RESUMEN
We examined the effects of a 2,2'-bipyridine containing natural product, collismycin C on high mobility group box 1 (HMGB1, septic mediator)-mediated septic responses and survival rate in a mouse sepsis model. Collismycin C inhibited the HMGB1 release and downregulated HMGB1-mediated inflammatory responses in human endothelial cells. Collismycin C also inhibited HMGB1-induced hyperpermeability and leukocyte migration in mice. In addition, collismycin C treatment reduced CLP-induced HMGB1 release and sepsis-related mortality and pulmonary damage in vivo. Our results indicate that collismycin C is a potential therapeutic agent for the treatment of severe vascular inflammatory diseases by inhibiting HMGB1 signaling pathway.
Asunto(s)
Proteína HMGB1 , Sepsis , 2,2'-Dipiridil , Animales , Proteína HMGB1/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Lipopolisacáridos , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Sepsis/tratamiento farmacológico , Tasa de SupervivenciaRESUMEN
The aim of this study was to investigate the effects of sulforaphane (SFN) on lipopolysaccharide (LPS)-induced liver failure, and to elucidate underlying mechanisms. SFN, a natural isothiocyanate present in cruciferous vegetables such as broccoli and cabbage, is effective in preventing carcinogenesis, diabetes, and inflammatory responses. Mice were treated intravenously with SFN at 12 h after LPS treatment. LPS significantly increased mortality, serum levels of liver damage markers, and inflammatory cytokines, and toll-like receptor 4 (TLR4) protein expression, which were reduced by SFN. Our results suggest that SFN protects against LPS-induced liver damage, indicating its potential to treat liver diseases.
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Isotiocianatos , Lipopolisacáridos , Animales , Hígado , Ratones , Estructura Molecular , SulfóxidosRESUMEN
Inhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity are emerging as attractive therapeutic strategies for the management of severe vascular inflammatory diseases. Recently, we found that JH-4, a synthesized decursin derivative, exhibited a strong anti-Hutchinson-Gilford progeria syndrome by efficiently blocking progerin-lamin A/C binding. In this study, we examined the effects of JH-4 on HMGB1-mediated septic responses and the survival rate in a mouse sepsis model. The anti-inflammatory activities of JH-4 were monitored based on its effects on lipopolysaccharide- or cecal ligation and puncture (CLP)-mediated release of HMGB1. The antiseptic activities of JH-4 were determined by measuring permeability, leukocyte adhesion, migration, and the activation of proinflammatory proteins in HMGB1-activated human umbilical vein endothelial cells and mice. JH-4 inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. JH-4 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with JH-4 reduced CLP-induced release of HMGB1, sepsis-related mortality, and pulmonary injury in vivo. Our results indicate that JH-4 is a possible therapeutic agent to treat various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.
Asunto(s)
Antiinfecciosos Locales/uso terapéutico , Antiinflamatorios/uso terapéutico , Benzopiranos/uso terapéutico , Butiratos/uso terapéutico , Proteína HMGB1/metabolismo , Extractos Vegetales/uso terapéutico , Sepsis/tratamiento farmacológico , Sepsis/mortalidad , Angelica/química , Animales , Antiinfecciosos Locales/farmacología , Antiinflamatorios/farmacología , Benzopiranos/farmacología , Butiratos/farmacología , Permeabilidad Capilar/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Proteína HMGB1/antagonistas & inhibidores , Proteína HMGB1/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Leucocitos/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Extractos Vegetales/farmacología , Sepsis/metabolismo , Tasa de SupervivenciaRESUMEN
Transforming growth factor ß-induced protein (TGFBIp) is an extracellular matrix protein; its expression by several cell types is greatly increased by TGF-ß. TGFBIp is released by primary human umbilical vein endothelial cells (HUVECs) and functions as a mediator of experimental sepsis. 2,2'-Bipyridine-containing natural products are generally accepted to have antimicrobial, cytotoxic and anti-inflammatory properties. We hypothesized that a 2,2'-bipyridine containing natural product, collismycin C, could reduce TGFBIp-mediated severe inflammatory responses in human endothelial cells and mice. Here we investigated the effects and underlying mechanisms of collismycin C against TGFBIp-mediated septic responses. Collismycin C effectively inhibited lipopolysaccharide-induced release of TGFBIp and suppressed TGFBIp-mediated septic responses. In addition, collismycin C suppressed TGFBIp-induced sepsis lethality and pulmonary injury. This suppression of TGFBIp-mediated and CLP-induced septic responses indicates that collismycin C is a potential therapeutic agent for various severe vascular inflammatory diseases, with inhibition of the TGFBIp signaling pathway as the mechanism of action.
