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1.
Chem Biol Interact ; 321: 109031, 2020 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-32142722

RESUMEN

Reactive oxygen species (ROS) is mainly produced as a by-product from electron transport chain (ETC) of mitochondria and effectively eliminated by cellular antioxidants. However, 2-chloroethyl ethyl sulfide (CEES) exposure to keratinocytes declined antioxidant capacity and increased accumulation of ROS triggered alteration of mitochondrial activity and apoptosis is lacking. Our findings demonstrated that the electron leakage from the impaired ETC, leading to the accumulation of ROS was gradually elevating with increasing concentration of CEES exposure, which decline the activity of superoxide dismutase (SOD), manganese SOD (MnSOD) and copper-zinc SOD (Cu-ZnSOD) in keratinocytes. Further, excess accumulation of ROS, decreased the mitochondrial membrane potential (ΔΨm) and increased the mitochondrial mass with increasing dose of CEES. CEES exposure provoked the decrease in expression of transcription factor A mitochondrial (TFAM), augmented mitochondrial DNA (mtDNA) damage and altered the mtDNA-encoded oxidative phosphorylation (OXPHOS) subunits. Moreover, fragmented mtDNA translocated into cytosol, where it activated cGAS-STING and interferon regulatory factor3 (IRF3), coinciding with the increased expression of inflammatory mediators and alteration of cell-to-cell communication markers. Pre-treatment of N-acetyl-l-cysteine (NAC) or L-Nω-nitroarginine methyl ester (NAME), hydralazine hydrochloride (Hyd·HCl) or ERK1/2 or phosphoinositide3-kinase (PI3-K)/Akt inhibitors in keratinocyte cells significantly restored the CEES effect. Our findings suggest that CEES-induced mitochondrial ROS production and accumulation leads to mitochondrial dysfunction and inflammatory response in keratinocytes. However, treatment of antioxidants or ERK1/2 or PI3-K/Akt inhibitors is a novel therapeutic option for the keratinocytes complication.


Asunto(s)
Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Gas Mostaza/análogos & derivados , Especies Reactivas de Oxígeno/metabolismo , Animales , Línea Celular , Sustancias para la Guerra Química/toxicidad , Daño del ADN , ADN Mitocondrial/metabolismo , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Irritantes/toxicidad , Queratinocitos/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Pelados , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Gas Mostaza/toxicidad , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
2.
Chem Biol Interact ; 318: 108971, 2020 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-32017913

RESUMEN

Pulpal infection is one of the most common causes of dental emergency admission. Tooth pain due to infection caused by gram-negative bacteria is the main manifestation of this sort of dental problem. The GPR173 signaling pathway is a highly conserved G-protein-coupled receptor that mediates neurological and reproductive function. In this study, we found that GPR173 was fairly expressed in isolated human dental pulp cells, and its expression was reduced in response to pro-inflammatory lipopolysaccharide (LPS) treatment. The activation of GPR173 by its ligand Phoenixin-20 reduced LPS-induced cytotoxicity, as revealed by a reduction in the release of LDH. Additionally, Phoenixin-20 suppressed LPS-induced release of pro-inflammatory cytokines and inflammatory mediators, including IL-6, MCP-1, VCAM-1, and ICAM-1, as well as MMP-2 and MMP-9. Mechanistically, we showed the suppressive action of Phoenixin-20 on LPS-induced activation of TLR-4 and Myd88 as well as the activation of the NF-κB pathway. Collectively, our study demonstrates that the GPR173 signaling pathway is an important mediator of LPS-induced inflammation, and the activation of GPR173 by its natural ligand Phoenixin-20 exhibits robust anti-inflammatory effects in dental pulp cells, suggesting that GPR173 is an interesting target molecule in the development of pulp cell-based therapies.


Asunto(s)
Pulpa Dental/citología , Inflamación/inducido químicamente , Lipopolisacáridos/toxicidad , Péptidos/farmacología , Células Cultivadas , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/metabolismo , Inflamación/prevención & control , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo
3.
Chem Biol Interact ; 319: 108984, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-32061742

RESUMEN

OBJECTIVES: As one of the main active ingredients of Chinese herbal medicine Andrographis paniculate, andrographolide is used in domestic clinical treatment for respiratory infections and inflammation. This study was designed to investigate the effects of andrographolide as an antioxidant on the level of oxidative stress, neutrophil accumulation and infiltration in joints and synovial tissue of arthritis rats induced by complete freund's adjuvant. METHODS: A rat model of rheumatoid arthritis was induced by subcutaneous injection of complete Freund's adjuvant in the footpad. The model was established 14 days after induction. The treatment was performed from 14th day to 35th day with different doses of andrographolide (25, 50, 100 mg/kg) and positive control methotrexate (3 mg/kg). The effects of andrographolide on oxidative stress, neutrophil accumulation and infiltration were measured by the paw swelling, arthritis score, the hot plate test, biochemical analysis, and histology. RESULTS: The medium and high-dose andrographolide (50, 100 mg/kg) group declined the levels of tumor necrosis factor-α, interleukin-6 and CXC chemokine ligand2, articular elastase and myeloperoxidase, and increased the levels of antioxidant enzymes superoxide dismutase, catalase, and glutathione. The activity of malondialdehyde and nitrite/nitrate in andrographolide (50, 100 mg/kg) group was weakened than the model group. The degree of swelling and arthritis score of andrographolide group was lower than the model group. The results of hot plate test showed that high dose of andrographolide significantly improved the anti-injury ability of rats; Radiological and histological results showed that the joint osteoporosis, inflammatory cell infiltration, synovial hyperplasia and other phenomena in the andrographolide group were significantly improved. CONCLUSIONS: Andrographolide acts as a protective agent for the treatment of complete freund's adjuvant induced rheumatoid arthritis by inhibiting lipid peroxidation and nitrite/nitrate levels in a dose-dependent manner, enhancing antioxidant enzyme activity, reducing levels of chemokines and inflammatory factors, preventing neutrophil accumulation and infiltration.


