RESUMEN
Cardiotoxicity caused by adrenergic receptor agonists overdosing or stress-induced catecholamine release promotes cardiomyopathy, resembling Takotsubo cardiomyopathy (TC). TC is characterized by transient regional systolic dysfunction of the left ventricle. The animal models of TC and modalities for assessing regional wall motion abnormalities in animal models are lacking. We previously reported the protective role of a small noncoding microRNA-204-5p (miR-204) in cardiomyopathies, but its role in TC remains unknown. Here we compared the impact of miR-204 absence on phenylephrine (PE)-induced and transaortic constriction (TAC)-induced changes in cardiac muscle motion in the posterior and anterior apical, mid, and basal segments of the left ventricle using 2-dimensional speckle-tracking echocardiography (2-STE). Wildtype and miR-204-/- mice were subjected to cardiac stress in the form of PE for four weeks or TAC-induced pressure overload for five weeks. PE treatment increased longitudinal and radial motion in the apex of the left ventricle and shortened the peak motion time of all left ventricle segments. The TAC led to decreased longitudinal and radial motion in the left ventricle segments, and there was no difference in the peak motion time. Compared to wildtype mice, PE-induced peak cardiac muscle motion time in the anterior base of the left ventricle was significantly earlier in the miR-204-/- mice. There was no difference in TAC-induced peak cardiac muscle motion time between wildtype and miR-204-/- mice. Our findings demonstrate that PE and TAC induce regional wall motion abnormalities that 2-STE can detect. It also highlights the role of miR-204 in regulating cardiac muscle motion during catecholamine-induced cardiotoxicity.
Asunto(s)
Cardiomiopatías , MicroARNs , Cardiomiopatía de Takotsubo , Animales , Ratones , Fenilefrina/farmacología , Cardiotoxicidad , Ecocardiografía/métodos , MicroARNs/genéticaRESUMEN
Zebrafish is a useful model for understanding human genetics and diseases and has evolved into a prominent scientific research model. The genetic structure of zebrafish is 70% identical to that of humans. Its small size, low cost, and transparent embryo make it a valuable tool in experimentation. Zebrafish and mammals possess the same molecular mechanism of thyroid organogenesis and development. Thus, thyroid hormone signaling, embryonic development, thyroid-related disorders, and novel genes involved in early thyroid development can all be studied using zebrafish as a model. Here in this review, we emphasize the evolving role of zebrafish as a possible tool for studying the thyroid gland in the context of physiology and pathology. The transcription factors nkx2.1a, pax2a, and hhex which contribute a pivotal role in the differentiation of thyroid primordium are discussed. Further, we have described the role of zebrafish as a model for thyroid cancer, evaluation of defects in thyroid hormone transport, thyroid hormone (TH) metabolism, and as a screening tool to study thyrotoxins. Hence, the present review highlights the role of zebrafish as a novel approach to understand thyroid development and organogenesis.
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Descubrimiento de Drogas , Enfermedades de la Tiroides , Pez Cebra , Animales , Modelos Animales de Enfermedad , Regulación del Desarrollo de la Expresión Génica , Humanos , Enfermedades de la Tiroides/tratamiento farmacológico , Enfermedades de la Tiroides/genética , Hormonas Tiroideas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Pez Cebra/metabolismoRESUMEN
MicroRNAs (miRs) are small non-coding RNAs that regulate the target gene expression. A change in miR profile in the pancreatic islets during diabetes is known, and multiple studies have demonstrated that miRs influence the pancreatic ß-cell function. The miR-204 is highly expressed in the ß-cells and reported to regulate insulin synthesis. Here we investigated whether the absence of miR-204 rescues the impaired glycemic control and obesity in the genetically diabetic (db/db) mice. We found that the db/db mice overexpressed miR-204 in the islets. The db/db mice lacking miR-204 (db/db-204-/-) initially develops hyperglycemia and obesity like the control (db/db) mice but later displayed a gradual improvement in glycemic control despite remaining obese. The db/db-204-/- mice had a lower fasting blood glucose and higher serum insulin level compared to the db/db mice. A homeostatic model assessment (HOMA) suggests the improvement of ß-cell function contributes to the improvement in glycemic control in db/db-204-/- mice. Next, we examined the cellular proliferation and endoplasmic reticulum (ER) stress and found an increased frequency of proliferating cells (PCNA + ve) and a decreased CHOP expression in the islets of db/db-204-/- mice. Next, we determined the effect of systemic miR-204 inhibition in improving glycemic control in the high-fat diet (HFD)-fed insulin-resistant mice. MiR-204 inhibition for 6 weeks improved the HFD-triggered impairment in glucose disposal. In conclusion, the absence of miR-204 improves ß-cell proliferation, decreases islet ER stress, and improves glycemic control with limited change in body weight in obese mice.
