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1.
Molecules ; 26(4)2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33671428

RESUMEN

The potential biological activities of Viburnum stellato-tomentosum (VS), a plant mainly found in Costa Rica, have yet to be reported. Supplementation of VS extract for 17 weeks significantly decreased body weight gain, fat weight, fasting glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglyceride levels in high-fat diet (HFD)-fed C57BL/6J mice. The molecular mechanisms underlying the anti-obesity and glucose-lowering effects of VS extract were investigated. VS extract suppressed adipocyte hypertrophy by regulating lipogenesis-related CCAAT/enhancer-binding protein α (C/EBPα) and insulin sensitivity-related peroxisome proliferator-activated receptor γ (Pparg) expression in adipose tissue (AT) and hepatic steatosis by inhibiting C/EBPα and lipid transport-related fatty acid binding protein 4 (FABP4) expression. VS extract enhanced muscular fatty acid ß-oxidation-related AMP-activated protein kinase (AMPK) and PPARα expression with increasing Pparg levels. Furthermore, VS extract contained a much higher content of amentoflavone (AMF) (29.4 mg/g extract) compared to that in other Viburnum species. AMF administration decreased Cebpa and Fabp4 levels in the AT and liver, as well as improved insulin signaling-related insulin receptor substrate 1 (Irs1) and glucose transporter 1 (Glut1) levels in the muscle of HFD-fed mice. This study elucidated the in vivo molecular mechanisms of AMF for the first time. Therefore, VS extract effectively diminished obesity and hyperglycemia by suppressing C/EBPα-mediated lipogenesis in the AT and liver, enhancing PPARα-mediated fatty acid ß-oxidation in muscle, and PPARγ-mediated insulin sensitivity in AT and muscle.


Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Dieta Alta en Grasa , Hiperglucemia/tratamiento farmacológico , Metabolismo de los Lípidos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Extractos Vegetales/uso terapéutico , Viburnum/química , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/patología , Adipogénesis/efectos de los fármacos , Tejido Adiposo Blanco/patología , Animales , Fármacos Antiobesidad/farmacología , Biflavonoides/farmacología , Peso Corporal/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Hígado Graso/sangre , Hígado Graso/complicaciones , Hígado Graso/tratamiento farmacológico , Conducta Alimentaria , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Homeostasis/efectos de los fármacos , Hiperglucemia/sangre , Hiperglucemia/complicaciones , Hiperglucemia/metabolismo , Hipertrofia , Insulina/metabolismo , Resistencia a la Insulina , Metabolismo de los Lípidos/efectos de los fármacos , Ratones Endogámicos C57BL , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Obesidad/sangre , Obesidad/complicaciones , Tamaño de los Órganos/efectos de los fármacos , Oxidación-Reducción , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos
2.
Nat Commun ; 12(1): 836, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547321

RESUMEN

Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we ask whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion leads to expanded tuft and goblet cell populations. Sprouty2 loss induces PI3K/Akt signaling, leading to GSK3ß inhibition and epithelial interleukin (IL)-33 expression. In vivo, this results in increased stromal IL-13+ cells. IL-13 in turn induces tuft and goblet cell expansion in vitro and in vivo. Sprouty2 is downregulated by acute inflammation; this appears to be a protective response, as VillinCre;Sprouty2F/F mice are resistant to DSS colitis. In contrast, Sprouty2 is elevated in chronic colitis and in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease.


Asunto(s)
Colitis/genética , Glucógeno Sintasa Quinasa 3 beta/genética , Homeostasis/genética , Interleucina-33/genética , Proteínas de la Membrana/genética , Proteínas Serina-Treonina Quinasas/genética , Animales , Recuento de Células , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Niño , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Femenino , Regulación de la Expresión Génica , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células Caliciformes/efectos de los fármacos , Células Caliciformes/metabolismo , Células Caliciformes/patología , Células HT29 , Homeostasis/efectos de los fármacos , Humanos , Interleucina-33/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Dodecil Sulfato de Sodio/administración & dosificación
3.
Life Sci ; 271: 119195, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33581125

RESUMEN

AIMS: Ulcerative colitis and Crohn's disease, collectively known as inflammatory bowel disease (IBD), are chronic inflammatory disorders of the intestine for which key elements in disease initiation and perpetuation are defects in epithelial barrier integrity. Achieving mucosal healing is essential to ameliorate disease outcome and so new therapies leading to epithelial homeostasis and repair are under investigation. This study was designed to determine the mechanisms by which IL-22 regulates intestinal epithelial cell function. MAIN METHODS: Human intestinal organoids and resections, as well as mice were used to evaluate the effect of IL-22 on stem cell expansion, proliferation and expression of mucus components. IL-22 effect on barrier function was assessed in polarized T-84 cell monolayers. Butyrate co-treatments and organoid co-cultures with immune cells were performed to monitor the impact of microbial-derived metabolites and inflammatory environments on IL-22 responses. KEY FINDINGS: IL-22 led to epithelial stem cell expansion, proliferation, barrier dysfunction and anti-microbial peptide production in human and mouse models evaluated. IL-22 also altered the mucus layer by inducing an increase in membrane mucus but a decrease in secreted mucus and goblet cell content. IL-22 had the same effect on anti-microbial peptides and membrane mucus in both healthy and IBD human samples. In contrast, this IL-22-associated epithelial phenotype was different when treatments were performed in presence of butyrate and organoids co-cultured with immune cells. SIGNIFICANCE: Our data indicate that IL-22 promotes epithelial regeneration, innate defense and membrane mucus production, strongly supporting the potential clinical utility of IL-22 as a mucosal healing therapy in IBD.


