressure in the adult offspring. In adulthood, disturbances in melatonin production negatively impact the progression of cardiovascular risk factors and promote cardiovascular and neurodegenerative diseases. The most studied cardiovascular effects of melatonin are linked to hypertension and myocardial ischemia/reperfusion injury, while the most promising ones are linked to regaining control of metabolic syndrome components. In addition, there might be an emerging role for melatonin as an adjuvant in treating coronavirus disease 2019 (COVID 19). The present review summarizes and comments on important data regarding the roles exerted by melatonin in homeostasis and oxidative stress and inflammation related pathologies.


Assuntos
Adjuvantes Farmacêuticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Melatonina/administração & dosagem , Melatonina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Adjuvantes Farmacêuticos/administração & dosagem , Adjuvantes Farmacêuticos/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Homeostase/efeitos dos fármacos , Humanos , Melatonina/farmacologia , Pandemias
2.
Chemosphere ; 258: 127408, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32782161

RESUMO

This study investigates the impacts of exposure to an environment Ca2+ challenge and the mechanism of action of dibutyl phthalate (DBP) on Ca2+ influx in the gills of Danio rerio. In vitro profile of 45Ca2+ influx in gills was verified through the basal time-course. Fish were exposed to low, normal and high Ca2+ concentrations (0.02, 0.7 and 2 mM) for 12 h. So, gills were morphologically analysed and ex vivo45Ca2+ influx at 30 and 60 min was determined. For the in vitro studies, gills were treated for 60 min with DBP (1 pM, 1 nM and 1 µM) with/without blockers/activators of ionic channels, Ca2+ chelator, inhibitors of ATPases, ionic exchangers and protein kinase C to study the mechanism of DBP-induced 45Ca2+ influx. Exposure to high environmental Ca2+ augmented 45Ca2+ influx when compared to fish exposed to normal and low Ca2+ concentrations. Additionally, histopathological changes were observed in the gills of fish maintained for 12 h in low and high Ca2+. In vitro exposure of gills to DBP (1 pM) disturbed Ca2+ homeostasis. DBP stimulated 45Ca2+ influx in gills through the transitory receptor potential vanilloid 1 (TRPV1), and reverse-mode Na+/Ca2+ exchanger (NCX) activation, protein kinase C and K+ channels and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). These data suggest that in vivo short-term exposure of gills to low and high Ca2+ leads to 45Ca2+ influx and histopathological changes. Additionally, the DBP-induced rapid 45Ca2+ influx is mediated by TRPV1, NCX activation with the involvement of PKC, K+-channels and SERCA, thereby altering Ca2+ homeostasis.


Assuntos
Radioisótopos de Cálcio/metabolismo , Cálcio/metabolismo , Dibutilftalato/toxicidade , Brânquias/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Cálcio/toxicidade , Dibutilftalato/metabolismo , Retículo Endoplasmático/metabolismo , Brânquias/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Canais de Cátion TRPV/metabolismo , Poluentes Químicos da Água/metabolismo
3.
Chem Biol Interact ; 330: 109234, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32860823

RESUMO

Cisplatin is an antineoplastic drug well recognized for its success in the battle against several types of cancer in adult, juvenile, and child populations. Meanwhile, this drug is also famous due to its serious side effects, such as hepatotoxicity. This study evaluated the hepatoprotective effectiveness of Diphenyl Diselenide (PhSe)2 and Ebselen in a model of cisplatin-induced toxicity in juvenile rats. Juvenile Wistar rats received a single intraperitoneal (i.p) injection of cisplatin (6 mg/kg) or saline solution, at postnatal day (PND) 21. Ebselen (11 mg/kg) or (PhSe)2 (12 mg/kg) was intragastrically (i.g) administered in rats from PND 21 to PND 25. At PND 26, the blood and liver were collected for the biochemistry assays. A single administration of cisplatin was enough to alter the makers of hepatic function (an increase of AST activity) and the blood lipid profile (an increase of cholesterol and triglycerides, TG). The cisplatin-induced metabolic disruption was demonstrated by the increase of hepatic glycogen and TG contents and hexokinase, glucose-6-phosphatase, and tyrosine aminotransferase activities; a decrease of citrate synthase activity and the levels of GLUT-2. Cisplatin-induced hepatic oxidative stress was characterized by an increase in reactive oxygen species, TBARS, protein carbonyl, and Nox levels as well as the decrease in NPSH levels. Ebselen and (PhSe)2 were effective against all alterations caused by this chemotherapy medication. The present findings highlight the (PhSe)2 and Ebselen similar hepatoprotective effectiveness against cisplatin-induced disruption of metabolic homeostasis and redox balance in juvenile rats.


