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1.
Int J Nanomedicine ; 16: 4559-4577, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267513

RESUMO

Purpose: Reactive oxygen species (ROS) are a group of signaling biomolecules that play important roles in the cell cycle. When intracellular ROS homeostasis is disrupted, it can induce cellular necrosis and apoptosis. It is desirable to effectively cascade-amplifying ROS generation and weaken antioxidant defense for disrupting ROS homeostasis in tumor microenvironment (TME), which has been recognized as a novel and ideal antitumor strategy. Multifunctional nanozymes are highly promising agents for ROS-mediated therapy. Methods: This study constructed a novel theranostic nanoagent based on PEG@Cu2-xS@Ce6 nanozymes (PCCNs) through a facile one-step hydrothermal method. We systematically investigated the photodynamic therapy (PDT)/photothermal therapy (PTT) properties, catalytic therapy (CTT) and glutathione (GSH) depletion activities of PCCNs, antitumor efficacy induced by PCCNs in vitro and in vivo. Results: PCCNs generate singlet oxygen (1O2) with laser (660 nm) irradiation and use catalytic reactions to produce hydroxyl radical (•OH). Moreover, PCCNs show the high photothermal performance under NIR II 1064-nm laser irradiation, which can enhance CTT/PDT efficiencies to increase ROS generation. The properties of O2 evolution and GSH consumption of PCCNs achieve hypoxia-relieved PDT and destroy cellular antioxidant defense system respectively. The excellent antitumor efficacy in 4T1 tumor-bearing mice of PCCNs is achieved through disrupting ROS homeostasis-involved therapy under the guidance of photothermal/photoacoustic imaging. Conclusion: Our study provides a proof of concept of "all-in-one" nanozymes to eliminate tumors via disrupting ROS homeostasis.


Assuntos
Homeostase/efeitos dos fármacos , Hipertermia Induzida/métodos , Raios Infravermelhos , Nanomedicina/métodos , Fotoquimioterapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Animais , Catálise , Linhagem Celular Tumoral , Cério/química , Cobre/química , Glutationa/metabolismo , Humanos , Camundongos , Polietilenoglicóis/química , Sulfetos/química
2.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199317

RESUMO

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Antígenos CD/metabolismo , Compostos Benzidrílicos/farmacologia , Biópsia , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Glucose/metabolismo , Glucosídeos/farmacologia , Homeostase/efeitos dos fármacos , Resistência à Insulina , Lactosilceramidas/metabolismo , Lipidômica , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismo
3.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204139

RESUMO

The prohibitin (PHB)-binding compound fluorizoline as well as PHB-downregulation activate the integrated stress response (ISR) in HEK293T and U2OS human cell lines. This activation is denoted by phosphorylation of eIF2α and increases in ATF4, ATF3, and CHOP protein levels. The blockage of the activation of the ISR by overexpression of GRP78, as well as an increase in IRE1 activity, indicate the presence of ER stress after fluorizoline treatment. The inhibition of the ER stress response in HEK293T and U2OS led to increased sensitivity to fluorizoline-induced apoptosis, indicating a pro-survival role of this pathway after fluorizoline treatment in these cell lines. Fluorizoline induced an increase in calcium concentration in the cytosol and the mitochondria. Finally, two different calcium chelators reduced fluorizoline-induced apoptosis in U2OS cells. Thus, we have found that fluorizoline causes increased ER stress and activation of the integrated stress response, which in HEK293T and U2OS cells are protective against fluorizoline-induced apoptosis.


Assuntos
Apoptose , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Tiazóis/farmacologia , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células HEK293 , Homeostase/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Molecules ; 26(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070111

