RESUMEN
Atopic dermatitis (AD) is a chronic inflammatory disease characterized by dry and itchy skin. Recently, it has been reported that oxidative stress is involved in skin diseases, possibly including AD. Vitamin C, also referred to as ascorbic acid, is a vital water-soluble compound that functions as an essential nutrient. It plays a significant role as both an antioxidant and an additive in various pharmaceutical and food products. Despite the fact that vitamin C is easily oxidized, we have developed NXP081, a single-stranded DNA aptamer that selectively binds to vitamin C, thereby inhibiting its oxidation. The objective of the current research was to examine the impact of NXP081, an animal model of AD induced by 2,4-dinitrofluorobenzene (DNFB). The experimental drug NXP081, when taken orally, showed promising results in reducing inflammation and improving the skin conditions caused by DNFB. The administration of NXP081 resulted in a significant reduction in ear swelling and a noticeable improvement in the appearance of skin lesions. In addition, the administration of NXP081 resulted in a significant decrease in the migration of mast cells in the skin lesions induced by DNFB. Moreover, NXP081 inhibited the production of interferon-gamma (IFN-γ) in CD4+ T cells that were activated and derived from the lymph nodes. Our findings provide useful information about the anti-inflammatory effect of NXP081 on AD.
Asunto(s)
Aptámeros de Nucleótidos , Dermatitis Atópica , Enfermedades de la Piel , Ratones , Animales , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/metabolismo , Dinitrofluorobenceno/efectos adversos , Ratones Endogámicos BALB C , Aptámeros de Nucleótidos/efectos adversos , Ácido Ascórbico/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Enfermedades de la Piel/metabolismo , Vitaminas/farmacología , Piel/metabolismo , Citocinas/metabolismoRESUMEN
Cynanchum wilfordii and Humulus lupulus L. have been used for their various pharmacological properties in South Korea as a traditional medicine or health functional food, respectively, and their intake may relieve menopausal symptoms. The purpose of current study was to determine the effect of compound of Cynanchum wilfordii and Humulus lupulus L. (CWHL) in menopausal symptoms of ovariectomized (OVX) mice. OVX mice received CWHL or caudatin (an active ingredient of CWHL) once daily for 7 weeks. Values for hypothalamic serotonin (5-HT), dopamine, norepinephrine, estrogen receptor (ER)-ß, 5-HT1A, and 5-HT2A were significantly enhanced, while value for hypothalamic monoamine oxidase A was reduced in CWHL and caudatin groups compared with the OVX group. CWHL and caudatin significantly reduced tail skin temperature and rectal temperature of OVX mice through partial recovering of the levels of serum estrogen, nitric oxide, follicle-stimulating hormone, luteinizing hormone, and receptor-activator of the NF-κB ligand (RANKL). Moreover, CWHL and caudatin improved bone mineral density via decreasing levels of serum RANKL, tartrate-resistant acid phosphatase, and collagen type 1 cross-linked N-telopeptide and improving levels of serum alkaline phosphatase, osteoprotegerin, and osteocalcin compared with the OVX group without adverse effects such as dyslipidemia. CWHL increased uterine ER-ß levels but did not change uterus and vaginal weights. Taken together, the results indicate that CWHL may relieve menopausal symptoms by controlling depression-, hot flashes-, and osteoporosis-associated biomarkers. Therefore, we propose that CWHL might be a safe and potential candidate for management of menopause as a health functional food.
Asunto(s)
Cynanchum , Humulus , Femenino , Ratones , Animales , Humanos , Humulus/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Densidad Ósea , Menopausia , OvariectomíaRESUMEN
BACKGROUND: Oxidative stress and inflammation are involved in chronic fatigue. Euscaphic acid (EA) is an active compound of Eriobotrya japonica (Loquat) and has anti-oxidative effect. METHODS: The goal of present study is to prove whether EA could relieve fatigue through enhancing anti-oxidant and anti-inflammatory effects in in vitro/in vivo models. RESULTS: EA notably improved activity of superoxide dismutase (SOD) and catalase (CAT), while EA reduced levels of malondiadehyde (MDA) and inflammatory cytokines without cytotoxicity in H2O2-stimulated in myoblast cell line, C2C12 cells. EA significantly reduced levels of fatigue-causing factors such as lactate dehydrogenase (LDH) and creatin kinase (CK), while EA significantly incresed levels of anti-fatigue-related factor, glycogen compared to the H2O2-stimulated C2C12 cells. In treadmill stress test (TST), EA significantly enhanced activities of SOD and CAT as well as exhaustive time and decreased levels of MDA and inflammatory cytokines. After TST, levels of free fatty acid, citrate synthase, and muscle glycogen were notably enhanced by oral administration of EA, but EA decreased levels of lactate, LDH, cortisol, aspartate aminotransferase, alanine transaminase, CK, glucose, and blood urea nitrogen compared to the control group. Furthermore, in forced swimming test, EA significantly increased levels of anti-fatigue-related factors and decreased excessive accumulations of fatigue-causing factors. CONCLUSIONS: Therefore, the results indicate that potent anti-fatigue effect of EA can be achieved via the improvement of anti-oxidative and anti-inflammatory properties, and this study will provide scientific data for EA to be developed as a novel and efficient component in anti-fatigue health functional food.