Asunto(s)
Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Diterpenos/farmacología , Adyuvante de Freund/farmacología , Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Artritis Experimental/metabolismo , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Catalasa/metabolismo , Modelos Animales de Enfermedad , Edema/inducido químicamente , Edema/tratamiento farmacológico , Edema/metabolismo , Glutatión/metabolismo , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Articulaciones/efectos de los fármacos , Articulaciones/metabolismo , Masculino , Metotrexato/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
4.
Life Sci ; 246: 117397, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32032646

RESUMEN

BACKGROUND: Paraoxonase (PON), an antioxidant enzyme, comprises of three members (PON1, 2 and 3). Hyperglycemia accelerates formation of AGE in diabetes which mediates endothelial dysfunction. PON1 is studied in diabetes due to its association with HDL, lipid peroxidation and vascular complications but PON2 is not explored much. Recently decreased PON2 activity is reported in monocytes of Type 2 diabetes mellitus (T2DM) patients but its regulation by factors like high glucose and AGE has not been studied. AIM: The aim of the current study is to identify the effect of AGEs on PON2 expression and activity and its implications on endothelial dysfunction in HUVECs. MAIN METHODS: HUVECs were exposed to Glycated albumin (GA)/Carboxymethyl lysine (CML) for 24 h to check for PON2 expression. The ER stress markers GRP78 and IRE1α, pro-inflammatory genes MCP-1, IL-6, IL-8, ICAM1, VCAM1 were assessed by qPCR, western blotting/ELISA. Endothelial-leukocyte adhesion and ROS were assessed using Calcein AM and DCFDA method. One-way ANOVA and student's t-test was done using Graphpad Prism. KEY FINDINGS: AGE exposure significantly decreased PON2 expression and activity with increased oxidative stress, ER stress and inflammation. PON2 overexpression significantly reduced ROS, ER stress and inflammation as well as inhibited NFκB, and ERK1/2, phosphorylation induced by GA/CML treatment. Concomitantly, silencing of PON2 accelerated AGEs induced effects. SIGNIFICANCE: This is the first study to show that both GA and CML down regulates the PON2 expression and activity in HUVECs and over expression of PON2 alleviates AGEs induced endothelial dysfunction.


Asunto(s)
Arildialquilfosfatasa/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Productos Finales de Glicación Avanzada/farmacología , Inflamación/tratamiento farmacológico , Ensayo de Inmunoadsorción Enzimática , Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Immunoblotting , Inflamación/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa
5.
Oncology ; 98(3): 131-137, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31958792

RESUMEN

Interleukin-6 (IL-6) is a member of the pro-inflammatory cytokine family, induces the expression of a variety of proteins responsible for acute inflammation, and plays an important role in the proliferation and differentiation of cells in humans. IL-6 signaling is mediated by building a complex of IL-6, the transmembrane IL-6 receptor (mIL-6R) or with soluble forms of IL-6R (sIL-6R), and the signal-transducing subunit molecule gp130. Therefore, three modes for IL-6 signaling may occur in which IL-6 is binding to mIL-6R (classic), to sIL-6R (trans-signaling), or is joined through IL-6R to gp130 on nearby located cells (trans-presentation). These pathways, and the fact that gp130 is ubiquitously expressed, lead to the pleiotropic functions of IL-6. The control of IL-6 signaling is regulated through the induction of suppressor molecules after activation of the IL-6 pathways as well as through the presence of sIL-6R and gp130 forms in the blood. Vice versa, an overproduction of IL-6 and dysregulation of the IL-6 signaling pathways can result in inflammatory and autoimmune disorders as well as cancer development suggesting that IL-6 plays a significant role in the human cytokine network. Several therapeutic agents have been evaluated for inhibiting the cytokine itself, the signaling via the IL-6 receptor, or target kinases (e.g., JAK/STAT) associated with the signaling pathways. Amongst others, tocilizumab (anti-IL-6R humanized antibody) has been approved for the treatment of rheumatoid arthritis, cytokine release syndrome, and idiopathic multicentric Castleman's disease (iMCD), whereas siltuximab (an IL-6 antagonist) received approval for iMCD only. Although not all IL-6-associated diseases respond to IL-6 blockade, a better understanding of the underlying mechanisms of the IL-6 pathways may, therefore, help to find the best treatment for IL-6-associated diseases in the near future.