Asunto(s)
Células Epiteliales/fisiología , Homeostasis/fisiología , Interleucinas/fisiología , Interleucinas/uso terapéutico , Mucosa Intestinal/fisiología , Animales , Línea Celular , Técnicas de Cocultivo , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Células Epiteliales/efectos de los fármacos , Homeostasis/efectos de los fármacos , Humanos , Interleucinas/farmacología , Mucosa Intestinal/citología , Mucosa Intestinal/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Organoides/efectos de los fármacos , Organoides/fisiología
4.
Medicine (Baltimore) ; 100(6): e23843, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578512

RESUMEN

BACKGROUND: Diabetes refers to any group of metabolic diseases characterized by high blood sugar and generally thought to be caused by insufficient production of insulin, impaired response to insulin. Globally, patients with type 2 diabetes account for more than 85% of the total diabetic patients, and due to factors, such as obesity, aging, environment and lifestyle, the incidence of diabetes is rising. Salvia miltiorrhiza (SM) is a medicine used to treat diabetes in China. In recent years, it has been reported that SM has the effect of improving type 2 diabetes. However, there is no systematic review of its efficacy and safety yet. Therefore, we propose a systematic review to evaluate the efficacy and safety of SM for T2D. METHODS: Six databases will be searched: China National Knowledge Infrastructure (CNKI), China Biological Medicine (CBM), China Scientific Journals Database (CSJD), Wanfang database, PubMed, and EMBASE. The information is searched from January 2010 to July 2020. Languages are limited to English and Chinese. The primary outcomes include 2 hour plasma glucose, fasting plasma glucose, hemoglobin A1c, homeostasis model assessment of insulin resistance, and fasting plasma insulin. The secondary outcomes include clinical efficacy and adverse events. RESULTS: This systematic review will evaluate the efficacy and safety of Salvia miltiorrhiza in the treatment of type 2 diabetes. CONCLUSION: This systematic review provides evidence as to whether Salvia miltiorrhiza is effective and safe for type 2 diabetes. ETHICS: Ethical approval is not necessary as this protocol is only for systematic review and does not involve in privacy data or an animal experiment. SYSTEMATIC REVIEW REGISTRATION: INPLASY2020110046.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Salvia miltiorrhiza/química , China/epidemiología , Manejo de Datos , Diabetes Mellitus Tipo 2/epidemiología , Ayuno/sangre , Femenino , Glucosa/análisis , Hemoglobina A Glucada/análisis , Homeostasis/efectos de los fármacos , Humanos , Incidencia , Insulina/sangre , Masculino , Medicina China Tradicional/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Seguridad , Resultado del Tratamiento
5.
Ecotoxicol Environ Saf ; 208: 111720, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396051

RESUMEN

Fine particulate matter (PM2.5), a ubiquitous environmental pollutant, has been indicated to affect thyroid hormone (TH) homeostasis in women, but the detailed mechanism behind this effect remains unclear. The objective of this study was to evaluate the roles of the hypothalamic-pituitary-thyroid (HPT) axis and hepatic transthyretin in the thyroid-disrupting effects of PM2.5. Sprague Dawley rats were treated with PM2.5 (0, 15 and 30 mg/kg) by passive pulmonary inhalation for 49 days; and recovery experimental group rats were dosed with PM2.5 (30 mg/kg) for 35 days, and no treatment was done during the subsequent 14 days. PM2.5 was handled twice a day by passive pulmonary inhalation throughout the study. After treatment, pathological changes were analyzed by performing haemotoxylin and eosin staining, measuring levels of THs and urine iodine (UI) in serum, plasma, and urine samples using enzyme-linked immunoabsorbent assay, and expression of proteins in the hypothalamus, pituitary, thyroid, and liver tissues of rats were analyzed by immunohistochemistry and Western blotting. The levels of oxidative stress factors, such as reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (Gpx), and nuclear factor-kappa B (NF-κB) in female rats' plasma were also evaluated by ELISA. The results of these analyses revealed that PM2.5 treatment induced pathologic changes in rat thyroid and liver characterized by increased follicular cavity size and decreased amounts of follicular epithelial cells and fat vacuoles, respectively. Serum levels of triiodothyronine, thyroxine, and thyroid stimulating hormone were significantly decreased, plasma NF-κB level was increased and plasma redox state was unbalanced (enhanced ROS, MDA and Gpx levels; reduced SOD activities) in female rats treated with PM2.5 (P < 0.05). PM2.5 treatment suppressed the biosynthesis and biotransformation of THs by increasing sodium iodide symporter, thyroid transcription factor 1, thyroid transcription factor 2, and paired box 8 protein expression levels (P < 0.05). Additionally, thyroid stimulating hormone receptor and thyroid peroxidase levels were significantly decreased (P < 0.05). Both thyrotropin releasing hormone receptor and thyroid stimulating hormone beta levels were enhanced (P < 0.05). Moreover, transport of THs was inhibited due to reduced protein expression of hepatic transthyretin upon treatment with PM2.5. In summary, PM2.5 treatment could perturb TH homeostasis by affecting TH biosynthesis, biotransformation, and transport, affecting TH receptor levels, and inducing oxidative stress and inflammatory responses. Activation of the HPT axis and altered hepatic transthyretin levels therefore appear to play a crucial role in PM2.5-induced thyroid dysfunction.