Asunto(s)
Peróxido de Hidrógeno , Estrés Oxidativo , Glucógeno/metabolismo , Glucógeno/farmacología , Creatina Quinasa , Superóxido Dismutasa/metabolismoRESUMEN
Crotonaldehyde is an extremely toxic α,ß-unsaturated aldehyde found in cigarette smoke, and it causes inflammation and vascular dysfunction. Autophagy has been reported to play a key role in the pathogenesis of vascular diseases. However, the precise mechanism underlying the role of acute exposure crotonaldehyde in vascular disease development remains unclear. In the present study, we aimed to investigate the effect of crotonaldehyde-induced autophagy in endothelial cells. Acute exposure to crotonaldehyde decreased cell viability and induced autophagy followed by cell death. In addition, inhibiting the autophagic flux markedly promoted the viability of endothelial cells exposed to high concentrations of crotonaldehyde. Crotonaldehyde activated the AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK) pathways, and pretreatment with inhibitors specific to these kinases showed autophagy inhibition and partial improvement in cell viability. These data show that acute exposure to high concentrations of crotonaldehyde induces autophagy-mediated cell death. These results might be helpful to elucidate the mechanisms underlying crotonaldehyde toxicity in the vascular system and contribute to environmental risk assessment.
Asunto(s)
Aldehídos/farmacología , Autofagia/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Humanos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Hepatitis C virus (HCV) is a major cause of end-stage liver disease. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment, but these are associated with increased drug resistance and toxicity. Thus, the development of host-targeted antiviral agents, such as cyclophilin A inhibitors, is an alternative approach for more effective, selective, and safer treatment. Starting with the discovery of a bis-amide derivative 5 through virtual screening, the lead compound 25 was developed using molecular modeling-based design and systematic exploration of the structure-activity relationship. The lead 25 lacked cytotoxicity, had potent anti-HCV activity, and showed selective and high binding affinity for CypA. Unlike cyclosporin A, 25 lacked immunosuppressive effects, successfully inhibited the HCV replication, restored host immune responses without acute toxicity in vitro and in vivo, and exhibited a high synergistic effect in combination with other drugs. These findings suggest that the bis-amides have significant potential to extend the arsenal of HCV therapeutics.
Asunto(s)
Antivirales/química , Ciclofilina A/antagonistas & inhibidores , Glicina/análogos & derivados , Hepacivirus/efectos de los fármacos , Ácidos Indolacéticos/química , Animales , Antivirales/farmacología , Antivirales/toxicidad , Línea Celular Tumoral , Sinergismo Farmacológico , Glicina/química , Glicina/farmacología , Glicina/toxicidad , Hepacivirus/fisiología , Hepatitis C/tratamiento farmacológico , Hepatitis C/inmunología , Hepatitis C/virología , Humanos , Terapia de Inmunosupresión , Ácidos Indolacéticos/farmacología , Ácidos Indolacéticos/toxicidad , Ratones Endogámicos NOD , Ratones SCID , Modelos Moleculares , Unión Proteica , Replicón/efectos de los fármacos , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Atopic dermatitis (AD) is a common multifactorial chronic skin disease that has a multiple and complex pathogenesis. AD is gradually increasing in prevalence globally. In NC/Nga mice, repetitive applications of 2, 4-dinitrofluorobenzene (DNFB) evoke AD-like clinical symptoms similar to human AD. Aspartame (N-L-α-aspartyl-L-phenylalanine 1-methyl ester) is a methyl ester of a dipeptide, which is used as an artificial non-nutritive sweetener. Aspartame has analgesic and anti-inflammatory functions that are similar to the function of nonsteroidal anti-inflammatory drugs such as aspirin. We investigated whether aspartame can relieve AD-like clinical symptoms induced by DNFB treatment in NC/Nga mice. Sucrose did not relieve AD-like symptoms, whereas aspartame at doses of 0.5 µg kg(-1) and 0.5 mg kg(-1) inhibited ear swelling and relieved AD-like clinical symptoms. Aspartame inhibited infiltration of inflammatory cells including eosinophils, mast cells, and CD4(+) T cells, and suppressed the expression of cytokines including IL-4 and IFN-γ, and total serum IgE levels. Aspartame may have therapeutic value in the treatment of AD.