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Células Secretoras de Insulina/fisiología , MicroARNs/genética , Obesidad/genética , Animales , Glucemia/genética , Glucemia/metabolismo , Proliferación Celular/fisiología , Diabetes Mellitus Experimental/genética , Dieta Alta en Grasa/efectos adversos , Estrés del Retículo Endoplásmico/fisiología , Femenino , Control Glucémico , Hiperglucemia/genética , Insulina/sangre , Insulina/genética , Masculino , Ratones Noqueados , Ratones Mutantes , MicroARNs/antagonistas & inhibidoresRESUMEN
SUMOylation is a posttranslational modification of lysine residues. Modification of proteins by small ubiquitin-like modifiers (SUMO)1, -2, and -3 can achieve varied, and often unique, physiological and pathological effects. We looked for SUMO2-specific effects on vascular endothelial function. SUMO2 expression was upregulated in the aortic endothelium of hypercholesterolemic low-density lipoprotein receptor-deficient mice and was responsible for impairment of endothelium-dependent vasorelaxation in these mice. Moreover, overexpression of SUMO2 in aortas ex vivo, in cultured endothelial cells, and transgenically in the endothelium of mice increased vascular oxidative stress and impaired endothelium-dependent vasorelaxation. Conversely, inhibition of SUMO2 impaired physiological endothelium-dependent vasorelaxation in normocholesterolemic mice. These findings indicate that while endogenous SUMO2 is important in maintenance of normal endothelium-dependent vascular function, its upregulation impairs vascular homeostasis and contributes to hypercholesterolemia-induced endothelial dysfunction.NEW & NOTEWORTHY Sumoylation is known to impair vascular function; however, the role of specific SUMOs in the regulation of vascular function is not known. Using multiple complementary approaches, we show that hyper-SUMO2ylation impairs vascular endothelial function and increases vascular oxidative stress, whereas endogenous SUMO2 is essential for maintenance of normal physiological function of the vascular endothelium.
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Endotelio Vascular/metabolismo , Hipercolesterolemia/metabolismo , Estrés Oxidativo , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Vasodilatación , Animales , Dieta Alta en Grasa/efectos adversos , Endotelio Vascular/fisiología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Hipercolesterolemia/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genéticaRESUMEN
BACKGROUND: The objective of this study was to determine if RAS bioactive enzymes and peptides are perturbed in acute pancreatitis and associated lung injury. METHODS: The intervention group of mice were treated with ten hourly intraperitoneal (i.p.) injections of caerulein (50 µg/kg) to induce acute pancreatitis. Animals were euthanized, samples of pancreas, lung and blood were collected, and plasma was prepared and stored for subsequent analysis. ACE and ACE2 activities were determined by spectrofluorometric assay. ACE, ACE2, Ang II and Ang-(1-7) levels were quantified by ELISA. RESULTS: There was a significant decrease in ACE2 enzymatic activity in pancreatic and lung tissues of mice with acute pancreatitis. In contrast, there were no significant changes in measured levels of ACE and ACE2 in the pancreas, and lung or activity of ACE in pancreatic and lung tissue following acute pancreatitis. There were no significant differences in the activities and levels of circulating ACE and ACE2 following acute pancreatitis. The ACE to ACE2 activity ratio was markedly increased in pancreatic and lung tissues of mice with acute pancreatitis. No significant changes were observed in the levels of Ang II except for a decrease in lung tissue. No changes were observed in Ang-(1-7) levels in pancreas, lung and plasma between the groups. The Ang II to Ang-(1-7) ratio was increased in the pancreas but was decreased in the lung following caerulein treatment. CONCLUSION: These data suggest dysregulation of RAS in acute pancreatitis as evidenced by altered Ang II/Ang-(1-7) levels induced by the imbalance of ACE/ACE2 activity.
