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1.
Br J Anaesth ; 123(5): 610-617, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31542162

RESUMO

BACKGROUND: Traumatic brain injury (TBI) is associated with reduced cerebral blood flow and impaired autoregulation after TBI, which may lead to poor outcome. Clinical evidence has implicated neurological injuries and associated neuroinflammation as causes of cardiac dysfunction. Studies on newborn pigs show an association of elevated catecholamines with a sex-dependent impairment of cerebral autoregulation after TBI. One strategy to decrease sympathetic hyperactivity is pharmacological intervention with beta blockade. We tested the hypothesis that propranolol would prevent the impairment of cerebral autoregulation and tissue changes after TBI via inhibition of interleukin-6 (IL-6) upregulation. METHODS: Using newborn pigs of both sexes equipped with a closed cranial window, TBI was induced via lateral fluid percussion injury. Propranolol was administered at 1 h post-TBI. Analyses included cerebral autoregulation (pial artery reactivity) before and 4 h post-TBI, CSF IL-6 analysed (enzyme-linked immunosorbent assay), and histopathology at 4 h post-TBI. RESULTS: Propranolol administration prevented impairment of hypotensive dilation in both male and female newborn pigs after fluid percussion injury, which was paralleled by reduced upregulation of IL-6 in the CSF. Moreover, propranolol prevented neuronal cell death in cornu amonis (CA)1 and CA3 hippocampus equivalently in male and female pigs after TBI. Papaverine-induced dilation was unchanged by TBI and propranolol. CONCLUSIONS: These data indicate that sympathetic hyperactivity noted after TBI can be limited by propranolol administration to result in improved brain outcome post-injury via block of IL-6 upregulation, and this effect is irrespective of sex.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Interleucina-6/antagonistas & inibidores , Propranolol/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Animais Recém-Nascidos , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , Modelos Animais de Doenças , Feminino , Hipocampo/fisiologia , Homeostase/fisiologia , Masculino , Neurônios/efeitos dos fármacos , Suínos , Regulação para Cima/efeitos dos fármacos
2.
J Agric Food Chem ; 67(42): 11616-11626, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31542929

RESUMO

Avocado peel, a byproduct from the avocado pulp industry, is a promising source of polyphenolic compounds. We evaluated the effect of a proanthocyanidin-rich avocado peel polyphenol extract (AvPPE) on the composition and metabolic activity of human fecal microbiota cultured for 24 h in a bioreactor in the presence of high protein (HP) amounts and the effect of the resulting culture supernatants (CSs) on HT-29Glc-/+ and Caco-2 cells. AvPPE decreased the HP-induced production of ammonia, H2S, propionate, and isovalerate and increased that of indole and butyrate. Microbiota composition was marginally affected by HP, whileAvPPE increased the microorganisms/abundance of phylum Actinobacteria, families Coriobacteriaceae and Ruminococcaceae, and genus Faecalibacterium. AvPPE failed to prevent the HP-induced decrease of HT-29Glc-/+ cell viability and energy efficiency but prevented the HP-induced alterations of barrier function in Caco-2 cells. Additionally, the genotoxic effect of the CSs upon HT-29Glc-/+ was attenuated by AvPPE. Therefore, AvPPE may be considered as a promising product for improving colonic homeostasis.


Assuntos
Colo/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Persea/química , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Proantocianidinas/farmacologia , Amônia/metabolismo , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Butiratos/metabolismo , Células CACO-2 , Colo/microbiologia , Dieta Rica em Proteínas , Fezes/microbiologia , Frutas/química , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Proantocianidinas/análise
3.
Food Chem ; 301: 125303, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31387045

RESUMO

The effects of exogenous polyamines treatment on reactive oxygen species (ROS) metabolism in apricot fruits were systematically analyzed through the investigation of their curative and preventive effects on black spot disease. Results showed that 1.5 mM spermine (Spm), 1.5 mM spermidine (Spd) and 10 mM putrescine (Put) treatment significantly inhibited black spot development, additionally, the efficacy of this control was dependent upon the type of polyamines used and concentration level applied. Further studies have shown that exogenous polyamines treatments significantly improved production of O2- and H2O2, and increased the activities and gene expression levels of NADPH oxidase (NOX), super oxide dismutase (SOD), catalase (CAT) ascorbate peroxidase (AXP) and glutathione reductase (GR) in apricot fruit. Increased ascorbic acid (AsA) and reduced glutathione (GSH) content were also observed after exogenous polyamines treatment. These results have revealed that postharvest polyamines treatment effectively enhanced disease resistance through the maintenance of homeostasis in apricot fruits.