Asunto(s)
Aspartame/administración & dosificación , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Dinitrofluorobenceno/farmacología , Flavanonas , Análisis de Varianza , Animales , Biopsia con Aguja , Citocinas/efectos de los fármacos , Citocinas/metabolismo , Dermatitis Atópica/inducido químicamente , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulina E/efectos de los fármacos , Inmunoglobulina E/metabolismo , Inmunohistoquímica , Masculino , Ratones , Distribución AleatoriaRESUMEN
Consumption of omega-3 polyunsaturated fatty acid, particularly eicosapentaenoic acid (EPA), is associated with a significant reduction in the risk of developing cardiovascular disease. The aim of this study was to investigate whether heme oxygenase-1 (HO-1) induction contributes to the cytoprotective effects of EPA in endothelial cells threatened with oxidative damage. In this study, we investigated the effect of EPA on the induction of HO-1 by NF-E2-related factor 2 (Nrf2) in human umbilical vein endothelial cells. In cells treated with low concentrations of EPA (10-25 µM), HO-1 expression increased in a time- and concentration-dependent manner. Additionally, EPA treatment increased Nrf2 nuclear translocation and antioxidant response element activity, leading to the upregulation of HO-1 expression. Furthermore, treatment with EPA reduced hydrogen peroxide (H(2)O(2))-induced cell death. The reduction in cell death was reversed by treatment with zinc protoporphyrin, an inhibitor of HO-1, indicating that HO-1 contributed to the protective effect of EPA. These data suggest that EPA protects against H(2)O(2)-induced oxidative stress in endothelial cells by activating Nrf2 and inducting HO-1 expression.
Asunto(s)
Citoprotección/fisiología , Ácido Eicosapentaenoico/farmacología , Hemo-Oxigenasa 1/fisiología , Células Endoteliales de la Vena Umbilical Humana/fisiología , Factor 2 Relacionado con NF-E2/fisiología , Citoprotección/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , HumanosRESUMEN
After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption by matrix metalloproteinases (MMPs) leads to BSCB permeability and blood cell infiltration, contributing to permanent neurological disability. Herein, we report that MMP-3 plays a critical role in BSCB disruption after SCI in mice. MMP-3 was induced in infiltrated neutrophils and blood vessels after SCI, and NF-κB as a transcription factor was involved in MMP-3 expression. BSCB permeability and blood cell infiltration after injury were more reduced in Mmp3 knockout (KO) mice than in wild-type (WT) mice, which was significantly inhibited by Mmp3 siRNA or a general inhibitor of MMPs, N-isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid. The level of tight junction proteins, such as occludin and zonula occludens-1, which decreased after SCI, was also higher in Mmp3 KO than in WT mice. Exogenously, MMP-3 injection into the normal spinal cord also induced BSCB permeability. Furthermore, MMP-9 activation after injury was mediated by MMP-3 activation. Finally, improved functional recovery was observed in Mmp3 KO mice compared with WT mice after injury. These results demonstrated the role of MMP-3 in BSCB disruption after SCI for the first time and suggest that the regulation of MMP-3 can be considered a therapeutic target to inhibit BSCB disruption and hemorrhage, and thereby enhance functional recovery after acute SCI.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Hemorragia/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/metabolismo , Médula Espinal/metabolismo , Animales , Permeabilidad Capilar , Modelos Animales de Enfermedad , Masculino , Metaloproteinasa 3 de la Matriz/genética , Ratones , Ratones Noqueados , FN-kappa B/metabolismoRESUMEN
AIMS: Atopic dermatitis (AD) is a chronic and relapsing inflammatory dermatitis characterized by pruritic and eczematous skin lesions. Here, we investigated the therapeutic effect of the fruit flavonoid naringenin on DNFB induced atopic dermatitis mice model. MAIN METHODS: AD-like skin lesion was induced by repetitive skin contact with DNFB in NC/Nga mice and the effects of the fruit flavonoid naringenin were evaluated on the basis of histopathological findings of skin, ear swelling and cytokine production of CD4(+)T cells. KEY FINDINGS: Intraperitoneal injection of naringenin for one week after DNFB challenge significantly lowered ear swelling and improved back skin lesions. In addition, naringenin significantly suppressed production of interferon-gamma (IFN-γ) by activated CD4(+) T cells and serum IgE level. Furthermore, naringenin reduced DNFB-induced infiltration of eosinophils, mast cells, CD4(+) T cells, and CD8(+) T cells in skin lesions. SIGNIFICANCE: Naringenin may suppress the development of AD-like skin lesions in DNFB-treated NC/Nga mice by reducing IFN-γ production of activated CD4(+) T cells, serum IgE levels and infiltration of immune cells to skin lesion.