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Angiotensina II/metabolismo , Ceruletida/toxicidad , Pancreatitis/inducido químicamente , Pancreatitis/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Angiotensina I/genética , Angiotensina I/metabolismo , Angiotensina II/sangre , Angiotensina II/genética , Enzima Convertidora de Angiotensina 2 , Animales , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Distribución Aleatoria , Sistema Renina-Angiotensina/fisiologíaRESUMEN
The activation of Kupffer cells, resident macrophages in the liver, is closely associated with the inflammatory response during sepsis, which leads to multiple-organ failure. However, how Kupffer cell activation affects adhesion molecules (ICAM-1 and VCAM-1) in sepsis has not been determined. This study investigated Kupffer cell inactivation's (by gadolinium chloride; GdCl3) effects on adhesion molecule expression in CLP-induced sepsis. The induction of sepsis resulted in increased expression of liver and lung ICAM-1 and VCAM-1. GdCl3 pretreatment significantly decreased liver ICAM-1 expression but had no effect on VCAM-1 expression. In contrast, GdCl3 pretreatment had no effect on sepsis-induced increased adhesion molecule expression in the lungs. Similarly, the immunoreactivity of ICAM-1 was decreased in liver sinusoidal endothelial cells but increased in pulmonary endothelial cells in septic mice pretreated with GdCl3. Further, GdCl3 pretreatment had no effect on the immunoreactivity of VCAM-1 in endothelial cells of the liver and lungs. Hence, the findings of this study demonstrate the differential effects of Kupffer cell inactivation on liver and lung adhesion molecules and suggest the complexity of their involvement in the pathophysiology of sepsis.
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Macrófagos del Hígado , Sepsis , Animales , Ratones , Molécula 1 de Adhesión Intercelular , Molécula 1 de Adhesión Celular Vascular , Células Endoteliales , PuncionesRESUMEN
Downregulation of endothelial Sirtuin1 (Sirt1) in insulin resistant states contributes to vascular dysfunction. Furthermore, Sirt1 deficiency in skeletal myocytes promotes insulin resistance. Here, we show that deletion of endothelial Sirt1, while impairing endothelial function, paradoxically improves skeletal muscle insulin sensitivity. Compared to wild-type mice, male mice lacking endothelial Sirt1 (E-Sirt1-KO) preferentially utilize glucose over fat, and have higher insulin sensitivity, glucose uptake, and Akt signaling in fast-twitch skeletal muscle. Enhanced insulin sensitivity of E-Sirt1-KO mice is transferrable to wild-type mice via the systemic circulation. Endothelial Sirt1 deficiency, by inhibiting autophagy and activating nuclear factor-kappa B signaling, augments expression and secretion of thymosin beta-4 (Tß4) that promotes insulin signaling in skeletal myotubes. Thus, unlike in skeletal myocytes, Sirt1 deficiency in the endothelium promotes glucose homeostasis by stimulating skeletal muscle insulin sensitivity through a blood-borne mechanism, and augmented secretion of Tß4 by Sirt1-deficient endothelial cells boosts insulin signaling in skeletal muscle cells.
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Resistencia a la Insulina , Sirtuina 1 , Animales , Masculino , Ratones , Células Endoteliales , Endotelio , Glucosa , Insulina , Músculo Esquelético , Secretoma , Sirtuina 1/genéticaRESUMEN
Endocytosis is a fundamental mechanism by which cells perform housekeeping functions. It occurs via a variety of mechanisms and involves many regulatory proteins. The GTPase dynamin acts as a "molecular scissor" to form endocytic vesicles and is a critical regulator among the proteins involved in endocytosis. Some GTPases (e.g., Cdc42, arf6, RhoA), membrane proteins (e.g., flotillins, tetraspanins), and secondary messengers (e.g., calcium) mediate dynamin-independent endocytosis. These pathways may be convergent, as multiple pathways exist in a single cell. However, what determines the specific path of endocytosis is complex and challenging to comprehend. This review summarizes the mechanisms of dynamin-independent endocytosis, the involvement of microRNAs, and factors that contribute to the cellular decision about the specific route of endocytosis.