Asunto(s)
Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Interleucina-6/metabolismo , Transducción de Señal , Antiinflamatorios/uso terapéutico , Humanos , Inflamación/tratamiento farmacológico , Inflamación/enzimología , Mediadores de Inflamación/antagonistas & inhibidores , Interleucina-6/antagonistas & inhibidores , Inhibidores de las Cinasas Janus/uso terapéutico , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Terapia Molecular Dirigida , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismo
6.
Chem Biol Interact ; 317: 108945, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31935363

RESUMEN

Liver fibrosis is a common pathological consequence of liver injury, which increases liver failure-related morbidity and mortality. Hence, anti-fibrotic treatment is urgently needed. Oxidative stress plays a pivotal role in the progression of liver fibrosis. Thus, targeting ROS may be an effective strategy for liver fibrosis treatment. In this study, we investigated four benzoquinones derivatives, including 5-isopropyl-2-methyl-1,4-benzoquinone (TQ), 2-tert-butyl-1,4-benzoquinone (tBu-Q) 2,5-dimethyl-p-benzoquinone (Dime-Q) and p-benzoquinone (Ph-Q), as well as the evaluation of their antioxidant activity and anti-fibrotic effects on activated hepatic stellate cells and TAA-induced mice. Electrochemical analysis showed that all compounds possessed antioxidant property. The result was first confirmed by in vitro experiments, which revealed potential anti-fibrotic activity of all four compounds at the cellular level. Benzoquinone derivatives act as ROS-scavenging molecules, which modulated the TLR4-CD14 signaling pathway to inhibit the expression of procaspase-1 and IL-1ß in cells, induced apoptosis via a mitochondrial pathway by upregulating the ratio of Bax/Bcl-2 and by activating caspase-3, as well as inhibited the expression of the anti-apoptotic proteins FLIP and XIAP in activated LX-2 cells. In addition, a TAA (Thioacetamide)-induced mouse model was used to further validate the results. Treatment with benzoquinone derivatives significantly decreased the levels of liver injury markers and lipid peroxidation caused by excessive ROS, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA). Moreover, treatment with benzoquinone derivatives significantly inhibited extracellular matrix (ECM) deposition and downregulated the mRNA and protein expression of liver fibrosis markers, such as collagen I, alpha-smooth muscle actin (α-SMA), and TIMP-1. In summary, these results indicate that benzoquinone derivatives may act as potential therapeutic drugs against liver fibrosis.


Asunto(s)
Antioxidantes/farmacología , Benzoquinonas/farmacología , Células Estrelladas Hepáticas/efectos de los fármacos , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Tioacetamida/toxicidad , Actinas/genética , Actinas/metabolismo , Animales , Biomarcadores , Línea Celular , Supervivencia Celular/efectos de los fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/metabolismo , Inflamación/prevención & control , Masculino , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo
7.
Adv Exp Med Biol ; 1216: 65-77, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31894548

RESUMEN

The aim of this chapter is to review the results of recent studies analyzing the role of oxidative stress and systemic inflammation as potential contributors to frailty and CVD, and to explain a possible pathogenic relationship between the latter two conditions. Available evidence suggests that frail patients have elevated levels of oxidative stress biomarkers and proinflammatory cytokines, as well as with reduced concentrations of endogenous antioxidants. This implies that oxidative stress and systemic inflammation might play a role in the pathogenesis of frailty, but an underlying mechanism of this relationship is still mostly hypothetical. Oxidative stress and systemic inflammation are also involved in the pathogenesis of CVD. Cardiovascular conditions are established risk factor for frailty and in turn, presence of frailty constitutes an unfavorable prognostic factor in cardiac patients. Finally, some cardiovascular risk factors, such as lack of physical activity, smoking, obesity and inappropriate diet, are also involved in the etiology of oxidative stress, chronic inflammation and frailty. This complex interplay between intrinsic and extrinsic elements should be considered during holistic management of older persons with frailty and/or cardiovascular conditions.


Asunto(s)
Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/metabolismo , Anciano Frágil , Fragilidad/complicaciones , Fragilidad/metabolismo , Inflamación/complicaciones , Inflamación/metabolismo , Estrés Oxidativo , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/patología , Fragilidad/patología , Humanos , Inflamación/patología
8.
Crit Rev Oncol Hematol ; 146: 102840, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31918344

RESUMEN

Neuroendocrine neoplasms (NENs) are a group of tumors originating from the neuroendocrine system. They mainly occur in the digestive system and the respiratory tract. It is well-know a strict interaction between neuroendocrine system and inflammation, which can play an important role in NEN carcinogenesis. Inflammatory mediators, which are produced by the tumor microenvironment, can favor cancer induction and progression, and can promote immune editing. On the other hand, a balanced immune system represents a relevant step in cancer prevention through the elimination of dysplastic and cancer cells. Therefore, an inflammatory response may be both pro- and anti-tumorigenic. In this review, we provide an overview concerning the complex interplay between inflammation and gastroenteropancreatic NENs, focusing on the tumorigenesis and clinical implications in these tumors.