Asunto(s)
Antiulcerosos/uso terapéutico , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/tratamiento farmacológico , Dinitrofluorobenceno/efectos adversos , Flavanonas/uso terapéutico , Inflamación/tratamiento farmacológico , Animales , Linfocitos T CD4-Positivos/metabolismo , Citocinas/biosíntesis , Dermatitis Atópica/sangre , Dermatitis Atópica/patología , Oído/patología , Edema/tratamiento farmacológico , Inmunoglobulina E/sangre , Interferón gamma/biosíntesis , Masculino , Ratones , Piel/efectos de los fármacos , Piel/patologíaRESUMEN
Ulinastatin is an intrinsic serine-protease urinary trypsin inhibitor that can be extracted and purified from human urine. Urinary trypsin inhibitors are widely used to treat patients with acute inflammatory disorders, such as shock and pancreatitis. However, although the anti-inflammatory activities of urinary trypsin inhibitors have been investigated, the mechanisms underlying their actions are not yet fully understood. In the present study, we evaluated the effect of ulinastatin on lipopolysaccharide (LPS)-induced inflammation in relation with nuclear factor-κB (NF-κB) activation using BV2 mouse microglial cells. To accomplish this, we performed a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, reverse transcription-polymerase chain reaction (RT-PCR), western blot analysis, electrophoretic mobility gel shift assay (EMSA), prostaglandin E(2) (PGE(2)) immunoassay and nitric oxide (NO) detection. The results demonstrated that ulinastatin suppressed PGE2 synthesis and NO production by inhibiting the LPS-induced mRNA and protein expression of cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) in BV2 mouse microglial cells. Ulinastatin suppressed the activation of NF-κB in the nucleus. These findings demonstrate that ulinastatin exerts analgesic and anti-inflammatory effects that possibly occur via the suppression of COX-2 and iNOS expression through the downregulation of NF-κB activity.
Asunto(s)
Dinoprostona/biosíntesis , Regulación hacia Abajo/efectos de los fármacos , Glicoproteínas/farmacología , Lipopolisacáridos/farmacología , Microglía/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico/biosíntesis , Animales , Western Blotting , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Citosol/efectos de los fármacos , Citosol/metabolismo , ADN/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas I-kappa B/metabolismo , Ratones , Microglía/efectos de los fármacos , Microglía/enzimología , Inhibidor NF-kappaB alfa , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Unión Proteica/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Although peptide vaccines have been actively studied in various animal models, their efficacy in treatment is limited. To improve the efficacy of peptide vaccines, we previously formulated an efficacious peptide vaccine without carriers using the natural phosphodiester bond CpG-DNA and a special liposome complex (Lipoplex(O)). Here, we show that immunization of mice with a complex consisting of peptide and Lipoplex(O) without carriers significantly induces peptide-specific IgG2a production in a CD4(+) cells- and Th1 differentiation-dependent manner. The transmembrane 4 superfamily member 5 protein (TM4SF5) has gained attention as a target for hepatocellular carcinoma (HCC) therapy because it induces uncontrolled growth of human HCC cells via the loss of contact inhibition. Monoclonal antibodies specific to an epitope of human TM4SF5 (hTM4SF5R2-3) can recognize native mouse TM4SF5 and induce functional effects on mouse cancer cells. Pre-immunization with a complex of the hTM4SF5R2-3 epitope and Lipoplex(O) had prophylactic effects against tumor formation by HCC cells implanted in an mouse tumor model. Furthermore, therapeutic effects were revealed regarding the growth of HCC when the vaccine was injected into mice after tumor formation. These results suggest that our improved peptide vaccine technology provides a novel prophylaxis measure as well as therapy for HCC patients with TM4SF5-positive tumors.