Assuntos
Azóis/farmacologia , Derivados de Benzeno/farmacologia , Cisplatino/toxicidade , Homeostase/efeitos dos fármacos , Fígado/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Lipídeos/sangue , Fígado/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos
5.
PLoS One ; 15(8): e0237400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32780768

RESUMO

Metformin, a biguanide agent, is the first-line treatment for type 2 diabetes mellitus due to its glucose-lowering effect. Despite its wide application in the treatment of multiple health conditions, the glycemic response to metformin is highly variable, emphasizing the need for reliable biomarkers. We chose the RNA-Seq-based comparative transcriptomics approach to evaluate the systemic effect of metformin and highlight potential predictive biomarkers of metformin response in drug-naïve volunteers with type 2 diabetes in vivo. The longitudinal blood-derived transcriptome analysis revealed metformin-induced differential expression of novel and previously described genes involved in cholesterol homeostasis (SLC46A1 and LRP1), cancer development (CYP1B1, STAB1, CCR2, TMEM176B), and immune responses (CD14, CD163) after administration of metformin for three months. We demonstrate for the first time a transcriptome-based molecular discrimination between metformin responders (delta HbA1c ≥ 1% or 12.6 mmol/mol) and non-responders (delta HbA1c < 1% or 12.6 mmol/mol), that is determined by expression levels of 56 genes, explaining 13.9% of the variance in the therapeutic efficacy of the drug. Moreover, we found a significant upregulation of IRS2 gene (log2FC 0.89) in responders compared to non-responders before the use of metformin. Finally, we provide evidence for the mitochondrial respiratory complex I as one of the factors related to the high variability of the therapeutic response to metformin in patients with type 2 diabetes mellitus.


Assuntos
Análise Química do Sangue , Perfilação da Expressão Gênica , Metformina/farmacologia , Idoso , Colesterol/metabolismo , Feminino , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Masculino , Pessoa de Meia-Idade
6.
Anesthesiology ; 133(2): 364-376, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32665491

RESUMO

BACKGROUND: Until recently, the mechanism for the malignant hyperthermia crisis has been attributed solely to sustained massive Ca release from the sarcoplasmic reticulum on exposure to triggering agents. This study tested the hypothesis that transient receptor potential cation (TRPC) channels are important contributors to the Ca dyshomeostasis in a mouse model relevant to malignant hyperthermia. METHODS: This study examined the mechanisms responsible for Ca dyshomeostasis in RYR1-p.G2435R mouse muscles and muscle cells using calcium and sodium ion selective microelectrodes, manganese quench of Fura2 fluorescence, and Western blots. RESULTS: RYR1-p.G2435R mouse muscle cells have chronically elevated intracellular resting calcium and sodium and rate of manganese quench (homozygous greater than heterozygous) compared with wild-type muscles. After exposure to 1-oleoyl-2-acetyl-sn-glycerol, a TRPC3/6 activator, increases in intracellular resting calcium/sodium were significantly greater in RYR1-p.G2435R muscles (from 153 ± 11 nM/10 ± 0.5 mM to 304 ± 45 nM/14.2 ± 0.7 mM in heterozygotes P < 0.001] and from 251 ± 25 nM/13.9 ± 0.5 mM to 534 ± 64 nM/20.9 ± 1.5 mM in homozygotes [P < 0.001] compared with 123 ± 3 nM/8 ± 0.1 mM to 196 ± 27 nM/9.4 ± 0.7 mM in wild type). These increases were inhibited both by simply removing extracellular Ca and by exposure to either a nonspecific (gadolinium) or a newly available, more specific pharmacologic agent (SAR7334) to block TRPC6- and TRPC3-mediated cation influx into cells. Furthermore, local pretreatment with SAR7334 partially decreased the elevation of intracellular resting calcium that is seen in RYR1-p.G2435R muscles during exposure to halothane. Western blot analysis showed that expression of TRPC3 and TRPC6 were significantly increased in RYR1-p.G2435R muscles in a gene-dose-dependent manner, supporting their being a primary molecular basis for increased sarcolemmal cation influx. CONCLUSIONS: Muscle cells in knock-in mice expressing the RYR1-p.G2435R mutation are hypersensitive to TRPC3/6 activators. This hypersensitivity can be negated with pharmacologic agents that block TRPC3/6 activity. This reinforces the working hypothesis that transient receptor potential cation channels play a critical role in causing intracellular calcium and sodium overload in malignant hyperthermia-susceptible muscle, both at rest and during the malignant hyperthermia crisis.


