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1.
Acta Diabetol ; 61(7): 869-878, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38507082

ABSTRACT

BACKGROUND: The associations of muscle mass and strength with new-onset Type 2 diabetes mellitus (T2DM) remain controversial. We aimed to longitudinally evaluate muscle mass and strength in predicting T2DM among Chinese middle-aged and older adults. METHODS: We enrolled 6033 participants aged ≥ 45 years from the China Health and Retirement Longitudinal Study (CHARLS), a cohort survey, between 2011 and 2012. The appendicular skeletal muscle mass (normalized by weight, ASM/BW%), relative hand grip strength (normalized by weight, HGS/BW), and five-repetition chair stand test (5CST). were all categorized into tertiles (lowest, middle, and highest groups) at baseline, respectively. Individuals were followed up until the occurrence of diabetes or the end of CHARLS 2018, whichever happened first. Cox proportional hazards models to calculate hazard ratios with 95% confidence intervals (CI) and mediation analysis were used. RESULTS: During follow-up, 815 (13.5%) participants developed T2DM. After adjusting for covariates, lower ASW/BW% was not associated with a higher risk of diabetes. Compared with individuals in the highest tertile of HGS/BW, those in the lowest tertile had 1.296 (95%CI 1.073-1.567) higher risk of diabetes. Compared with individuals in the lowest tertile of 5CST, those in the highest tertile had 1.329 times (95%CI 1.106-1.596) higher risk of diabetes. By subgroup, both the lowest HGS/BW and highest 5CST were risk factors for diabetes among obesity. The mediation analysis revealed that the effect of HGS/BW on the risk of diabetes is mainly mediated by insulin resistance. CONCLUSIONS: Lower muscle strength is associated with an increased risk of diabetes, especially in obese populations.


Subject(s)
Diabetes Mellitus, Type 2 , Muscle, Skeletal , Humans , Male , Female , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/physiopathology , Middle Aged , Longitudinal Studies , China/epidemiology , Aged , Muscle, Skeletal/physiopathology , Muscle Strength/physiology , Hand Strength/physiology , Risk Factors , Retirement/statistics & numerical data
2.
Eur Geriatr Med ; 15(1): 95-104, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37466901

ABSTRACT

PURPOSE: To cross-sectionally and longitudinally investigate the correlations of sarcopenia and its components with peak expiratory flow (PEF) among Chinese community-dwelling elderly people. METHODS: The data were extracted from the China Health and Retirement Longitudinal Study (CHARLS). A total of 4053 participants aged ≥ 60 years were enrolled from CHARLS 2011, and 2810 were followed up until 2015. Participants were classified into no-sarcopenia, non-severe sarcopenia, and severe sarcopenia groups based on skeletal muscle mass index (SMI), hand grip strength (HGS), and physical performance [gait speed, five-repetition chair stand test (5CST) and short physical performance battery (SPPB)]. Multivariate linear and logistic regression analyses were used to evaluate the associations of sarcopenia and its components with PEF cross-sectionally and longitudinally. RESULTS: In the cross-sectional analysis, the prevalence of non-severe sarcopenia was 14.6% and severe sarcopenia was 4.9%. The results of linear regression analysis revealed that sarcopenia and its components were all correlated with PEF and PEF%pred. In the longitudinal analysis, compared with non-sarcopenia, subjects with severe sarcopenia were associated with a higher risk of PEF (OR = 2.05, 95%CI = 1.30-3.26) and PEF%pred (OR = 1.83, 95%CI = 1.17-2.86) decline. The changes in physical performance were correlated with changes in PEF and PEF%pred. No associations were observed between changes in SMI and PEF as well as PEF%pred. CONCLUSIONS: We demonstrated the associations of baseline sarcopenia status with PEF and longitudinal PEF decline. Also, the changes in physical performance were associated with changes in PEF during a 4-year follow-up. It indicates that improving sarcopenia, especially physical performance may increase PEF.


