RESUMEN
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but its overdose can cause acute liver failure. The dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1, NR0B1), is an orphan nuclear receptor that acts as a transcriptional co-repressor of various genes. In this study, we identified the role of DAX-1 in APAP-induced liver injury using hepatocyte-specific Dax-1 knockout (Dax-1 LKO) mice. Mouse primary hepatocytes were used as a comparative in vitro study. APAP overdose led to decreased plasma alanine aminotransferase and aspartate aminotransferase levels in Dax-1 LKO mice compared to C57BL/6J (WT) controls, accompanied by reduced liver necrosis. The expression of the genes encoding the enzymes catalyzing glutathione (GSH) synthesis and metabolism and antioxidant enzymes was increased in the livers of APAP-treated Dax-1 LKO mice. The rapid recovery of GSH levels in the mitochondrial fraction of APAP-treated Dax-1 LKO mice led to reduced reactive oxygen species levels, resulting in the inhibition of the prolonged JNK activation. The hepatocyte-specific DAX-1 deficiency increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) compared with WT controls after APAP administration. These results indicate that DAX-1 deficiency in hepatocytes protects against APAP-induced liver injury by Nrf2-regulated antioxidant defense.
Asunto(s)
Antipiréticos , Enfermedad Hepática Inducida por Sustancias y Drogas , Receptor Nuclear Huérfano DAX-1 , Factor 2 Relacionado con NF-E2 , Acetaminofén/toxicidad , Alanina Transaminasa/metabolismo , Animales , Antioxidantes/metabolismo , Aspartato Aminotransferasas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Proteínas Co-Represoras/metabolismo , Receptor Nuclear Huérfano DAX-1/genética , Glutatión/metabolismo , Hepatocitos/metabolismo , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Receptores Nucleares Huérfanos/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Fulminant hepatitis is characterized by rapid and massive immune-mediated liver injury. Dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX1; NR0B1) represses the transcription of various genes. Here, we determine whether DAX1 serves as a regulator of inflammatory liver injury induced by concanavalin A (ConA). C57BL/6J (WT), myeloid cell-specific Dax1 knockout (MKO), and hepatocyte-specific Dax1 knockout (LKO) mice received single intravenous administration of ConA. Histopathological changes in liver and plasma alanine aminotransferase and aspartate aminotransferase levels in Dax1 MKO mice were comparable with those in WT mice following ConA administration. Unlike Dax1 MKO mice, Dax1 LKO mice were greatly susceptible to ConA-induced liver injury, which was accompanied by enhanced infiltration of immune cells, particularly CD4+ and CD8+ T cells, in the liver. Factors related to T-cell recruitment, including chemokines and adhesion molecules, significantly increased following enhanced and prolonged phosphorylation of NF-κB p65 in the liver of ConA-administered Dax1 LKO mice. This is the first study to demonstrate that hepatocyte-specific DAX1 deficiency exacerbates inflammatory liver injury via NF-κB p65 activation, thereby causing T-cell infiltration by modulating inflammatory chemokines and adhesion molecules. Our results suggest DAX1 as a therapeutic target for fulminant hepatitis treatment.
Asunto(s)
Linfocitos T CD8-positivos , Necrosis Hepática Masiva , Ratones , Animales , FN-kappa B , Ratones Endogámicos C57BL , Hepatocitos , Transducción de Señal , Concanavalina A/toxicidad , Linfocitos T CD4-PositivosRESUMEN
Fulminant hepatitis is a serious inflammatory condition of the liver characterized by massive necrosis of liver parenchyma following excessive immune cell infiltration into the liver, and possibly causing sudden hepatic failure and medical emergency. However, the underlying mechanisms are not fully understood. Here, we investigated the role of cyclic AMP-responsive element-binding protein, hepatocyte specific (CREBH) in concanavalin A (ConA)-driven hepatitis-evoked liver injury. C57BL/6J (WT) and Crebh knockout (KO) mice injected with ConA (7.5 or 25 mg/kg) and bone marrow (BM) chimeric mice, generated by injection of BM cells into sub-lethally irradiated recipients followed by ConA injection (22.5 or 27.5 mg/kg) 8 weeks later, were used for in vivo study. Primary mouse hepatocytes and HEK293T cells were used for a comparative in vitro study. Crebh KO mice are highly susceptible to ConA-induced liver injury and prone to death due to increased neutrophil infiltration driven by enhanced hepatic expression of neutrophil-attracting chemokines. Notably, BM chimera experiment demonstrated that Crebh-deficient hepatocytes have an enhanced ability of recruiting neutrophils to the liver, thereby promoting hepatotoxicity by ConA. Intriguingly, in vitro assays showed that p65, a subunit of NF-κB and common transcription factor for various chemokines, dependent transactivation was inhibited by CREBH. Furthermore, p65 expression was inversely correlated with CREBH level in ConA-treated mice liver and TNFα-stimulated primary mouse hepatocytes. This is the first demonstration that CREBH deficiency aggravates inflammatory liver injury following chemokine-dependent neutrophil infiltration via NF-κB p65 upregulation. CREBH is suggested to be a novel therapeutic target for treatment of fulminant hepatitis.