Asunto(s)
Neoplasias Gastrointestinales/inmunología , Mediadores de Inflamación/inmunología , Inflamación/inmunología , Neoplasias Intestinales/inmunología , Tumores Neuroendocrinos/inmunología , Neoplasias Pancreáticas/inmunología , Neoplasias Gástricas/inmunología , Citocinas/metabolismo , Neoplasias Gastrointestinales/patología , Humanos , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Neoplasias Intestinales/patología , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patología , Neoplasias Gástricas/patología , Microambiente Tumoral
9.
Adv Clin Chem ; 94: 155-218, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31952571

RESUMEN

Bone and skeletal muscle are integrated organs and their coupling has been considered mainly a mechanical one in which bone serves as attachment site to muscle while muscle applies load to bone and regulates bone metabolism. However, skeletal muscle can affect bone homeostasis also in a non-mechanical fashion, i.e., through its endocrine activity. Being recognized as an endocrine organ itself, skeletal muscle secretes a panel of cytokines and proteins named myokines, synthesized and secreted by myocytes in response to muscle contraction. Myokines exert an autocrine function in regulating muscle metabolism as well as a paracrine/endocrine regulatory function on distant organs and tissues, such as bone, adipose tissue, brain and liver. Physical activity is the primary physiological stimulus for bone anabolism (and/or catabolism) through the production and secretion of myokines, such as IL-6, irisin, IGF-1, FGF2, beside the direct effect of loading. Importantly, exercise-induced myokine can exert an anti-inflammatory action that is able to counteract not only acute inflammation due to an infection, but also a condition of chronic low-grade inflammation raised as consequence of physical inactivity, aging or metabolic disorders (i.e., obesity, type 2 diabetes mellitus). In this review article, we will discuss the effects that some of the most studied exercise-induced myokines exert on bone formation and bone resorption, as well as a brief overview of the anti-inflammatory effects of myokines during the onset pathological conditions characterized by the development a systemic low-grade inflammation, such as sarcopenia, obesity and aging.


Asunto(s)
Huesos/metabolismo , Citocinas/metabolismo , Músculo Esquelético/metabolismo , Envejecimiento/metabolismo , Animales , Ejercicio , Homeostasis , Humanos , Inflamación/metabolismo , Obesidad/metabolismo
10.
Medicine (Baltimore) ; 99(4): e18607, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31977852

RESUMEN

Systemic inflammatory response markers are associated with poor survival in many types of malignances. This study aimed to evaluate the prognostic value of preoperative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and C-reactive protein (CRP) in patients with non-small cell lung cancer (NSCLC).We retrospectively evaluated 254 NSCLC patients who underwent radical surgery between January 2012 and April 2014 in the Sichuan Provincial Cancer Hospital. The cut-off values of NLR, PLR, LMR, and CRP were determined according to the receiver operating characteristic curve, and the correlation of NLR, PLR, LMR, and CRP with prognosis was analyzed based on the cut-off value.The cut-off value for NLR, PLR, LMR, and CRP were 3.18, 122, 4.04, and 8.8, respectively. Univariate analysis showed that age (P = .022), tumor-node-metastasis (TNM) stage (P < .001), T stage (P = .001), and N stage (P < .001) were significantly correlated with disease-free survival (DFS), while age (P = .011), TNM stage (P < .001), T stage (P = .008), N stage (P < .001), and PLR (P = .001) were significantly correlated with overall survival (OS). In multivariate analysis, age (hazard ratio [HR]: 1.564, 95% confidence interval [CI]: 1.087-2.252, P = .016) and TNM stage (HR: 1.704, 95% CI: 1.061-2.735, P = .027) remained independent risk factors affecting DFS, while age (HR: 1.721, 95% CI: 1.153-2.567, P = .008), TNM stage (HR: 2.198, 95% CI: 1.263-3.824, P = .005), and PLR (HR: 1.850, 95% CI: 1.246-2.746, P = .002) were independent risk factors affecting OS.The preoperative PLR is superior to NLR, LMR, and CRP as a biomarker for evaluating the prognosis of patients undergoing curative surgery for NSCLC.


Asunto(s)
Plaquetas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Inflamación/metabolismo , Neoplasias Pulmonares/patología , Linfocitos/metabolismo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Proteína C-Reactiva/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/sangre , Femenino , Humanos , Neoplasias Pulmonares/sangre , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neutrófilos/metabolismo , Análisis de Supervivencia
11.
Life Sci ; 244: 117346, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31978448

RESUMEN

AIM: Emerging studies have shown that application of low concentration of bioactive phytomolecules can confer anti-proliferative effects on tumour cells by inducing senescence pathways. The alkaloid berberine is recognized for its anti-cancer attributes but its potential to induce senescence in tumour cells is least understood. MATERIALS AND METHODS: The present work assessed the mechanisms pertaining to dose-dependent anti-proliferative effects of berberine in the perspective of senescence and inflammation using human non-small cell lung cancer cell line (A549). KEY FINDINGS: Amongst the different tested bioactive phytomolecules, berberine treatment suppressed the proliferation of A549 cells regardless of the concentration applied. Application of low doses of berberine induced a weak SA-ß-gal activity and p21WAF1 expression but did not show evidence of SASP activation due to absence of NF-κB activation and expression of proinflammatory genes. However, treatment with higher dose of berberine showed no evidence of SA-ß-gal activity or p21WAF1 expression, but instead induced apoptosis and suppressed the expression of cell cyclins. The proliferative capacity of berberine treated cells was at par with control cells and no SA-ß-gal activity could be observed in first generation of berberine treated cells. mTOR pathway showed no distinct activation on account of berberine treatment thereby further emphasizing that low dose of berberine induced quiescence and not senescence in A549 cells. SIGNIFICANCE: Taken together, our observations indicate that despite its strong anti-proliferative effects, low dose berberine treatment may only induce transient changes akin to quiescence that needs to be considered before implying pro-senescence attributes of berberine in cancer therapeutics.