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Dinaminas , Endocitosis , Dinaminas/metabolismo , Endocitosis/fisiología , Vesículas Transportadoras/metabolismoRESUMEN
The blood levels of microRNA-122 (miR-122) is associated with the severity of cardiovascular disorders, and targeting it with efficient and safer miR inhibitors could be a promising approach. Here, we report the generation of a γ-peptide nucleic acid (γPNA)-based miR-122 inhibitor (γP-122-I) that rescues vascular endothelial dysfunction in mice fed a high-fat diet. We synthesized diethylene glycol-containing γP-122-I and found that its systemic administration counteracted high-fat diet (HFD)-feeding-associated increase in blood and aortic miR-122 levels, impaired endothelial function, and reduced glycemic control. A comprehensive safety analysis established that γP-122-I affects neither the complete blood count nor biochemical tests of liver and kidney functions during acute exposure. In addition, long-term exposure to γP-122-I did not change the overall adiposity, or histology of the kidney, liver, and heart. Thus, γP-122-I rescues endothelial dysfunction without any evidence of toxicity in vivo and demonstrates the suitability of γPNA technology in generating efficient and safer miR inhibitors.
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Enfermedades Cardiovasculares/tratamiento farmacológico , Endotelio Vascular/efectos de los fármacos , MicroARNs/antagonistas & inhibidores , Ácidos Nucleicos de Péptidos/farmacología , Adiposidad/efectos de los fármacos , Animales , Recuento de Células Sanguíneas , Glucemia/metabolismo , Peso Corporal , Dieta Alta en Grasa , Diseño de Fármacos , Pruebas de Función Renal , Pruebas de Función Hepática , Ratones , Ratones Endogámicos C57BL , MicroARNs/sangre , Músculo Liso Vascular/efectos de los fármacos , Ácidos Nucleicos de Péptidos/efectos adversosRESUMEN
BACKGROUND: MicroRNAs regulate cardiac hypertrophy development, which precedes and predicts the risk of heart failure. microRNA-204-5p (miR-204) is well expressed in cardiomyocytes, but its role in developing cardiac hypertrophy and cardiac dysfunction (CH/CD) remains poorly understood. METHODS: We performed RNA-sequencing, echocardiographic, and molecular/morphometric analysis of the heart of mice lacking or overexpressing miR-204 five weeks after trans-aortic constriction (TAC). The neonatal rat cardiomyocytes, H9C2, and HEK293 cells were used to determine the mechanistic role of miR-204. RESULTS: The stretch induces miR-204 expression, and miR-204 inhibits the stretch-induced hypertrophic response of H9C2 cells. The mice lacking miR-204 displayed a higher susceptibility to CH/CD during pressure overload, which was reversed by the adeno-associated virus serotype-9-mediated cardioselective miR-204 overexpression. Bioinformatic analysis of the cardiac transcriptomics of miR-204 knockout mice following pressure overload suggested deregulation of apelin-receptor (APJ) signalling. We found that the stretch-induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation and hypertrophy-related genes expression depend on the APJ, and both of these effects are subject to miR-204 levels. The dynamin inhibitor dynasore inhibited both stretch-induced APJ endocytosis and ERK1/2 activation. In contrast, the miR-204-induced APJ endocytosis was neither inhibited by dynamin inhibitors (dynasore and dyngo) nor associated with ERK1/2 activation. We find that the miR-204 increases the expression of ras-associated binding proteins (e.g., Rab5a, Rab7) that regulate cellular endocytosis. CONCLUSIONS: Our results show that miR-204 regulates trafficking of APJ and confers resistance to pressure overload-induced CH/CD, and boosting miR-204 can inhibit the development of CH/CD.