Assuntos
Alternaria/patogenicidade , Frutas/efeitos dos fármacos , Doenças das Plantas/microbiologia , Poliaminas/farmacologia , Prunus armeniaca/efeitos dos fármacos , Ascorbato Peroxidases/metabolismo , Catalase/metabolismo , Resistência à Doença/efeitos dos fármacos , Frutas/metabolismo , Frutas/microbiologia , Glutationa/metabolismo , Glutationa Redutase/metabolismo , Homeostase/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Oxirredução , Prunus armeniaca/metabolismo , Prunus armeniaca/microbiologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
4.
Ecotoxicol Environ Saf ; 183: 109499, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31398581

RESUMO

Perfluoroalkyl acids (PFAAs) are anthropogenic compounds used globally in a variety of commercial products. Perfluorononanoic acid (PFNA), a member of PFAAs, is detected in human blood and this has been reported to cause hepatotoxic, immunotoxic, and developmental and testicular toxic effects in laboratory animals. We have recently shown that the acute exposure to PFNA in prepubertal Parkes (P) mice impairs spermatogenesis by inducing oxidative stress and inhibiting testosterone biosynthesis in the testis. The present study was aimed to examine the effect of acute exposure to PFNA in prepubertal P mice on germ cell dynamics and to understand the possible mechanisms of action of this compound on testicular functions. PFNA (2 and 5 mg/kg body weight) was orally administered to male mice for 14 days from postnatal day 25-38. The treatment caused a decrease in overall germ cell transformation. The results also reveal that impairment in testicular functions in treated mice is associated with alterations in cholesterol and glucose homeostasis; further, an inhibition in expressions of growth hormone receptor (GHR), insulin-like growth factor-1 (IGF-1), insulin-like growth factor-1 receptor (IGF-1R), androgen receptor (AR), phosphorylated mammalian target of rapamycin (p-mTOR) and peroxisome proliferator activated receptor α (PPAR α) in the testis is also implicated in this action. The findings thus suggest involvement of multiple factors which altogether contribute to the alterations in spermatogenic process and testosterone production following acute exposure to PFNA in prepubertal mice.


Assuntos
Fluorcarbonetos/toxicidade , Células Germinativas/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Glicemia/metabolismo , Colesterol/sangue , Fluorcarbonetos/administração & dosagem , Células Germinativas/metabolismo , Células Germinativas/patologia , Masculino , Camundongos , Testículo/metabolismo , Testes de Toxicidade Aguda
5.
J Agric Food Chem ; 67(35): 9831-9839, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31407897

RESUMO

Probiotic lactobacilli and their exopolysaccharides (EPS) are thought to modulate mucosal homeostasis; however, their mechanisms remain elusive. Thus, we tried to clarify the role of exopolysaccharides from Lactobacillus plantarum NCU116 (EPS116) in the intestinal mucosal homeostasis. Our results indicated that EPS116 regulated the colon mucosal healing and homeostasis, enhanced the goblet cell differentiation, and promoted the expression of Muc2 gene in vivo and in vitro. Further experiments showed that EPS116 promoted the expression and phosphorylation of transcription factor c-Jun and facilitated its binding to the promoter of Muc2. Moreover, knocking down c-Jun or inhibiting its function in LS 174T cells treated with EPS116 led to decreased expression of Muc2, implying that EPS116 promoted the colonic mucosal homeostasis and Muc2 expression via c-Jun. Therefore, our study uncovered a novel model where EPS116 enhanced colon mucosal homeostasis by controlling the epithelial cell differentiation and c-Jun/Muc2 signaling.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Colo/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Lactobacillus plantarum/química , Mucina-2/metabolismo , Polissacarídeos Bacterianos/farmacologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Animais , Linhagem Celular Tumoral , Colo/citologia , Colo/metabolismo , Colo/fisiopatologia , Homeostase/efeitos dos fármacos , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucina-2/genética , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-jun/genética , Transdução de Sinais/efeitos dos fármacos
6.
Aquat Toxicol ; 215: 105283, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31470336

RESUMO

Recent studies have demonstrated that white sturgeon are more sensitive to acute exposure to Cu than rainbow trout (Oncorhynchus mykiss), especially during early life-stages. However, the physiological mechanisms underlying this difference in sensitivity to Cu is not known. In the present study, we first confirmed the higher sensitivity (lower 96 h LC50 values) of white sturgeon to Cu at three different life stages (larva, swim-up, and juvenile) relative to their counterparts in rainbow trout. We also demonstrated that acute exposure to Cu (50 µg/L for 4.5 h) caused a significantly greater reduction in the rate of waterborne Na uptake in white sturgeon relative to that in rainbow trout across all three life-stages. In agreement with this observation, we also found that acute exposure to Cu (20 µg/L for 48 h) elicits a significantly greater decrease in whole body Na level in all life stages of white sturgeon compared to rainbow trout. In contrast, white sturgeon demonstrated a higher or similar level of Cu body burden relative to rainbow trout during acute Cu exposure (20 µg/L for 24 h), thereby indicating that Cu bioaccumulation is not a good indicator of its toxicity in these species. Overall, our study demonstrated that the differences in sensitivity to acute Cu exposure between white sturgeon and rainbow trout can be explained on the basis of differential effects of Cu on Na homeostasis.