RESUMO

Cephalotaxine (CET) is a natural alkaloid with potent antileukemia effects. However, its underlying molecular mechanism has not been well understood. In this study, we verified that CET significantly inhibited the viability of various leukemia cells, including HL-60, NB4, Jurkat, K562, Raji and MOLT-4. RNA-sequencing and bioinformatics analysis revealed that CET causes mitochondrial function change. Mechanism research indicated that CET activated the mitochondrial apoptosis pathway by reducing the mitochondrial membrane potential, downregulating anti-apoptotic Bcl-2 protein and upregulating pro-apoptotic Bak protein. In addition, the autophagy signaling pathway was highly enriched by RNA-seq analysis. Then, we found that CET blocked the fluorescence colocation of MitoTracker Green and LysoTracker Red and upregulated the level of LC3-II and p62, which indicated that autophagy flow was impaired. Further results demonstrated that CET could impair lysosomal acidification and block autophagy flow. Finally, inhibiting autophagy flow could aggravate apoptosis of HL-60 cells induced by CET. In summary, this study demonstrated that CET exerted antileukemia effects through activation of the mitochondria-dependent pathway and by impairing autophagy flow. Our research provides new insights into the molecular mechanisms of CET in the treatment of leukemia.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Mepesuccinato de Omacetaxina/farmacologia , Leucemia/patologia , Mitocôndrias/metabolismo , Apoptose/genética , Autofagia/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Mepesuccinato de Omacetaxina/química , Humanos , Leucemia/genética , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
5.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071169

RESUMO

Polygodial is a "hot" peppery-tasting sesquiterpenoid that was first described for its anti-feedant activity against African armyworms. Using the haploid deletion mutant library of Saccharomyces cerevisiae, a genome-wide mutant screen was performed to shed more light on polygodial's antifungal mechanism of action. We identified 66 deletion strains that were hypersensitive and 47 that were highly resistant to polygodial treatment. Among the hypersensitive strains, an enrichment was found for genes required for vacuolar acidification, amino acid biosynthesis, nucleosome mobilization, the transcription mediator complex, autophagy and vesicular trafficking, while the resistant strains were enriched for genes encoding cytoskeleton-binding proteins, ribosomal proteins, mitochondrial matrix proteins, components of the heme activator protein (HAP) complex, and known regulators of the target of rapamycin complex 1 (TORC1) signaling. WE confirm that polygodial triggers a dose-dependent vacuolar alkalinization and that it increases Ca2+ influx and inhibits glucose-induced Ca2+ signaling. Moreover, we provide evidence suggesting that TORC1 signaling and its protective agent ubiquitin play a central role in polygodial resistance, suggesting that they can be targeted by polygodial either directly or via altered Ca2+ homeostasis.


Assuntos
Antifúngicos/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo , Antifúngicos/química , Cálcio , Farmacorresistência Fúngica/genética , Homeostase/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Testes de Sensibilidade Microbiana , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Nucleossomos , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Transdução de Sinais , ATPases Vacuolares Próton-Translocadoras
6.
Ecotoxicol Environ Saf ; 221: 112429, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34147864

RESUMO

Rare earth elements (REEs) are emerging as a serious threat to ecological safety due to their increasing accumulation in environments. The accumulation of REEs in environments has significantly increased its accumulation in the leaves of edible plants. However, the accumulation pathway of REEs in the leaves of edible plants are still unknown. In this study, lanthanum [La(III), a widely used and accumulated REE] and four edible plants (soybean, lettuce, pakchoi, and celery) with short growth cycles were selected as research objects. By using interdisciplinary research techniques, we found that low-dose La(III) activated endocytosis (mainly the clathrin-mediated endocytosis) in the leaf cells of four edible plants, which provided an accumulation pathway for low-dose La in the leaf cells of these edible plants. The accumulation of La in the leaf cells was positively correlated with the intensity of endocytosis, while the intensity of endocytosis was negatively correlated with the density of leaf trichomes. In addition to the accumulation of La, low-dose La(III) also brought other risks. For example, the harmful element (Pb) can also be accumulated in the leaf cells via La(III)-activated endocytosis; the homeostasis of the essential elements (K, Ca, Fe, Mg) was disrupted, although the chlorophyll synthesis and the growth of these leaf cells were accelerated; and the expression of stress response genes (GmNAC20, GmNAC11) in soybean leaves was increased. These results provided an insight to further analyze the toxicity and mechanism of REEs in plants, and sounded the alarm for the application of REEs in agriculture.