Subject(s)
Sarcopenia , Humans , Aged , Sarcopenia/epidemiology , Longitudinal Studies , Hand Strength/physiology , Retirement , Independent Living , Cross-Sectional Studies , China/epidemiology
3.
Oncol Lett ; 17(2): 1523-1530, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30675208

ABSTRACT

Research on mevalonate kinase deficiency has revealed that it may lead to the development of renal angiomyolipomas (RAMLs). Thus, it was suspected that geranylgeranyl pyrophosphate synthase (GGPPS), a key enzyme in the mevalonate pathway, may be involved in the development of RAMLs. In the present study, the expression of GGPPS in RAMLs and renal epithelioid angiomyolipomas (REAs) was assessed, and paraffin embedded specimens from 60 patients, including 9 cases with REA and 51 cases with RAML, were examined. Immunoreactivity was evaluated semi-quantitatively according to the intensity of staining and the percentage of positively stained cells. The results indicated that GGPPS was predominantly present in the cytoplasm, and REA tissues exhibited higher expression of GGPPS in the cytoplasm compared with RAML tissues. It was also identified that GGPPS was upregulated in TSC2-null cells, and inhibition of GGPPS could induce apoptosis of TSC2-null cells by autophagy. In conclusion, the increased expression of GGPPS in RAMLs and REAs indicated that mevalonate pathways may be involved in disease progression. GGPPS may serve as a potential therapeutic target and the current results may provide a novel therapeutic strategy for RAML and lymphangioleiomyomatosis.

4.
Environ Toxicol Pharmacol ; 62: 1-10, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29908432

ABSTRACT

Acute and chronic inflammatory diseases are associated with excessive inflammation due to the accumulation of pro-inflammatory mediators and cytokines produced by macrophages. In the present study, we investigated the anti-inflammatory properties of neochlorogenic acid (nCGA) from Lonicera japonica on lipopolysaccharide (LPS)-activated inflammation in macrophages and participation of the AMPK/Nrf2 pathway. nCGA pretreatment significantly reduced the production of nitric oxide, prostaglandin E2, TNF-α, reactive oxygen species, IL-1ß, and IL-6 by LPS-activated macrophages. Moreover, both transcript and protein levels of inducible nitric oxide synthase and cyclooxygenase-2 were reduced by nCGA in LPS-activated macrophages. nCGA inhibited NF-κB activation by attenuating IKKα/ß and IκBα phosphorylation in LPS-stimulated macrophages. Moreover, nCGA attenuated LPS-elevated JAK-1, STAT-1, and MAPK phosphorylation. We further evaluated the possible role of nCGA in the induction of AMPK/Nrf2 signal pathways required for the protein expression of HO-1 and NQO-1. nCGA induced AMPK activation via phosphorylation of LKB1 and CaMKII and by the inhibitory phosphorylation of GSK3ß. It stimulated the overexpression of Nrf2/ARE-regulated downstream proteins, such as NQO-1 and HO-1. Furthermore, the anti-inflammatory effects of nCGA were attenuated in macrophages subjected to siRNAs specific for HO-1, NQO-1, Nrf2, and AMPK. Accordingly, these results indicate that nCGA, as an AMPK/Nrf2 signal activator, prevents excessive macrophage-mediated responses associated with acute and chronic inflammatory disorders.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Anti-Inflammatory Agents/pharmacology , Chlorogenic Acid/analogs & derivatives , Heme Oxygenase-1/metabolism , Macrophages, Peritoneal/drug effects , Membrane Proteins/metabolism , NF-E2-Related Factor 2/metabolism , Quinic Acid/analogs & derivatives , Animals , Chlorogenic Acid/pharmacology , Cytokines/metabolism , Dinoprostone/metabolism , Lipopolysaccharides/pharmacology , Macrophages, Peritoneal/metabolism , Mice , Mice, Inbred C57BL , Nitric Oxide/metabolism , Quinic Acid/pharmacology , RAW 264.7 Cells , Signal Transduction/drug effects , Up-Regulation
5.
Oncotarget ; 8(29): 47533-47546, 2017 Jul 18.
Article in English | MEDLINE | ID: mdl-28472780

