Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 60.752
Filtrar
1.
Arch Immunol Ther Exp (Warsz) ; 69(1): 10, 2021 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-33811524

RESUMEN

The review discusses a new approach to the prevention and treatment of viral infections based on the use of pine needles polyprenyl phosphate (PPP) and associated with the infringement of prenylation process-the attachment of farnesol or geranyl geraniol to the viral protein. Currently, prenylation has been detected in type 1 adenovirus, hepatitis C virus, several herpes viruses, influenza virus, HIV. However, this list is far from complete, given that prenylated proteins play an extremely important role in the activity of the virus. We assume that the interferon produced in response to PPP may suppress expression of the SREBP2 transcription factor. As a result, the mevalonic acid pathway is violated and, as a result, the formation of early polyprenols precursors (geraniol, geranyl geraniol, farnesol), which are necessary for the prenylation of viral proteins, is blocked and the formation of mature, virulent virus particles is broken. As a consequence, the maturation of viral particles is inhibited, and defective particles are formed. Polyprenol was extracted from greenery (pine, fir and spruce needles, mulberry leaves, etc.), purified by chromatography, phosphorylated and identified by HPLC and NMR. Obtained PPP was used as antiviral in some experimental models in vitro and in vivo. During numerous studies, it was found that PPP manifested versatile antiviral effects, both in vitro and in vivo. The maximum effect was observed with viruses in which the presence of prenylated proteins was established, namely influenza A virus, HIV-1, tick-borne encephalitis virus, hepatitis A and C viruses, herpes simplex viruses type 1 and 2, some coronavirus. The available data obtained both in the experimental conditions and during clinical trials allow us to regard PPPs as safe and effective medicine for prevention and treatment of viral diseases.


Asunto(s)
Antivirales/farmacología , Pinus/química , Fosfatos de Poliisoprenilo/farmacología , Prenilación de Proteína/efectos de los fármacos , Virosis/tratamiento farmacológico , Animales , Antivirales/uso terapéutico , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Interferones/metabolismo , Microscopía Electrónica , Fosfatos de Poliisoprenilo/uso terapéutico , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Resultado del Tratamiento , Proteínas Virales/metabolismo , Virión/efectos de los fármacos , Virión/ultraestructura , Virosis/inmunología , Virosis/prevención & control , Replicación Viral/efectos de los fármacos , Replicación Viral/inmunología
2.
Ecotoxicol Environ Saf ; 214: 112058, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33714136

RESUMEN

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a nuclear transcription factor of great concern which is widely involved in physiological and pathological processes of the organism, but the role and regulatory mechanism of Nrf2 in kidney exposed to cadmium (Cd) remain largely unknown. Here we demonstrated that Cd exposure induced injury in primary rat proximal tubular (rPT) cells and NRK-52E cell line, which was accompanied by autophagic flux blockade and subsequent accumulation of p62. Cd-activated nucleus translocation of Nrf2 depended on p62, which promoted antioxidant genes transcription, but it failed to against Cd-induced cell injury and ultimately succumbed to Cd toxicity. CDDO Methyl Ester (CDDO-ME) or ML385 treatment aggravated or alleviated rPT cells injury induced by Cd respectively, indicating that Nrf2 nucleus translocation played a negative role during Cd-induced rPT cells injury. Phosphorylation of 5' AMP-activated protein kinase (AMPK) decreased together with enhanced Nrf2 nucleus translocation in rPT cells exposed to Cd. Dephosphorylation of AMPK induced by Cd were facilitated or restored by CDDO-ME or ML385 treatment, which confirmed AMPK is a downstream factor of Nrf2. Simultaneously, CDDO-ME further enhanced Phosphorylation of mTOR and AKT which increased during Cd exposure. While, Cd-induced phosphorylation of mTOR and AKT were reversed by ML385 treatment. These results illustrated that Cd mediated Nrf2 nucleus translocation depends on p62 accumulation which results from autophagic flux inhibition. The enhanced nucleus translocation of Nrf2 suppresses phosphorylation of AMPK to inactivate AKT/mTOR signaling, and results in rPT cells injury finally.


Asunto(s)
Cadmio/toxicidad , Contaminantes Ambientales/toxicidad , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Antioxidantes/metabolismo , Autofagia/efectos de los fármacos , Núcleo Celular/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Túbulos Renales Proximales/citología , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo
3.
Life Sci ; 273: 119261, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33652036

RESUMEN

AIMS: Liver cirrhosis leads to cirrhotic cardiomyopathy (CCM) and chronotropic incompetence (CI). Heat shock protein 70 (Hsp70) regulates cellular apoptosis and autophagy in stress. Teprenone modulates the Hsp70 and protects against cellular injury. Thus, we aimed to evaluate the effect of teprenone on CI in biliary cirrhotic rats. MAIN METHODS: Liver cirrhosis was induced in male Wistar rats through bile duct ligation (BDL). The chronotropic responses and QT interval were studied through electrocardiography (ECG) in sham, cirrhotic, and cirrhotic/teprenone (100 mg/kg) pre-treated groups. Brain natriuretic peptide (BNP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and monocyte chemo-attractant protein-1 (MCP-1), and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were investigated in serum. The Hsp70, B-cell lymphoma 2 (Bcl-2), and B-cell lymphoma 2-associated X protein (Bax) expressions were quantified through real-time polymerase chain reaction (Real-time PCR). KEY FINDINGS: The chronotropic responses were decreased significantly in cirrhotic and cirrhotic/teprenone groups. The QT interval and serum BNP, TNF-α, IL-6, ALT, AST, and MCP-1 levels were increased significantly in the cirrhotic and decreased significantly, except BNP, in the cirrhotic/teprenone group. The Hsp70 and Bax expressions increased significantly in cirrhotic and decreased significantly in the cirrhotic/teprenone group while the Bcl-2 decreased significantly in cirrhotic and increased significantly in the cirrhotic/teprenone group. SIGNIFICANCE: Teprenone does not relieve the CI and BNP changes in CCM while other indices are treated. Given that CCM is a multifactorial disease and needs to target other genes and proteins concurrent with Hsp70 to relieve CCM.