Assuntos
Endocitose/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Lantânio/metabolismo , Lantânio/toxicidade , Chumbo/metabolismo , Folhas de Planta/efeitos dos fármacos , Plantas Comestíveis/efeitos dos fármacos , Agricultura , Metais Terras Raras/metabolismo , Metais Terras Raras/toxicidade , Folhas de Planta/metabolismo , Plantas Comestíveis/metabolismo , Oligoelementos/metabolismo
7.
Ecotoxicol Environ Saf ; 220: 112394, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34091186

RESUMO

Arsenic (As) and antimony (Sb) are known as an environmental contaminant with cardiotoxicity properties. The endoplasmic reticulum (ER) is the largest calcium reservoir in the cell, and its calcium homeostasis disorder plays a vital role in endoplasmic reticulum stress (ERS) and apoptosis. The objective of this study was to investigate whether As and Sb induced apoptosis via endoplasmic reticulum stress (ERS) linked to calcium homeostasis disturbance. In this study, thirty-two adult mice were gavage-fed daily with As2O3 (4 mg/kg), SbCl3 (15 mg/kg) and co-treat with SbCl3 (15 mg/kg) and As2O3 (4 mg/kg) daily for 60 days. It was observed that As or/and Sb caused histopathological lesions and ER expansion of the heart. Meanwhile, the gene expression of ER Ca2+ release channels (RyR2 and IP3R) and calmodulin-dependent protein kinase II (CaMKII) increased while the levels of mRNA and protein of ER Ca2+ uptake channel (SERCA2) downregulated significantly compared to the controls. Then, As or/and Sb induced ERS and triggered the ER apoptotic pathway by activating unfolded protein response (UPR)-associated genes ((PERK, ATF6, IRE1, XBP1, JNK, GRP78), and apoptosis-related genes (Caspase12, Caspase3, p53, CHOP). Above indicators in As + Sb group became more severe than that of As group and Sb group. Overall, our results proved that the cardiotoxicity caused by As or/and Sb might be concerning disturbing calcium homeostasis, which induced apoptosis through the ERS pathway.


Assuntos
Antimônio/toxicidade , Arsênio/toxicidade , Cálcio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Coração/efeitos dos fármacos , Animais , Antimônio/metabolismo , Apoptose , Arsênio/metabolismo , Canais de Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiotoxicidade/metabolismo , Cardiotoxinas , Caspase 3/metabolismo , Morte Celular , Regulação para Baixo , Retículo Endoplasmático/metabolismo , Poluentes Ambientais/toxicidade , Homeostase/efeitos dos fármacos , Masculino , Metais Pesados/toxicidade , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Resposta a Proteínas não Dobradas
8.
FASEB J ; 35(7): e21737, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143495

RESUMO

Relaxin is an insulin-like hormone with pleiotropic protective effects in several organs, including the liver. We aimed to characterize its role in the control of hepatic metabolism in healthy rats. Sprague-Dawley rats were treated with human recombinant relaxin-2 for 2 weeks. The hepatic metabolic profile was analyzed using UHPLC-MS platforms. Hepatic gene expression of key enzymes of desaturation (Fads1/Fads2) of n-6 and n-3 polyunsaturated fatty acids (PUFAs), of phosphatidylethanolamine (PE) N-methyltransferase (Pemt), of fatty acid translocase Cd36, and of glucose-6-phosphate isomerase (Gpi) were quantified by Real Time-PCR. Activation of 5'AMP-activated protein kinase (AMPK) was analyzed by Western Blot. Relaxin-2 significantly modified the hepatic levels of 19 glycerophospholipids, 2 saturated (SFA) and 1 monounsaturated (MUFA) fatty acids (FA), 3 diglycerides, 1 sphingomyelin, 2 aminoacids, 5 nucleosides, 2 nucleotides, 1 carboxylic acid, 1 redox electron carrier, and 1 vitamin. The most noteworthy changes corresponded to the substantially decreased lysoglycerophospholipids, and to the clearly increased FA (16:1n-7/16:0) and MUFA + PUFA/SFA ratios, suggesting enhanced desaturase activity. Hepatic gene expression of Fads1, Fads2, and Pemt, which mediates lipid balance and liver health, was increased by relaxin-2, while mRNA levels of the main regulator of hepatic FA uptake Cd36, and of the essential glycolysis enzyme Gpi, were decreased. Relaxin-2 augmented the hepatic activation of the hepatoprotector and master regulator of energy homeostasis AMPK. Relaxin-2 treatment also rised FADS1, FADS2, and PEMT gene expression in cultured Hep G2 cells. Our results bring to light the hepatic metabolic features stimulated by relaxin, a promising hepatoprotective molecule.