ABSTRACT

This study explored the effects of microRNA-19b (miR-19b) on airway remodeling, airway inflammation, and degree of oxidative stress in a mouse model of asthma. Bioinformatics analyses and dual luciferase reporter gene assays revealed that thymic stromal lymphopoietin (TSLP) is a direct target of miR-19b. An asthma model was established via ovalbumin (OVA) sensitization and challenge in 72 female BALB/c mice. Mice were then assigned to saline, OVA-sensitized, saline+miR-19b mimics, saline+anti-TSLP, OVA-sensitized+miR-19b mimics, OVA-sensitized+mimics scramble, OVA-sensitized+anti-TSLP, and OVA-sensitized+IgG2a groups. Pathological morphology changes were detected through hematoxylin/eosin, Masson, and periodic acid-Schiff staining. miR-19b was downregulated while TSLP and Stat3 were upregulated in the OVA-sensitized group compared with the saline group. Bronchoalveolar lavage fluid samples from OVA-sensitized mice showed increased total protein, IL-4, IL-5 and IL-6 levels, numbers of inflammatory cells, eosinophils, neutrophils, mononuclear macrophages and lymphocytes, and eosinophil% compared to controls. Lung tissues from sensitized mice exhibited decreased superoxide dismutase activity and increased methane dicarboxylic aldehyde levels. The effects of OVA sensitization were reversed in the OVA-sensitized+miR-19b mimics and OVA-sensitized+anti-TSLP groups. These findings suggest miR-19b reduces airway remodeling, airway inflammation, and degree of oxidative stress by inhibiting Stat3 signaling through TSLP downregulation in a mouse asthma model.


Subject(s)
Airway Remodeling/genetics , Asthma/genetics , Asthma/metabolism , Cytokines/genetics , MicroRNAs/genetics , Oxidative Stress , STAT3 Transcription Factor/metabolism , Signal Transduction , 3' Untranslated Regions , Animals , Asthma/immunology , Asthma/pathology , Biomarkers , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Cytokines/metabolism , Disease Models, Animal , Female , Gene Expression Regulation , Inflammation Mediators , Mice , Ovalbumin/adverse effects , Oxidation-Reduction , RNA Interference , Thymic Stromal Lymphopoietin
6.
Neurosci Lett ; 651: 43-51, 2017 06 09.
Article in English | MEDLINE | ID: mdl-28458018

ABSTRACT

The incorporation of Polygonum multiflorum into the diet can result in anti-aging effects owing to its wide range of biological and pharmaceutical properties. We investigated the anti-neuroinflammatory properties of CRPE56IGIH isolated from P. multiflorum by focusing on its role in the induction of phase II antioxidant enzymes and the modulation of upstream signaling pathways. In microglia, CRPE56IGIH significantly inhibited lipopolysaccharide (LPS)-stimulated nitric oxide and prostaglandin E2 production with nonspecific cytotoxicity. CRPE56IGIH also markedly inhibited LPS-inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 protein and mRNA expression in the same manner as it inhibited nitric oxide and prostaglandin E2 production. In the control cells, NF-κB transactivation and nuclear translocation occurred at a baseline level, which was significantly increased in response to LPS. However, pretreatment with CRPE56IGIH concentration-dependently inhibited the LPS-induced NF-κB transactivation and nuclear translocation. The phosphorylation of Janus kinase-signal transducers and activators of transcription and mitogen-activated protein kinases was markedly upregulated by LPS, but considerably and dose-dependently inhibited by pretreatment with CRPE56IGIH. Furthermore, CRPE56IGIH induced the expression of phase II antioxidant enzymes, including heme oxygenase-1 (HO-1) and NADPH dehydrogenase quinone-1 (NQO-1). The activation of upstream signaling pathways, such as the Nrf2 pathway, was significantly increased following CRPE56IGIH treatment. Furthermore, the anti-neuroinflammatory effect of CRPE56IGIH was reversed by transfection of Nrf2, HO-1, and NQO-1 siRNA. Our results indicated that CRPE56IGIH isolated from P. multiflorum could be used as a natural anti-neuroinflammatory agent that induces phase II antioxidant enzymes via Nrf2 signaling.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Encephalitis/metabolism , Fallopia multiflora/chemistry , Microglia/drug effects , Mitogen-Activated Protein Kinases/antagonists & inhibitors , NF-E2-Related Factor 2/metabolism , NF-kappa B/antagonists & inhibitors , Plant Extracts/administration & dosage , Animals , Cells, Cultured , Encephalitis/chemically induced , Encephalitis/prevention & control , Lipopolysaccharides , Mice, Inbred ICR , Microglia/metabolism , Plant Extracts/chemistry , Signal Transduction , Up-Regulation
7.
Oncol Lett ; 12(5): 3755-3762, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27895727