Asunto(s)
Antiulcerosos/farmacología , Biomarcadores/metabolismo , Cardiomiopatías/tratamiento farmacológico , Diterpenos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Cirrosis Hepática Biliar/complicaciones , Animales , Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Masculino , Ratas , Ratas Wistar
4.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652584

RESUMEN

The purpose of the research was to examine the protective effect of essential oil from Thymus serrulatus Hochst. ex Benth. (TSA oil) against cadmium (Cd)-induced renal toxicity. The experimental protocol was designed using 30 healthy adult Wistar albino rats allocated into five groups containing six animals in each group. Group 1 was treated as normal control and groups 2, 3, 4, and 5 were treated with cadmium chloride (CdCl2, 3 mg/kg, IP) for 7 days. Group 3 was also treated with silymarin (100 mg/kg, PO) as a standard group, while groups 4 and 5 were administered with TSA oil at doses of 100 and 200 mg/kg PO, respectively. The nephrotoxicity was measured with various parameters such as kidney function markers, oxidative stress markers (glutathione (GSH) and malondialdehyde (MDA)), and messenger ribonucleic acid (mRNA) expression levels of inflammatory factors. The histological studies were also evaluated in the experimental protocol. The CdCl2-treated groups showed a significant increase in the levels of serum kidney function markers along with MDA levels in kidney homogenate. However, renal GSH level was found to be reduced significantly. It was found that CdCl2 significantly upregulated the nuclear factor levels of kappaB (NF-κB p65), inducible nitric oxide synthase (iNOS), and small mothers against decapentaplegic (Smad2) as compared to the normal control group. On the other hand, TSA oil significantly improved the increased levels of serum kidney function markers, non-enzymatic antioxidants, and lipid peroxidation. In addition, TSA oil significantly downregulated the increased expression of NF-κB p65, iNOS, and Smad2 in Cd-intoxicated rats. Moreover, the histological changes in the tissue samples of the kidney of Cd-treated groups were significantly ameliorated in the silymarin- and TSA-oil-treated groups. The present study reveals that TSA oil ameliorates Cd-induced renal injury, and it is also proposed that the observed nephroprotective effect could be due to the antioxidant potential of TSA oil and healing due to its anti-inflammatory action.


Asunto(s)
Enfermedades Renales/tratamiento farmacológico , Aceites Volátiles/química , Estrés Oxidativo/efectos de los fármacos , Thymus (Planta)/química , Animales , Antioxidantes/química , Antioxidantes/farmacología , Cadmio/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Riñón/efectos de los fármacos , Riñón/patología , Enfermedades Renales/inducido químicamente , FN-kappa B/genética , Óxido Nítrico Sintasa de Tipo II/genética , Aceites Volátiles/farmacología , Ratas , Proteína Smad2/genética
5.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652665

RESUMEN

The aim of the study was to investigate combined effects of flavonoids (apigenin, baicalein, chrysin, quercetin, and scutellarin) and methyldopa on the expression of selected proinflammatory and vascular factors in vitro for prediction of their action in pregnancy-induced hypertension. The research was conducted on a trophoblast-derived human choriocarcinoma cell line and a primary human umbilical vein endothelial cell line. Cytotoxicity of compounds in selected concentrations (20, 40, and 100 µmol) was measured using the MTT test and the concentration of 40 µmol was selected for further analysis. Subsequently, their effects with methyldopa on the expression of selected markers responsible for inflammation (TNF-α; IL-1ß; IL-6) and vascular effects (hypoxia-inducible factor 1α-HIF-1α; placental growth factor-PIGF; transforming growth factor ß-TGF-ß; vascular endothelial growth factor-VEGF) at the mRNA and protein levels were assessed. It was found that every combined administration of a flavonoid and methyldopa in these cells induced a down-regulating effect on all tested factors, except PIGF, especially at the mRNA expression level. As hypertension generally raises TNF-α, IL-1ß, IL-6, HIF-1α, TGF-ß, and VEGF mRNA expression and/or protein levels, the results obtained in the studied model may provide a positive prognostic factor for such activity in vivo.


Asunto(s)
Flavonoides/farmacología , Inflamación/tratamiento farmacológico , Metildopa/farmacología , Enfermedades Vasculares/tratamiento farmacológico , Línea Celular , Proliferación Celular/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Técnicas In Vitro , Inflamación/genética , Inflamación/patología , Placenta/efectos de los fármacos , Placenta/patología , Factor de Crecimiento Placentario/genética , Embarazo , Trofoblastos/efectos de los fármacos , Enfermedades Vasculares/genética , Enfermedades Vasculares/patología
6.
Life Sci ; 274: 119291, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33667515