Assuntos
Cobre/toxicidade , Peixes/fisiologia , Homeostase/efeitos dos fármacos , Oncorhynchus mykiss/fisiologia , Sódio/metabolismo , Poluentes Químicos da Água/toxicidade , Animais , Exposição Ambiental , Dose Letal Mediana , Oncorhynchus mykiss/sangue , ATPases Translocadoras de Prótons/metabolismo , Sódio/sangue , ATPase Trocadora de Sódio-Potássio/metabolismo , Testes de Toxicidade Aguda , Qualidade da Água
7.
BMC Plant Biol ; 19(1): 323, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319801

RESUMO

BACKGROUND: Exogenous 5-aminolevulinic acid (ALA) positively regulates plants chlorophyll synthesis and protects them against environmental stresses, although the protection mechanism is not fully clear. Here, we explored the effects of ALA on chlorophyll synthesis in tomato plants, which are sensitive to low temperature. We also examined the roles of the glutathione S-transferase (GSTU43) gene, which is involved in ALA-induced tolerance to oxidation stress and regulation of chlorophyll synthesis under low temperature. RESULTS: Exogenous ALA alleviated low temperature caused chlorophyll synthesis obstacle of uroporphyrinogen III (UROIII) conversion to protoporphyrin IX (Proto IX), and enhanced the production of chlorophyll and its precursors, including endogenous ALA, Proto IX, Mg-protoporphyrin IX (Mg-proto IX), and protochlorophyll (Pchl), under low temperature in tomato leaves. However, ALA did not regulate chlorophyll synthesis at the level of transcription. Notably, ALA up-regulated the GSTU43 gene and protein expression and increased GST activity. Silencing of GSTU43 with virus-induced gene silencing reduced the activities of GST, superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase, and increased the membrane lipid peroxidation; while fed with ALA significant increased all these antioxidase activities and antioxidant contents, and alleviated the membrane damage. CONCLUSIONS: ALA triggered GST activity encoded by GSTU43, and increased tomato tolerance to low temperature-induced oxidative stress, perhaps with the assistance of ascorbate- and/or a glutathione-regenerating cycles, and actively regulated the plant redox homeostasis. This latter effect reduced the degree of membrane lipid peroxidation, which was essential for the coordinated synthesis of chlorophyll.


Assuntos
Ácido Aminolevulínico/metabolismo , Clorofila/metabolismo , Genes de Plantas/fisiologia , Glutationa Transferase/metabolismo , Lycopersicon esculentum/genética , Proteínas de Plantas/metabolismo , Ácido Aminolevulínico/farmacologia , Resposta ao Choque Frio , Glutationa Transferase/genética , Homeostase/efeitos dos fármacos , Peroxidação de Lipídeos , Lycopersicon esculentum/efeitos dos fármacos , Lycopersicon esculentum/metabolismo , Lycopersicon esculentum/fisiologia , Oxirredução/efeitos dos fármacos , Proteínas de Plantas/genética
8.
Environ Pollut ; 253: 889-898, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349198

RESUMO

Atrazine (ATR), one of the most widely used pesticides in agricultural production, are gradually concerned due to potential ecosystem and health risks. Further, the induction of ATR nephrotoxicity and detoxification response is still unknown. To evaluate ATR-induced nephrotoxicity, quails were treated with 0, 50, 250 or 500 mg/kg ATR by gavage administration for 45 days. Histopathology indicated that ATR exposure caused renal tubular epithelial cell swelling and endoplasmic reticulum degeneration, suggesting that ATR exposure causes renal impairment even renal diseases. Notably, ATR interfered cytochrome P450 system (CYP450s) homeostasis by enhancing contents or activities of CYP450s (total CYP450, Cyt b5, AH, APND, NCR and ERND) and the expression of CYP450 isoforms (CYP1A, CYP1B, CYP2C and CYP3A). ATR triggered phase II detoxifying reaction, reflected by the elevated GSH level, GST activity and the up-regulation of GST isoforms (GSTa, GSTa3 and GSTt1) and GSH synthetase (GCLC). Moreover, ABC transporters were activated to expel ATR from the body by increasing expression of MRP1 and P-GP gene. Accompanying these alterations, the nuclear receptors (AHR, CAR and PXR) were activated by ATR in a dose-dependent manner. Analysis results of present study demonstrated that the induction of phase II detoxifying enzyme system and ABC transporters could be modulated by nuclear receptors response and CYP450s disturbance in low-dose ATR-treated quail. In conclusion, all data suggested that nuclear receptors AHR-mediated detoxification pathway was involved in ATR-induced nephrotoxicity. These results provided new evidence about the nephrotoxic effects of ATR on the response of biotransformation and detoxification system.