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Receptores de Apelina/antagonistas & inhibidores , Cardiomegalia/prevención & control , MicroARNs/farmacología , Animales , Receptores de Apelina/metabolismo , Cardiomegalia/tratamiento farmacológico , Modelos Animales de Enfermedad , Cardiopatías/tratamiento farmacológico , Cardiopatías/prevención & control , MicroARNs/metabolismo , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
Significance: Inflammation is a normal response to injury, but uncontrolled inflammation can lead to several diseases. In recent years, research has shown endogenously synthesized hydrogen sulfide (H2S) to be a novel mediator of inflammation. This review summarizes the current understanding and recent advances of H2S role with respect to inflammation in different diseases. Recent Advances: Promising early results from clinical studies suggest an important role of H2S in human inflammatory disease. Critical Issues: Defining the precise mechanism by which H2S contributes to inflammation is a complex challenge, and there is active ongoing research that is focused on addressing this question. Most of this work has been conducted on animal models of human disease and isolated/cultured cells, and its translation to the clinic is another challenge in the area of H2S research. Future Directions: Defining the mechanism by which H2S acts as an inflammatory mediator will help us better understand different inflammatory diseases and help develop novel therapeutic approaches for these diseases.
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Sulfuro de Hidrógeno/metabolismo , Inflamación/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Técnicas In Vitro , Transducción de SeñalRESUMEN
miRNA-155 (miR-155) is overexpressed in various types of lymphomas and leukemias, suggesting that targeting miR-155 could be a potential platform for the development of precision medicine. Here, we tested the anticancer activity of novel, chemically modified, triplex peptide nucleic acid (PNA)-based antimiRs compared with the current state-of-the-art conventional full-length antimiRs. Next-generation modified PNAs that bound miR-155 by Watson-Crick and Hoogsteen domains possessed superior therapeutic efficacy in vivo and ex vivo compared with conventional full-length anti-miR-155. The efficacy of anti-miR-155 targeting in multiple lymphoma cell lines was comprehensively corroborated by gene expression, Western blot analysis, and cell viability-based functional studies. Finally, preclinical testing in vivo in xenograft mouse models containing lymphoma cell lines demonstrated that treatment with the miR-155-targeting next-generation antimiR resulted in a significant decrease in miR-155 expression, followed by reduced tumor growth. These findings support the effective therapeutic application of chemically modified triplex PNAs to target miR-155 to treat lymphoma. Overall, the present proof-of-concept study further implicates the potential for next-generation triplex gamma PNAs to target other miRNAs for treating cancer. SIGNIFICANCE: This study demonstrates the utility of novel oncomiR inhibitors as cancer therapeutics, providing a new approach for targeting miRNAs and other noncoding RNAs.
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Regulación Neoplásica de la Expresión Génica , Linfoma/terapia , MicroARNs/antagonistas & inhibidores , Ácidos Nucleicos de Péptidos/química , Ácidos Nucleicos de Péptidos/farmacología , Animales , Apoptosis , Proliferación Celular , Femenino , Humanos , Linfoma/genética , Linfoma/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , MicroARNs/genética , Prueba de Estudio Conceptual , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
microRNAs (miRs) are emerging as attractive therapeutic targets because of their small size, specific targetability, and critical role in disease pathogenesis. However, <20 miR targeting molecules have entered clinical trials, and none progressed to phase III. The difficulties in miR target identification, the moderate efficacy of miR inhibitors, cell type-specific delivery, and adverse outcomes have impeded the development of miR therapeutics. These hurdles are rooted in the functional complexity of miR's role in disease and sequence complementarity-dependent/-independent effects in nontarget tissues. The advances in understanding miR's role in disease, the development of efficient miR inhibitors, and innovative delivery approaches have helped resolve some of these hurdles. In this review, we provide a multidisciplinary viewpoint on the challenges and opportunities in the development of miR therapeutics.