RESUMEN

AIMS: Most therapeutic drugs of endometriosis have been contraceptives but symptoms recur in up to 75% of cases, which makes it a presses need to try to find novel and safer therapeutic drugs. Imperatorin is a furanocoumarin existing in many plants, possessing multiple activities, including anti-inflammatory. The purpose of this study was to assess the effects and mechanisms of imperatorin in endometriosis. MAIN METHODS: Ectopic endometrial volume and hematoxylin-eosin staining were used to estimate the effects of imperatorin in experimental endometriosis model rats. Potential mechanisms of imperatorin in endometriosis were systematically analyzed by network pharmacology and molecular docking. Western blotting and enzyme-linked immunosorbent assay were employed to evaluate proteins expression and cytokines levels in PI3K/Akt/NF-κB pathway. KEY FINDINGS: Imperatorin could significantly inhibit the growth and ameliorate the histopathological features of ectopic endometrium in experimental endometriosis rats. Network pharmacology approaches showed that imperatorin might regulate inflammatory response and cellular function via primarily affecting PI3K-Akt pathway, Endocrine resistance, Th17 cell differentiation in endometriosis. Moreover, 7 core targets (PIK3CA, AKT1, SRC, MAPK8, MAPK14, ERBB2 and CCND1) resulted from the intersection of KEGG and PPI network topological analysis were used to dock with imperatorin, which indicated that imperatorin could preferably fit in the binding pocket of the above target proteins, except for CCND1. Lastly, imperatorin markedly inhibited the activation of PI3K/Akt/NF-κB pathway via suppressing the phosphorylation levels of PI3K, Akt and p65 in the ectopic endometrium tissue. SIGNIFICANCE: Our findings revealed that imperatorin is a significant multi-target natural active ingredient for treatment endometriosis.


Asunto(s)
Endometriosis/tratamiento farmacológico , Furocumarinas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Animales , Endometriosis/metabolismo , Endometriosis/patología , Femenino , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal
7.
Life Sci ; 274: 119324, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33711382

RESUMEN

AIMS: Intervertebral Disc Degeneration (IDD) is a key factor involved in low back pain (LBP) which affects approximately 540 million individuals worldwide. Chlorogenic Acid (CGA), a natural compound, exerts anti-inflammatory property in several diseases. Here, we aim to investigate the biological effect of CGA on IDD and explore the underlying mechanism. MATERIALS AND METHODS: Lumbar spine instability (LSI) model in mice was utilized to mimic process of IDD. The effects of CGA in response to LSI were evaluated by luminescent imaging, micro-CT, histomorphology, and immunohistochemistry in vivo. Besides, the cytotoxicity of CGA on chondrocytes was detected by cell counting kit-8 (CCK-8) and the biological effects were assessed by polymerase chain reaction (PCR) in vitro. KEY FINDINGS: We found that CGA treatment dramatically suppressed the NF-κB activity in LSI mice. Moreover, administration of CGA mitigated cartilaginous endplate degeneration and postponed IDD development accompanying a decrease of inflammatory and catabolic mediators. Specifically, CGA ameliorated endplate degeneration might be related to its protective effects against endplate chondrocytes apoptosis and trans-differentiation. We further elucidated that CGA exerted these biological effects mainly by repressing NF-κB signaling in cartilage endplate. SIGNIFICANCE: Our study has illustrated, for the first time, the curative effects as well as the latent mechanism of CGA in IDD and our results suggested that CGA administration might be used as an alternative therapy for IDD.


Asunto(s)
Apoptosis , Cartílago/efectos de los fármacos , Ácido Clorogénico/farmacología , Condrocitos/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Degeneración del Disco Intervertebral/tratamiento farmacológico , FN-kappa B/antagonistas & inhibidores , Animales , Cartílago/patología , Células Cultivadas , Condrocitos/patología , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/patología , Masculino , Ratones , Ratones Endogámicos C57BL
8.
Life Sci ; 274: 119331, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33716060

RESUMEN

AIMS: Cyclophosphamide (CP) is a common therapeutic drug for cancer, but exposure to CP can cause acute hepatotoxicity. This study aimed to elucidate the protective effects of Ligustrazine (2, 3, 5, 6-tetramethylpyrazine, TMP) on hepatotoxicity induced by CP or its active metabolite 4-hydroperoxycyclophosphamide (4-HC). MAIN METHODS: We presented a comprehensive investigation about the hepatoprotection of TMP on CP-induced mice and 4-HC-treated HSC-LX2 cells. Liver function was detected via enzyme-linked immunosorbent assay (ELISA). Hepatic histopathology analysis was performed via hematoxylin and eosin (H&E) and Masson staining. Survival of hepatocytes was detected by TUNEL assay. Related proteins in the thioredoxin (Trx)-interacting protein (Txnip)/Trx/Nuclear factor-kappa B (NF-κB) pathway were measured by western blotting. KEY FINDINGS: The results indicated that CP or 4-HC could increase the levels of alanine aminotransferase and aspartate aminotransferase, enhance inflammatory factors and oxidative indicators, and suppress the activity of oxidoreductases. Moreover, significant changes in liver histological structure, fibrosis, and cell death were observed through the activation of Txnip/Trx/NF-κB pathway. In contrast, administration of TMP significantly reversed these above changes. Furthermore, TMP intervention participated in the inhibition of NLRP3 inflammasome accompanied with pyroptosis, as well as upregulating Trx expression and downregulating p-NF-κB, while the protective effect of TMP was limited to the involvement of Txnip overexpression. SIGNIFICANCE: TMP treatment could significantly alleviate the hepatotoxicity process as evidenced by improving the structure and function of the liver, inhibiting oxidative stress and inflammation accompanied with pyroptosis, which was positively correlated with the inhibition of Txnip/Trx/NF-κB pathway.


Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Ciclofosfamida/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Pirazinas/farmacología , Tiorredoxinas/antagonistas & inhibidores , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Inflamasomas/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Mutágenos/toxicidad , Vasodilatadores/farmacología
9.
Life Sci ; 274: 119363, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33737083

RESUMEN

AIMS: Post-fracture calcium and phosphorus excretion is greater than influx, which might be caused by stress. Glucocorticoid is known to enhance calcium and phosphorous excretion, and hydrogen sulfide (H2S) has been shown to exert inhibitory effects on glucocorticoid. Therefore, this study explored whether H2S could inhibit calcium and phosphorus loss after fracture by regulating glucocorticoid and/or its receptor. MAIN METHODS: The following properties were analyzed in rats with femur fractures: serum and urinary calcium and phosphorus (by colorimetry); bone turnover markers alkaline phosphatase, serum type 1 collagen amino terminal peptide, type 1 procollagen carboxy terminal peptide, and anti-tartaric acid phosphatase (by ELISA); factors related to calcium-phosphorus metabolism including glucocorticoid, parathyroid hormone, calcitonin, fibroblast growth factor 23, and 1,25(OH)2D3 (by ELISA); and sulfhydration of glucocorticoid receptor α in the kidney (by immunoprecipitation linked biotin-switch assay), after supplementing with mifepristone, the H2S donor GYY4137 or H2S generating enzyme inhibitors aminooxyacetic acid and propargylglycine. KEY FINDINGS: Serum H2S decreased and glucocorticoid secretion increased in rats post-fracture. The glucocorticoid receptor inhibitor mifepristone partly blunted calcium and phosphorus loss. Furthermore, supplementation with GYY4137 reduced glucocorticoid secretion; inhibited glucocorticoid receptor α activity by sulfhydration; downregulated vitamin D 1α-hydroxylase expression; and upregulated 24-hydroxylase, calbindin-D28k, and sodium phosphate cotransporter 2a expression in the kidney; thereby inhibiting calcium and phosphorus loss induced by fracture. Moreover, inhibiting endogenous H2S generation showed opposite effects. SIGNIFICANCE: Our findings suggest that H2S antagonized calcium and phosphorus loss after fracture by reducing glucocorticoid secretion and inhibiting glucocorticoid receptor α activity by sulfhydration.


Asunto(s)
Calcio/metabolismo , Fracturas del Fémur/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Sulfuro de Hidrógeno/farmacología , Morfolinas/farmacología , Compuestos Organotiofosforados/farmacología , Fósforo/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Animales , Fracturas del Fémur/metabolismo , Fracturas del Fémur/patología , Gasotransmisores/farmacología , Masculino , Ratas , Ratas Sprague-Dawley
10.
Life Sci ; 273: 119297, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33689686

RESUMEN

Stress-induced gastritis is a common problem in the intensive care unit. Zeaxanthin (ZE), a non-provitamin A carotenoid has been known to exert antioxidant and anti-inflammatory effects. In this study, we examined the effect of ZE on water avoidance stress (WAS)-induced gastritis in rats. 24 Sprague' Dawley male rats were divided into four groups; control, ZE, WAS and WAS+ZE. In the stressed rats, treatment with ZE effectively downregulated the gastric levels of total oxidant status (TOS), myeloperoxidase (MPO) and malondialdehyde (MDA), with significant upregulation of the antioxidant enzymes' activities and gastric levels of prostagladin-E2 (PGE2) as compared to the untreated stressed one. As noticed in the present study, ZE significantly decrease the gastric levels of interleukin-1 ß (IL-1ß) and IL-6 as well as suppression of nuclear transcription factor kappa-B (NF-κB) immunohistochemical expression together with upregulation of trefoil factor-1 (TFF-1) gene expression. Moreover, in the untreated WAS-induced gastritis group, gastrin and corticosterone levels were significantly increased together with upregulation of the gene expression of hypoxia inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), PI3K, Akt and JNK in the gastric tissues, which significantly improved by ZE administration. These all positive effects of ZE reflected on reduction of microscopic gastric mucosal damage and inflammatory cell infiltration with improvement of ulcer score. Our results discover that ZE has a new gastroprotective effect against stress-induced gastritis in rats, primarily through its antioxidative and anti-inflammatory effects, which are expressed in the regulation of the MMP-9 and HIF-1α signaling pathways.


Asunto(s)
Biomarcadores/análisis , Gastritis/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Sustancias Protectoras/farmacología , Estrés Fisiológico , Zeaxantinas/farmacología , Animales , Antioxidantes/metabolismo , Citocinas/metabolismo , Gastritis/etiología , Gastritis/metabolismo , Gastritis/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , MAP Quinasa Quinasa 4/genética , MAP Quinasa Quinasa 4/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Estrés Oxidativo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Factor Trefoil-1/genética , Factor Trefoil-1/metabolismo
11.
Life Sci ; 273: 119293, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33705733