Assuntos
Fígado/efeitos dos fármacos , Fígado/enzimologia , Relaxina/farmacologia , Animais , Linhagem Celular Tumoral , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos/metabolismo , Ácidos Graxos Monoinsaturados/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Glicerofosfolipídeos/metabolismo , Células Hep G2 , Homeostase/efeitos dos fármacos , Humanos , Lipidômica/métodos , Fígado/metabolismo , Masculino , Metaboloma/efeitos dos fármacos , Fosfatidiletanolamina N-Metiltransferase/metabolismo , Fosfatidiletanolaminas/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia
9.
Nutrients ; 13(5)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946356

RESUMO

Due to the global increase in lifespan, the proportion of people showing cognitive impairment is expected to grow exponentially. As target-specific drugs capable of tackling dementia are lagging behind, the focus of preclinical and clinical research has recently shifted towards natural products. Curcumin, one of the best investigated botanical constituents in the biomedical literature, has been receiving increased interest due to its unique molecular structure, which targets inflammatory and antioxidant pathways. These pathways have been shown to be critical for neurodegenerative disorders such as Alzheimer's disease and more in general for cognitive decline. Despite the substantial preclinical literature on the potential biomedical effects of curcumin, its relatively low bioavailability, poor water solubility and rapid metabolism/excretion have hampered clinical trials, resulting in mixed and inconclusive findings. In this review, we highlight current knowledge on the potential effects of this natural compound on cognition. Furthermore, we focus on new strategies to overcome current limitations in its use and improve its efficacy, with attention also on gender-driven differences.


Assuntos
Anti-Inflamatórios/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Curcuma , Inflamação/tratamento farmacológico , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Humanos
10.
Life Sci ; 277: 119599, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33989666

RESUMO

The cellular damage caused by redox imbalance is involved in the pathogenesis of many cardiovascular diseases. Besides, redox imbalance is related to the alteration of protein acetylation processes, causing not only chromatin remodeling but also disturbances in so many processes where protein acetylation is involved, such as metabolism and signal transduction. The modulation of acetylases and deacetylases enzymes aids in maintaining the redox homeostasis, avoiding the deleterious cellular effects associated with the dysregulation of protein acetylation. Of note, regulation of protein acetylation has shown protective effects to ameliorate cardiovascular diseases. For instance, HDAC inhibition has been related to inducing cardiac protective effects and it is an interesting approach to the management of cardiovascular diseases. On the other hand, the upregulation of SIRT protein activity has also been implicated in the relief of cardiovascular diseases. This review focuses on the major protein acetylation modulators described, involving pharmacological and bioactive compounds targeting deacetylase and acetylase enzymes contributing to heart protection through redox homeostasis.


Assuntos
Acetilação/efeitos dos fármacos , Doenças Cardiovasculares/enzimologia , Coração/fisiologia , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Miocárdio/metabolismo , Oxirredução , Substâncias Protetoras/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos
11.
Front Immunol ; 12: 608875, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968013