Asunto(s)
Apoptosis/efectos de los fármacos , Berberina/farmacología , Senescencia Celular/efectos de los fármacos , Ciclinas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inflamación/tratamiento farmacológico , Neoplasias Pulmonares/patología , Serina-Treonina Quinasas TOR/metabolismo , Células A549 , Proliferación Celular/efectos de los fármacos , Ciclinas/genética , Humanos , Inflamación/metabolismo , Inflamación/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/genética
12.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 64-71, 2020 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-31889183

RESUMEN

Previous studies have shown that during severe acute pancreatitis (SAP) attacks, hydrogen sulfide (H2S) is released in the colon. However, the roles played by H2S in regulating enteric nerves remain unclear. In this study, we examined the association between SAP-induced H2S release and loss of intestinal motility, and also explored the relevant mechanism in enteric nerve cells. A rat SAP model was constructed and enteric nerve cells were prepared. Intestinal mobility was evaluated by measuring the number of bowel movements at indicated time points and by performing intestinal propulsion tests. The production of inflammatory cytokines during a SAP attack was quantified by ELISA, and the levels of cystathionine-γ-lyase (CSE) and cystathionine-ß-synthase (CBS) were examined by immunohistochemistry and western blot analysis. In vivo studies showed that PI3K/Akt/Sp1 signaling in enteric nerve cells was blocked, confirming the mechanism of endogenous H2S formation by western blot analysis and immunofluorescence. Our results also showed that rats with SAP symptoms had reduced intestinal motility. Furthermore, PI3K/Akt/Sp1 signaling was triggered and CSE expression was up-regulated, and these changes were associated with H2S formation in the colon. In addition, propargylglycine reduced the levels of inflammatory cytokines and suppressed the release of H2S. Enteric nerve cells that were incubated with LY294002 and transfected with a Sp1-knockdown vector displayed decreased levels of CSE production, which led to a decrease in H2S production. These results suggest that SAP symptoms suppressed the intestinal motility of rats via the release of H2S in enteric nerve cells, which was dependent on the inflammation-induced PI3K/Akt/Sp1 signaling pathway.


Asunto(s)
Movimiento Celular , Sistema Nervioso Entérico/patología , Sulfuro de Hidrógeno/metabolismo , Neuronas/metabolismo , Pancreatitis/metabolismo , Animales , Cromonas/farmacología , Cistationina betasintasa/metabolismo , Cistationina gamma-Liasa/metabolismo , Citocinas/metabolismo , Motilidad Gastrointestinal , Técnicas de Silenciamiento del Gen , Inflamación/metabolismo , Masculino , Morfolinas/farmacología , Pancreatitis/inducido químicamente , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Factor de Transcripción Sp1/genética , Factor de Transcripción Sp1/metabolismo , Ácido Taurocólico/efectos adversos , Ácido Taurocólico/farmacología , Transfección
13.
Infect Immun ; 88(2)2020 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-31685547

RESUMEN

The fungus Mucor circinelloides undergoes yeast-mold dimorphism, a developmental process associated with its capability as a human opportunistic pathogen. Dimorphism is strongly influenced by carbon metabolism, and hence the type of metabolism likely affects fungus virulence. We investigated the role of ethanol metabolism in M. circinelloides virulence. A mutant in the adh1 gene (M5 strain) exhibited higher virulence than the wild-type (R7B) and the complemented (M5/pEUKA-adh1 +) strains, which were nonvirulent when tested in a mouse infection model. Cell-free culture supernatant (SS) from the M5 mutant showed increased toxic effect on nematodes compared to that from R7B and M5/pEUKA-adh1 + strains. The concentration of acetaldehyde excreted by strain M5 in the SS was higher than that from R7B, which correlated with the acute toxic effect on nematodes. Remarkably, strain M5 showed higher resistance to H2O2, resistance to phagocytosis, and invasiveness in mouse tissues and induced an enhanced systemic inflammatory response compared with R7B. The mice infected with strain M5 under disulfiram treatment exhibited only half the life expectancy of those infected with M5 alone, suggesting that acetaldehyde produced by M. circinelloides contributes to the toxic effect in mice. These results demonstrate that the failure in fermentative metabolism, in the step of the production of ethanol in M. circinelloides, contributes to its virulence, inducing a more severe tissue burden and inflammatory response in mice as a consequence of acetaldehyde overproduction.