Assuntos
Atrazina/toxicidade , Coturnix/fisiologia , Receptores de Hidrocarboneto Arílico/metabolismo , Xenobióticos/toxicidade , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Homeostase/efeitos dos fármacos , Inativação Metabólica , Codorniz , Receptores Citoplasmáticos e Nucleares/metabolismo , Xenobióticos/metabolismo
9.
Gen Physiol Biophys ; 38(4): 353-363, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31241042

RESUMO

Intracellular calcium concentration ([Ca2+]i) may have an important role in the development of chemoresistance, which is an essential problem in cancer chemotherapy. Cisplatin (DDP), which modulates the intracellular calcium concentration by different mechanisms, is an antineoplastic agent with high success rate in cancer therapies. We investigated the regulatory role of [Ca2+] in cisplatin resistance in epithelial ovarian cancer cell line, in MDAH-2774, and its chemoresistant subclone MDAH-2774/DDP. The measurement of [Ca2+]i using fluorescence microscope, and flow cytometry revealed that the amount of intracellular calcium decreased in cisplatin resistant cells compared to the amounts in parental cells. mRNA expression profiles of calcium homeostasis-associated major genes (IP3R1/2/3, RYR1/2, SERCA1/2/3, NCX1/2/3, PMCA1/2/3, and PMCA4) decreased in cisplatin resistant cell line in comparison to the expression profiles in parental cells. Owing to the changes in the expression of genes involved in calcium regulation, these results show, drug resistance may be prevented by introducing a new perspective on the use of inhibitors and activators of these genes, and thus of cytostatic treatment strategies, due to changes in the expression of genes involved in calcium regulation.


Assuntos
Antineoplásicos/farmacologia , Cálcio/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Homeostase , Neoplasias Ovarianas/metabolismo , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Homeostase/efeitos dos fármacos , Humanos , Neoplasias Ovarianas/tratamento farmacológico
10.
J Agric Food Chem ; 67(27): 7694-7705, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31250637

RESUMO

Liver plays a central role in modulating blood glucose level. Our most recent findings suggested that supplementation with microbiota metabolite sodium butyrate (NaB) could ameliorate progression of type 2 diabetes mellitus (T2DM) and decrease blood HbA1c in db/db mice. To further investigate the role of butyrate in homeostasis of blood glucose and glycogen metabolism, we carried out the present study. In db/db mice, we found significant hypertrophy and steatosis in hepatic lobules accompanied by reduced glycogen storage, and expression of GPR43 was significantly decreased by 59.38 ± 3.33%; NaB administration significantly increased NaB receptor G-protein coupled receptor 43 (GPR43) level and increased glycogen storage in both mice and HepG2 cells. Glucose transporter 2 (GLUT2) and sodium-glucose cotransporter 1 (SGLT1) on cell membrane were upregulated by NaB. The activation of intracellular signaling Protein kinase B (PKB), also known as AKT, was inhibited while glycogen synthase kinase 3 (GSK3) was activated by NaB in both in vivo and in vitro studies. The present study demonstrated that microbiota metabolite NaB possessed beneficial effects on preserving blood glucose homeostasis by promoting glycogen metabolism in liver cells, and the GPR43-AKT-GSK3 signaling pathway should contribute to this effect.


Assuntos
Ácido Butírico/administração & dosagem , Diabetes Mellitus Tipo 2/metabolismo , Glicogênio Hepático/metabolismo , Animais , Glicemia/análise , Ácido Butírico/metabolismo , Imunofluorescência , Microbioma Gastrointestinal/fisiologia , Transportador de Glucose Tipo 2/análise , Hemoglobina A Glicada/análise , Quinase 3 da Glicogênio Sintase/metabolismo , Células Hep G2 , Homeostase/efeitos dos fármacos , Humanos , Fígado/química , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Acoplados a Proteínas-G/análise , Transdução de Sinais/efeitos dos fármacos , Transportador 1 de Glucose-Sódio/análise
11.
Nat Commun ; 10(1): 2701, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221965