Assuntos
Cálcio/metabolismo , Modelos Animais de Doenças , Hipertermia Maligna/metabolismo , Canais de Cátion TRPC/metabolismo , Canal de Cátion TRPC6/metabolismo , Animais , Feminino , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Indanos/farmacologia , Masculino , Hipertermia Maligna/genética , Hipertermia Maligna/patologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Canal de Liberação de Cálcio do Receptor de Rianodina/biossíntese , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canais de Cátion TRPC/antagonistas & inibidores , Canais de Cátion TRPC/genética , Canal de Cátion TRPC6/antagonistas & inibidores , Canal de Cátion TRPC6/genética
7.
Aquat Toxicol ; 225: 105524, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32610223

RESUMO

In the present research, the effects of exposure to a sublethal concentration of zinc (Zn) on metal and ion homeostasis, and the regulation and the localization of various Zn transporters (i.e., the Zrt-Irt Like Protein (ZIP) family of Zn transporters), were investigated in zebrafish (Danio rerio) during early development. Exposure to an elevated level of Zn [4 µM (high) vs. 0.25 µM (control)] from 0 day post-fertilization (dpf) resulted in a significant increase in the whole body content of Zn at 5 dpf. A transient decrease in the whole body calcium (Ca) level was observed in 3 dpf larvae exposed to high Zn. Similarly, whole body nickel (Ni) and copper (Cu) contents were also reduced in 3 dpf larvae exposed to high Zn. Importantly, the magnitude of reduction in whole body Ni and Cu contents following Zn exposure was markedly higher than that in Ca content, suggesting that internal Ni and Cu balance were likely more sensitive to Zn exposure in developing zebrafish. Exposure to high Zn altered the mRNA expression levels of specific zip transporters, with an increase in zip1 (at 3 dpf) and zip8 (at 5 dpf), and a decrease in zip4 (at 5 dpf). The expression levels of most zip transporters tended to decrease from 3 dpf to 5 dpf with the exception of zip4 and zip8. Results from in situ hybridization revealed that several zip transporters exhibited distinct spatial distribution (e.g., zip8 in the intestinal tract, zip14 in the pronephric tubules). Overall, our findings suggested that exposure to sublethal concentrations of Zn disrupts the homeostasis of essential metals during early development and that different ZIP transporters may play unique roles in regulating Zn homeostasis in various organs in developing zebrafish.


Assuntos
Proteínas de Transporte de Cátions/genética , Homeostase/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Proteínas de Peixe-Zebra/genética , Peixe-Zebra , Zinco/toxicidade , Animais , Cálcio/metabolismo , Cobre/metabolismo , Relação Dose-Resposta a Droga , Larva/efeitos dos fármacos , Larva/metabolismo , Nível de Efeito Adverso não Observado , Poluentes Químicos da Água/metabolismo , Peixe-Zebra/fisiologia , Zinco/metabolismo
8.
Aquat Toxicol ; 226: 105561, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32688145

RESUMO

In the aquatic environment, metals are present as mixtures, therefore studies on mixture toxicity are crucial to thoroughly understand their toxic effects on aquatic organisms. Common carp (Cyprinus carpio) were used to assess the effects of short-term Cu(II) and Cd(II) mixtures, using a fixed concentration of one of the metals, representing 25 % of its individual 96h-LC50 (concentration lethal for 50 % of the population) combined with a variable concentration of the other metal corresponding to 10, 25 or 50 % of its 96h-LC50, and vice versa. Our results showed a fast Cu and Cd bioaccumulation, with the percentage of increase in the order gill > liver > carcass. An inhibitory effect of Cu on Cd uptake was observed; higher Cu concentrations at fixed Cd levels resulted in a decreased accumulation of Cd. The presence of the two metal ions resulted in losses of total Na, K and Ca. Fish tried to compensate for the Na loss through the induction of the genes coding for Na+/K+-ATPase and H+-ATPase. Additionally, a counterintuitive induction of the gene encoding the high affinity copper transporter (CTR1) occurred, while a downregulation was expected to prevent further metal ion uptake. An induction of defensive mechanisms, both metal ion binding protein and anti-oxidant defences, was observed. Despite the metal accumulation and electrolyte loss, the low mortality suggest that common carp is able to cope with these metal levels, at least during a one-week exposure.


Assuntos
Bioacumulação/efeitos dos fármacos , Cádmio/toxicidade , Carpas/metabolismo , Cobre/toxicidade , Homeostase/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Cádmio/metabolismo , Carpas/genética , Cobre/metabolismo , Transportador de Cobre 1/genética , Transportador de Cobre 1/metabolismo , Eletrólitos/metabolismo , Brânquias/efeitos dos fármacos , Brânquias/metabolismo , Transporte de Íons , Dose Letal Mediana , Potássio/metabolismo , Sódio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Poluentes Químicos da Água/metabolismo
9.
Chemosphere ; 259: 127356, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32650176