RESUMEN

Experimental studies have shown that ß-caryophyllene (BCP) improved neurological deficits of cerebral ischemia-reperfusion injury (CIRI) rats resulting from Middle Cerebral Artery Occlusion (MCAO). However, research on targets of BCP on CIRI has not been completed. In this study, the mRNA sequencing was used to distinguish various therapeutic multiple targets of BCP on CIRI. Differentially expressed genes (DEGs) were identified from RNA-seq analysis. CIRI induced up-regulated genes (CIRI vs. Sham) and BCP -induced down-regulated genes (BCP vs CIRI) were identified. Significant DEGs were identified only that expressed in each of all samples. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis of significant DEGs were determined by cluster Profiler. Protein interactive network (PPI) was analyzed using the String tool and Hub genes was identified by cytoHubba. Transcription factor (TF) regulatory network for the potential Hub genes was constructed. Western blot and ELISA were used to verified hub genes and relative inflammatory cytokines. After mRNA sequencing, a total of 411 DEGs were filtered based on the 2 series (CIRI vs. Sham and CIRI vs. BCP), with Pax1, Cxcl3 and Ccl20 are the most remarkable ones reversed by BCP. GO analysis was represented by DEGs involved in multiple biological process such as extra-cellular matrix organization, leukocyte migration, regulation of angiogenesis, reactive oxygen species metabolic process, etc. KEGG analysis showed that DEGs participated several signaling pathways including MAPK signaling pathway (rno04010), Cytokine-cytokine receptor interaction (rno04060), JAK-STAT signaling pathway (rno04630), and others. The protein-protein interaction (PPI) network consisted of 339 nodes and 1945 connections, and top ten Hub genes were identified by cytoHubba such as TIMP1, MMP-9, and STAT3. Subsequently, a TFs-miRNAs-targets regulatory network was established, involving 6 TFs, 5 miRNAs, and 10 hub genes, consisting of several regulated models such as Brd4 - rno-let-7e - Mmp9, Brd4 - rno-let-7i - Stat3, and Hnf4a- rno-let-7b -Timp1. Finally, western blot demonstrated that BCP could inhibit the increased TIMP1, MMP-9 and STAT3 expression in rat brains after I/R. ELISA represented that BCP could suppress inflammatory cytokines caused by CIRI and present anti-oxidative property. In conclusion, this study shows that the intervention of BCP can significantly reduce neurologic deficit, improve the cerebral ischemia, and a total of ten hub genes were found closely related to the treatment of BCP on CIRI. Prudent experimental validation suggests that the BCP might have the neuro-protective effects in CIRI by decreasing the expression of MMP-9 and TIMP-1, STAT3. In a sense, this study reveals that the MMP-9/TIMP-1 signaling pathway may be involved in the injury after CIRI and thus provides a new treatment strategy as well as a researching method for stroke.


Asunto(s)
Biomarcadores/análisis , Isquemia Encefálica/genética , Regulación de la Expresión Génica/efectos de los fármacos , Infarto de la Arteria Cerebral Media/complicaciones , Sesquiterpenos Policíclicos/farmacología , Daño por Reperfusión/genética , Animales , Antiinflamatorios no Esteroideos/farmacología , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Biología Computacional , Perfilación de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Masculino , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/etiología , Daño por Reperfusión/patología
12.
Nat Commun ; 12(1): 1379, 2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33654074

RESUMEN

Many immune responses depend upon activation of NF-κB, an important transcription factor in the elicitation of a cytokine response. Here we show that N4BP1 inhibits TLR-dependent activation of NF-κB by interacting with the NF-κB signaling essential modulator (NEMO, also known as IκB kinase γ) to attenuate NEMO-NEMO dimerization or oligomerization. The UBA-like (ubiquitin associated-like) and CUE-like (ubiquitin conjugation to ER degradation-like) domains in N4BP1 mediate interaction with the NEMO COZI domain. Both in vitro and in mice, N4bp1 deficiency specifically enhances TRIF-independent (TLR2, TLR7, or TLR9-mediated) but not TRIF-dependent (TLR3 or TLR4-mediated) NF-κB activation, leading to increased production of proinflammatory cytokines. In response to TLR4 or TLR3 activation, TRIF causes activation of caspase-8, which cleaves N4BP1 distal to residues D424 and D490 and abolishes its inhibitory effect. N4bp1-/- mice also have diminished numbers of T cells in the peripheral blood. Our work identifies N4BP1 as an inhibitory checkpoint protein that must be overcome to activate NF-κB, and a TRIF-initiated caspase-8-dependent mechanism by which this is accomplished.


Asunto(s)
Proteínas Portadoras/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , FN-kappa B/metabolismo , Multimerización de Proteína , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Proteínas Portadoras/química , Proteínas Portadoras/genética , Caspasa 8/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Herpesvirus Humano 1/fisiología , Humanos , Interleucina-6/sangre , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Ratones Endogámicos C57BL , Mutación/genética , Inhibidor NF-kappaB alfa/metabolismo , Oligodesoxirribonucleótidos/farmacología , Fosforilación/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Dominios Proteicos , Multimerización de Proteína/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ubiquitina/metabolismo
13.
Comput Biol Med ; 131: 104293, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33662681

RESUMEN

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Up to 20%-30% of patients hospitalized with COVID-19 have evidence of cardiac dysfunction. Xuebijing injection is a compound injection containing five traditional Chinese medicine ingredients, which can protect cells from SARS-CoV-2-induced cell death and improve cardiac function. However, the specific protective mechanism of Xuebijing injection on COVID-19-induced cardiac dysfunction remains unclear. METHODS: The therapeutic effect of Xuebijing injection on COVID-19 was validated by the TCM Anti COVID-19 (TCMATCOV) platform. RNA-sequencing (RNA-seq) data from GSE150392 was used to find differentially expressed genes (DEGs) from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) infected with SARS-CoV-2. Data from GSE151879 was used to verify the expression of Angiotensin I Converting Enzyme 2 (ACE2) and central hub genes in both human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) and adult human CMs with SARS-CoV-2 infection. RESULTS: A total of 97 proteins were identified as the therapeutic targets of Xuebijing injection for COVID-19. There were 22 DEGs in SARS-CoV-2 infected hiPSC-CMs overlapped with the 97 therapeutic targets, which might be the therapeutic targets of Xuebijing injection on COVID-19-induced cardiac dysfunction. Based on the bioinformatics analysis, 7 genes (CCL2, CXCL8, FOS, IFNB1, IL-1A, IL-1B, SERPINE1) were identified as central hub genes and enriched in pathways including cytokines, inflammation, cell senescence and oxidative stress. ACE2, the receptor of SARS-CoV-2, and the 7 central hub genes were differentially expressed in at least two kinds of SARS-CoV-2 infected CMs. Besides, FOS and quercetin exhibited the tightest binding by molecular docking analysis. CONCLUSION: Our study indicated the underlying protective effect of Xuebijing injection on COVID-19, especially on COVID19-induced cardiac dysfunction, which provided the theoretical basis for exploring the potential protective mechanism of Xuebijing injection on COVID19-induced cardiac dysfunction.