Asunto(s)
Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Material Particulado/toxicidad , Prealbúmina/metabolismo , Glándula Tiroides/efectos de los fármacos , Hormonas Tiroideas/metabolismo , Animales , Femenino , Homeostasis/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , Material Particulado/química , Ratas , Ratas Sprague-Dawley , Receptores de Hormona Tiroidea/metabolismo , Glándula Tiroides/metabolismo , Glándula Tiroides/patología
6.
Ecotoxicol Environ Saf ; 211: 111901, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33453640

RESUMEN

The effects of fullerenol nanopriming (0, 10, 40, 80 and 120 nM concentration) on salt stressed-wheat (0 and 150 mM NaCl) were investigated under natural conditions. Salinity resulted in a shift in wheat growth pattern in the form of LAR (+ 40.9% increase) and RGR (+ 13.4% increase) while decreased NAR (- 31.7%). It also disturbed shoot and root biomass, ion uptake and reduced chlorophyll contents. Despite increase in enzyme activities, higher ROS generation (+ 48.1% O2- anion; and + 62.2% H2O2) and lipid peroxidation (+ 40.8% MDA) were detected in salt-stressed wheat plants. Possibly, the increases in enzyme activities were not up to the level to completely counteract the salinity induced oxidative stress. Nanopriming with fullerenol improved NAR (+ 8.77% to 23.2%), ROS metabolism and decreased indicators of oxidative stress. Hydropriming treatment also promoted NAR recovery by 21.9% than control plants. Compared to Na+ ions, improvements in shoot relative concentrations of K+, Ca2+ and P also recorded along with soluble sugars and amino acids, which improved osmotic balance. These biochemical modifications contributed to improvements in grain yield attributes (+11.8% to 18.3% in 100 grain-weight) than salinity stressed control. Hydropriming also contributed to a recovery in grain yield attributes by 12.6%. Above all, the harvested seeds from fullerenol treated plants also showed better germination and seedlings growth traits. Conclusively, we report non-toxic, growth-promoting effects of fullerenol nanoparticles on wheat crop and as a way forward; we suggest its exogenous application to recover crop productivity under saline environments.


Asunto(s)
Fulerenos/metabolismo , Estrés Oxidativo/fisiología , Estrés Salino/fisiología , Triticum/fisiología , Antioxidantes/metabolismo , Clorofila/metabolismo , Germinación/efectos de los fármacos , Homeostasis/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , Iones/metabolismo , Peroxidación de Lípido , Salinidad , Estrés Salino/efectos de los fármacos , Plantones/efectos de los fármacos , Semillas/metabolismo , Sodio/metabolismo , Triticum/crecimiento & desarrollo
7.
Nat Commun ; 12(1): 613, 2021 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-33504774

RESUMEN

Induction of intrinsic liver regeneration is an unmet need that can be achieved by temporally activating key hepatocyte regenerative pathways. Here, we establish an efficient, safe, non-integrative method to transiently express hepatocyte-growth-factor (HGF) and epidermal-growth-factor (EGF) in hepatocytes via nucleoside-modified, lipid-nanoparticle-encapsulated mRNA (mRNA-LNP) delivery in mice. We confirm specific hepatotropism of mRNA-LNP via intravenous injection of firefly luciferase encoding mRNA-LNP, with protein expression lasting about 3 days. In the liver, virtually all hepatocytes are transfected along with a subpopulation of endothelial and Kupffer cells. In homeostasis, HGF mRNA-LNP efficiently induce hepatocyte proliferation. In a chronic liver injury mouse model recapitulating non-alcoholic fatty liver disease, injections of both HGF and EGF mRNA-LNP sharply reverse steatosis and accelerate restoration of liver function. Likewise, HGF and EGF mRNA-LNP accelerate liver regeneration after acetaminophen-induced acute liver injury with rapid return to baseline ALT levels. This study introduces mRNA-LNP as a potentially translatable safe therapeutic intervention to harness liver regeneration via controlled expression of endogenous mitogens in vivo.