RESUMO

Adipose tissue is now recognized as an active organ with an important homeostatic function in glucose and lipid metabolism and the development of insulin resistance. The present research investigates the role of lipid mediators and lipid profiling for controlling inflammation and the metabolic normal function of white adipose tissue from rats suffering from diet-induced prediabetes. Additionally, the contribution to the adipose lipidome induced by the consumption of marine ω-3 PUFAs as potential regulators of inflammation is addressed. For that, the effects on the inflammatory response triggered by high-fat high-sucrose (HFHS) diets were studied in male Sprague-Dawley rats. Using SPE-LC-MS/MS-based metabolo-lipidomics, a range of eicosanoids, docosanoids and specialized pro-resolving mediators (SPMs) were measured in white adipose tissue. The inflammatory response occurring in prediabetic adipose tissue was associated with the decomposition of ARA epoxides to ARA-dihydroxides, the reduction of oxo-derivatives and the formation of prostaglandins (PGs). In an attempt to control the inflammatory response initiated, LOX and non-enzymatic oxidation shifted toward the production of the less pro-inflammatory EPA and DHA metabolites rather than the high pro-inflammatory ARA hydroxides. Additionally, the change in LOX activity induced the production of intermediate hydroxides precursors of SPMs as protectins (PDs), resolvins (Rvs) and maresins (MaRs). This compensatory mechanism to achieve the restoration of tissue homeostasis was significantly strengthened through supplementation with fish oils. Increasing proportions of ω-3 PUFAs in adipose tissue significantly stimulated the formation of DHA-epoxides by cytochrome P450, the production of non-enzymatic EPA-metabolites and prompted the activity of 12LOX. Finally, protectin PDX was significantly reduced in the adipose tissue of prediabetic rats and highly enhanced through ω-3 PUFAs supplementation. Taken together, these actively coordinated modifications constitute key mechanisms to restore adipose tissue homeostasis with an important role of lipid mediators. This compensatory mechanism is reinforced through the supplementation of the diet with fish oils with high and balanced contents of EPA and DHA. The study highlights new insides on the targets for effective treatment of incipient diet-induced diabetes and the mechanism underlying the potential anti-inflammatory action of marine lipids.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Óleos de Peixe/administração & dosagem , Homeostase/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipidômica , Redes e Vias Metabólicas/efeitos dos fármacos , Animais , Biomarcadores , Cromatografia Líquida , Dieta , Mediadores da Inflamação , Lipidômica/métodos , Masculino , Ratos , Espectrometria de Massas em Tandem
12.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802759

RESUMO

This review describes current evidence supporting butyrate impact in the homeostatic regulation of the digestive ecosystem in health and inflammatory bowel diseases (IBDs). Butyrate is mainly produced by bacteria from the Firmicutes phylum. It stimulates mature colonocytes and inhibits undifferentiated malignant and stem cells. Butyrate oxidation in mature colonocytes (1) produces 70-80% of their energetic requirements, (2) prevents stem cell inhibition by limiting butyrate access to crypts, and (3) consumes oxygen, generating hypoxia and maintaining luminal anaerobiosis favorable to the microbiota. Butyrate stimulates the aryl hydrocarbon receptor (AhR), the GPR41 and GPR109A receptors, and inhibits HDAC in different cell types, thus stabilizing the gut barrier function and decreasing inflammatory processes. However, some studies indicate contrary effects according to butyrate concentrations. IBD patients exhibit a lower abundance of butyrate-producing bacteria and butyrate content. Additionally, colonocyte butyrate oxidation is depressed in these subjects, lowering luminal anaerobiosis and facilitating the expansion of Enterobacteriaceae that contribute to inflammation. Accordingly, gut dysbiosis and decreased barrier function in IBD seems to be secondary to the impaired mitochondrial disturbance in colonic epithelial cells.


Assuntos
Butiratos/farmacologia , Colo/patologia , Homeostase , Doenças Inflamatórias Intestinais/patologia , Animais , Colo/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos
13.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809409

RESUMO

Yellow lupine is a great model for abscission-related research given that excessive flower abortion reduces its yield. It has been previously shown that the EPIP peptide, a fragment of LlIDL (INFLORESCENCE DEFICIENT IN ABSCISSION) amino-acid sequence, is a sufficient molecule to induce flower abortion, however, the question remains: What are the exact changes evoked by this peptide locally in abscission zone (AZ) cells? Therefore, we used EPIP peptide to monitor specific modifications accompanied by early steps of flower abscission directly in the AZ. EPIP stimulates the downstream elements of the pathway-HAESA and MITOGEN-ACTIVATED PROTEIN KINASE6 and induces cellular symptoms indicating AZ activation. The EPIP treatment disrupts redox homeostasis, involving the accumulation of H2O2 and upregulation of the enzymatic antioxidant system including superoxide dismutase, catalase, and ascorbate peroxidase. A weakening of the cell wall structure in response to EPIP is reflected by pectin demethylation, while a changing pattern of fatty acids and acyl lipids composition suggests a modification of lipid metabolism. Notably, the formation of a signaling molecule-phosphatidic acid is induced locally in EPIP-treated AZ. Collectively, all these changes indicate the switching of several metabolic and signaling pathways directly in the AZ in response to EPIP, which inevitably leads to flower abscission.