Asunto(s)
/metabolismo , Medicamentos Herbarios Chinos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Miocitos Cardíacos/metabolismo , RNA-Seq , /metabolismo , /tratamiento farmacológico , Línea Celular , Células Madre Embrionarias Humanas/metabolismo , Células Madre Embrionarias Humanas/patología , Células Madre Embrionarias Humanas/virología , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Células Madre Pluripotentes Inducidas/virología , Miocitos Cardíacos/patología , Miocitos Cardíacos/virología
14.
FASEB J ; 35(4): e21441, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33749902

RESUMEN

An excessive, non-resolving inflammatory response underlies severe COVID-19 that may have fatal outcomes. Therefore, the investigation of endogenous pathways leading to resolution of inflammation is of interest to uncover strategies for mitigating inflammation in people with SARS-CoV-2 infection. This becomes particularly urgent in individuals with preexisting pathologies characterized by chronic respiratory inflammation and prone to bacterial infection, such as cystic fibrosis (CF). Here, we analyzed the immune responses to SARS-CoV-2 virion spike 1 glycoprotein (S1) of macrophages (MΦ) from volunteers with and without CF and tested the efficacy of resolvins (Rv) D1 and D2 in regulating the inflammatory and antimicrobial functions of MΦ exposed to S1. S1 significantly increased chemokine release, including interleukin (IL)-8, in CF and non-CF MΦ, while it enhanced IL-6 and tumor necrosis factor (TNF)-α in non-CF MΦ, but not in CF cells. S1 also triggered the biosynthesis of RvD1 and modulated microRNAs miR-16, miR-29a, and miR-103, known to control the inflammatory responses. RvD1 and RvD2 treatment abated S1-induced inflammatory responses in CF and non-CF MΦ, significantly reducing the release of select chemokines and cytokines including IL-8 and TNF-α. RvD1 and RvD2 both restored the expression of miR-16 and miR-29a, while selectively increasing miR-223 and miR-125a, which are involved in NF-κB activation and MΦ inflammatory polarization. During Pseudomonas aeruginosa infection, S1 stimulated the MΦ phagocytic activity that was further enhanced by RvD1 and RvD2. These results provide a map of molecular responses to SARS-CoV-2 in MΦ, key determinants of COVID-19-related inflammation, unveiling some peculiarity in the response of cells from individuals with CF. They also demonstrate beneficial, regulatory actions of RvD1 and RvD2 on SARS-CoV-2-induced inflammation.


Asunto(s)
Fibrosis Quística , Ácidos Docosahexaenoicos/farmacología , Macrófagos , Infecciones por Pseudomonas , Pseudomonas aeruginosa/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , /inmunología , /patología , Fibrosis Quística/inmunología , Fibrosis Quística/microbiología , Fibrosis Quística/patología , Fibrosis Quística/virología , Citocinas/inmunología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Inflamación/virología , Macrófagos/inmunología , Macrófagos/microbiología , Macrófagos/patología , Macrófagos/virología , Masculino , MicroARNs/inmunología , Infecciones por Pseudomonas/inmunología , Infecciones por Pseudomonas/patología , Infecciones por Pseudomonas/virología
15.
FASEB J ; 35(4): e21360, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33749932

RESUMEN

The novel coronavirus disease, COVID-19, has grown into a global pandemic and a major public health threat since its breakout in December 2019. To date, no specific therapeutic drug or vaccine for treating COVID-19 and SARS has been FDA approved. Previous studies suggest that berberine, an isoquinoline alkaloid, has shown various biological activities that may help against COVID-19 and SARS, including antiviral, anti-allergy and inflammation, hepatoprotection against drug- and infection-induced liver injury, as well as reducing oxidative stress. In particular, berberine has a wide range of antiviral activities such as anti-influenza, anti-hepatitis C, anti-cytomegalovirus, and anti-alphavirus. As an ingredient recommended in guidelines issued by the China National Health Commission for COVID-19 to be combined with other therapy, berberine is a promising orally administered therapeutic candidate against SARS-CoV and SARS-CoV-2. The current study comprehensively evaluates the potential therapeutic mechanisms of berberine in preventing and treating COVID-19 and SARS using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analysis, and in silico molecular docking. An orally available immunotherapeutic-berberine nanomedicine, named NIT-X, has been developed by our group and has shown significantly increased oral bioavailability of berberine, increased IFN-γ production by CD8+ T cells, and inhibition of mast cell histamine release in vivo, suggesting a protective immune response. We further validated the inhibition of replication of SARS-CoV-2 in lung epithelial cells line in vitro (Calu3 cells) by berberine. Moreover, the expression of targets including ACE2, TMPRSS2, IL-1α, IL-8, IL-6, and CCL-2 in SARS-CoV-2 infected Calu3 cells were significantly suppressed by NIT-X. By supporting protective immunity while inhibiting pro-inflammatory cytokines; inhibiting viral infection and replication; inducing apoptosis; and protecting against tissue damage, berberine is a promising candidate in preventing and treating COVID-19 and SARS. Given the high oral bioavailability and safety of berberine nanomedicine, the current study may lead to the development of berberine as an orally, active therapeutic against COVID-19 and SARS.