ABSTRACT

Small ubiquitin-like modifier (SUMO)/sentrin-specific protease 1 (SENP1), a member of the SENP family, is highly expressed in several neoplastic tissues. However, the effect of SENP1 in acute promyelocytic leukemia (APL) has not been elucidated. In the present study, it was observed that SENP1 deficiency had no effect on the spontaneous apoptosis or differentiation of NB4 cells. Arsenic trioxide (As2O3) could induce the upregulation of endoplasmic reticulum (ER) stress, resulting in the apoptosis of NB4 cells. Additionally, knockdown of SENP1 significantly increased As2O3-induced apoptosis in NB4 cells transfected with small interfering RNA targeting SENP1. SENP1 deficiency also increased the accumulation of SUMOylated X-box binding protein 1 (XBP1), which was accompanied by the downregulation of the messenger RNA expression and transcriptional activity of the XBP1 target genes endoplasmic reticulum-localized DnaJ 4 and Sec61a, which were involved in ER stress and closely linked to the apoptosis of NB4 cells. Taken together, these results revealed that the specific de-SUMOylation activity of SENP1 for XBP1 was involved in the ER stress-mediated apoptosis caused by As2O3 treatment in NB4 cells, thus providing insight into potential therapeutic targets for APL treatment via manipulating XBP1 signaling during ER stress by targeting SENP1.

8.
Food Chem Toxicol ; 97: 159-167, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27621050

ABSTRACT

2,3,4',5-Tetrahydroxystilbene-2-O-ß-d-glucoside (THSG) affects neuroinflammation-related neurodegenerative diseases and inhibits neuroinflammatory mediators. However, the detailed impacts and underlying mechanisms of THSG on neuroinflammatory responses are still unclear. The aim of this study was to investigate the anti-neuroinflammatory mechanism of THSG via AMPK/Nrf2 signaling pathways. This study showed that THSG attenuated LPS-induced iNOS, COX-2, TNF-α, and IL-6 activation in microglia. Furthermore, it was observed that activation of IκBα and NF-κB was significantly increased upon LPS stimulation, and suppressed by THSG treatment in a dose-dependent manner. The expression of HO-1 and NQO1, as well as Nrf2 activation, was induced by THSG in microglia. The promoter activity of ARE and HO-1 also increased in a dose-dependent manner following THSG treatment. Nrf2/HO-1/NQO1 has anti-inflammatory properties; the knock-down of Nrf2/HO-1/NQO1 by specific siRNA prevented the THSG-mediated inhibition of iNOS and COX-2 promoter activity. Consistent with this concept, the phosphorylation of LKB1, CaMKII, and AMPK were elevated after THSG treatment. The blockade of AMPK by a pharmacological inhibitor prevented THSG-induced HO-1 and NQO1 expression. The anti-inflammatory properties of THSG were also reversed by treatment with an AMPK inhibitor. In conclusion, we demonstrated that THSG attenuates the LPS-induced neuroinflammatory response mediated by AMPK/Nrf2 signaling pathways.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Glucosides/pharmacology , Inflammation/drug therapy , Lipopolysaccharides/pharmacology , Microglia/drug effects , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Stilbenes/pharmacology , AMP-Activated Protein Kinases/genetics , Animals , Anti-Inflammatory Agents/pharmacology , Apoptosis/drug effects , Blotting, Western , Cell Proliferation/drug effects , Cells, Cultured , Cytokines/metabolism , Inflammation/chemically induced , Inflammation/metabolism , Inflammation/pathology , Mice , Mice, Inbred ICR , Microglia/metabolism , NF-E2-Related Factor 2/genetics , NF-kappa B/genetics , Nitric Oxide/metabolism , Phosphorylation/drug effects , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects
9.
Neurochem Res ; 41(11): 2981-2992, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27538959