Asunto(s)
Carcinoma Hepatocelular/prevención & control , Carcinoma Hepatocelular/terapia , Regulación Neoplásica de la Expresión Génica/inmunología , Liposomas/uso terapéutico , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/terapia , Proteínas de la Membrana/inmunología , Animales , Anticuerpos Monoclonales/farmacología , Bromodesoxiuridina , Linfocitos T CD4-Positivos/inmunología , Línea Celular Tumoral , Cartilla de ADN/genética , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunización/métodos , Inmunoglobulina G/inmunología , Inmunohistoquímica , Inmunoterapia/métodos , Interleucina-12/inmunología , Estimación de Kaplan-Meier , Liposomas/metabolismo , Proteínas de la Membrana/genética , Ratones , Oligodesoxirribonucleótidos , Sales de Tetrazolio , TiazolesRESUMEN
Allergy is characterized by an overreaction of the immune system. Perilla frutescens leaf extract has been reported to exhibit antiallergic inflammatory activity. To investigate precisely the effect and mechanism of 30% ethanol extract powder of P. frutescens var. acuta Kudo (EPPF) and rosmarinic acid (RA), a component of EPPF in allergic rhinitis and rhinoconjunctivitis, the antiallergic effects of EPPF and RA were analyzed using in vivo and in vitro models. Cytokine production was analyzed by means of an enzyme-linked immunosorbent assay. Cytokine expression was analyzed via reverse transcription-polymerase chain reaction and Western blotting. Transcription factor and caspase-1 activity were analyzed by a luciferase assay and caspase-1 assay, respectively. The number of nasal, ear and eye rubs after an ovalbumin (OVA) challenge in OVA-sensitized mice was significantly higher than that in OVA-unsensitized mice. Increased number of rubs was inhibited by administration of EPPF or RA. Increased levels of IgE in the serum, spleen and nasal mucosa of OVA-sensitized mice were reduced by EPPF or RA administration. The histamine level was also reduced by EPPF or RA administration in the serum of OVA-sensitized mice. Protein levels and mRNA expressions of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α were inhibited by EPPF or RA administration in the nasal mucosa tissue or spleen of OVA-sensitized mice. In EPPF or RA-administered mice, the mast cell and eosinophil infiltration increase as caused by OVA-sensitization was decreased. In addition, EPPF or RA inhibited both cyclooxygenase-2 protein expression and caspase-1 activity in the same nasal mucosa tissue. In activated human mast cells, nuclear factor-kappa B (NF-κB)/Rel A and caspase-1 activation increased, whereas NF-κB/Rel A and caspase-1 activation was inhibited after a treatment of EPPF or RA. These results indicate that EPPF and RA ameliorate allergic inflammatory reactions such as allergic rhinitis and allergic rhinoconjunctivitis.