RESUMO

One of the biggest hurdles for the development of metabolism-targeted therapies is to identify the responsive tumor subsets. However, the metabolic vulnerabilities for most human cancers remain unclear. Establishing the link between metabolic signatures and the oncogenic alterations of receptor tyrosine kinases (RTK), the most well-defined cancer genotypes, may precisely direct metabolic intervention to a broad patient population. By integrating metabolomics and transcriptomics, we herein show that oncogenic RTK activation causes distinct metabolic preference. Specifically, EGFR activation branches glycolysis to the serine synthesis for nucleotide biosynthesis and redox homeostasis, whereas FGFR activation recycles lactate to fuel oxidative phosphorylation for energy generation. Genetic alterations of EGFR and FGFR stratify the responsive tumors to pharmacological inhibitors that target serine synthesis and lactate fluxes, respectively. Together, this study provides the molecular link between cancer genotypes and metabolic dependency, providing basis for patient stratification in metabolism-targeted therapies.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Mutação com Ganho de Função , Perfilação da Expressão Gênica/métodos , Glicólise/efeitos dos fármacos , Glicólise/genética , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Metabolômica/métodos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Seleção de Pacientes , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Serina/biossíntese , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Inorg Chem ; 58(20): 13528-13545, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31247859

RESUMO

The indispensable requirement for metals in life processes has led to the evolution of sophisticated mechanisms that allow organisms to maintain dynamic equilibria of these ions. This dynamic control of the level, speciation, and availability of a variety of metal ions allows organisms to sustain biological processes while avoiding toxicity. When functioning properly, these mechanisms allow cells to return to their metal homeostatic set points following shifts in the metal availability or other stressors. These periods of transition, when cells are in a state of flux in which they work to regain homeostasis, present windows of opportunity to pharmacologically manipulate targets associated with metal-trafficking pathways in ways that could either facilitate a return to homeostasis and the recovery of cellular function or further push cells outside of homeostasis and into cellular distress. The purpose of this Viewpoint is to highlight emerging opportunities for chemists and chemical biologists to develop compounds to manipulate metal-trafficking processes for therapeutic benefit.


Assuntos
Doenças Metabólicas/tratamento farmacológico , Metais/metabolismo , Neoplasias/tratamento farmacológico , Compostos Orgânicos/farmacologia , Homeostase/efeitos dos fármacos , Humanos , Doenças Metabólicas/metabolismo , Neoplasias/metabolismo
13.
J Dairy Sci ; 102(7): 6056-6064, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079910

RESUMO

Hypocalcemia is a common postpartum condition in dairy cows, which negatively affects health and production. Intravenous Ca infusions are commonly included in calving protocols to prevent or mitigate the effect of hypocalcemia in multiparous cows. Thus, we sought to contrast the effect of intravenous Ca infusion against voluntary oral Ca intake on Ca metabolism. Serum total Ca (tCa) and whole-blood ionized Ca (iCa) were monitored in 24 multiparous Holstein cows after parturition. Precalving diets were formulated with a positive dietary cation-anion difference of 172 mEq/kg of DM and contained 4.1 g of Ca/kg of DM. At parturition, cows were blocked by calving sequence and calcemic status as either normocalcemic (cutoff threshold of iCa ≥1.10 mmol/L) or hypocalcemic (cutoff threshold of iCa <1.10 mmol/L). Cows in each block were randomly assigned to 1 of 2 treatments: either an oral source of Ca (Ca-Oral; n = 12) or an intravenous source of Ca (Ca-IV; n = 12). Cows in the Ca-Oral group were offered a 20-L commercial Ca suspension (48 g of Ca) for voluntary consumption. The supplement contained Ca carbonate, Ca formate, Ca propionate, and other minerals and vitamins (Farm-O-San Reviva, Trouw Nutrition, Amersfoort, the Netherlands). Cows in the Ca-IV group received a 450-mL intravenous Ca solution (13 g of Ca) that contained 298 mg/mL of Ca gluconate, 33 mg/mL of magnesium chloride, and 82 mg/mL of boric acid (AmosCAL, Kommer-Biopharm BV, Heiloo, the Netherlands). Both treatments were initiated within 25 ± 10 min after calving. The oral Ca suspension was offered to cows in a 25-L bucket and was available for 10 min. All cows in the Ca-Oral group voluntarily consumed the entire 20 L of the Ca suspension within 5 min. Blood samples for Ca analyses were collected at 0 (before treatment initiation), 1, 3, 10, and 18 h relative to treatment, and at 0700 and 1900 h for the next 2 consecutive days, to represent the 24-, 36-, 48-, and 60-h sampling time points. In Ca-IV cows, both iCa and tCa concentrations peaked at 1 h (1.54 mmol/L for iCa and 2.85 mmol/L for tCa) and declined to a nadir at 24 h following treatment initiation (0.94 mmol/L for iCa and 1.74 mmol/L for tCa). Although whole-blood iCa and serum tCa were higher at 1 and 3 h in Ca-IV cows, concentrations of iCa were greater for Ca-Oral cows at 18, 24, and 36 h and for tCa at 24 and 36 h. Our data indicate that intravenous Ca infusion immediately induced a state of hypercalcemia followed by lower whole-blood iCa and serum tCa concentrations 24 h later compared with oral Ca.