Asunto(s)
Quimiocinas/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Necrosis Hepática Masiva/patología , Infiltración Neutrófila , Factor de Transcripción ReIA/metabolismo , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Concanavalina A/toxicidad , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Citocinas/sangre , Citocinas/metabolismo , Células HEK293 , Humanos , Masculino , Necrosis Hepática Masiva/inducido químicamente , Necrosis Hepática Masiva/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Sqstm1/p62 functions in the non-canonical activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, its physiological relevance is not certain. Here, we show that p62(-/-) mice exhibited an accelerated presentation of ageing phenotypes, and tissues from these mice created a pro-oxidative environment owing to compromised mitochondrial electron transport. Accordingly, mitochondrial function rapidly declined with age in p62(-/-) mice. In addition, p62 enhanced basal Nrf2 activity, conferring a higher steady-state expression of NAD(P)H dehydrogenase, quinone 1 (Nqo1) to maintain mitochondrial membrane potential and, thereby, restrict excess oxidant generation. Together, the p62-Nrf2-Nqo1 cascade functions to assure mammalian longevity by stabilizing mitochondrial integrity.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas del Citoesqueleto/metabolismo , Proteínas de Choque Térmico/metabolismo , Longevidad/fisiología , Mamíferos/fisiología , Mitocondrias/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Animales , Autofagia , Femenino , Proteínas de Choque Térmico/deficiencia , Proteína 1 Asociada A ECH Tipo Kelch , Masculino , Ratones , Oxidación-Reducción , Proteína Sequestosoma-1 , Transducción de SeñalRESUMEN
Akkermansia muciniphila has received great attention because of its beneficial roles in gut health by regulating gut immunity, promoting intestinal epithelial development, and improving barrier integrity. However, A. muciniphila-derived functional molecules regulating gut health are not well understood. Microbiome-secreted proteins act as key arbitrators of host-microbiome crosstalk through interactions with host cells in the gut and are important for understanding host-microbiome relationships. Herein, we report the biological function of Amuc_1409, a previously uncharacterised A. muciniphila-secreted protein. Amuc_1409 increased intestinal stem cell (ISC) proliferation and regeneration in ex vivo intestinal organoids and in vivo models of radiation- or chemotherapeutic drug-induced intestinal injury and natural aging with male mice. Mechanistically, Amuc_1409 promoted E-cadherin/ß-catenin complex dissociation via interaction with E-cadherin, resulting in the activation of Wnt/ß-catenin signaling. Our results demonstrate that Amuc_1409 plays a crucial role in intestinal homeostasis by regulating ISC activity in an E-cadherin-dependent manner and is a promising biomolecule for improving and maintaining gut health.