Asunto(s)
Cinamatos/uso terapéutico , Depsidos/uso terapéutico , Perilla frutescens , Fitoterapia/métodos , Extractos Vegetales/uso terapéutico , Hojas de la Planta , Hipersensibilidad Respiratoria/tratamiento farmacológico , Animales , Western Blotting , Línea Celular , Cinamatos/administración & dosificación , Conjuntivitis Alérgica/tratamiento farmacológico , Ciclooxigenasa 2/biosíntesis , Citocinas/biosíntesis , Depsidos/administración & dosificación , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Histamina/biosíntesis , Humanos , Inmunoglobulina E/biosíntesis , Mastocitos/efectos de los fármacos , Mastocitos/fisiología , Ratones , Ratones Endogámicos BALB C , FN-kappa B/biosíntesis , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/inmunología , Extractos Vegetales/administración & dosificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ácido RosmarínicoRESUMEN
AIM OF THIS STUDY: Citrus unshiu (Satsuma mandarin, SM) is a citrus fruit the peel of which has been used as a traditional Chinese medicine to treat common cold, relieve exhaustion, and cancer. In this study, we examined how effectively the content and peel extracts of SM can suppress cancer growth. The mechanism underlying cancer-suppressing properties of SM was investigated in tumor-bearing mice with renal carcinoma cell, Renca. MATERIALS AND METHODS: Effectiveness of SM in tumor suppression was evaluated by measuring size of tumor mass in tumor-bearing mice treated with various doses of SM content and peel extracts. Proliferation of tumor cells and splenocytes was determined by MTT assay and [³H]TdR uptake, respectively. Relevant immunological mechanisms were chased by assaying cytokines including TGF-ß, IL-6, IFN-γ, and TNF-α by ELISA. RESULTS: The content and peel extracts of SM inhibited the growth of tumor cells in tumor-bearing mice. Especially, average tumor volume of two groups treated with 3 and 30 mg peel extracts per mouse weight (kg) were significantly decreased to 52.32% (p<0.05) and 68.72% (p<0.01), respectively. To identify tumor regression mechanism, anti-tumor cytokines measured in Con A-activated splenocytes from tumor-bearing mice. IFN-γ was increased in both of the peel extract-treated groups, while TNF-α, which had been decreased by tumor growth, was rescued to the normal level in SM content and peel extracts-treated groups. However, SM content and peel extracts did not inhibit proliferation and tumor-proliferative cytokines including TGF-ß and IL-6 production of tumor cells. CONCLUSION: These results indicate that SM content and peel extracts have anti-tumor properties in the tumor-bearing murine model. The mechanism underlying the anti-tumor effects of SM extracts is strongly suggested to be via boosting cytokines such as IFN-γ and TNF-α, enhancing immune-mediated anti-tumor properties.
Asunto(s)
Carcinoma de Células Renales/patología , División Celular/efectos de los fármacos , Citrus/química , Modelos Animales de Enfermedad , Neoplasias Renales/patología , Extractos Vegetales/farmacología , Animales , Carcinoma de Células Renales/metabolismo , División Celular/inmunología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Flavonoides/análisis , Neoplasias Renales/metabolismo , Linfocitos/citología , Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Bazo/citología , Bazo/efectos de los fármacosRESUMEN
Atopic dermatitis (AD) is a common skin disease that has complex pathogenic mechanisms. Under specific pathogen-free conditions, repeated epicutaneous treatment of 2-4-dinitrofluorobenzene (DNFB) evokes AD-like clinical symptoms in NC/Nga mice. α-Lipoic acid (α-LA; 1, 2-dithiolane-3-pentanoic acid) is a dietary component that is synthesized in bacteria, yeast, plants, and mammals. α-LA and its reduced form, dihydrolipoic acid, are powerful antioxidants that have many physiological functions, including free radical scavenging of reactive oxygen species, generation of cellular antioxidants, chelation of metal ions, and inflammatory suppression. In this study, we investigated whether α-LA suppresses AD-like skin lesions induced by repeated DNFB application in NC/Nga mice. α-LA significantly suppressed production of interferon (IFN)-γ and interleukin (IL)-4 by activated CD4(+) T cells. We found that the oral administration of α-LA reduced AD-like clinical symptoms and inhibited increases of epidermal thickness in DNFB-induced AD-like skin lesions of NC/Nga mice. Furthermore, total serum IgE levels were dramatically reduced by topical α-LA treatment. Our findings suggest that oral administration of α-LA suppresses the development of AD in DNFB-treated NC/Nga mice and reduces IFN-γ and IL-4 production from activated CD4(+) T cells as well as total serum IgE levels.