Assuntos
Cálcio/administração & dosagem , Doenças dos Bovinos/prevenção & controle , Homeostase/efeitos dos fármacos , Hipocalcemia/veterinária , Administração Intravenosa/veterinária , Animais , Cálcio/sangue , Cálcio na Dieta/administração & dosagem , Bovinos , Doenças dos Bovinos/sangue , Dieta/veterinária , Feminino , Hipocalcemia/prevenção & controle , Lactação , Países Baixos , Parto , Gravidez , Distribuição Aleatória
14.
Chemosphere ; 229: 618-630, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102917

RESUMO

Bisphenol-A (BPA) is a representative exogenous endocrine disruptor, which is extensively composed in plastic products. Due to the capability of passing through the blood-brain barrier, evidence has linked BPA exposure with multiple neuropsychological dysfunctions, neurobehavioral disorders and neurodegenerative diseases. However, the underlying mechanism by which BPA induces neurodegeneration still remains unclear. Our study used human embryonic stem cells-derived human cortical neurons (hCNs) as a cellular model to investigate the adverse neurotoxic effects of BPA. hCNs were treated with 0, 0.1, 1 and 10 µM BPA for 14 days. Impacts of BPA exposure on cell morphology, cell viability and neural marker (MAP2) were measured for evaluating the neurodegeneration. The intracellular calcium homeostasis, reactive oxygen species (ROS) generation and organelle functions were also taken into consideration. Results revealed that chronic exposure of BPA damaged the neural morphology, induced neuronal apoptosis and decreased MAP2 expression at the level of both transcription and translation. The intracellular calcium levels were elevated in hCNs after BPA exposure through NMDARs-nNOS-PSD-95 mediating. Meanwhile, BPA led to oxidative stress by raising the ROS generation and attenuating the antioxidant defense in hCNs. Furthermore, BPA triggered ER stress and increased cytochrome c release by impairing the mitochondrial function. Ultimately, BPA triggered the cell apoptosis by regulating Bcl-2 family and caspase-dependent signaling pathway. Taken together, BPA exerted neurotoxic effects on hCNs by eliciting apoptosis, which might due to the intracellular calcium homeostasis perturbation and cell organellar dysfunction.


Assuntos
Compostos Benzidrílicos/toxicidade , Cálcio/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Neurônios/efeitos dos fármacos , Fenóis/toxicidade , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Proteína 4 Homóloga a Disks-Large/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
15.
Int J Mol Sci ; 20(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075962

RESUMO

This study focuses on the effect of honokiol (HON) on glucose homeostasis, insulin resistance, dyslipidemia, hepatic steatosis, and inflammation in type 2 diabetic db/db mice. Male C57BL/KsJ-db/db mice were fed a normal diet with or without HON (0.02%, w/w) or pioglitazone (PIO, anti-diabetic agent, 0.01%, w/w) for 5 weeks. Blood biomarker, tissue morphology and enzymatic and genetic parameters were determined. PIO significantly decreased food intake, fasting blood glucose, and glycosylated hemoglobin (HbA1c) levels, but markedly increased body weight, adipose tissue weight, and plasma leptin levels. HON did not significantly affect food intake, body weight, or levels of plasma leptin and blood glucose. However, HON led to significant decreases in adipose tissue weight, plasma insulin, blood HbA1c and HOMA-IR levels and improved glucose tolerance. The anti-diabetic and anti-adiposity effects of HON were partially related to the inhibition of gluconeogenic enzymes and their mRNA expression in the liver; and the inhibition of lipogenic enzymes in adipose tissue, respectively. Unlike PIO, HON did not affect dyslipidemia, but ameliorated hepatic steatosis by inhibiting hepatic lipogenic enzymes activity. Moreover, HON exhibited anti-inflammatory effects similar to PIO. These results suggest that HON can protect against type 2 diabetes by improving insulin resistance, glucose and lipid metabolism, and inflammation.