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2,2'-Dipiridil/uso terapéutico , Antiinflamatorios/uso terapéutico , Proteínas de la Matriz Extracelular/uso terapéutico , Inflamación/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Factor de Crecimiento Transformador beta/uso terapéutico , 2,2'-Dipiridil/farmacología , Animales , Proteínas de la Matriz Extracelular/farmacología , Humanos , Ratones , Ratones Endogámicos C57BL , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
Zingerone (ZGR), a phenolic alkanone isolated from ginger, has been reported to possess pharmacological activities such as anti-inflammatory and anti-apoptotic effects. This study was initiated to determine whether ZGR could modulate renal functional damage in a mouse model of sepsis and to elucidate the underlying mechanisms. The potential of ZGR treatment to reduce renal damage induced by cecal ligation and puncture (CLP) surgery in mice was measured by assessment of serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, total glutathione, glutathione peroxidase activity, catalase activity, and superoxide dismutase activity. Treatment with ZGR resulted in elevated plasma levels of BUN and creatinine, and of protein in urine in mice with CLP-induced renal damage. Moreover, ZGR inhibited nuclear factor-κB activation and reduced the induction of nitric oxide synthase and excessive production of nitric acid. ZGR treatment also reduced the plasma levels of interleukin-6 and tumor necrosis factor-α, reduced lethality due to CLP-induced sepsis, increased lipid peroxidation, and markedly enhanced the antioxidant defense system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase in kidney tissues. Our study showed renal suppressive effects of zingerone in a mouse model of sepsis, suggesting that ZGR protects mice against sepsis-triggered renal injury. [BMB Reports 2019; 52(4): 271-276].
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Guayacol/análogos & derivados , Riñón/efectos de los fármacos , Sepsis/tratamiento farmacológico , Animales , Antioxidantes/farmacología , Nitrógeno de la Urea Sanguínea , Modelos Animales de Enfermedad , Zingiber officinale , Glutatión Peroxidasa/metabolismo , Guayacol/metabolismo , Guayacol/farmacología , Riñón/lesiones , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Sepsis/metabolismo , Sepsis/fisiopatología , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
High mobility group box 1 (HMGB1) is recognized as a late mediator of sepsis, and the inhibition of HMGB1 release and recovery of vascular barrier integrity have emerged as attractive therapeutic strategies for the management of sepsis. We tested the hypothesis that aloin induces sirtuin 1 (SIRT1) and heme oxygenase (HO)-1, which inhibit HMGB1 release in lipopolysaccharide (LPS)-stimulated cells, thereby inhibiting HMGB1-induced hyperpermeability and increasing the survival of septic mice. Aloin was administered after LPS or HMGB1 challenge, and the antiseptic activity of aloin was determined from measurements of permeability, activation of pro-inflammatory proteins and production of markers for tissue injury in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model. Aloin significantly reduced HMGB1 release in LPS-activated HUVECs via SIRT1-mediated HMGB1 deacetylation and the PI3K/Nrf2/heme oxygenase (HO)-1 signaling axis. Aloin also suppressed the production of tumor necrosis factor (TNF)- α and interleukin (IL)-6, as well as the activation of nuclear factor (NF)- κ B and extracellular signal-regulated kinase 1/2 (ERK 1/2) by HMGB1. Moreover, aloin restored HMGB1-mediated vascular disruption and inhibited vascular hyperpermeability in mice. In addition, treatment with aloin reduced the CLP-induced release of HMGB1, sepsis-related mortality and tissue injury in vivo. Our results suggest that aloin reduces HMGB1 release and sepsis-related mortality by activating SIRT1 and PI3K/Nrf2/HO-1 signals, indicating that aloin has potential for the treatment of sepsis.