Asunto(s)
Antioxidantes/uso terapéutico , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/tratamiento farmacológico , Dinitrofluorobenceno/efectos adversos , Ácido Tióctico/uso terapéutico , Administración Oral , Animales , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Proliferación Celular/efectos de los fármacos , Dermatitis Atópica/metabolismo , Modelos Animales de Enfermedad , Inmunoglobulina E/sangre , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Masculino , Ratones , Ratones Endogámicos , Ácido Tióctico/administración & dosificación , Ácido Tióctico/farmacologíaRESUMEN
The present study shows the expression profile and function of the homeobox gene, satb2 during zebrafish embryonic development. Satb2 was ubiquitously expressed from the 1 cell stage to the 10-somite stage in zebrafish embryos. Satb2 showed stage-specific expression profiles such as in the pronephric duct at 24 hpf, the branchial arches at 36 hpf, and the ganglion cell layer of the retina and fins at 48 hpf. Additionally, satb2 knockdown embryos were arrested at 50-60% epiboly, and transplantation experiments with satb2 knockdown cells showed migration defects. Interestingly, satb2 knockdown cells also exhibited down-regulation of dynamin II and VAMP4, which are involved in exocytosis and endocytosis, respectively. Furthermore, satb2 knockdown cells have a disorganized actin distribution and an underdeveloped external yolk syncytial layer, both of which are involved in epiboly. These results suggest that satb2 has a functional role in epiboly. This role may potentially be the regulation of endo-exocytic vesicle transport-dependent cell migration and/or the regulation of the development of the yolk syncytial layer.
Asunto(s)
Genes Homeobox , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Pez Cebra/genética , Pez Cebra/metabolismo , Animales , Región Branquial/citología , Región Branquial/embriología , Región Branquial/metabolismo , Movimiento Celular/genética , Regulación hacia Abajo , Dinamina II/análisis , Embrión no Mamífero/embriología , Embrión no Mamífero/metabolismo , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Hibridación in Situ , Ratones , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/metabolismoRESUMEN
Atopic dermatitis (AD) is a common disease in children, and epicutaneous treatment with a chemical hapten such as 2,4-dinitrofluorobenzene (DNFB) evokes an AD-like reaction in NC/Nga mice under specific pathogen-free conditions. Melatonin (N-acetyl-5-methoxytryptamine) is synthesized by the pineal gland, has several different physiologic functions, which include seasonal reproduction control, immune system modulation, free radical scavenging, and inflammatory suppression. In the present study, we investigated whether melatonin suppresses DNFB-induced AD-like skin lesions in NC/Nga mice. The topical administration of melatonin to DNFB-treated NC/Nga mice was found to inhibit ear thickness increases and the skin lesions induced by DNFB. Furthermore, interleukin (IL)-4 and interferon (IFN)-gamma secretion by activated CD4(+) T cells from the draining lymph nodes of DNFB-treated NC/Nga mice were significantly inhibited by melatonin, and total IgE levels in serum were reduced. Our findings suggest that melatonin suppresses the development of AD-like dermatitis in DNFB-treated NC/Nga mice by reducing total IgE in serum, and IL-4 and IFN-gamma production by activated CD4(+) T cells.
Asunto(s)
Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/tratamiento farmacológico , Melatonina/uso terapéutico , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/tratamiento farmacológico , Animales , Antioxidantes/uso terapéutico , Dinitrofluorobenceno , Masculino , RatonesRESUMEN
Epicutaneously administered chemical antigens like 2,4-dinitrofluorobenzene (DNFB), evoke an atopic dermatitis (AD)-like dermatitis reaction in NC/Nga mice under specific pathogen free (SPF) conditions. Astragalus membranaceus (AM), is a popular herbal medicine used to treat allergic diseases in East Asia. In the present study, we examined whether AM suppress AD-like skin lesions in NC/Nga mice treated with DNFB under SPF conditions. Oral administration of AM to DNFB-treated NC/Nga mice was found to inhibit ear thickness increases and the skin lesions induced by DNFB. Moreover, IFN-gamma production by CD4(+) T cells from the lymph nodes of DNFB-treated NC/Nga mice was significantly inhibited by AM treatment, although levels of IL-4 and total IgE in serum were not. Study findings suggest that AM may suppress the development of AD-like dermatitis in DNFB-treated NC/Nga mice by reducing IFN-gamma production.