Asunto(s)
Hepatocitos/patología , Lípidos/química , Regeneración Hepática/fisiología , Hígado/patología , Nanopartículas/química , Nucleósidos/metabolismo , ARN Mensajero/metabolismo , Acetaminofén , Animales , Proliferación Celular/efectos de los fármacos , Enfermedad Crónica , Modelos Animales de Enfermedad , Factor de Crecimiento Epidérmico/farmacología , Femenino , Proteínas Fluorescentes Verdes/metabolismo , Factor de Crecimiento de Hepatocito/farmacología , Hepatocitos/efectos de los fármacos , Homeostasis/efectos de los fármacos , Inyecciones , Hígado/efectos de los fármacos , Hígado/lesiones , Hígado/fisiopatología , Pruebas de Función Hepática , Regeneración Hepática/efectos de los fármacos , Ratones Endogámicos C57BL
8.
Nat Commun ; 12(1): 290, 2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33436590

RESUMEN

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. Here, the authors report that the lysosomal copper transporter SLC46A3 is induced by TCDD and underlies the hepatic lipid accumulation in mice, potentially via effects on mitochondrial function. SLC46A3 was localized to the lysosome where it modulated intracellular copper levels. Forced expression of hepatic SLC46A3 resulted in decreased mitochondrial membrane potential and abnormal mitochondria morphology consistent with lower copper levels. SLC46A3 expression increased hepatic lipid accumulation similar to the known effects of TCDD exposure in mice and humans. The TCDD-induced hepatic triglyceride accumulation was significantly decreased in Slc46a3-/- mice and was more pronounced when these mice were fed a high-fat diet, as compared to wild-type mice. These data are consistent with a model where lysosomal SLC46A3 induction by TCDD leads to cytosolic copper deficiency resulting in mitochondrial dysfunction leading to lower lipid catabolism, thus linking copper status to mitochondrial function, lipid metabolism and TCDD-induced liver toxicity.


Asunto(s)
Proteínas Transportadoras de Cobre/metabolismo , Cobre/metabolismo , Citosol/metabolismo , Homeostasis , Lisosomas/metabolismo , Transportador de Folato Acoplado a Protón/metabolismo , Animales , Proteínas Transportadoras de Cobre/genética , Citosol/efectos de los fármacos , Proteínas Fluorescentes Verdes/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/ultraestructura , Homeostasis/efectos de los fármacos , Iones , Hígado/metabolismo , Lisosomas/efectos de los fármacos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Dibenzodioxinas Policloradas/toxicidad , Transportador de Folato Acoplado a Protón/genética , Receptores de Hidrocarburo de Aril/metabolismo , Especificidad por Sustrato/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Triglicéridos/metabolismo
9.
Cell Prolif ; 54(3): e12990, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33458941

RESUMEN

OBJECTIVES: S-nitrosoglutathione reductase (GSNOR), a protein denitrosylase, protects the mitochondria from mitochondrial nitrosative stress. Mammalian preimplantation embryos are mitochondria-rich, but the effects of GSNOR on mitochondrial function in preimplantation embryos are not well-studied. In the present study, we investigate whether GSNOR plays a role in mitochondrial regulation during porcine preimplantation embryo development. MATERIALS AND METHODS: GSNOR dsRNA was employed to knock down the expression of GSNOR, and Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME), a pan-NOS inhibitor, was used to prevent protein S-nitrosylation. Mitochondrial amount and function in embryo development were assessed by performing immunofluorescence staining, Western blot, fluorescent probe and real-time reverse transcription PCR. RESULTS: GSNOR knock-down significantly impaired blastocyst formation and quality and markedly induced the increase in protein S-nitrosylation. Notably, GSNOR knock-down-induced overproduction of S-nitrosylation caused mitochondrial dysfunction, including mitochondrial membrane potential depolarization, mitochondria-derived reactive oxygen species (ROS) increase and ATP deficiency. Interestingly, GSNOR knock-down-induced total mitochondrial amount increase, but the ratio of active mitochondria reduction, suggesting that the damaged mitochondria were accumulated and mitochondrial clearance was inhibited. In addition, damaged mitochondria produced more ROS, and caused DNA damage and apoptosis. Importantly, supplementation with L-NAME reverses the increase in S-nitrosylation, accumulation of damaged mitochondria, and oxidative stress-induced cell death. Interestingly, autophagy was downregulated after GSNOR knock-down, but reversed by L-NAME treatment. Thus, GSNOR maintains mitochondrial homeostasis by promoting autophagy and the clearing of damaged mitochondria in porcine preimplantation embryos.


Asunto(s)
Homeostasis/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , S-Nitrosoglutatión/farmacología , Aldehído Oxidorreductasas/efectos de los fármacos , Animales , Autofagia/efectos de los fármacos , Blastocisto/metabolismo , Mitocondrias/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Oxidorreductasas/metabolismo , Porcinos
10.
Food Chem ; 335: 127505, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32739823

RESUMEN

Dysregulation of glucose homeostasis result in hyperglycemia and pigmented rice, unique combination of high quality starch and phenolics has the potential in regulating it. In this study, pigmented rice was characterized in terms of nutraceutical starch (NS) and phenolic content. Further the effect of rice phenolics on carbolytic enzyme inhibition, glucose uptake, hepatic glucose homeostasis and anti-glycation ability was analyzed in vitro. The most relevant effect on enzyme inhibition (α-amylase: IC50-42.34 µg/mL; α-glucosidase: IC50:63.89 µg/mL), basal uptake of glucose (>39.5%) and anti-glycation ability (92%) was found in red rice (RR), than black rice (BR). The role of RR phenolics in regulating glucose homeostasis was deciphered using hepatic cell line system, which found up-regulation of glucose transporter 2 (GLUT2) and glycogen synthase 2 (GYS2); while expression of gluconeogenic genes were found down regulated. To our knowledge this study is the first report validating the role of starch-phenolic quality towards anti-hyperglycemic effect of RR.