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MicroARNs/uso terapéutico , Animales , Exosomas/metabolismo , Técnicas de Transferencia de Gen , Humanos , Liposomas/química , MicroARNs/administración & dosificación , MicroARNs/sangre , Modelos Biológicos , Nanopartículas/químicaRESUMEN
Cationic polymeric nanoformulations have been explored to increase the transfection efficiency of small molecules and nucleic acid-based drugs. However, an excessive positive charge density often leads to severe cell and tissue-based toxicity that restricts the clinical translation of cationic polymeric nanoformulations. Herein, we investigate a series of cationic poly(lactic-co-glycolic acid) (PLGA)-histidine-based nanoformulations for enhanced cytoplasmic delivery with minimal toxicity. PLGA/poly-l-histidine nanoparticles show promising physico-biochemical features and transfection efficiency in a series of in vitro and cell culture-based studies. Further, the use of acetone/dichloromethane as a solvent mixture during the formulation process significantly improves the morphology and size distribution of PLGA/poly-l-histidine nanoparticles. PLGA/poly-l-histidine nanoformulations undergo clathrin-mediated endocytosis. A contrast-matched small-angle neutron scattering experiment confirmed poly-l-histidine's distribution on the PLGA nanoformulations. PLGA/poly-l-histidine formulations containing paclitaxel as a small molecule-based drug and peptide nucleic acids targeting microRNA-155 as nucleic acid analog are efficacious in in vitro and in vivo studies. PLGA/poly-l-histidine NPs significantly decrease tumor growth in PNA-155 (â¼6 fold) and paclitaxel (â¼6.5 fold) treatment groups in a lymphoma cell line derived xenograft mice model without inducing any toxicity. Hence, PLGA/poly-l-histidine nanoformulations exhibit substantial transfection efficiency and are safe to deliver reagents ranging from small molecules to synthetic nucleic acid analogs and can serve as a novel platform for drug delivery.
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Antineoplásicos/uso terapéutico , Portadores de Fármacos/química , Linfoma/tratamiento farmacológico , Nanopartículas/química , Paclitaxel/uso terapéutico , Ácidos Nucleicos de Péptidos/uso terapéutico , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Portadores de Fármacos/metabolismo , Endocitosis/fisiología , Femenino , Histidina/química , Histidina/metabolismo , Humanos , Ratones Endogámicos NOD , MicroARNs/antagonistas & inhibidores , Nanopartículas/metabolismo , Paclitaxel/farmacología , Ácidos Nucleicos de Péptidos/farmacología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Methionine is one of the essential amino acids and plays a vital role in various cellular processes. Reports advocate that methionine restriction and supplementation provide promising outcomes, and its regulation is critical for maintaining a healthy life. Dietary methionine restriction in houseflies and rodents has been proven to extend lifespan. Contrary to these findings, long-term dietary restriction of methionine leads to adverse events such as bone-related disorders, stunted growth, and hyperhomocysteinemia. Conversely, dietary supplementation of methionine improves hepatic steatosis, insulin resistance, inflammation, fibrosis, and bone health. However, a high level of methionine intake shows adverse effects such as hyperhomocysteinemia, reduced body weight, and increased cholesterol levels. Therefore, dietary methionine in a safe dose could have medicinal values. Hence, this review is aimed to provide a snapshot of the dietary role and regulation of methionine in the modulation of health and age-related diseases.
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Resistencia a la Insulina , Metionina , Peso Corporal , Dieta , Humanos , LongevidadRESUMEN
An impaired decline in blood pressure at rest is typical in people with diabetes, reflects endothelial dysfunction, and increases the risk of end-organ damage. Here we report that microRNA-204 (miR-204) promotes endothelial dysfunction and impairment in blood pressure decline during inactivity. We show that db/db mice overexpress miR-204 in the aorta, and its absence rescues endothelial dysfunction and impaired blood pressure decline during inactivity despite obesity. The vascular miR-204 is sensitive to microbiota, and microbial suppression reversibly decreases aortic miR-204 and improves endothelial function, while the endothelial function of mice lacking miR-204 remained indifferent to the microbial alterations. We also show that the circulating miR-122 regulates vascular miR-204 as miR-122 inhibition decreases miR-204 in endothelial cells and aorta. This study establishes that miR-204 impairs endothelial function, promotes impairment in blood pressure decline during rest, and opens avenues for miR-204 inhibition strategies against vascular dysfunction.