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Emodina/análogos & derivados , Proteína HMGB1/metabolismo , Hemo-Oxigenasa 1/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Sepsis/tratamiento farmacológico , Sepsis/etiología , Transducción de Señal/efectos de los fármacos , Sirtuina 1/metabolismo , Aloe/química , Animales , Modelos Animales de Enfermedad , Emodina/administración & dosificación , Emodina/farmacología , Proteína HMGB1/antagonistas & inhibidores , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , Fitoterapia , Sepsis/genética , Sepsis/metabolismoRESUMEN
Pelargonidin (PEL) is a well-known red pigment found in plants, and has been reported as having important biological activities that are potentially beneficial for human health. Here, we tested the possible use of PEL in the treatment of lipopolysaccharide (LPS)-mediated vascular inflammatory responses. The anti-inflammatory activities of PEL were determined by measuring permeability, neutrophils adhesion and migration, and activation of pro-inflammatory proteins in LPS-activated human umbilical vein endothelial cells (HUVECs) and mice. We found that PEL inhibited LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs), and adhesion/transendothelial migration of neutrophils to human endothelial cells. PEL also suppressed LPS-induced hyperpermeability and leukocytes migration in vivo. Furthermore, PEL suppressed the production of tumor necrosis factor-α (TNF-α) or Interleukin (IL)-6 and the activation of nuclear factor-κB (NF-κB) or extracellular regulated kinases (ERK) 1/2 by LPS. Moreover, treatment with PEL resulted in reduced LPS-induced lethal endotoxemia. These results suggest that PEL possesses anti-inflammatory functions by inhibiting hyperpermeability, expression of CAMs, and adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases.
Asunto(s)
Antocianinas/farmacología , Antiinflamatorios/farmacología , Adhesión Celular/efectos de los fármacos , Lipopolisacáridos/toxicidad , Animales , Antocianinas/uso terapéutico , Antiinflamatorios/uso terapéutico , Moléculas de Adhesión Celular/metabolismo , Movimiento Celular/efectos de los fármacos , Endotoxemia/tratamiento farmacológico , Endotoxemia/patología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Interleucina-6/metabolismo , Leucocitos/citología , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Permeabilidad/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Aspalathin (Aspt) and nothofagin (Not) were reported to have antioxidant activity and are the two major active dihydrochalcones in green rooibos. This study was conducted to determine whether Asp and Not can modulate renal functional damage in a mouse model of sepsis and to elucidate the underlying mechanisms. METHODS: The potential of Aspt and Not treatment to reduce renal damage induced by cecal ligation and puncture (CLP) surgery in mice was measured by assessing blood urea nitrogen (BUN), serum creatinine, total urine protein, levels of lactate dehydrogenase (LDH), nitric oxide (NO), tumour necrosis factor (TNF)-α, interleukin (IL)-6, and myeloperoxidase (MPO), lipid peroxidation, total glutathione, glutathione peroxidase activity, catalase activity, and superoxide dismutase activity. RESULTS: Treatment with Aspt and Not decreased plasma levels of BUN, creatinine, urine protein, and LDH in mice with CLP-induced renal damage. Moreover, Aspt and Not inhibited nuclear factor (NF)-κB activation and reduced the induction of NO synthase and excessive production of nitric acid. Aspt and Not treatment also reduced the plasma levels of NO, TNF-α, IL-6, and MPO and reduced lethality due to CLP-induced sepsis, increased lipid peroxidation, and markedly enhanced the antioxidant defence system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase in the kidney tissues. CONCLUSION: Our results suggest that Aspt and Not protect mice against sepsis-triggered renal injury.
Asunto(s)
Aspalathus , Chalconas/uso terapéutico , Modelos Animales de Enfermedad , Riñón/efectos de los fármacos , Sepsis/tratamiento farmacológico , Animales , Chalconas/aislamiento & purificación , Chalconas/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Riñón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Sustancias Protectoras/aislamiento & purificación , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Sepsis/metabolismoRESUMEN
Enzymatic browning is a major issue that needs to be solved in the food industry. Although swertiajaponin is a flavonoid rich in the whole herb of Swertia japonica that has been clinically used, its biological functions and applicatâion in the foods have not been fully elucidated. Here, we showed that swertiajaponin efficiently blocked enzymatic browning in potatoes possibly by direct binding to and inactivating polyphenol oxidase. Furthermore, swertiajaponin showed potent antioxidant activity proven by markedly suppressed reactive oxygen species. Swertiajaponin significantly increased antioxidant properties of potato extract when it is added since it additively elevated total flavonoid content. Considering numerous beneficial effects of antioxidants, swertiajaponin may be used as a functional food additive to suppress enzymatic browning and elevate the antioxidant capacity of foods including beverages and soups by fortification of flavonoids.