Asunto(s)
Glucosa/metabolismo , Homeostasis , Hiperglucemia/metabolismo , Hígado/metabolismo , Oryza/química , Proantocianidinas/análisis , Almidón/análisis , Transporte Biológico/efectos de los fármacos , Suplementos Dietéticos/análisis , Inhibidores de Glicósido Hidrolasas/farmacología , Homeostasis/efectos de los fármacos , Hígado/efectos de los fármacos , Fenol/análisis , Fenol/farmacología , alfa-Amilasas/antagonistas & inhibidores
11.
Biochim Biophys Acta Mol Cell Res ; 1868(1): 118881, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33022276

RESUMEN

Heme, as a hydrophobic iron-containing organic ring, is lipid soluble and can interact with biological membranes. The very same properties of heme that nature exploits to support life also renders heme potentially cytotoxic. In order to utilize heme, while also mitigating its toxicity, cells are challenged to tightly control the concentration and bioavailability of heme. On the bright side, it is reasonable to envision that, analogous to other transition metals, a combination of membrane-bound transporters, soluble carriers, and chaperones coordinate heme trafficking to subcellular compartments. However, given the dual properties exhibited by heme as a transition metal and lipid, it is compelling to consider the dark side: the potential role of non-proteinaceous biomolecules including lipids and nucleic acids that bind, sequester, and control heme trafficking and bioavailability. The emergence of inter-organellar membrane contact sites, as well as intracellular vesicles derived from various organelles, have raised the prospect that heme can be trafficked through hydrophobic channels. In this review, we aim to focus on heme delivery without deliverers - an alternate paradigm for the regulation of heme homeostasis through chaperone-less pathways for heme trafficking.


Asunto(s)
Hemo/metabolismo , Homeostasis/efectos de los fármacos , Lípidos/química , Transporte de Proteínas/genética , Citotoxinas/farmacología , Hemo/química , Homeostasis/genética , Hierro/química , Hierro/metabolismo , Metales/química , Chaperonas Moleculares/química , Solubilidad/efectos de los fármacos
12.
Chem Biol Interact ; 334: 109306, 2021 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-33309544

RESUMEN

Oxidative stress (OS)-induced glutathione (GSH) depletion plays an essential role in several kidney diseases such as chronic kidney disease and nephrotoxicity. The OS-dependent activation of TRPM2 cation channel in several neurons and cells were modulated by the concentration of intracellular GSH. However, the effects of GSH alteration on TRPM2 activation, OS, and apoptosis in the cortical collecting duct (mpkCCDc14) cells still remain elusive. We investigated the effects of GSH supplementation on OS-induced TRPM2 activation, mitochondrial oxidative stress, and apoptosis in the human embryonic kidney 293 (HEK293) and mpkCCDc14 cells treated with buthionine-sulfoximine (BSO), a GSH synthase inhibitor. The HEK293 and mpkCCDc14 cells were divided into five groups as control, GSH (10 mM for 2 h), BSO (0.5 mM for 6 h), BSO + GSH, and BSO + TRPM2 channel blockers. Apoptosis, cell death, mitochondrial OS, caspase -3, caspase -9, cytosolic free Zn2+, and Ca2+ concentrations were increased in the BSO group of the TRPM2 expressing mpkCCDc14 cells, although they were diminished by the treatments of GSH, PARP-1 inhibitors (PJ34 and DPQ), and TRPM2 blockers (ACA and 2-APB). The BSO-induced decreases in the levels of cell viability and cytosolic GSH were increased by the treatments of GSH, ACA, and 2-APB. However, the effects of BSO and GSH were not observed in the non-TRPM2 expressing HEK293 cells. Current results show that maintaining GSH homeostasis is not only important for quenching OS in the cortical collecting duct cells but equally critical to modulate TRPM2 activation. Thus, suppressing apoptosis and mitochondrial OS responses elicited by oxidant action of GSH depletion.