Asunto(s)
Astragalus propinquus/química , Dermatitis Atópica/prevención & control , Dinitrofluorobenceno/antagonistas & inhibidores , Dinitrofluorobenceno/toxicidad , Animales , Antiinflamatorios/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Citocinas/biosíntesis , Dermatitis Atópica/inducido químicamente , Oído Externo/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Inmunoglobulina E/sangre , Interferón gamma/biosíntesis , Interleucina-4/biosíntesis , Ratones , Ratones Endogámicos , Prednisolona/farmacología , Piel/patologíaRESUMEN
Cybr (also known as Cytip, CASP, and PSCDBP) is an interleukin-12-induced gene expressed exclusively in hematopoietic cells and tissues that associates with Arf guanine nucleotide exchange factors known as cytohesins. Cybr levels are dynamically regulated during T-cell development in the thymus and upon activation of peripheral T cells. In addition, Cybr is induced in activated dendritic cells and has been reported to regulate dendritic cell (DC)-T-cell adhesion. Here we report the generation and characterization of Cybr-deficient mice. Despite the selective expression in hematopoietic cells, there was no intrinsic defect in T- or B-cell development or function in Cybr-deficient mice. The adoptive transfer of Cybr-deficient DCs showed that they migrated efficiently and stimulated proliferation and cytokine production by T cells in vivo. However, competitive stem cell repopulation experiments showed a defect in the abilities of Cybr-deficient T cells to develop in the presence of wild-type precursors. These data suggest that Cybr is not absolutely required for hematopoietic cell development or function, but stem cells lacking Cybr are at a developmental disadvantage compared to wild-type cells. Collectively, these data demonstrate that despite its selective expression in hematopoietic cells, the role of Cybr is limited or largely redundant. Previous in vitro studies using overexpression or short interfering RNA inhibition of the levels of Cybr protein appear to have overestimated its immunological role.
Asunto(s)
Proteínas Portadoras/metabolismo , Diferenciación Celular , Reactividad Cruzada/inmunología , Células Dendríticas/citología , Células Dendríticas/inmunología , Proteínas de la Membrana/metabolismo , Linfocitos T/citología , Linfocitos T/inmunología , Animales , Proteínas Portadoras/genética , Diferenciación Celular/efectos de los fármacos , Citocinas/farmacología , Células Dendríticas/efectos de los fármacos , Exones/genética , Regulación de la Expresión Génica/efectos de los fármacos , Marcación de Gen , Humanos , Inmunidad Innata/inmunología , Lipopolisacáridos/inmunología , Subgrupos Linfocitarios/inmunología , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Células Mieloides/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Linfocitos T/efectos de los fármacosRESUMEN
As an important cellular component of the innate immune system, NK cells constitute a first line of defense against various infections and malignancies. Previous studies have reported electroacupuncture (EA) modulation of natural killer cell (NK cell) activities. Our study confirmed that EA treatment increases NK cell activity using (51)Cr release assay. Furthermore, in order to better understand the activation mechanism of NK cell by EA, we employed a cDNA microarray technique to elucidate how EA alters gene expressions in the spleen of rats. We screened EA responsive genes using a high-throughput screening and identified 154 genes. Among those genes we selected 4 genes that are known to play a crucial role in NK cell activation and examined their mRNA expressions after EA treatment using RT-PCR. Our data shows that EA treatment increased CD94, PTK and VCAM-1 expressions while decreased PTP and SHP-1. These results imply that EA treatment increase PTK expression, which increases NK cell activity, through induction of CD94 while decreases SHP-1, which inhibits NK cell activity, simultaneously so that it activates NK cell with high efficacy. It seems that increased VCAM-1 expression is due to INF-gamma produced by activated NK cell. Increased production of VCAM-1 is expected to play an important role in binding of NK cell to the target cell. The result of our study may provide key insights in understanding the mechanisms of activation of NK cell induced by EA.
Asunto(s)
Electroacupuntura/métodos , Células Asesinas Naturales/efectos de la radiación , Regulación hacia Arriba/efectos de la radiación , Puntos de Acupuntura , Animales , Northern Blotting/métodos , Western Blotting/métodos , Isótopos de Cromo/metabolismo , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Integrina alfa1/genética , Integrina alfa1/metabolismo , Células Asesinas Naturales/fisiología , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Vasopresinas/genética , Receptores de Vasopresinas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Estadísticas no ParamétricasRESUMEN
Statin, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has an anti-inflammatory effect. The aim of this study was to investigate the effect of Lovastatin (statin) on the cholecystokinin-octapeptide (CCK)-induced acute pancreatitis in rats. In statin treated group, the pancreas weight/body weight (pw/bw) ratio in CCK-induced acute pancreatitis was significantly lower than DMSO-treated group. Statin also increased the pancreatic level of HSP 60. Additionally, the secretions of IL-1beta, TNF-alpha and IL-6 and the lipase levels were decreased in statin treated group. These results suggest that statin may play an important role in mitigating the progression of the inflammatory reactions during acute pancreatitis.