Assuntos
Flores/crescimento & desenvolvimento , Homeostase , Lipídeos/química , Lupinus/crescimento & desenvolvimento , Pectinas/metabolismo , Peptídeos/farmacologia , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Flores/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Lupinus/efeitos dos fármacos , Oxirredução , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
14.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915783

RESUMO

Obesity has recently emerged as a public health issue facing developing countries in the world. It is caused by the accumulation of fat in adipose, characterized by insulin resistance, excessive lipid accumulation, inflammation, and oxidative stress, leading to an increase in adipokine levels. Herein, we investigated the capacity of a bioactive polyphenolic compound (ferulic acid (FA)) to control adipocyte dysfunction in 3T3-L1 adipocytes (in vitro). Key adipocyte differentiation markers, glycerol content, lipolysis-associated mRNA, and proteins were measured in experimental adipocytes. FA-treated adipocytes exhibited downregulated key adipocyte differentiation factors peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAT enhancer binding-proteins-α (C/EBP-α) and its downstream targets in a time-dependent manner. The FA-treated 3T3-L1 adipocytes showed an increased release of glycerol content compared with non-treated adipocytes. Also, FA treatment significantly up-regulated the lipolysis-related factors, including p-HSL, and p-perilipin, and down-regulated ApoD, Sema3C, Cxcl12, Sfrp2, p-stearoyl-CoA desaturase 1 (SCD1), adiponectin, and Grk5. Also, the FA treatment showed significantly down-regulated adipokines leptin, chemerin, and irisin than the non-treated cells. The present findings indicated that FA showed significant anti-adipogenic and lipogenic activities by regulating key adipocyte factors and enzyme, enhanced lipolysis by HSL/perilipin cascade. FA is considered a potent molecule to prevent obesity and its associated metabolic changes in the future.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Ácidos Cumáricos/farmacologia , Homeostase/efeitos dos fármacos , Células 3T3-L1 , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Biomarcadores , Diferenciação Celular/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Camundongos
15.
Nutrients ; 13(5)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33921980

RESUMO

Iron-fortified formulas and iron drops (both usually ferrous sulfate, FS) prevent early life iron deficiency, but may delay growth and adversely affect neurodevelopment by providing excess iron. We used a rat pup model to investigate iron status, growth, and development outcomes following daily iron supplementation (10 mg iron/kg body weight, representative of iron-fortified formula levels) with FS or an alternative, bioavailable form of iron, ferrous bis-glycinate chelate (FC). On postnatal day (PD) 2, sex-matched rat litters (n = 3 litters, 10 pups each) were randomly assigned to receive FS, FC, or vehicle control until PD 14. On PD 15, we evaluated systemic iron regulation and CNS mineral interactions and we interrogated iron loading outcomes in the hippocampus, in search of mechanisms by which iron may influence neurodevelopment. Body iron stores were elevated substantially in iron-supplemented pups. All pups gained weight normally, but brain size on PD 15 was dependent on iron source. This may have been associated with reduced hippocampal oxidative stress but was not associated with CNS mineral interactions, iron regulation, or myelination, as these were unchanged with iron supplementation. Additional studies are warranted to investigate iron form effects on neurodevelopment so that iron recommendations can be optimized for all infants.


Assuntos
Sistema Nervoso Central/crescimento & desenvolvimento , Suplementos Nutricionais , Compostos Ferrosos/farmacologia , Glicina/farmacologia , Quelantes de Ferro/farmacologia , Ferro/metabolismo , Ferro/farmacologia , Animais , Animais Recém-Nascidos , Sistema Nervoso Central/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Homeostase/efeitos dos fármacos , Ferro/sangue , Bainha de Mielina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Oligoelementos/análise , Ganho de Peso/efeitos dos fármacos
16.
J Plant Physiol ; 261: 153415, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33894579

RESUMO

Ammonium (NH4+) inhibits primary root (PR) growth in most plant species when present even at moderate concentrations. Previous studies have shown that transport of indole-3-acetic acid (IAA) is critical to maintaining root elongation under high-NH4+ stress. However, the precise regulation of IAA homeostasis under high-NH4+ stress (HAS) remains unclear. In this study, qRT-PCR, RNA-seq, free IAA and IAA conjugate and PR elongation measurements were conducted in genetic mutants to investigate the role of IAA biosynthesis and conjugation under HAS. Our data clearly show that HAS decreases free IAA in roots by increasing IAA inactivation but does not decrease IAA biosynthesis, and that the IAA-conjugating genes GH3.1, GH3.2, GH3.3, GH3.4, and GH3.6 function as the key genes in regulating high-NH4+ sensitivity in the roots. Furthermore, the analysis of promoter::GUS staining in situ and genetic mutants reveals that HAS promotes IAA conjugation in the elongation zone (EZ), which may be responsible for the PR inhibition observed under HAS. This study provides potential new insight into the role of auxin in the improvement of tolerance to NH4+.