Assuntos
Compostos de Bifenilo/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Inflamação/tratamento farmacológico , Resistência à Insulina , Lignanas/uso terapêutico , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Compostos de Bifenilo/farmacologia , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Dislipidemias/sangue , Dislipidemias/complicações , Fígado Gorduroso/sangue , Fígado Gorduroso/complicações , Fígado Gorduroso/patologia , Comportamento Alimentar/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Leptina/sangue , Lignanas/farmacologia , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos
16.
Cell Host Microbe ; 25(5): 668-680.e7, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071294

RESUMO

Sphingolipids are structural membrane components and important eukaryotic signaling molecules. Sphingolipids regulate inflammation and immunity and were recently identified as the most differentially abundant metabolite in stool from inflammatory bowel disease (IBD) patients. Commensal bacteria from the Bacteroidetes phylum also produce sphingolipids, but the impact of these metabolites on host pathways is largely uncharacterized. To determine whether bacterial sphingolipids modulate intestinal health, we colonized germ-free mice with a sphingolipid-deficient Bacteroides thetaiotaomicron strain. A lack of Bacteroides-derived sphingolipids resulted in intestinal inflammation and altered host ceramide pools in mice. Using lipidomic analysis, we described a sphingolipid biosynthesis pathway and revealed a variety of Bacteroides-derived sphingolipids including ceramide phosphoinositol and deoxy-sphingolipids. Annotating Bacteroides sphingolipids in an IBD metabolomic dataset revealed lower abundances in IBD and negative correlations with inflammation and host sphingolipid production. These data highlight the role of bacterial sphingolipids in maintaining homeostasis and symbiosis in the gut.


Assuntos
Bacteroides thetaiotaomicron/crescimento & desenvolvimento , Bacteroides thetaiotaomicron/metabolismo , Interações entre Hospedeiro e Microrganismos , Intestinos/microbiologia , Intestinos/fisiologia , Esfingolipídeos/metabolismo , Simbiose/efeitos dos fármacos , Animais , Vida Livre de Germes , Homeostase/efeitos dos fármacos , Doenças Inflamatórias Intestinais/prevenção & controle , Intestinos/efeitos dos fármacos , Camundongos
17.
Mol Biol (Mosk) ; 53(2): 200-217, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31099771

RESUMO

Heat shock proteins (HSPs) are important factors of protein homeostasis and possess chaperone properties, providing for a folding and intracellular transport of proteins and facilitating the recovery or utilization of proteins partly denatured on exposure to various stress factors. Proteins of the Hsp70 family are the most universal molecular chaperones and interact with the greatest number of protein substrates. Several proteins of the Hsp70 family are released into the extracellular space, where they play an important role in intercellular communications and act as alarmins, or "danger signals," to modulate the immune response. The secreted Hsp70 can additionally act as an effective neuroprotector, increasing the survival of neurons in various proteinopathies, as has been demonstrated in Alzheimer's and Parkinson's disease models. In this regard, recombinant Hsp70 and inducers of endogenous Hsp70 synthesis may be considered as candidate therapeutics with immune-modulating and neuroprotective properties.Heat shock proteins (HSPs) are important factors of protein homeostasis and possess chaperone properties, providing for a folding and intracellular transport of proteins and facilitating the recovery or utilization of proteins partly denatured on exposure to various stress factors. Proteins of the Hsp70 family are the most universal molecular chaperones and interact with the greatest number of protein substrates. Several proteins of the Hsp70 family are released into the extracellular space, where they play an important role in intercellular communications and act as alarmins, or "danger signals," to modulate the immune response. The secreted Hsp70 can additionally act as an effective neuroprotector, increasing the survival of neurons in various proteinopathies, as has been demonstrated in Alzheimer's and Parkinson's disease models. In this regard, recombinant Hsp70 and inducers of endogenous Hsp70 synthesis may be considered as candidate therapeutics with immune-modulating and neuroprotective properties.


Assuntos
Citocinas/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Homeostase , Proteostase , Citocinas/imunologia , Citocinas/farmacologia , Citocinas/uso terapêutico , Proteínas de Choque Térmico HSP70/imunologia , Proteínas de Choque Térmico HSP70/farmacologia , Proteínas de Choque Térmico HSP70/uso terapêutico , Homeostase/efeitos dos fármacos , Humanos , Proteostase/efeitos dos fármacos
18.
Ecotoxicol Environ Saf ; 179: 290-300, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31071567