ABSTRACT

AMPK/Nrf2 signaling regulates multiple antioxidative factors and exerts neuroprotective effects. Emodin is one of the main bioactive components extracted from Polygonum multiflorum, a plant possessing important activities for human health and for treating a variety of diseases. This study examined whether emodin can activate AMPK/Nrf2 signaling and induce the expression of genes targeted by this pathway. In addition, the anti-neuroinflammatory properties of emodin in lipopolysaccharide (LPS)-stimulated microglia were examined. In microglia, the emodin treatment increased the levels of LKB1, CaMKII, and AMPK phosphorylation. Emodin increased the translocation and transactivity of Nrf2 and enhanced the levels of HO-1 and NQO1. In addition, the emodin-mediated expression of HO-1 and NQO1 was attenuated completely by an AMPK inhibitor (compound C). Moreover, emodin decreased dramatically the LPS-induced production of NO and PGE2 as well as the protein expression and promoter activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition, emodin effectively inhibited the production of pro-inflammatory cytokines, TNF-α and IL-6, and reduced the level of IκBα phosphorylation, leading to the suppression of the nuclear translocation, phosphorylation, and transactivity of NF-κB. Emodin also suppressed the LPS-stimulated activation of STATs, JNK, and p38 MAPK. The anti-inflammatory effects of emodin were reversed by transfection with Nrf-2 and HO-1 siRNA and by a co-treatment with an AMPK inhibitor. These results suggest that emodin isolated from P. multiflorum can be used as a natural anti-neuroinflammatory agent that exerts its effects by inducing HO-1 and NQO1 via AMPK/Nrf2 signaling in microglia.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Emodin/pharmacology , Microglia/drug effects , NF-E2-Related Factor 2/metabolism , Signal Transduction/drug effects , Animals , Antioxidants/pharmacology , Lipopolysaccharides/pharmacology , Mice , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , Phosphorylation , Tumor Necrosis Factor-alpha/metabolism
10.
Neurochem Int ; 100: 21-29, 2016 11.
Article in English | MEDLINE | ID: mdl-27545975

ABSTRACT

Polygonum multiflorum extracts are known to improve memory and learning ability, and have neuroprotective and anti-aging activity. However, its function and the underlying mechanisms in neuroinflammation-mediated neurodegenerative disease remain poorly understood. In the present study, we investigated the anti-neuroinflammatory effects of several compounds from P. multiflorum, and found a novel compound, CRPE55IB. The CRPE55IB-induced suppression of NO and PGE2 production correlated with inhibition of iNOS and COX-2 protein expression and promoter activity in lipopolysaccharide (LPS)-stimulated microglia. CRPE55IB also reduced the production of pro-inflammatory cytokines (TNF-α and IL-6) induced by LPS. Furthermore, investigation of the molecular mechanism indicated that CRPE55IB inhibited LPS-induced NF-κB activation by inactivating phosphorylation of IKKα/ß, and phosphorylation and degradation of IκBα. We further found that CRPE55IB inhibited the phosphorylation of ERK and JNK at a lower concentration than that for p38 MAPK. Further experiments revealed that CRPE55IB treatment considerably increased the activation of Nrf2/ARE, and the expression of its target genes, including HO-1 and NQO1. Moreover, the Knockdown of Nrf2, HO-1, and NQO1 by siRNA abrogated the inhibitory effect of CRPE55IB on iNOS and COX-2 promoter activity. CRPE55IB also induced phosphorylation of AMPK/LKB/CaMKII in microglia. Analysis using a specific inhibitor of AMPK demonstrated that AMPK activation was involved in CRPE55IB-induced HO-1 and NQO1 expression. In addition, the CRPE55IB-induced anti-neuroinflammatory effect was abrogated by a specific inhibitor of AMPK, indicating the important role of AMPK in CRPE55IB-induced anti-neuroinflammation. Collectively, these results demonstrate that CRPE55IB exerts anti-neuroinflammatory effects against LPS via the Nrf2/AMPK signaling pathways.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Fallopia multiflora/chemistry , Inflammation/drug therapy , Microglia/drug effects , Signal Transduction/drug effects , AMP-Activated Protein Kinases/metabolism , Animals , Cell Line , Cyclooxygenase 2/metabolism , Inflammation/metabolism , Lipopolysaccharides/pharmacology , Mice , Microglia/metabolism , NF-kappa B/metabolism , Phosphorylation , Transcriptional Activation/drug effects
11.
Immunopharmacol Immunotoxicol ; 37(5): 473-80, 2015.
Article in English | MEDLINE | ID: mdl-26466646