Asunto(s)
Apoptosis/fisiología , Glutatión/metabolismo , Corteza Renal/metabolismo , Estrés Oxidativo/fisiología , Canales Catiónicos TRPM/metabolismo , Animales , Apoptosis/efectos de los fármacos , Butionina Sulfoximina/farmacología , Calcio/metabolismo , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Citosol/efectos de los fármacos , Citosol/metabolismo , Células HEK293 , Homeostasis/efectos de los fármacos , Homeostasis/fisiología , Humanos , Activación del Canal Iónico/efectos de los fármacos , Activación del Canal Iónico/fisiología , Corteza Renal/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Estrés Oxidativo/efectos de los fármacos
13.
J Ethnopharmacol ; 266: 113394, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-32941971

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disease of the gastrointestinal tract, consisting of ulcerative colitis (UC) and Crohn's disease (CD). Gut microbiota and their metabolites may play a role in the pathogen of IBD, especially of the UC. Qingchang Huashi Formula (QHF), a traditional Chinese medicine formula, has shown therapeutic effect on treating UC based on the clinical practice without clear pharmacological mechanism. AIM OF THE STUDY: The aim of this study was to clearly define the effect of QHF and its components, Baitouweng (PBR) and Baizhi (ADR) on treating UC. MATERIALS AND METHODS: Pharmacodynamic effects of QHF and single herb were evaluated in dextran sulfate sodium (DSS) induced acute or chronic colitis mice. Body weight loss, disease activity index (DAI) and colon length were estimated. Histological changes were observed by H&E staining. The number and abundance of gut microbiota were measured with 16S rRNA sequencing. LC-MS and GC-MS were used to detect the concentration of metabolites (e.g., bile acids (BAs) and short chain fatty acids (SCFAs)). The goblet cell was observed by Alcian blue/periodic acid-Schiff (AB/PAS) straining and the crypt stem cell was estimated by immunohistochemical analyses. The colorectal tissues were used to detect levels of IL-1ß, IL-6 and TNF-α by ELISA or qRT-PCR. The expression of NLRP3, Caspase 1 and IL-1ß were examined by western blotting. RESULTS: QHF significantly inhibited colitis, protected mice from the loss of body weight and colon shorten. Comparatively, ADR and PBR showed strong efficacy in inhibiting DSS-induced colitis. We verified that while ADR was responsible for QHF's effect on maintaining gut microbiota homeostasis and metabolism, PBR was more prominent in keeping crypt stem cells proliferation and colonic goblet cells function. Moreover, we demonstrated that the alleviation of colitis by QHF was associated with the restoration of gut microbiota-metabolism homeostasis, protection of intestinal epithelial barrier and regulation of NLRP3/IL-1ß pathway. CONCLUSIONS: The finding of the present study suggested that QHF is curative in DSS-induced colitis by restoring gut microbiota-metabolism homeostasis and goblet cells function. An optimized QHF was constituted by ADR and PBR, which showed comparable efficacy on colitis to that of QHF. Our work probed out the active constitutes as well as the relevant pharmacological mechanisms of QHF, shedding light on potential new drug combination for the treatment of IBD.


Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Células Caliciformes/efectos de los fármacos , Animales , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/patología , Colon/efectos de los fármacos , Colon/microbiología , Colon/patología , Sulfato de Dextran , Modelos Animales de Enfermedad , Células Caliciformes/patología , Homeostasis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Ribosómico 16S
14.
Ecotoxicol Environ Saf ; 207: 111264, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-32911184

RESUMEN

This study investigated the effect of the herbicide metolachlor (MET) on the redox homeostasis of the freshwater green alga Pseudokirchneriella subcapitata. At low MET concentrations (≤40 µg L-1), no effects on algal cells were detected. The exposure of P. subcapitata to 45-235 µg L-1 MET induced a significant increase of reactive oxygen species (ROS). The intracellular levels of ROS were particularly increased at high (115 and 235 µg L-1) but environmentally relevant MET concentrations. The exposure of algal cells to 115 and 235 µg L-1 MET originated a decrease in the levels of antioxidants molecules (reduced glutathione and carotenoids) as well as a reduction of the activity of scavenging enzymes (superoxide dismutase and catalase). These results suggest that antioxidant (non-enzymatic and enzymatic) defenses were affected by the excess of MET. As consequence of this imbalance (ROS overproduction and decline of the antioxidant system), ROS inflicted oxidative injury with lipid peroxidation and damage of cell membrane integrity. The results provide further insights about the toxic modes of action of MET on a non-target organism and emphasize the relevance of toxicological studies in the assessment of the impact of herbicides in freshwater environments.


Asunto(s)
Acetamidas/toxicidad , Chlorophyceae/efectos de los fármacos , Herbicidas/toxicidad , Contaminantes Químicos del Agua/toxicidad , Antioxidantes/metabolismo , Catalasa/metabolismo , Chlorophyceae/fisiología , Agua Dulce , Glutatión/metabolismo , Homeostasis/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo
15.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artículo en Inglés | MEDLINE | ID: mdl-33374906

RESUMEN

Plant vacuoles are unique compartments that play a critical role in plant growth and development. The vacuolar H+-ATPase (V-ATPase), together with the vacuolar H+-pyrophosphatase (V-PPase), generates the proton motive force that regulates multiple cell functions and impacts all aspects of plant life. We investigated the effect of V-ATPase activity in the vacuole on plant growth and development. We used an Arabidopsisthaliana (L.) Heynh. double mutant, vha-a2 vha-a3, which lacks two tonoplast-localized isoforms of the membrane-integral V-ATPase subunit VHA-a. The mutant is viable but exhibits impaired growth and leaf chlorosis. Nitrate assimilation led to excessive ammonium accumulation in the shoot and lower nitrogen uptake, which exacerbated growth retardation of vha-a2 vha-a3. Ion homeostasis was disturbed in plants with missing VHA-a2 and VHA-a3 genes, which might be related to limited growth. The reduced growth and excessive ammonium accumulation of the double mutant was alleviated by potassium supplementation. Our results demonstrate that plants lacking the two tonoplast-localized subunits of V-ATPase can be viable, although with defective growth caused by multiple factors, which can be alleviated by adding potassium. This study provided a new insight into the relationship between V-ATPase, growth, and ammonium accumulation, and revealed the role of potassium in mitigating ammonium toxicity.