RESUMO

Growth of the most important nitrogen fixing cyanobacterium Nostoc muscorum is reported to be badly affected by the application of insecticides. To overcome their damaging effects, several strategies are being used. Out of these, some works on kinetin (KN, a synthetic cytokinin) has been recognized that it can overcome toxicity of insecticides in cyanobacteria. Besides this, it is now known that every hormone needs certain second messengers such as nitric oxide (NO) for its action. But implication of NO in KN-mediated regulation of insecticide toxicity is yet to be investigated. Hence in the current study, we have investigated the possible involvement of NO in KN-mediated regulation of cypermethrin toxicity in the cyanobacterium Nostoc muscorum. Cypermethrin decreased growth of Nostoc muscorum which was accompanied by decreased pigment contents and altered photosystem II (PS II) photochemistry that resulted in inhibition of photosynthetic process but KN significantly ameliorated cypermethrin toxicity. Cypermethrin induced production of free radicals (in-vivo and in-vitro) and weakened defensive mechanism (enzymatic and non-enzymatic defense system) which was restored by KN. Further, the results revealed that NG-nitro-l-arginine methyl ester (l-NAME, an inhibitor of nitric oxide synthase) worsened the effect of cypermethrin toxicity even in the presence of KN while 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO, a scavenger of NO) reversed KN-mediated amelioration even in the presence of sodium nitroprusside (SNP, an NO donor), suggesting that endogenous NO is required for mitigation of cypermethrin toxicity. Overall, our results first time show that endogenous NO is essential for KN-mediated mitigation of cypermethrin toxicity in the Nostoc muscorum.


Assuntos
Citocininas/farmacologia , Nostoc muscorum/fisiologia , Reguladores de Crescimento de Planta/farmacologia , Polissacarídeos Bacterianos/metabolismo , Piretrinas/toxicidade , Cianobactérias/metabolismo , Homeostase/efeitos dos fármacos , Inseticidas/farmacologia , Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/farmacologia , Nitroprussiato/farmacologia , Nostoc muscorum/efeitos dos fármacos , Nostoc muscorum/metabolismo , Fotoquímica , Fotossíntese/efeitos dos fármacos , Complexo de Proteína do Fotossistema II/metabolismo , Espécies Reativas de Oxigênio/farmacologia
10.
J Pharmacol Sci ; 143(4): 307-314, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32536591

RESUMO

Rutaecarpine, an indolopyridoquinazoline alkaloid, attracted attentions because of possessing various biological activities. The objective of this study was to investigate the effect of rutaecarpine on glucose and lipid metabolism in high fat diet-multiple low dose streptozotocin induced type 2 diabetic (HFD-db) mice and to understand the mechanism of action. HFD-db mice showed impaired glucose metabolism and lipid profile. Oral administration of rutaecarpine reduced the blood glucose levels, decreased blood hemoglobin A1c (HbA1c) levels, improved glucose tolerance and restored insulin sensitivity in HFD-db mice. Rutaecarpine also decreased body weight gain, water intake and visceral fat gain in HFD-db mice. Total cholesterol, triglycerides, very low density lipoprotein and low density lipoprotein were reduced and high density lipoprotein level was augmented in rutaecarpine treated HFD-db mice. Rutaecarpine also reduced the elevated levels of serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, urea and creatinine in HFD-db mice. Rutaecarpine significantly promoted the rate of glucose consumption, glucose uptake and glycolysis in C2C12 myotubes. Western blotting results showed that rutaecarpine augmented p-GSK-3ß and p-AMPK expression, and suppressed G6Pase expression in HepG2 cells. These results suggest that rutaecarpine might be having therapeutic importance to fight against type 2 diabetes mellitus associated with dyslipidemia.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Hipoglicemiantes , Alcaloides Indólicos/farmacologia , Fígado/metabolismo , Quinazolinas/farmacologia , Animais , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Tipo 2/etiologia , Modelos Animais de Doenças , Alcaloides Indólicos/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL , Quinazolinas/uso terapêutico
11.
Hipertens. riesgo vasc ; 37(2): 72-77, abr.-jun. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-189194

RESUMO

El sistema renina-angiotensina (SRA) es una cascada hormonal que regula presión arterial, electrólitos y balance hídrico. La angiotensinaII (AII) ejerce sus efectos a través de los receptores AT1 y AT2. El AT1 se encuentra en el sincitiotrofoblasto; el AT2 predomina durante el desarrollo fetal y su estimulación inhibe el crecimiento celular, aumenta la apoptosis, causa vasodilatación y regula el desarrollo del tejido fetal. Existe además un SRA en la placenta, y la generación local de AII es responsable de la activación de los receptores AT1 del trofoblasto. En el embarazo normal, concomitantemente con reducción de los niveles de presión arterial, se produce un aumento del SRA circulante, pero la presión arterial no sube porque existe refractariedad a la AII, cosa que no ocurre en la preeclampsia. Revisamos la función del SRA en el embarazo normal y en la preeclampsia