Asunto(s)
Antivirales/farmacología , Berberina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Modelos Biológicos , Virus del SRAS/metabolismo , Síndrome Respiratorio Agudo Grave , Administración Oral , /metabolismo , Línea Celular , Simulación por Computador , Humanos , Pandemias , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/metabolismo
16.
mBio ; 12(2)2021 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-33727347

RESUMEN

An emerging class of cellular inhibitory proteins has been identified that targets viral glycoproteins. These include the membrane-associated RING-CH (MARCH) family of E3 ubiquitin ligases that, among other functions, downregulate cell surface proteins involved in adaptive immunity. The RING-CH domain of MARCH proteins is thought to function by catalyzing the ubiquitination of the cytoplasmic tails (CTs) of target proteins, leading to their degradation. MARCH proteins have recently been reported to target retroviral envelope glycoproteins (Env) and vesicular stomatitis virus G glycoprotein (VSV-G). However, the mechanism of antiviral activity remains poorly defined. Here we show that MARCH8 antagonizes the full-length forms of HIV-1 Env, VSV-G, Ebola virus glycoprotein (EboV-GP), and the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), thereby impairing the infectivity of virions pseudotyped with these viral glycoproteins. This MARCH8-mediated targeting of viral glycoproteins requires the E3 ubiquitin ligase activity of the RING-CH domain. We observe that MARCH8 protein antagonism of VSV-G is CT dependent. In contrast, MARCH8-mediated targeting of HIV-1 Env, EboV-GP, and SARS-CoV-2 S protein by MARCH8 does not require the CT, suggesting a novel mechanism of MARCH-mediated antagonism of these viral glycoproteins. Confocal microscopy data demonstrate that MARCH8 traps the viral glycoproteins in an intracellular compartment. We observe that the endogenous expression of MARCH8 in several relevant human cell types is rapidly inducible by type I interferon. These results help to inform the mechanism by which MARCH proteins exert their antiviral activity and provide insights into the role of cellular inhibitory factors in antagonizing the biogenesis, trafficking, and virion incorporation of viral glycoproteins.IMPORTANCE Viral envelope glycoproteins are an important structural component on the surfaces of enveloped viruses that direct virus binding and entry and also serve as targets for the host adaptive immune response. In this study, we investigate the mechanism of action of the MARCH family of cellular proteins that disrupt the trafficking and virion incorporation of viral glycoproteins across several virus families. This research provides novel insights into how host cell factors antagonize viral replication, perhaps opening new avenues for therapeutic intervention in the replication of a diverse group of highly pathogenic enveloped viruses.


Asunto(s)
Proteínas de la Membrana/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas del Envoltorio Viral/metabolismo , Secuencia de Aminoácidos , Células Cultivadas , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Interferones/farmacología , Espacio Intracelular/metabolismo , Proteínas de la Membrana/genética , Mutación , Virus ARN/clasificación , Virus ARN/metabolismo , Especificidad de la Especie , Ubiquitina-Proteína Ligasas/genética , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/genética , Virión/metabolismo , Replicación Viral
17.
J Enzyme Inhib Med Chem ; 36(1): 659-668, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33641565

RESUMEN

Human intestinal epithelial cell line-6 (HIEC-6) cells and primary human hepatocytes (PHHs) were treated with 3-amidinophenylalanine-derived inhibitors of trypsin-like serine proteases for 24 hours. It was proven that treatment with MI-1900 and MI-1907 was tolerated up to 50 µM in HIEC-6. These inhibitors did not cause elevations in extracellular H2O2 levels and in the concentrations of interleukin (IL)-6 and IL-8 and did not alter occludin distribution in HIEC-6. It was also found that MI-1900 and MI-1907 up to 50 µM did not affect cell viability, IL-6 and IL-8 and occludin levels of PHH. Based on our findings, these inhibitors could be safely applicable at 50 µM in HIEC-6 and in PHH; however, redox status was disturbed in case of PHH. Moreover, it has recently been demonstrated that MI-1900 prevents the replication and spread of the new SARS-CoV-2 in infected Calu-3 cells, most-likely via an inhibition of the membrane-bound host protease TMPRSS2.


Asunto(s)
Antivirales/farmacología , Células Epiteliales/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Fenilalanina/farmacología , Inhibidores de Proteasas/farmacología , Serina Endopeptidasas/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Epiteliales/citología , Células Epiteliales/enzimología , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/citología , Hepatocitos/enzimología , Humanos , Peróxido de Hidrógeno/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/enzimología , Ocludina/genética , Ocludina/metabolismo , Oxidación-Reducción/efectos de los fármacos , Fenilalanina/análogos & derivados , Cultivo Primario de Células , Serina Endopeptidasas/genética
18.
DNA Cell Biol ; 40(3): 543-552, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33687272