Asunto(s)
Fermentación/fisiología , Mucor/metabolismo , Mucor/patogenicidad , Virulencia/fisiología , Alcohol Deshidrogenasa/metabolismo , Animales , Línea Celular , Fermentación/efectos de los fármacos , Proteínas Fúngicas/metabolismo , Peróxido de Hidrógeno/farmacología , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Mucor/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Fagocitosis/fisiología , Células RAW 264.7 , Virulencia/efectos de los fármacos
14.
Int Arch Allergy Immunol ; 181(1): 56-70, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31707382

RESUMEN

INTRODUCTION: Phospholipases are enzymes that occur in many types of human cells, including mast cells, and play an important role in the molecular background of asthma pathogenesis, and the development of inflammation NF-κB activities that affect numerous biological processes has been reported in many inflammatory diseases including asthma. Vitamin D is a widely studied factor that affects many diseases, including asthma. The aim of this study is to assess the influence of 1,25-(OH)2D3 on regulation of chosen phospholipase-A2 (PLA2) expression-selected inflammation mediators. METHODS: LUVA mast cells were stimulated with 1,25(OH)2D3, and inhibitors of NF-κB p65 and ubiquitination. Expression analysis of phospholipases (PLA2G5, PLA2G10, PLA2G12, PLA2G15, PLA2G4A, PLA2G4B, PLA2G4C, PLAA, NF-κB p65, and UBC) was done utilizing real-time PCR and Western blot. Eicosanoid (LTC4, LXA4, 15[S]-HETE, and PGE2) levels and sPLA2 were also measured. RESULTS: We found that 1,25(OH)2D3 decreased the expression of PLA2G5, PLA2G15, PLA2G5,UBC, and NF-κB p65 but increased expression of PLAA and PLA2G4C (p < 0.05). Moreover, the expression of PLA2G5 and PLA2G15 decreased after inhibition of NF-κB p65 and UBC. Increased levels of released LXA4 and 15(S)-HETE, decreased levels of LTC4, and sPLA2s enzymatic activity in response to 1,25(OH)2D3 were also observed. Additionally, NF-κB p65 inhibition led to an increase in the LXA4 concentration. CONCLUSION: Future investigations will be needed to further clarify the role of 1,25(OH)2D3 in the context of asthma and the inflammatory process; however, these results confirm a variety of effects which can be caused by this vitamin. 1,25(OH)2D3-mediated action may result in the development of new therapeutic strategies for asthma treatment.


Asunto(s)
Asma/metabolismo , Colecalciferol/metabolismo , Inflamación/metabolismo , Mastocitos/metabolismo , FN-kappa B/metabolismo , Fosfolipasas A2/metabolismo , Asma/genética , Línea Celular Transformada , Regulación de la Expresión Génica , Humanos , Inflamación/genética , Lipoxinas/metabolismo , FN-kappa B/genética , Fosfolipasas A2/genética , Transducción de Señal , Ubiquitinación
15.
Chem Biol Interact ; 315: 108891, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31697926

RESUMEN

BACKGROUND AND AIMS: Pregnane X receptor (PXR) is a ligand-activated transcription factor and nuclear receptor expressed ubiquitously along gut-liver-axis. Inflammatory bowel disorders have been reported to implicate PXR in maintaining tight junction (TJ) integrity and countering inflammation. However, the hepatoprotective role of PXR activation in soothing bacterial translocation in liver cirrhosis has not been explored. Ginkgolide A (GA), a terpene trilactone from Ginkgo Biloba extract, is a natural ligand of rodent and human PXR. This study aims to investigate the effect of GA in activating PXR and improving associated tight junction integrity and reducing bacterial translocation in gut-liver axis of CCl4 induced cirrhosis model. METHODS: Swiss albino mice were administered with CCl4 (0.5 ml/kg body weight, i.p) in corn oil for 12 weeks at an interval of two times a week. Following ascites induction, mice were randomized & administered 100 mg/kg body weight of GA through oral gavage for 2 weeks. At termination, blood, gut and liver tissues were collected for biochemical and molecular studies. RESULTS: When compared to naïve mice, protein expression of hepatic and small intestinal PXR, CYP3A, ZO-1 and occludin were found to be significantly (p < 0.01) decreased in CCl4 induced cirrhotic mice. Treatment with GA to cirrhotic mice significantly (p < 0.05) induced the expression of both hepatic and small intestinal PXR, CYP3A, ZO-1 and Occludin. Furthermore, increased (p < 0.01) hepatic and small intestinal NFκB was observed in CCl4 induced cirrhotic mice that was significantly (p < 0.05) lowered following GA treatment. Over expression of TLR4/MyD88/NFκB axis and its downstream pro-inflammatory mediators TNF-α, IL6 and IFN-γ were observed in CCl4 induced mice, and these indices were abrogated significantly after GA treatment. Furthermore, significantly increased plasma levels of bacterial translocation markers LBP and procalcitonin were found in CCl4 mice, which were reduced significantly (p < 0.05 & p < 0.0001) after GA treatment. CONCLUSION: In conclusion, our data supports the hypothesis that, GA treatment to CCl4 induced cirrhotic mice, activated hepatic and small intestinal PXR and diminished inflammation, thereby improving tight junction integrity and attenuating bacterial translocation.