The renin-angiotensin system (ARS) is a hormonal cascade that regulates blood pressure, electrolytes and water balance. AngiotensinII (AII) exerts its effects through the AT1 and AT2 receptors. AT1 is found in the syncytiotrophoblast, AT2 predominates during foetal development and its stimulation inhibits cell growth, increases apoptosis, causes vasodilation and regulates the development of foetal tissue. There is also an SRA in the placenta. The local generation of AII is responsible for the activation of AT1 receptors in the trophoblast. In normal pregnancy, concomitantly with reduction of blood pressure the circulating RAS increases, but blood pressure does not rise due to AII refractoriness, which does not occur in preeclampsia. We review the role of the SRA in normal pregnancy and preeclampsia


Assuntos
Humanos , Feminino , Gravidez , Sistema Renina-Angiotensina/efeitos dos fármacos , Pré-Eclâmpsia/metabolismo , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Hemodinâmica/efeitos dos fármacos , Albumina Sérica/efeitos dos fármacos , Índice de Gravidade de Doença , Espaço Extracelular/efeitos dos fármacos , Homeostase/efeitos dos fármacos
12.
Toxicol Lett ; 332: 97-106, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32599024

RESUMO

As important members in steroids related signal pathways, bile acids are very important in regulating substance metabolism and immune homeostasis. However, bile acids are highly cytotoxic, and the excessive accumulation can induce several abnormalities such as cholestatic liver injury. It is known that the bile acid metabolism alters during pregnancy and mostly will not result in pathologies. However, the effect of dexamethasone exposure during pregnancy on bile acid metabolism is still unknown. In this study, pregnant Wistar rats were subcutaneously administered dexamethasone (0.2 mg/kg.d) or saline from gestation day 9-21, while virgin rats were given the same treatment for 13 days. We found that, physiological pregnancy or dexamethasone exposure during non-pregnancy did not affect maternal serum TBA level and liver function. Nevertheless, dexamethasone exposure during pregnancy increased serum TBA level and accompanied with liver injury. Furthermore, we discovered that the conservation of bile acid homeostasis under pregnancy or dexamethasone exposure was maintained through compensatory pathways. However, dexamethasone exposure during pregnancy tipped the balance of liver bile acid homeostasis by increasing classical synthesis and decreasing efflux and uptake. In addition, dexamethasone exposure during pregnancy also increased serum estrogen level and nuclear receptors mRNA expression levels. Finally, two-way ANOVA analysis showed that dexamethasone exposure during pregnancy could induce or facilitate maternal cholestasis and liver injury by up-regulating ERα and CYP7A1 expression. This study confirmed that dexamethasone exposure during pregnancy was related to maternal intrahepatic cholestasis of pregnancy and should be carefully monitored in clinical settings.


Assuntos
Ácidos e Sais Biliares/metabolismo , Dexametasona/toxicidade , Animais , Colestase Intra-Hepática , Colesterol 7-alfa-Hidroxilase/biossíntese , Estrogênios/sangue , Feminino , Hormônios Esteroides Gonadais/sangue , Homeostase/efeitos dos fármacos , Infusões Subcutâneas , Testes de Função Hepática , Gravidez , Ratos , Ratos Wistar , Receptores Estrogênicos/biossíntese
13.
Neuron ; 106(5): 715-726, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32497508

RESUMO

Ketamine exerts rapid antidepressant action in depressed and treatment-resistant depressed patients within hours. At the same time, ketamine elicits a unique form of functional synaptic plasticity that shares several attributes and molecular mechanisms with well-characterized forms of homeostatic synaptic scaling. Lithium is a widely used mood stabilizer also proposed to act via synaptic scaling for its antimanic effects. Several studies to date have identified specific forms of homeostatic synaptic plasticity that are elicited by these drugs used to treat neuropsychiatric disorders. In the last two decades, extensive work on homeostatic synaptic plasticity mechanisms have shown that they diverge from classical synaptic plasticity mechanisms that process and store information and thus present a novel avenue for synaptic regulation with limited direct interference with cognitive processes. In this review, we discuss the intersection of the findings from neuropsychiatric treatments and homeostatic plasticity studies to highlight a potentially wider paradigm for treatment advance.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Homeostase/efeitos dos fármacos , Ketamina/farmacologia , Compostos de Lítio/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Animais , Antimaníacos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Ketamina/uso terapêutico , Compostos de Lítio/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Sinapses/efeitos dos fármacos
14.
Eur J Endocrinol ; 183(2): 181-189, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32454455