Asunto(s)
Compuestos de Amonio/metabolismo , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , ATPasas de Translocación de Protón Vacuolares/metabolismo , Vacuolas/metabolismo , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Proteínas de Arabidopsis/genética , Regulación del Desarrollo de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Homeostasis/efectos de los fármacos , Homeostasis/genética , Pirofosfatasa Inorgánica/genética , Pirofosfatasa Inorgánica/metabolismo , Transporte Iónico/efectos de los fármacos , Transporte Iónico/genética , Mutación , Nitrógeno/metabolismo , Raíces de Plantas/genética , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/metabolismo , Brotes de la Planta/genética , Brotes de la Planta/crecimiento & desarrollo , Brotes de la Planta/metabolismo , Potasio/farmacología , Fuerza Protón-Motriz , ATPasas de Translocación de Protón Vacuolares/genética , Vacuolas/genética
16.
Int J Mol Sci ; 22(1)2020 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-33375448

RESUMEN

Lithium is the prototype mood-stabilizer used for acute and long-term treatment of bipolar disorder. Cumulated translational research of lithium indicated the drug's neuroprotective characteristics and, thereby, has raised the option of repurposing it as a drug for neurodegenerative diseases. Lithium's neuroprotective properties rely on its modulation of homeostatic mechanisms such as inflammation, mitochondrial function, oxidative stress, autophagy, and apoptosis. This myriad of intracellular responses are, possibly, consequences of the drug's inhibition of the enzymes inositol-monophosphatase (IMPase) and glycogen-synthase-kinase (GSK)-3. Here we review lithium's neurobiological properties as evidenced by its neurotrophic and neuroprotective properties, as well as translational studies in cells in culture, in animal models of Alzheimer's disease (AD) and in patients, discussing the rationale for the drug's use in the treatment of AD.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Autofagia/efectos de los fármacos , Homeostasis/efectos de los fármacos , Litio/uso terapéutico , Fármacos Neuroprotectores/farmacología , Animales , Apoptosis/efectos de los fármacos , Trastorno Bipolar/tratamiento farmacológico , Reposicionamiento de Medicamentos , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Litio/farmacología , Litio/toxicidad , Enfermedades Neurodegenerativas/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Monoéster Fosfórico Hidrolasas/metabolismo
17.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-33334069

RESUMEN

Inflammatory colon diseases, which are a global health concern, include a variety of gastrointestinal tract disorders, such as inflammatory bowel disease and colon cancer. The pathogenesis of these colon disorders involves immune alterations with the pronounced infiltration of innate and adaptive immune cells into the intestines and the augmented expression of mucosal pro-inflammatory cytokines stimulated by commensal microbiota. Epidemiological studies during the past half century have shown that the proportion of obese people in a population is associated with the incidence and pathogenesis of gastrointestinal tract disorders. The advancement of understanding of the immunological basis of colon disease has shown that adipocyte-derived biologically active substances (adipokines) modulate the role of innate and adaptive immune cells in the progress of intestinal inflammation. The biomedical significance in immunological homeostasis of adipokines, including adiponectin, leptin, apelin and resistin, is clear. In this review, we highlight the existing literature on the effect and contribution of adipokines to the regulation of immunological homeostasis in inflammatory colon diseases and discuss their crucial roles in disease etiology and pathogenesis, as well as the implications of these results for new therapies in these disorders.


Asunto(s)
Adipoquinas/metabolismo , Susceptibilidad a Enfermedades , Homeostasis , Inmunomodulación , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/metabolismo , Adipoquinas/farmacología , Tejido Adiposo/inmunología , Tejido Adiposo/metabolismo , Animales , Biomarcadores , Homeostasis/efectos de los fármacos , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Sistema Inmunológico/patología , Inmunomodulación/efectos de los fármacos , Enfermedades Inflamatorias del Intestino/patología
18.
ACS Appl Mater Interfaces ; 12(52): 57757-57767, 2020 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-33319976