RESUMO

Epidemiological and experimental studies have indicated that ambient fine particulate matter (PM2.5) exposure is associated with the occurrence and development of metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM). However, the mechanism is not clear yet, and there are few studies to explore the possible prevention measure. In this study, C57BL/6 and db/db mice were exposed to concentrated PM2.5 or filtered air using Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) for 12 weeks. From week 11, some of the mice were assigned to receive a subcutaneous injection of AMPK activator (AICAR). Lipid metabolism, glucose tolerance, insulin sensitivity and energy homeostasis were measured. Meanwhile, the respiratory, systemic and visceral fat inflammatory response was detected. The results showed that PM2.5 exposure induced the impairments of glucose tolerance, insulin resistance, lipid metabolism disorders and disturbances of energy metabolism in both C57BL/6 and db/db mice. These impairments might be consistent with the increased respiratory, circulating and visceral adipose tissue (VAT) inflammatory response, which was characterized by the release of IL-6 and TNF-α in lung, serum and VAT. More importantly, AICAR administration led to the significant enhancement of energy metabolism, elevation of AMPK as well as the decreased IL-6 and TNF-α in VAT of PM2.5-exposed mice, which suggesting that AMPK activation might attenuate the inflammatory responses in VAT via the inhibition of MAPKs and NFκB. The study indicated that exposure to ambient PM2.5 under the concentration which is often seen in some developing countries could induce the occurrence of metabolic disorders in normal healthy mice and exacerbate metabolic disorders in diabetic mice. The adverse impacts of PM2.5 on insulin sensitivity, energy homeostasis, lipid metabolism and inflammatory response were associated with AMPK inhibition. AMPK activation might inhibit PM2.5-induced metabolic disorders via inhibition of inflammatory cytokines release. These findings suggested that AMPK activation is a potential therapy to prevent some of the metabolic disorders attributable to air pollution exposure.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Poluição do Ar/efeitos adversos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 2/induzido quimicamente , Metabolismo Energético/efeitos dos fármacos , Obesidade/induzido quimicamente , Material Particulado/toxicidade , Animais , China , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Homeostase/efeitos dos fármacos , Exposição por Inalação , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Tamanho da Partícula , Fator de Necrose Tumoral alfa/metabolismo
19.
Nat Med ; 25(4): 690-700, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30936544

RESUMO

Epithelial barrier loss is a driver of intestinal and systemic diseases. Myosin light chain kinase (MLCK) is a key effector of barrier dysfunction and a potential therapeutic target, but enzymatic inhibition has unacceptable toxicity. Here, we show that a unique domain within the MLCK splice variant MLCK1 directs perijunctional actomyosin ring (PAMR) recruitment. Using the domain structure and multiple screens, we identify a domain-binding small molecule (divertin) that blocks MLCK1 recruitment without inhibiting enzymatic function. Divertin blocks acute, tumor necrosis factor (TNF)-induced MLCK1 recruitment as well as downstream myosin light chain (MLC) phosphorylation, barrier loss, and diarrhea in vitro and in vivo. Divertin corrects barrier dysfunction and prevents disease development and progression in experimental inflammatory bowel disease. Beyond applications of divertin in gastrointestinal disease, this general approach to enzymatic inhibition by preventing access to specific subcellular sites provides a new paradigm for safely and precisely targeting individual properties of enzymes with multiple functions.


Assuntos
Homeostase , Mucosa Intestinal/metabolismo , Espaço Intracelular/enzimologia , Quinase de Cadeia Leve de Miosina/metabolismo , Actomiosina/metabolismo , Animais , Células CACO-2 , Doença Crônica , Homeostase/efeitos dos fármacos , Humanos , Inflamação/patologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Jejuno/patologia , Camundongos , Cadeias Leves de Miosina/metabolismo , Quinase de Cadeia Leve de Miosina/química , Fosforilação/efeitos dos fármacos , Domínios Proteicos , Bibliotecas de Moléculas Pequenas/farmacologia , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
20.
Int J Mol Sci ; 20(8)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995806

RESUMO

The intestinal epithelium constitutes an indispensable single-layered barrier to protect the body from invading pathogens, antigens or toxins. At the same time, beneficial nutrients and water have to be absorbed by the epithelium. To prevent development of intestinal inflammation or tumour formation, intestinal homeostasis has to be tightly controlled and therefore a strict balance between cell death and proliferation has to be maintained. The proinflammatory cytokine tumour necrosis factor alpha (TNFα) was shown to play a striking role for the regulation of this balance in the gut. Depending on the cellular conditions, on the one hand TNFα is able to mediate cell survival by activating NFκB signalling. On the other hand, TNFα might trigger cell death, in particular caspase-dependent apoptosis but also caspase-independent programmed necrosis. By regulating these cell death and survival mechanisms, TNFα exerts a variety of beneficial functions in the intestine. However, TNFα signalling is also supposed to play a critical role for the pathogenesis of inflammatory bowel disease (IBD), infectious diseases, intestinal wound healing and tumour formation. Here we review the literature about the physiological and pathophysiological role of TNFα signalling for the maintenance of intestinal homeostasis and the benefits and difficulties of anti-TNFα treatment during IBD.


Assuntos
Gastroenteropatias/imunologia , Homeostase , Intestinos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Anticorpos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/imunologia , Infecções Bacterianas/patologia , Descoberta de Drogas , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/patologia , Homeostase/efeitos dos fármacos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Intestinos/efeitos dos fármacos , Intestinos/patologia , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Viroses/tratamento farmacológico , Viroses/imunologia , Viroses/patologia
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