RESUMO

Objective: Long-term androgen deprivation therapy (ADT) negatively influences bone. The short-term effects on bone and mineral homeostasis are less known. Therefore, we aimed to investigate the early effects of ADT on calcium/phosphate homeostasis and bone turnover. Design: Prospective cohort study. Methods: Eugonadal adult, male sex offenders, who were referred for ADT to the endocrine outpatient clinic, received cyproterone acetate. Changes in blood markers of calcium/phosphate homeostasis and bone turnover between baseline and first follow-up visit were studied. Results: Of 26 screened patients, 17 were included. The median age was 44 (range 20-75) years. The median time interval between baseline and first follow-up was 13 (6-27) weeks. Compared to baseline, an 81% decrease was observed for median total testosterone (to 3.4 nmol/L (0.4-12.2); P < 0.0001) and free testosterone (to 0.06 nmol/L (0.01-0.18); P < 0.0001). Median total estradiol decreased by 71% (to 17.6 pmol/L (4.7-35.6); P < 0.0001). Increased serum calcium (P < 0.0001) and phosphate (P = 0.0016) was observed, paralleled by decreased PTH (P = 0.0156) and 1,25-dihydroxyvitamin D3 (P = 0.0134). The stable calcium isotope ratio (δ44/42Ca) decreased (P = 0.0458), indicating net calcium loss from bone. Bone-specific alkaline phosphatase and osteocalcin decreased (P < 0.0001 and P = 0.0056, respectively), periostin tended to decrease (P = 0.0500), whereas sclerostin increased (P < 0.0001), indicating suppressed bone formation. Serum bone resorption markers (TRAP, CTX) were unaltered. Conclusions: In adult men, calcium release from the skeleton occurs early following sex steroid deprivation, reflecting early bone resorption. The increase of sclerostin and reduction of bone formation markers, without changes in resorption markers, suggests a dominant negative effect on bone formation in the acute phase.


Assuntos
Antagonistas de Androgênios/farmacologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Calcificação Fisiológica/efeitos dos fármacos , Acetato de Ciproterona/farmacologia , Adulto , Idoso , Bélgica , Remodelação Óssea/efeitos dos fármacos , Cálcio/sangue , Estudos de Coortes , Homeostase/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatos/sangue , Estudos Prospectivos , Delitos Sexuais , Testosterona/sangue
15.
Toxicol Lett ; 331: 11-21, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32439580

RESUMO

Cholestasis represents pathophysiologic syndromes defined as impaired bile flow from the liver. As an outcome, bile acids accumulate and promote hepatocyte injury, followed by liver cirrhosis and liver failure. Glycochenodeoxycholic acid (GCDCA) is relatively toxic and highly concentrated in bile and serum after cholestasis. However, the mechanism underlying GCDCA-induced hepatotoxicity remains unclear. In this study, we found that GCDCA inhibits autophagosome formation and impairs lysosomal function by inhibiting lysosomal proteolysis and increasing lysosomal pH, contributing to defects in autophagic clearance and subsequently leading to the death of L02 human hepatocyte cells. Notably, through tandem mass tag (TMT)-based quantitative proteomic analysis and database searches, 313 differentially expressed proteins were identified, of which 71 were increased and 242 were decreased in the GCDCA group compared with those in the control group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that GCDCA suppressed the signaling pathway of transcription factor E3 (TFE3), which was the most closely associated with autophagic flux impairment. In contrast, GCDCA-inhibited lysosomal function and autophagic flux were efficiently attenuated by TFE3 overexpression. Specifically, the decreased expression of TFE3 was closely related to the disruption of reactive oxygen species (ROS) homeostasis, which could be prevented by inhibiting intracellular ROS with N-acetyl cysteine (NAC). In summary, our study is the first to demonstrate that manipulation of ROS/TFE3 signaling may be a therapeutic approach for antagonizing GCDCA-induced hepatotoxicity.


Assuntos
Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Ácido Glicoquenodesoxicólico/toxicidade , Hepatócitos/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Ácidos e Sais Biliares/metabolismo , Linhagem Celular , Expressão Gênica/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Lisossomos/efeitos dos fármacos , Proteômica
16.
Toxicol Appl Pharmacol ; 398: 115009, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32353385

RESUMO

Significant attention has been given to the potential of environmental chemicals to disrupt lipid homeostasis at the cellular level. These chemicals, classified as obesogens, are abundantly used in a wide variety of consumer products. However, there is a significant lack of information regarding the mechanisms by which environmental exposure can contribute to the onset of obesity and non-alcoholic fatty liver disease (NAFLD). Several studies have described the interaction of potential obesogens with lipid-related peroxisome proliferator-activated receptors (PPAR). However, no studies have quantified the degree of modification to lipidomic profiles in relevant human models, making it difficult to directly link PPAR agonists to the onset of lipid-related diseases. A quantitative metabolomic approach was used to examine the dysregulation of lipid metabolism in human liver cells upon exposure to potential obesogenic compounds. The chemicals rosiglitazone, perfluorooctanoic acid, di-2-ethylexylphthalate, and tributyltin significantly increased total lipids in liver cells, being diglycerides, triglycerides and phosphatidylcholines the most prominent. Contrarily, perfluorooctane sulfonic acid and the pharmaceutical fenofibrate appeared to lower total lipid concentrations, especially those belonging to the acylcarnitine, ceramide, triglyceride, and phosphatidylcholine groups. Fluorescence microscopy analysis for cellular neutral lipids revealed significant lipid bioaccumulation upon exposure to obesogens at environmentally relevant concentrations. This integrated omics analysis provides unique mechanistic insight into the potential of these environmental pollutants to promote diseases like obesity and NAFLD. Furthermore, this study provides a significant contribution to advance the understanding of molecular signatures related to obesogenic chemicals and to the development of alternatives to in vivo experimentation.