Asunto(s)
Verrucomicrobia , beta Catenina , Masculino , Ratones , Animales , beta Catenina/metabolismo , Verrucomicrobia/metabolismo , Intestinos , Cadherinas/metabolismo , AkkermansiaRESUMEN
BACKGROUND: Neuroinflammation plays an important role in cognitive decline and memory impairment in neurodegenerative disorders. Previously, we demonstrated that Humulus japonicus (HJ) has anti-inflammatory effects in rodent models of Alzheimer's disease and Parkinson's disease. The present study aimed to examine the protective potential of HJ extracts against lipopolysaccharide (LPS)-induced cognitive impairment and scopolamine-induced amnesia in mouse models. Cognitive improvement of mice was investigated by novel object recognition test. For analyzing effects on neuroinflammation, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed. RESULTS: We found that the oral administration of HJ significantly improved cognitive dysfunction induced by LPS in a novel object recognition test. The LPS-induced activation of microglia was notably decreased by HJ treatment in the cortex and hippocampus. HJ administration with LPS also significantly increased the mRNA expression of interleukin (IL)-10 and decreased the mRNA expression of IL-12 in the parietal cortex of mice. The increased expression of LPS-induced complement C1q B chain (C1bq) and triggering receptor expressed on myeloid cells 2 (Trem2) genes was significantly suppressed by HJ treatment. In addition, HJ administration significantly improved novel object recognition in a scopolamine-induced amnesia mouse model. CONCLUSIONS: These findings revealed that HJ has a beneficial effect on cognitive impairment and neuroinflammation induced by systemic inflammation and on amnesia induced by scopolamine in mice.
RESUMEN
Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to motor symptoms. Despite the remarkable improvements in the management of PD in recent decades, many patients remain significantly disabled. Metformin is a primary medication for the management of type 2 diabetes. We previously showed that co-treatment with metformin and 3,4-dihydroxyphenyl-l-alanine (l-DOPA) prevented the development of l-DOPA-induced dyskinesia in a 6-hydroxydopamine (6-OHDA)-lesioned animal model of PD. However, effects of metformin on PD- and aging-induced genes in reactive astrocytes remain unknown. In this study, we assessed the effect of metformin on motor function, neuroprotection, and reactive astrocytes in the 6-OHDA-induced PD animal model. In addition, the effects of metformin on the genes expressed by specific types of astrocytes were analyzed in PD model and aged mice. Here, we showed that metformin treatment effectively improves the motor symptoms in the 6-OHDA-induced PD mouse model, whereas metformin had no effect on tyrosine hydroxylase-positive neurons. The activation of AMPK and BDNF signaling pathways was induced by metformin treatment on the 6-OHDA-lesioned side of the striatum. Metformin treatment caused astrocytes to alter reactive genes in a PD animal model. Moreover, aging-induced genes in reactive astrocytes were effectively regulated or suppressed by metformin treatment. Taken together, these results suggest that metformin should be evaluated for the treatment of Parkinson's disease and related neurologic disorders characterized by astrocyte activation.
Asunto(s)
Envejecimiento/fisiología , Astrocitos/efectos de los fármacos , Astrocitos/fisiología , Cuerpo Estriado/fisiología , Metformina/administración & dosificación , Enfermedad de Parkinson/fisiopatología , Animales , Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacosRESUMEN
We investigated the effect of tilianin upon inducible nitric oxide synthesis in the plasma of low-density lipoprotein receptor knock-out (Ldlr-/-) mice fed with high cholesterol diet and in primary peritoneal macrophages of Ldlr-/- mice. High cholesterol diet induced nitric oxide production in the plasma of Ldlr-/- mice. Tilianin reduced the level of nitric oxide (NO) in plasma from Ldlr-/- mice induced by the high cholesterol diet. Tilianin also inhibited the NO production from the primary culture of peritoneal macrophages treated with lipopolysaccharide. The inhibition of NO production was caused by the suppression of inducible nitric oxide synthase (iNOS) gene expression in peritoneal macrophages isolated from Ldlr-/- mice. Moreover, tilianin inhibited the transcriptional activation of iNOS promoter that has NF-kappaB binding element. Thus, these results provide the first evidence that tilianin inhibit iNOS expression and production of NO and may act as a potential anti-inflammatory agent.