RESUMEN

As a rapid proliferating tissue, tumor cells have to optimize nutrient utilization to withstand harsh conditions. Several approaches have been explored to inhibit the growth and metastasis of tumor by disrupting the reprogrammed tumor metabolism. However, nutrient limitations within solid tumors may induce the metabolic flexibility of malignant cells to sustain growth and survival using one nutrient to fill metabolite pools normally supplied by the other. To overcome this predicament, a promising click-nucleic-acid-containing platform for codelivery of rapamycin, anti-PFKFB4 siRNA, and targeting ligand aptamer AS1411 was applied. PFKFB4 could act as a promising target for tumor therapy for being a molecular fulcrum that could couple glycolysis to autophagy by promoting aggressive metastatic tumors. The downregulation of PFKFB4 can help inhibit the SRC3/Akt/mTOR pathway, leading autophagy to the direction of promoting apoptosis of tumor cells, which is induced by the collapse of tumor cellular homeostasis, while low dosages of rapamycin could decrease surgery-induced immune dysfunction. Enhanced tumor autophagy, favorable in vivo antitumor efficacy, and effective systematic immune activation are observed after treatment, suggesting that autophagy and glycolysis can serve as an integrated target for tumor treatment.


Asunto(s)
Autofagia , Portadores de Fármacos/química , Glucólisis/efectos de los fármacos , Homeostasis , Neoplasias/terapia , Poli T/química , Animales , Aptámeros de Nucleótidos/metabolismo , Autofagia/efectos de los fármacos , Autofagia/genética , Secuencia de Bases , Células HEK293 , Homeostasis/efectos de los fármacos , Homeostasis/genética , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Fosfofructoquinasa-2/deficiencia , Fosfofructoquinasa-2/genética , Polietilenglicoles/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/química , ARN Interferente Pequeño/genética , Sirolimus/administración & dosificación , Sirolimus/química , Sirolimus/farmacología
19.
Mem Inst Oswaldo Cruz ; 115: e200458, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33237133

RESUMEN

BACKGROUND: Calotropis procera latex protein fraction (LP) was previously shown to protect animals from septic shock. Further investigations showed that LP modulate nitric oxide and cytokines levels. OBJECTIVES: To evaluate whether the protective effects of LP, against lethal bacterial infection, is observed in its subfractions (LPPII and LPPIII). METHODS: Subfractions (5 and 10 mg/kg) were tested by i.p. administration, 24 h before challenging with lethal injection (i.p.) of Salmonella Typhimurium. LPPIII (5 mg/kg) which showed higher survival rate was assayed to evaluate bacterial clearance, histopathology, leukocyte recruitment, plasma coagulation time, cytokines and NO levels. FINDINGS: LPPIII protected 70% of animals of death. The animals given LPPIII exhibited reduced bacterial load in blood and peritoneal fluid after 24 h compared to the control. LPPIII promoted macrophage infiltration in spleen and liver. LPPIII restored the coagulation time of infected animals, increased IL-10 and reduced NO in blood. MAIN CONCLUSIONS: LPPIII recruited macrophages to the target organs of bacterial infection. This addressed inflammatory stimulus seems to reduce bacterial colonisation in spleen and liver, down regulate bacterial spread and contribute to avoid septic shock.


Asunto(s)
Antibacterianos/uso terapéutico , Calotropis/química , Homeostasis/efectos de los fármacos , Inflamación/tratamiento farmacológico , Látex/química , Extractos Vegetales/farmacología , Proteínas de Plantas/uso terapéutico , Infecciones por Salmonella/tratamiento farmacológico , Animales , Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Regulación hacia Abajo , Proteínas de Plantas/aislamiento & purificación , Proteínas de Plantas/farmacología , Infecciones por Salmonella/inmunología , Infecciones por Salmonella/microbiología
20.
Nat Commun ; 11(1): 5808, 2020 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-33199701

RESUMEN

Skeletal muscle promotes metabolic balance by regulating glucose uptake and the stimulation of multiple interorgan crosstalk. We show here that the catalytic activity of Vav2, a Rho GTPase activator, modulates the signaling output of the IGF1- and insulin-stimulated phosphatidylinositol 3-kinase pathway in that tissue. Consistent with this, mice bearing a Vav2 protein with decreased catalytic activity exhibit reduced muscle mass, lack of proper insulin responsiveness and, at much later times, a metabolic syndrome-like condition. Conversely, mice expressing a catalytically hyperactive Vav2 develop muscle hypertrophy and increased insulin responsiveness. Of note, while hypoactive Vav2 predisposes to, hyperactive Vav2 protects against high fat diet-induced metabolic imbalance. These data unveil a regulatory layer affecting the signaling output of insulin family factors in muscle.


Asunto(s)
Biocatálisis , Homeostasis , Metabolismo , Músculo Esquelético/crecimiento & desarrollo , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogénicas c-vav/metabolismo , Transducción de Señal , Adipocitos Blancos/efectos de los fármacos , Adipocitos Blancos/metabolismo , Tejido Adiposo Pardo/metabolismo , Animales , Biocatálisis/efectos de los fármacos , Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Línea Celular , Tamaño de la Célula/efectos de los fármacos , Genotipo , Glucosa/farmacología , Homeostasis/efectos de los fármacos , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Células Musculares/citología , Células Musculares/efectos de los fármacos , Células Musculares/metabolismo , Músculo Esquelético/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Proteína de Unión al GTP rac1/metabolismo
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