Assuntos
Compostos de Amônio/metabolismo , Arabidopsis/crescimento & desenvolvimento , Ácidos Indolacéticos/farmacologia , Raízes de Plantas/crescimento & desenvolvimento , Compostos de Amônio/administração & dosagem , Arabidopsis/efeitos dos fármacos , Arabidopsis/metabolismo , Homeostase/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos , Estresse Fisiológico
17.
Biomed Res Int ; 2021: 5551504, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33928148

RESUMO

Background: Previous studies have demonstrated the ubiquitin-proteasome inhibitor bortezomib (BTZ) can effectively alleviate hypoxia-induced pulmonary hypertension (HPH) by suppressing the intracellular calcium homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Further evaluation showed that the antiproliferation roles of BTZ are mainly mediated by inhibition of the intracellular calcium homeostasis. Caveolin-1 belongs to one of the key regulators of the intracellular calcium homeostasis in PASMCs, which can regulate the store-operated calcium entry (SOCE). However, the effects of BTZ on Caveolin-1 remain unclear. Methods: Primarily cultured human PASMCs were used as the cell model. CCK-8 assay was performed to assess the PASMCs proliferation. Western blotting and real-time qPCR were used to detect the mRNA and protein expressions. Fura-2-based fluorescence imaging experiments were used to determine the intracellular calcium concentration ([Ca2+]i). The protein synthesis inhibitor cycloheximide (CHX) was utilized to determine the protein degradation process. Results: Firstly, in cultured human PASMCs, treatment of BTZ for 24 or 60 hours significantly downregulates Caveolin-1 at both mRNA and protein levels. Secondly, in the presence CHX, BTZ treatment also leads to downregulated protein expression and fastened protein degradation of Caveolin-1, indicating that BTZ can promote the Caveolin-1 protein degradation, other than the BTZ on Caveolin-1 mRNA transcription. Then, BTZ significantly attenuates the hypoxia-elevated baseline [Ca2+]i, SOCE, and cell proliferation. Conclusion: We firstly observed that the ubiquitin-proteasome inhibitor BTZ can inhibit the Caveolin-1 expression at both mRNA transcription and protein degradation processes, providing new mechanistic basis of BTZ on PASMC proliferation.


Assuntos
Bortezomib/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Caveolina 1/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Artéria Pulmonar/patologia , Caveolina 1/genética , Hipóxia Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cloroquina/farmacologia , Homeostase/efeitos dos fármacos , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Proteólise/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
18.
Ecotoxicol Environ Saf ; 217: 112248, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33901782

RESUMO

Melatonin (Mel), a powerful antioxidant that has the ability to regulate physiological and biochemical processes in plants under abiotic stresses. However, its roles in pesticide detoxification is poorly understood. Herein, selecting leaf spraying insecticide imidacloprid (IMD) as the model, we demonstrated the detoxification mechanism underlying root pretreatment of Mel on IMD in cucumber. IMD treatment affected the primary light conversion efficiency of photosystem II (Fv/Fm), reduced the quantum yield, and increased hydrogen peroxide and superoxide anions contents as well as the levels of membrane lipid peroxidation, indicating that excessive IMD treatment induces oxidative stress. Nonetheless, by increasing the appropriate levels of exogenous Mel, the photosynthesis of cucumber under IMD treatment reached the control levels, effectively removing reactive oxygen species. Furthermore, the content and ratio of ascorbate (AsA) and glutathione (GSH) were decreased under IMD treatment; Mel treatment enhanced the AsA/DHA and GSH/GSSG ratios, as well as the activities of MDHAR, DHAR and GR, suggesting that Mel could alleviate oxidative stress of cucumber treated with IMD by regulating the ascorbic acid-glutathione cycle. Importantly, IMD degradation rate and glutathione S-transferase (GST) activity increased after Mel treatment. The levels of transcripts encoding antioxidant enzymes GPX and GST (GST1,2 and 3) were also increased, indicating that Mel accelerated IMD degradation. These results suggest that Mel plays an important role in the detoxification of IMD by promoting GST activity and transcription and the AsA-GSH cycle, thus providing an approach for plants to reduce IMD residue through the plant's own detoxification mechanism.