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Antioxidantes/farmacología , Flavonoides/farmacología , Aditivos Alimentarios/farmacología , Catecol Oxidasa/metabolismo , Activación Enzimática/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Solanum tuberosum/efectos de los fármacos , Solanum tuberosum/metabolismoRESUMEN
Due to the impermeable structure and barrier function of the blood-brain barrier (BBB), the delivery of therapeutic molecules into the CNS is extremely limited. Nanodelivery systems are regarded as the most effective and versatile carriers for the CNS, as they can transport cargo molecules across the BBB via various mechanisms. This review emphasizes the multi-functionalization strategies of nanodelivery systems and combinatorial approaches for the delivery of therapeutic drugs and genes into the CNS. The characteristics and functions of the BBB and underlying mechanisms of molecular translocation across the BBB are also described.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Nanotecnología , Animales , Portadores de Fármacos/química , HumanosRESUMEN
Mylabris phalerata (MP) is an insect used in oriental herbal treatments for tumor, tinea infections, and stroke. Recent studies have shown that tumor-associated macrophages (TAM) have detrimental roles such as tumor progression, angiogenesis, and metastasis. Although TAM has phenotypes and characteristics in common with M2-polarized macrophages, M1 macrophages have tumor suppression and immune stimulation effects. Medicines polarizing macrophages to M1 have been suggested to have anticancer effects via the modulation of the tumor microenvironment. In this line, we screened oriental medicines to find M1 polarizing medicines in M2-polarized macrophages. Among approximately 400 types of oriental medicine, the ethanol extract of M. phalerata (EMP) was the most proficient in increasing TNF-α secretion in M2-polarized macrophages and TAM. Although EMP enhanced the levels of an M1 cytokine (TNF-α) and a marker (CD86), it significantly reduced the levels of an M2 marker (arginase-1) in M2-polarized macrophages. In addition, EMP-treated macrophages increased the levels of M1 markers (Inos and Tnf-α) and reduced those of the enhanced M2 markers (Fizz-1, Ym-1, and arginase-1). EMP-treated macrophages significantly reduced Lewis lung carcinoma cell migration in a transwell migration assay and inhibited EL4-luc2 lymphoma proliferation. In our mechanism study, EMP was found to inhibit STAT3 phosphorylation in M2-polarized macrophages. These results suggest that EMP is effective in treating TAM-mediated tumor progression and metastasis.
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Many skin-whitening compounds target tyrosinase because it catalyzes two rate-limiting steps in melanin synthesis. Although many tyrosinase inhibitors are currently available for a skin-whitening purpose, undesirable adverse effects are also reported. Thus, numerous efforts have been made to develop safer tyrosinase inhibitors from natural products. In line with this, we tested fifty flavonoids, a group of naturally occurring antioxidants and metal chelators, and screened swertiajaponin as the strongest tyrosinase inhibitor in cell-free experiments. Swertiajaponin did not show cytotoxicity in B16F10, HaCat, and Hs27 cells and exhibited strong anti oxidative activity in experiments using the cell-free system and B16F10 cells. It markedly inhibited αMSH- or UVB-induced melanin accumulation in B16F10 cells and suppressed skin pigmentation in a human skin model. As underlying mechanisms, in silico and Lineweaver-Burk plot analyses exhibited that swertiajaponin may directly bind to and inhibit tyrosinase activity by forming multiple hydrogen bonds and hydrophobic interactions with the binding pocket of tyrosinase. In addition, western blotting results indicated that swertiajaponin inhibited oxidative stress-mediated MAPK/MITF signaling, leading to decrease in tyrosinase protein level. Together, swertiajaponin suppresses melanin accumulation by inhibiting both activity and protein expression levels of tyrosinase. Thus, it would be a novel additive for whitening cosmetics.