ABSTRACT

Cucurbitacin B (CuB) is a triterpenoid that is widely distributed in the plant kingdom and has a variety of biological activities. However, the immunomodulatory and anti-inflammatory effects of CuB have not been well characterized. Therefore, in this study, we investigated the effects of CuB on parameters related to antigen presentation and T-cell activation. Specifically, we examined the effects of CuB on basal and lipopolysaccharide (LPS)-induced expression of class I and II MHC molecules, CD40, CD54, CD80, and CD86 in peritoneal macrophages. The LPS-a expression of MHC II, CD40, CD54, and CD80 was significantly attenuated by CuB. However, expression levels of MHC I and CD86 were not changed by CuB. CuB inhibited the production of intracellular reactive oxygen species induced by LPS and blocked the LPS-activated release of pro-inflammatory mediators, such as nitric oxide (NO), prostaglandin E2, tumor necrosis factor-α, interleukin (IL)-6, IL-12, and IL-1ß, without any cytotoxicity. Consistent with this, CuB also reduced the expression levels of inducible NO synthase and cyclooxygenase-2 induced by LPS. Furthermore, we demonstrated that the anti-inflammatory effects of CuB were dependent on the induction of heme oxygenase-1 expression via Nrf2 activation. Taken together, these data indicate that CuB possesses immunomodulatory and anti-inflammatory effects, and it may be used as an effective herbal remedy for the treatment and prevention of inflammation.


Subject(s)
Immunomodulation/drug effects , Macrophages, Peritoneal/immunology , Triterpenes/pharmacology , Animals , Antigens, CD/immunology , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Histocompatibility Antigens Class II/immunology , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/immunology , Lipopolysaccharides/toxicity , Macrophages, Peritoneal/pathology , Mice
12.
Neurosci Lett ; 588: 101-7, 2015 Feb 19.
Article in English | MEDLINE | ID: mdl-25562207

ABSTRACT

In this study, a neurite outgrowth-inducing substance was isolated from the ethylacetate extract of the Polygonum multiflorum roots and identified as emodin by gas-liquid chromatography-mass spectrometry and (1)H NMR and (13)C NMR. Emodin displayed remarkable neurite outgrowth-inducing activity in Neuro2a cells, as demonstrated by morphological changes and immunocytochemistry for class III ß-tubulin. Emodin exhibited a stronger neutrophic activity than retinoic acid (RA) known as inducer of neurite outgrowth in Neuro2a cells. Emodin treatment resulted in marked increases in phosphorylation of Akt a direct downstream signaling molecule of phosphatidylinositol 3-kinase (PI3K), but upstream of glycogen synthase kinase-3ß (GSK-3ß) and cAMP response element-binding protein (CREB). These augmentations and neurite-bearing cells induced by emodin were remarkably reduced by the addition of PI3K inhibitor LY294002. These results demonstrate that emodin induces neuronal differentiation of Neuro2a cells via PI3K/Akt/GSK-3ß pathway.


Subject(s)
Emodin/pharmacology , Glycogen Synthase Kinase 3/metabolism , Neurites/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Animals , Cell Line, Tumor , Cell Survival/drug effects , Emodin/isolation & purification , Glycogen Synthase Kinase 3 beta , Mice , Neurites/physiology , Plant Extracts/chemistry , Polygonum/chemistry , Signal Transduction
13.
Environ Toxicol Pharmacol ; 38(3): 701-10, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25299846

ABSTRACT

Sanguinarine is a natural compound isolated from the roots of Macleaya cordata and M. microcarpa, has been reported to possess several biological activities such as anti-inflammatory and anti-oxidant effects. In the present study, we demonstrated that sanguinarine markedly induces the expression of HO-1 which leads to a neuroprotective response in mouse hippocampus-derived neuronal HT22 cells from apoptotic cell death induced by glutamate. Sanguinarine significantly attenuated the loss of mitochondrial function and membrane integrity associated with glutamate-induced neurotoxicity. Sanguinarine protected against glutamate-induced neurotoxicity through inhibition of HT22 cell apoptosis. JC-1 staining, which is a well-established measure of mitochondrial damage, was decreased after treatment with sanguinarine in glutamate-challenged HT22cells. In addition, sanguinarine diminished the intracellular accumulation of ROS and Ca(2+). Sanguinarine also induced HO-1, NQO-1 expression via activation of Nrf2. Additionally, we found that si RNA mediated knock-down of Nrf2 or HO-1 significantly inhibited sanguinarine-induced neuroprotective response. These findings revealed the therapeutic potential of sanguinarine in preventing the neurodegenerative diseases.