Asunto(s)
Traslocación Bacteriana/efectos de los fármacos , Ginkgólidos/farmacología , Lactonas/farmacología , Cirrosis Hepática/metabolismo , Receptor X de Pregnano/metabolismo , Proteínas de Uniones Estrechas/metabolismo , Animales , Citocromo P-450 CYP3A/metabolismo , Inflamación/metabolismo , Interferón gamma/metabolismo , Interleucina-6/metabolismo , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Ligandos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Proteína de la Zonula Occludens-1/metabolismo
16.
Histochem Cell Biol ; 153(1): 49-62, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31637472

RESUMEN

Endoplasmic reticulum (ER) stress could participate in high-fat diet (HFD)-induced hepatic steatosis. The current study aims to investigate the role of ER stress as well as inflammation as possible pathophysiologic mechanisms of HFD-induced hepatic steatosis at ultrastructure and molecular levels. Fifteen control rats on ordinary diet and 30 HFD-fed rats were enrolled in the study. Histological and EM examinations of rats' liver were carried out. Molecular study of TNF-α, CRP, and HNF4α by RT qPCR as well as biochemical investigation of liver function and lipids profile were done. Hepatic steatosis was induced with lipid droplets accumulation at histological level and mega-mitochondria with reduced ER-mitochondrial distance at EM level. Increased gene expression of TNF-α and CRP was significantly correlated with the reduced HNF4α expression and with other ER stress markers. In conclusion, endoplasmic reticulum stress, confirmed at ultrastructure level, plays an important role in pathogenesis of HFD-induced hepatic steatosis. HNF4α downregulation as well as increased expression of hs-CRP and TNF-α enforce the concept of interplay between ER stress, hepatic subclinical inflammation, and disturbed gene expression regulation in the pathogenesis of HFD-induced hepatic steatosis.


Asunto(s)
Estrés del Retículo Endoplásmico , Hígado Graso/metabolismo , Factor Nuclear 4 del Hepatocito/metabolismo , Mediadores de Inflamación/metabolismo , Animales , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Inflamación/metabolismo , Inflamación/fisiopatología , Masculino , Ratas , Ratas Sprague-Dawley
17.
Chem Biol Interact ; 315: 108874, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31669322

RESUMEN

Allergic rhinitis (AR) is a type I hypersensitivity immune response and is a common chronic allergic respiratory disorder characterized by one or more nasal symptoms. Despite many studies on AR therapy, the drugs of treatment for AR remain limited in effect. In the present study, we aimed to elucidate the effects of saikosaponin A (SSA) on nasal inflammation, T helper (Th)2 and Th17 cytokines, retinoic acid-related orphan nuclear receptor (ROR)-γt, signal transducer and activator of transcription (STAT)3, and nuclear factor (NF)-κB signalings in ovalbumin (OVA)-induced AR mice model. OVA-induced AR mice exhibited increase in nasal symptoms, histological alteration, OVA-specific immunoglobulin (Ig)E/IgG1, ROR-γt, STAT3 and NF-κB signalings. However, the administration of SSA significantly decreased allergic symptoms including nasal rubbing and sneezing. Additionally, histological alterations such as mucosa layer thickness, goblet cell hyperplasia, eosinophils and mast cell infiltration in nasal tissues dramatically improved by treatment with SSA. Also, SSA treatment decreased the levels of OVA-specific IgE/IgG1 in serum and the levels of Th2 and Th17 cytokines such as interleukin (IL)-6 and IL-17 in nasal lavage fluid (NALF). Moreover, SSA inhibited the activation of transcription factor ROR-γt, STAT3 and phosphorylated STAT3 in both NALF and lung. Futher, SSA could also significantly inhibit the expressions of NF-κB p65 and phosphorylated NF-κB p65 in NALF and lung. These present results suggested that SSA may attenuate OVA-induced allergic rhinitis through regulating the expression of IL-6/ROR-γt/STAT3/IL-17/NF-κB signaling. The results indicate that SSA may be used as a therapeutic candidate for allergic rhinitis disease.


Asunto(s)
Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Mucosa Nasal/efectos de los fármacos , Ácido Oleanólico/análogos & derivados , Rinitis Alérgica/tratamiento farmacológico , Rinitis Alérgica/metabolismo , Saponinas/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inmunoglobulina E/metabolismo , Inmunoglobulina G/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Mucosa Nasal/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Ácido Oleanólico/farmacología , Ovalbúmina/farmacología , Rinitis Alérgica/inducido químicamente , Factor de Transcripción STAT3/metabolismo , Células Th17/efectos de los fármacos , Células Th17/metabolismo , Células Th2/efectos de los fármacos , Células Th2/metabolismo
18.
Chem Biol Interact ; 315: 108876, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31669340