Assuntos
Cucumis sativus/fisiologia , Glutationa/metabolismo , Inseticidas/toxicidade , Melatonina/metabolismo , Neonicotinoides/toxicidade , Nitrocompostos/toxicidade , Antioxidantes/metabolismo , Ácido Ascórbico/metabolismo , Cucumis sativus/metabolismo , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Peróxido de Hidrogênio/metabolismo , Inativação Metabólica/efeitos dos fármacos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Plântula/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos
19.
Int J Mol Sci ; 22(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924461

RESUMO

Signaling through GPR109a, the putative receptor for the endogenous ligand ß-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles. To better understand the involvement of GPR109a signaling in regulating glucose and lipid metabolism, we treated GPR109a wild-type (+/+) and knockout (-/-) mice with repeated overnight injections of saline or niacin in physiological states characterized by low (ad libitum fed) or high (16 h fasted) concentrations of the endogenous ligand, ß-OH butyrate. In the fed state, niacin increased expression of apolipoprotein-A1 mRNA and decreased sterol regulatory element-binding protein 1 mRNA independent of genotype, suggesting a possible GPR109a independent mechanism by which niacin increases high-density lipoprotein (HDL) production and limits transcriptional upregulation of lipogenic genes. Niacin decreased fasting serum non-esterified fatty acid concentrations in both GPR109a +/+ and -/- mice. Independent of GPR109a expression, niacin blunted fast-induced hepatic triglyceride accumulation and peroxisome proliferator-activated receptor α mRNA expression. Although unaffected by niacin treatment, fasting serum HDL concentrations were lower in GPR109a knockout mice. Surprisingly, GPR109a knockout did not affect glucose or lipid homeostasis or hepatic gene expression in either fed or fasted mice. In turn, GPR109a does not appear to be essential for the metabolic response to the fasting ketogenic state or the acute effects of niacin.


Assuntos
Jejum , Comportamento Alimentar , Fígado/metabolismo , Niacina/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Animais , Colesterol/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Glicogênio/metabolismo , Homeostase/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos Knockout , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais/efeitos dos fármacos
20.
Int J Mol Sci ; 22(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924609

RESUMO

Osmotic stress severely inhibits plant growth and development, causing huge loss of crop quality and quantity worldwide. Melatonin is an important signaling molecule that generally confers plant increased tolerance to various environmental stresses, however, whether and how melatonin participates in plant osmotic stress response remain elusive. Here, we report that melatonin enhances plant osmotic stress tolerance through increasing ROS-scavenging ability, and melatonin receptor CAND2 plays a key role in melatonin-mediated plant response to osmotic stress. Upon osmotic stress treatment, the expression of melatonin biosynthetic genes including SNAT1, COMT1, and ASMT1 and the accumulation of melatonin are increased in the wild-type plants. The snat1 mutant is defective in osmotic stress-induced melatonin accumulation and thus sensitive to osmotic stress, while exogenous melatonin enhances the tolerance of the wild-type plant and rescues the sensitivity of the snat1 mutant to osmotic stress by upregulating the expression and activity of catalase and superoxide dismutase to repress H2O2 accumulation. Further study showed that the melatonin receptor mutant cand2 exhibits reduced osmotic stress tolerance with increased ROS accumulation, but exogenous melatonin cannot revert its osmotic stress phenotype. Together, our study reveals that CADN2 functions necessarily in melatonin-conferred osmotic stress tolerance by activating ROS-scavenging ability in Arabidopsis.


Assuntos
Adaptação Fisiológica , Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , Melatonina/farmacologia , Pressão Osmótica , Receptores Acoplados a Proteínas G/metabolismo , Estresse Fisiológico , Adaptação Fisiológica/efeitos dos fármacos , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Catalase/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Mutação/genética , Espécies Reativas de Oxigênio/metabolismo , Plântula/efeitos dos fármacos , Plântula/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
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