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Abstract RGX-365 is the main fraction of black ginseng conmprising protopanaxatriol (PPT)-type rare ginsenosides (ginsenosides Rg4, Rg6, Rh4, Rh1, and Rg2). No studies on the antiseptic activity of RGX-365 have been reported. High mobility group box 1 (HMGB1) is recognized as a late mediator of sepsis, and the inhibition of HMGB1 release and recovery of vascular barrier integrity have emerged as attractive therapeutic strategies for the management of sepsis. In this study, we examined the effects of RGX-365 on HMGB1-mediated septic responses and survival rate in a mouse sepsis model. RGX-365 was administered to the mice after HMGB1 challenge. The antiseptic activity of RGX-365 was assessed based on the production of HMGB1, measurement of permeability, and septic mouse mortality using a cecal ligation and puncture (CLP)-induced sepsis mouse model and HMGB1-activated human umbilical vein endothelial cells (HUVECs). We found that RGX-365 significantly reduced HMGB1 release from LPS- activated HUVECs and CLP-induced release of HMGB1 in mice. RGX-365 also restored HMGB1-mediated vascular disruption and inhibited hyperpermeability in the mice. In addition, treatment with RGX-365 reduced sepsis-related mortality in vivo. Our results suggest that RGX- 365 reduces HMGB1 release and septic mortality in vivo, indicating that it is useful in the treatment of sepsis.
Asunto(s)
Proteína HMGB1/análisis , Panax/efectos adversos , Permeabilidad , Sepsis/patología , Ginsenósidos , Células Endoteliales de la Vena Umbilical Humana/clasificación , Antiinfecciosos Locales/efectos adversosRESUMEN
Tyrosinase is a key player in ultraviolet-induced melanogenesis. Because excessive melanin accumulation in the skin can induce hyperpigmentation, the development of tyrosinase inhibitors has attracted attention in cosmetic-related fields. However, side effects including toxicity and low selectivity have limited the use of many tyrosinase inhibitors in cosmetics. We synthesized 12 novel 2-(substituted benzylidene)malononitrile derivatives and investigated their anti-melanogenic activities. Of these 12 compounds, 2-(3, 4-dihydroxy benzylidene)malononitrile (BMN11) exhibited the strongest inhibitory activity against tyrosinase (IC50 = 17.05 µM). In parallel with this, BMN11 treatment notably decreased alpha-melanocyte-stimulating hormone-induced melanin accumulation in B16F10, cells without toxicity and also decreased melanin accumulation in a human skin model. As a mechanism underlying the BMN11-mediated anti-melanogenic effect, docking simulation showed that BMN11 can directly bind to tyrosinase by forming two hydrogen bonds with GLY281 and ASN260 residues, and via three hydrophobic interactions with VAL283, PHE264, and ALA286 residues in the tyrosinase binding pocket, and this likely contributes to its inhibitory effect on tyrosinase. Consistently, Lineweaver-Burk and Cornish-Bowden plots showed that BMN11 is a competitive inhibitor of tyrosinase. We concluded that BMN11 may be a novel tyrosinase inhibitor that could be used in cosmetics.
RESUMEN
This study was initiated to determine whether 2 structurally related flavonoids found in Cyclopia subternata-vicenin-2 (VCN) and scolymoside (SCL)-could modulate renal functional damage in a mouse model of sepsis, and to elucidate the relevant underlying mechanisms. The potential of VCN and SCL treatment to reduce renal damage induced by cecal ligation and puncture (CLP) surgery in mice was measured via assessment of serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, total glutathione, glutathione peroxidase activity, catalase activity, and superoxide dismutase activity. Treatment with either VCN or SCL resulted in elevated plasma levels of BUN and creatinine, and of protein in the urine of mice with CLP-induced renal damage. Moreover, both VCN and SCL inhibited nuclear factor κB activation and reduced the induction of nitric oxide synthase and excessive production of nitric acid. VCN and SCL treatment also reduced the plasma levels of interleukin-6, and tumor necrosis factor-α, reduced lethality due to CLP-induced sepsis, increased lipid peroxidation, and markedly enhanced the antioxidant defense system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase in kidney tissues. The present results suggest that VCN and SCL protect mice from sepsis-triggered renal injury