RESUMEN

Obesity in puberty, already a time of insulin resistance, increases the risk of developing type 2 diabetes. Human (h) growth hormone (GH) levels also peak during puberty, where it contributes to growth and energy homeostasis through positive effects on maintaining pancreatic ß cell mass. Thus, it is important to understand the effects of overeating and obesity on hGH production in puberty. Three days of overeating in young male adults or high-fat diet (HFD) in pubescent male transgenic (171hGH/CS) CD-1 mice containing the hGH gene (hGH-N) results in excess insulin and a decrease in hGH production. This reduction in these mice occurred during the light phase of the daily cycle, and was associated with decreased availability of the clock-related transcription factor Brain and Muscle ARNT-Like 1 (Bmal1). However, the HFD-induced decrease in hGH-N expression was blocked by forced daily swim activity, which is expected to increase glucocorticoid (GC) levels. The aim of the study was to assess whether GCs, specifically daily injections with a pharmacological dose of dexamethasone (DEX) in the light or dark phase of the daily cycle, can limit the negative effect of HFD for 3 days on hGH-N expression in male 171hGH/CS mice. DEX treatment increased or rescued hGH-N RNA levels, and was associated with elevated Bmal1 transcripts when assessed 12 h after final treatment, and at a time when serum corticosterone levels were suppressed >90%. In addition, a diet-dependent effect on hGH-N RNA levels was observed at 36 h after final treatment, but only in the light stage, presumably due to residual effects of DEX treatment and/or recovery of endogenous corticosterone levels. This is the first evidence for a direct effect of GCs on hGH-N expression in vivo and the ability to potentially limit the negative effect of overeating/obesity on hGH production in puberty.


Asunto(s)
Dexametasona/farmacología , Dieta Alta en Grasa/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Hormona de Crecimiento Humana/biosíntesis , Animales , Hormona de Crecimiento Humana/genética , Masculino , Ratones , Ratones Transgénicos , Factores de Tiempo
19.
Nat Commun ; 12(1): 1141, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602926

RESUMEN

The composition of the gastrointestinal microbiota influences systemic immune responses, but how this affects infectious disease pathogenesis and antibiotic therapy outcome is poorly understood. This question is rarely examined in humans due to the difficulty in dissociating the immunologic effects of antibiotic-induced pathogen clearance and microbiome alteration. Here, we analyze data from two longitudinal studies of tuberculosis (TB) therapy (35 and 20 individuals) and a cross sectional study from 55 healthy controls, in which we collected fecal samples (for microbiome analysis), sputum (for determination of Mycobacterium tuberculosis (Mtb) bacterial load), and peripheral blood (for transcriptomic analysis). We decouple microbiome effects from pathogen sterilization by comparing standard TB therapy with an experimental TB treatment that did not reduce Mtb bacterial load. Random forest regression to the microbiome-transcriptome-sputum data from the two longitudinal datasets reveals that renormalization of the TB inflammatory state is associated with Mtb pathogen clearance, increased abundance of Clusters IV and XIVa Clostridia, and decreased abundance of Bacilli and Proteobacteria. We find similar associations when applying machine learning to peripheral gene expression and microbiota profiling in the independent cohort of healthy individuals. Our findings indicate that antibiotic-induced reduction in pathogen burden and changes in the microbiome are independently associated with treatment-induced changes of the inflammatory response of active TB, and the response to antibiotic therapy may be a combined effect of pathogen killing and microbiome driven immunomodulation.


Asunto(s)
Microbioma Gastrointestinal , Inflamación/microbiología , Inflamación/patología , Tuberculosis/complicaciones , Tuberculosis/microbiología , Adulto , Algoritmos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Carga Bacteriana/efectos de los fármacos , Biodiversidad , Estudios de Casos y Controles , Estudios de Cohortes , Microbioma Gastrointestinal/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/complicaciones , Modelos Biológicos , Reproducibilidad de los Resultados , Tuberculosis/tratamiento farmacológico , Tuberculosis/patología
20.
Life Sci ; 273: 119235, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33607152

RESUMEN

Although the central role of Nurr-1/GDNF has been reviewed amply, scarce data are available on their peripheral impact. Carvedilol and morin hydrate have previously conferred their hepatic anti-fibrotic action. AIM: Thus, our aim was to unveil the potential hepatoprotective role of carvedilol (CR) and/or morin hydrate (MH) using a hepatic 70% partial warm ischemia/reperfusion (I/R) rat model. MAIN METHOD: Rats were allocated into sham-operated, hepatic I/R, and I/R preceded by oral administration of CR (10 and 30 mg/kg; CR10/CR30), MH (30 mg/kg), or CR10 + MH for one week. KEY FINDINGS: On the molecular level, pretreatment with CR and/or MH increased the hepatic contents of Nurr-1, GDNF, and the protein expression of active/p-AKT. On the other hand, they inactivated GSK3ß and NF-κB to increase the antioxidant enzymes (GPx, SOD, CAT). All regimens also enhanced the autophagy/lysosomal function and boosted the protein expression of beclin-1, LC3II, and TFEB. Moreover, their antiapoptotic effect was signified by increasing the anti-apoptotic molecule Bcl2 and inhibiting Bax, Bax/Bcl2 ratio, and caspase-3, effects that were confirmed by the TUNEL assay. These improvements were reflected on liver function, as they decreased serum aminotransferases and liver structural alterations induced by I/R. Despite its mild impact, CR10 showed marked improvements when combined with MH; this synergistic interaction overrides the effect of either regimen alone. SIGNIFICANCE: In conclusion, CR, MH, and especially the combination regimen, conferred hepatoprotection against I/R via activating the Nurr-1/GDNF/AKT trajectory to induce autophagy/lysosomal biogenesis, inhibit GSK3ß/NF-кB hub and apoptosis, and amend redox balance.


Asunto(s)
Carvedilol/farmacología , Flavonoides/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Isquemia/tratamiento farmacológico , Hepatopatías/tratamiento farmacológico , Sustancias Protectoras/farmacología , Daño por Reperfusión/tratamiento farmacológico , Animales , Antioxidantes/farmacología , Apoptosis , Autofagia , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Isquemia/metabolismo , Isquemia/patología , Hepatopatías/metabolismo , Hepatopatías/patología , Masculino , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...