RESUMEN

4-methylesculetin (4 ME) is a natural antioxidant coumarin with protective effects on the intestinal inflammation, in which oxidative stress plays a key role in its aetiology and pathophysiology. Based on this, we examined the antioxidant molecular mechanisms involved in the intestinal anti-inflammatory activity of the 4 ME. For this purpose, we investigated the effects of the 4 ME on the modulation of gene expression and antioxidant-related enzyme activities in TNBS model of intestinal inflammation as well as the molecular interaction between 4 ME and glutathione reductase. Our results showed that 4 ME modulated glutathione-related enzymes, mainly increasing glutathione reductase activity. These effects were related to upregulation of glutathione reductase and Nrf2 gene expression. Fluorescence and nuclear magnetic resonance data showed that interaction between 4 ME and glutathione reductase is collisional, hydrophobic and spontaneous, in which C4 methyl group is the second epitope most buried into glutathione reductase. Molecular modelling calculation showed Lys70-B, Arg81-A, Glu381-B, Asp443-A, Ser444-A, Glu447-B and Ser475-A participated in electrostatic interaction, Lys70-B, Glu381-B and Arg81-A acted in the hydrophobic interactions and Trp73, Phe377 and Ala446 are responsible for the hydrogen bonds. Based on this, our results showed 4 ME acted by different mechanisms to control oxidative stress induced by intestinal damage, controlling the imbalance between myeloperoxidase activity and glutathione production, upregulating the glutathione S-transferase and glutathione reductase activities, preventing the Nrf2 and glutathione gene expression downregulation with consequent glutathione maintenance. Finally, 4 ME interacted at molecular level with glutathione reductase, stabilizing its enzymatic activity and reducing oxidative stress to take place in intestinal inflammatory process.


Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Cumarinas/farmacología , Inflamación/tratamiento farmacológico , Umbeliferonas/farmacología , Animales , Glutatión/metabolismo , Glutatión Reductasa/metabolismo , Inflamación/metabolismo , Masculino , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Peroxidasa/metabolismo , Ratas , Ratas Wistar
19.
Food Chem Toxicol ; 135: 110922, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31669599

RESUMEN

Anthocyanins are natural bioactive compounds that have several health benefits. This systematic review and meta-analysis assessed the impact of dietary anthocyanins on markers of systemic and vascular inflammation. Meta-analysis of 32 randomised controlled trials indicated that dietary anthocyanins significantly decreased levels of C-reactive protein (CRP; -0.33 mg/l, 95% CI: -0.55 to -0.11, P = 0.003), interleukin-6 (IL-6; -0.41 ρg/ml, 95% CI: -0.70 to -0.13, P = 0.004), tumor necrosis factor-alpha (TNF-α; -0.64 ρg/ml, 95% CI: -1.18 to -0.09, P = 0.023), intercellular adhesion molecule-1 (-52.4 ng/ml, 95% CI: -85.7 to -19.1, P = 0.002), and vascular adhesion molecule-1 (VCAM-1; -49.6 ng/ml, 95% CI: -72.7 to -26.5, P < 0.001) while adiponectin level was significantly increased (0.75 µg/ml, 95% CI: 0.23 to 1.26, P = 0.004). The levels of interleukin-1ß (IL-1ß; -0.45 ρg/ml, 95% CI: -3.77 to 2.88, P = 0.793) and P-selectin (-6.98 ng/ml, 95% CI: -18.1 to 4.15, P = 0.219) did not significantly change. Subgroup analyses showed that administration of higher doses of anthocyanins (>300 mg/day) significantly decreased levels of CRP, IL-6, TNF-α, and VCAM-1. The results indicate that dietary anthocyanins reduce the levels of systemic and vascular inflammation in the subjects.


Asunto(s)
Antocianinas/farmacología , Ensayos Clínicos como Asunto/estadística & datos numéricos , Inflamación/dietoterapia , Adiponectina/sangre , Adiponectina/metabolismo , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Citocinas/sangre , Citocinas/metabolismo , Humanos , Inflamación/metabolismo
20.
Food Chem Toxicol ; 135: 110929, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31678262

RESUMEN

One of the most spread group of phenolics are flavonoids. Many studies focusing on the digestion and bioavailability of flavonoids have been carried out. Several possible directions of flavonoid metabolism are suspected and described in the literature. The aim of the present study was to evaluate the bioactivity of 8 flavonoid 3-O- and 7-O- glucuronides and 7 free aglycones on inflammatory response of PMNs and HUVECs in the context of their fate in humans after oral intake. The present study for the first time compared the activity of several most popular in plant flavonol and flavone aglycones and their beta-glucuronides. The results showed that in all in vitro experiments only aglycones have anti-inflammatory activity in PMNs and HUVECs models in the concentration range 1-50 µM. The most significant influence on the inflammatory response was observed in the case of HUVECs. Compounds were able to down-regulate levels of adhesion molecules (ICAM, VCAM and E-selectin). The possible deconjugation phenomenon at the inflammation site was evaluated using enzymes produces by stimulated PMNs. This is the first report suggesting the role of ß-glucuronidase in the inflammatory process taking place on the inflammation site. Additionally, the anti-inflammatory effect was significantly better for flavones.


Asunto(s)
Antiinflamatorios/farmacología , Flavonoides/farmacología , Glucurónidos/farmacología , Neutrófilos/efectos de los fármacos , Antiinflamatorios/toxicidad , Moléculas de Adhesión Celular/metabolismo , Endotelio/metabolismo , Flavonoides/toxicidad , Glucurónidos/toxicidad , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inflamación/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Neutrófilos/metabolismo
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