Assuntos
Exposição Ambiental/efeitos adversos , Poluentes Ambientais/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Obesidade/induzido quimicamente , Obesidade/metabolismo , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolômica/métodos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR gama/metabolismo
17.
Gene ; 753: 144780, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32439374

RESUMO

Marine mollusks suffer harmful effects due to environmental organotin compounds such as tributyltin (TBT) and triphenyltin (TPT). It is known that gastropod imposex caused by organotins is mediated by a key nuclear receptor, retinoid X receptor (RXR). The organotin-mediated toxic effects on oysters grown in seawater include a thicker shell, incomplete growth, disrupted development and a high rate of mortality. However, few studies have been conducted to determine the role of RXR in the toxic effects of organotins on bivalves. Here, we cloned an RXR homolog (CgRXR) from the Pacific oyster (Crassostrea gigas) and characterized its molecular function. Expression of the CgRXR RNA transcripts was assessed in whole developmental stages and tissues, with the highest expression detected in the blastula and mantle, respectively. The subcellular localization experiment confirmed that CgRXR protein was expressed in the nucleus exclusively as a nuclear receptor. Electrophoretic mobility shift assay indicated that CgRXR could bind to the DNA motifs DR0-DR5. The dual-luciferase reporter assay demonstrated that the transcriptional activity of CgRXR was activated by conserved ligands (9-cis retinoic acid and cis-4,7,10,13,16,19-docosahexanoic acid) and endocrine-disrupting chemicals (TBT and TPT). These results revealed the conserved gene function involved in protein localization, ligand binding and heterodimer formation with thyroid hormone receptor. However, the DNA binding properties of CgRXR differed from those of other invertebrate and vertebrate RXRs. CgRXR had the highest expression level in the blastula and mantle, and the disrupted development or shell malformation induced by organotins suggested a possible correlation of CgRXR with shell formation in bivalves. The results indicated the potential involvement of CgRXR in the toxic effects of organotins (TBT and TPT) through signaling pathway disruption. Functional characterization of CgRXR will help us better understand the endocrinology of bivalves.


Assuntos
Crassostrea/genética , Compostos Orgânicos de Estanho/toxicidade , Receptores X Retinoide/genética , Animais , Crassostrea/metabolismo , Disruptores Endócrinos/farmacologia , Gastrópodes/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Compostos Orgânicos de Estanho/metabolismo , Compostos Orgânicos de Estanho/farmacologia , Receptores dos Hormônios Tireóideos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Compostos de Trialquitina/metabolismo , Compostos de Trialquitina/toxicidade
18.
Pharmacol Res ; 158: 104904, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32430286

RESUMO

The anti-malarial drugs chloroquine (CQ) and primarily the less toxic hydroxychloroquine (HCQ) are currently used to treat autoimmune diseases for their immunomodulatory and anti-thrombotic properties. They have also been proposed for the treatment of several viral infections, due to their anti-viral effects in cell cultures and animal models, and, currently, for the treatment of coronavirus disease 2019 (COVID-19), the pandemic severe acute respiratory syndrome caused by coronavirus 2 (Sars-Cov-2) infection that is spreading all over the world. Although in some recent studies a clinical improvement in COVID-19 patients has been observed, the clinical efficacy of CQ and HCQ in COVID-19 has yet to be proven with randomized controlled studies, many of which are currently ongoing, also considering pharmacokinetics, optimal dosing regimen, therapeutic level and duration of treatment and taking into account patients with different severity degrees of disease. Here we review what is currently known on the mechanisms of action of CQ and HCQ as anti-viral, anti-inflammatory and anti-thrombotic drugs and discuss the up-to-date experimental evidence on the potential mechanisms of action of CQ/HCQ in Sars-Cov2 infection and the current clinical knowledge on their efficacy in the treatment of COVID-19 patients. Given the role of iron in several human viral infections, we also propose a different insight into a number of CQ and HCQ pharmacological effects, suggesting a potential involvement of iron homeostasis in Sars-Cov-2 infection and COVID-19 clinical course.