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Endotelio Vascular/fisiopatología , MicroARNs/genética , Obesidad/genética , Animales , Determinación de la Presión Sanguínea , Heces/microbiología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Microbiota , Obesidad/fisiopatología , Regulación hacia ArribaRESUMEN
OBJECTIVE: To determine alterations of circulating levels of hydrogen sulfide and substance P in patients with sepsis compared to non-sepsis patients with similar disease severity and organ dysfunction. METHODS: This study included 23 septic and 14 non-septic patients during 2015-16 study period at the Christchurch Hospital Intensive Care Unit, Christchurch, New Zealand. Blood samples were collected from the time of admission to 96 h, with collection at different time points (0 h, 12 h, 24 h, 48 h, 72 h and 96 h) and subjected to measurement of hydrogen sulfide, substance P, procalcitonin, C-reactive protein, interleukin-6 and lactate levels. RESULTS: Patients with sepsis showed higher circulating hydrogen sulfide and substance P levels compared to patients without sepsis. Hydrogen sulfide levels were significantly higher at 12 h (1.45 vs 0.75 µM; p < 0.05) and 24 h (1.11 vs 0.72 µM; p < 0.01), whereas substance P levels were higher at 48 h (0.55 vs 0.31 ng/mL; p < 0.05). Increased hydrogen sulfide and substance P levels in septic patients were associated with increased levels of inflammatory mediators - procalcitonin, C-reactive protein and interleukin-6. CONCLUSIONS: These results provide evidence that higher circulating levels of hydrogen sulfide and substance P are associated with increased inflammatory response in patients with sepsis.
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Sulfuro de Hidrógeno/sangre , Sepsis/sangre , Sustancia P/sangre , Anciano , Proteína C-Reactiva/análisis , Calcitonina/sangre , Femenino , Humanos , Unidades de Cuidados Intensivos , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Precursores de Proteínas/sangre , Sepsis/tratamiento farmacológicoRESUMEN
Sepsis remains a common clinical problem with significant mortality. Activation of the Kupffer cells during sepsis is associated with systemic inflammatory response and multiple organ failure. Kupffer cell activation also leads to structural changes in the liver sinusoidal endothelial cells (LSECs) during endotoxemia. However, these effects remain to be elucidated in caecal-ligation and puncture (CLP)-induced polymicrobial sepsis. To investigate the role of Kupffer cells on LSECs fenestrae and inflammation during CLP-induced sepsis, sepsis was induced by CLP and mice were treated with gadolinium chloride (GdCl3) before CLP-induced sepsis, to inactivate Kupffer cells. Mice were sacrificed after 8âh. Blood, liver, and lung tissues were collected and processed to measure LSECs fenestration, myeloperoxidase (MPO) activity, alanine transaminase (ALT) and aspartate aminotransferase (AST) activity, histological examination, and various cytokines/chemokines levels. LSECs fenestrae was studied using scanning electron micrographs of the LSECs. Strikingly, CLP mice treated with GdCl3 were protected against liver injury as evidenced by decreased LSECs defenestration and damage, MPO, ALT and AST activities, liver tissue damage, and inflammatory cytokines TNF-α, IL-6 and IL-1ß, and chemokines MCP-1 and MIP-2α. However, CLP mice treated with GdCl3 had no protection against increased lung MPO activity, tissue damage, inflammatory cytokines, and chemokines. Treatment with GdCl3 also had no effect on the systemic inflammatory response as shown by no change in the circulatory inflammatory cytokines and chemokines following CLP-induced sepsis. Collectively, these data suggest that inactivation of Kupffer cells by GdCl3 protects the liver but had no effect on lung injury or inflammation and systemic inflammatory response following CLP-induced sepsis.
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Inflamación/metabolismo , Macrófagos del Hígado/metabolismo , Hígado/inmunología , Hígado/metabolismo , Sepsis/inmunología , Sepsis/metabolismo , Alanina Transaminasa/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CXCL2/metabolismo , Ensayo de Inmunoadsorción Enzimática , Gadolinio/toxicidad , Inflamación/inmunología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Macrófagos del Hígado/inmunología , Hígado/lesiones , Pulmón/inmunología , Pulmón/metabolismo , Lesión Pulmonar/inmunología , Lesión Pulmonar/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Electrónica de Rastreo , Peroxidasa/metabolismo , Sepsis/etiología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0160521.].