Asunto(s)
Flavonoides/farmacología , Glicósidos/farmacología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Receptores de LDL/genética , Animales , Aterosclerosis/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Inflamación/metabolismo , Masculino , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Óxido Nítrico/biosíntesis , Óxido Nítrico/sangre , Regiones Promotoras Genéticas/efectos de los fármacos , Seno Aórtico/metabolismo , Seno Aórtico/patología , Seno Aórtico/ultraestructura , Distribución Tisular , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
To determine whether the PPARalpha agonist fenofibrate regulates obesity and lipid metabolism with sexual dimorphism, we examined the effects of fenofibrate on body weight, white adipose tissue (WAT) mass, circulating lipids, and the expression of PPARalpha target genes in both sexes of high fat diet-fed C57BL/6J mice. Both sexes of mice fed a high-fat diet for 14 weeks exhibited increases in body weight, visceral WAT mass, as well as serum triglycerides and cholesterol, although these effects were more pronounced among males. Feeding a high fat diet supplemented with fenofibrate (0.05% w/w) reduced all of these effects significantly in males except serum cholesterol level. Females on a fenofibrate-enriched high fat diet had reduced serum triglyceride levels, albeit to a smaller extent compared to males, but did not exhibit decreases in body weight, WAT mass, and serum cholesterol. Fenofibrate treatment resulted in hepatic induction of PPARalpha target genes encoding enzymes for fatty acid beta-oxidation, the magnitudes of which were much higher in males compared to females, as evidenced by results for acyl-CoA oxidase, a first enzyme of the beta-oxidation system. These results suggest that observed sexually dimorphic effects on body weight, WAT mass and serum lipids by fenofibrate may involve sexually related elements in the differential activation of PPARalpha.
Asunto(s)
Fenofibrato/farmacología , Metabolismo de los Lípidos , Obesidad/metabolismo , Receptores Citoplasmáticos y Nucleares/agonistas , Caracteres Sexuales , Factores de Transcripción/agonistas , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Dieta , Grasas de la Dieta/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Lípidos/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/patología , Tamaño de los Órganos/efectos de los fármacos , Factores de TiempoRESUMEN
OBJECTIVES: This study aimed to check the status of the contact investigation in congregate settings to eradicate tuberculosis (TB) in the Republic of Korea. METHODS: The "Integrated System for Disease and Public Health Management" is used for care and follow-up for patients and contacts of TB. We downloaded data for contact investigations conducted from January to December 2013. RESULTS: A total of 1,200 contact investigations in congregate settings were carried out by 25 field investigators in 2013. We performed the status of contact investigation, TB, and LTBI rate by age, accept rate of LTBI treatment, and complete rate of LTBI treatment during 2013. A total of 1,547 index TB patients, 149,166 contacts, and 259 additional TB patients were found through the investigation. Kindergartens showed the highest LTBI rate, 19.8%, among educational facilities. The second highest was in elementary schools and the subtotal LTBI rate of educational facilities was 7.8%. Social welfare/correctional facilities and workplaces showed relatively high LTBI rates of 23.8% and 23.6%, respectively. By age, individuals >35 years showed the highest LTBI rate, followed by those aged 0-4 years, 30-34 years, and 5-9 years, with rates of 18.1%, 16.4%, and 15.4% respectively. When comparing the tuberculin skin test (TST) positive conversion ratio by facility, middle school and high school were relatively high compared to the others. The accept rate of LTBI treatment in the workplace was lowest at 63% and the complete rate in elementary schools was lowest at 76.5%. CONCLUSION: TB contact investigation is considered as a meaningful strategy for preventing TB outbreaks in congregate settings and decreasing the prevalence of TB in young people. Results of this study could be used to establish the LTBI management policy.
RESUMEN
OBJECTIVE: To investigate the effects of meditation on anxiety, depression, fatigue, and quality of life in women who are receiving radiation therapy for breast cancer. DESIGN: Randomized, non-program controlled, parallel intervention clinical trial. SETTING: The ASAN Cancer Center located in Seoul, Korea. INTERVENTION: The subjects of this study included 102 female breast cancer patients who had undergone breast-conserving surgery; these female patients were randomized into equally assigned meditation control groups, with each group consisting of 51 patients. The test group received a total of 12 meditation therapy sessions during their 6-week radiation therapy period, and the control group underwent only a conventional radiation therapy. OUTCOME: The tools used to evaluate the effects of meditation were Hospital Anxiety and Depression scale, Revised Piper Fatigue scale, and European Organization for Research and Treatment of Cancer-Quality of Life Core-30. The results were analyzed based on the principles of intention-to-treat analysis, and, as a corollary analysis, per-protocol analysis was conducted. RESULTS: The breast cancer patients who received meditation therapy compared with the non-intervention group saw improvements in reduction of anxiety (p=.032), fatigue (p=.030), and improvement in global quality of life (p=.028). CONCLUSIONS: Based on the results of this study, an affirmation can be made that meditation can be used as a non-invasive intervention treatment for improving fatigue, anxiety, quality of life, and emotional faculties of women with breast cancer.