Assuntos
Betacoronavirus/efeitos dos fármacos , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Homeostase/efeitos dos fármacos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Ferro/metabolismo , Pneumonia Viral/tratamento farmacológico , Antivirais/farmacologia , Antivirais/uso terapêutico , Infecções por Coronavirus/metabolismo , Humanos , Pandemias , Pneumonia Viral/metabolismo
19.
Invest Ophthalmol Vis Sci ; 61(4): 23, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32301974

RESUMO

Purpose: To determine the effects of airborne particulate matter (PM) <2.5 µm in vitro and on the normal and Pseudomonas aeruginosa (PA)-infected cornea. Methods: An MTT viability assay tested the effects of PM2.5 on mouse corneal epithelial cells (MCEC) and human corneal epithelial cells (HCET). MCEC were tested for reactive oxygen species using a 2',7'-dichlorodihydrofluorescein assay; RT-PCR determined mRNA levels of inflammatory and oxidative stress markers in MCEC (HMGB1, toll-like receptor 2, IL-1ß, CXCL2, GPX1, GPX2, GR1, superoxide dismutase 2, and heme oxygenase 1) and HCET (high mobility group box 1, CXCL2, and IL-1ß). C57BL/6 mice also were infected and after 6 hours, the PM2.5 was topically applied. Disease was graded by clinical score and evaluated by histology, plate count, myeloperoxidase assay, RT-PCR, ELISA, and Western blot. Results: After PM2.5 (25-200 µg/mL), 80% to 90% of MCEC and HCET were viable and PM exposure increased reactive oxygen species in MCEC and mRNA expression levels for inflammatory and oxidative stress markers in mouse and human cells. In vivo, the cornea of PA+PM2.5 exposed mice exhibited earlier perforation over PA alone (confirmed histologically). In cornea, plate counts were increased after PA+PM2.5, whereas myeloperoxidase activity was significantly increased after PA+PM2.5 over other groups. The mRNA levels for several proinflammatory and oxidative stress markers were increased in the cornea in the PA+PM2.5 over other groups; protein levels were elevated for high mobility group box 1, but not toll-like receptor 4 or glutathione reductase 1. Uninfected corneas treated with PM2.5 did not differ from normal. Conclusions: PM2.5 triggers reactive oxygen species, upregulates mRNA levels of oxidative stress, inflammatory markers, and high mobility group box 1 protein, contributing to perforation in PA-infected corneas.


Assuntos
Epitélio Anterior/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Material Particulado/farmacologia , Animais , Biomarcadores/metabolismo , Western Blotting , Sobrevivência Celular , Células Cultivadas , Úlcera da Córnea/tratamento farmacológico , Úlcera da Córnea/metabolismo , Úlcera da Córnea/patologia , Ensaio de Imunoadsorção Enzimática , Epitélio Anterior/metabolismo , Epitélio Anterior/patologia , Infecções Oculares Bacterianas/tratamento farmacológico , Infecções Oculares Bacterianas/metabolismo , Infecções Oculares Bacterianas/patologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/fisiologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/patologia , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
20.
Chemosphere ; 254: 126602, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32334241

RESUMO

Water fluoridation is an important public health measure for the control of dental caries. Recent animal studies have shown that low doses of fluoride (F) in the drinking water, similar to those found in public water supplies, increase insulin sensitivity and reduce blood glucose. In the present study we evaluated the effects of low-level F exposure through the drinking water on glucose homeostasis in female NOD mice. Seventy-two 6-week mice were randomly divided into 2 groups according to the concentration of F in the drinking water (0-control, or 10 mg/L) they received for 14 weeks. After the experimental period the blood was collected for analyses of plasma F, glucose and insulin. Liver and gastrocnemius muscle were collected for proteomic analysis. Plasma F concentrations were significantly higher in the F-treated than in the control group. Despite treatment with fluoridated water reduced plasma levels glucose by 20% compared to control, no significant differences were found between the groups for plasma glucose and insulin. In the muscle, treatment with fluoridated water increased the expression of proteins related to muscle contraction, while in the liver, there was an increase in expression of antioxidant proteins and in proteins related to carboxylic acid metabolic process. Remarkably, phosphoenolpyruvate carboxykinase (PEPCK) was found exclusively in the liver of control mice. The reduction in PEPCK, a positive regulator of gluconeogenesis, thus increasing glucose uptake, might be a probable mechanism to explain the anti-diabetic effects of low doses of F, which should be evaluated in further studies.


Assuntos
Poluentes Ambientais/toxicidade , Fluoretos/toxicidade , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Animais , Glicemia/análise , Cárie Dentária , Poluentes Ambientais/metabolismo , Feminino , Fluoretos/metabolismo , Gluconeogênese , Insulina/metabolismo , Resistência à Insulina , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Músculo Esquelético/metabolismo , Proteômica , Testes de Toxicidade
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