Subject(s)
Benzophenanthridines/pharmacology , Glutamic Acid/adverse effects , Heme Oxygenase-1/metabolism , Hippocampus/drug effects , Isoquinolines/pharmacology , Membrane Proteins/metabolism , Neuroprotective Agents/pharmacology , Animals , Apoptosis , Calcium/metabolism , Cell Line , Cell Survival/drug effects , Gene Expression Regulation/drug effects , Heme Oxygenase-1/genetics , Hippocampus/cytology , Membrane Potentials/drug effects , Membrane Proteins/genetics , Mice , Mitochondrial Membranes/drug effects , NAD(P)H Dehydrogenase (Quinone)/genetics , NAD(P)H Dehydrogenase (Quinone)/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Reactive Oxygen Species/metabolism
14.
Neurotoxicology ; 41: 102-11, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24486958

ABSTRACT

Glutamate toxicity increases the formation of reactive oxygen species (ROS) and intracellular calcium levels, resulting in neuronal dysfunction, neurodegenerative disorders, and death. Cordycepin is a derivative of the nucleoside adenosine, and is believed to exert neuroprotective effects against glutamate-induced oxidative toxicity in HT22 neuronal cells. Excessive glutamate induces oxidative and endoplasmic reticulum (ER) stress, gradually increasing ER-related pro-apoptotic transcription factor C/EBP homologous protein (CHOP) expression, and eventually up-regulating expression of the pro-apoptotic factor Bax. Cordycepin inhibits CHOP and Bax expressions, as well as p-ERK, p-JNK, and p-p38, all of which are involved in oxidative or ER stress-induced apoptosis. In addition, the increased production of ROS from excessive glutamate leads to elevation of mitochondrial membrane potential (MMP), a hallmark of mitochondrial dysfunction. Cordycepin retains MMP and reduces the elevated levels of ROS and Ca(2+) induced by glutamate. Caspases are crucial mediators involved in mitochondrial apoptosis, and while glutamate disrupts mitochondrial function, it does not change expression levels of caspase 3 and caspase 9. Similarly, cordycepin has no effect on caspase 3 and caspase 9 expressions; however, it decreases the expression of ER stress-specific caspase 12, which plays a key role in the initiation of ER stress-induced apoptosis. Finally, we found that the anti-apoptotic effects of cordycepin are partially dependent on activation of the adenosine A1 receptor, whereas an antagonist selectively attenuated the neuroprotective effects of cordycepin. Collectively, these results suggest that cordycepin could be a potential future therapeutic agent for neuronal disorders.


Subject(s)
Apoptosis/drug effects , Deoxyadenosines/pharmacology , Endoplasmic Reticulum Stress/drug effects , Neurons/drug effects , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Animals , Cell Cycle/drug effects , Cell Line, Transformed , Dose-Response Relationship, Drug , Drug Interactions , Glutamic Acid/pharmacology , Hippocampus/cytology , In Situ Nick-End Labeling , Membrane Potential, Mitochondrial/drug effects , Mice , Neurons/ultrastructure , Reactive Oxygen Species/metabolism , Statistics, Nonparametric
15.
Oncol Rep ; 31(1): 497-504, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24220687

ABSTRACT

Most complications of breast cancer are attributed to metastasis to distant organs, including lymph nodes, bone, lung and liver. Metastasis is considered the leading cause of mortality in patients with breast cancer. The emergence of anti-metastatic properties in breast cancer is an important clinical phenomenon affecting long-term survival. In the present study, we investigated the anti-invasive mechanism of sanguinarine by focusing on its role in inducing HO-1 in breast cancer cells. The results showed that sanguinarine inhibited TPA-induced MMP-9 and COX-2 mRNA and protein expression in a dose-dependent manner at non-cytotoxic concentrations. Similarly, the MMP-9 enzymatic activity and the PGE2 levels significantly decreased in MCF-7 breast cancer cells. TIMP-1 and TIMP-2, specific endogenous inhibitors of MMP-9, were slightly induced by sanguinarine. Subsequent studies revealed that sanguinarine suppressed TPA-induced NF-κB and AP-1 activation, as well as the phosphorylation of Akt and ERK. Furthermore, sanguinarine significantly inhibited TPA-induced invasion and migration in breast cancer cells. We also demonstrated that sanguinarine induced HO-1 expression, and that the inhibition of MMP-9 and COX-2 expression and the enzymatic activity of sanguinarine were abrogated by siRNA-mediated knockdown of HO-1 expression. Thus, knockdown of endogenous HO-1 decreased TPA-induced cell invasion. Overall, the results of the present study demonstrate that HO-1 plays a pivotal role in the anti-invasive response of sanguinarine in TPA-stimulated breast cancer cells.


Subject(s)
Anti-Infective Agents/pharmacology , Benzophenanthridines/pharmacology , Breast Neoplasms/pathology , Cyclooxygenase 2/biosynthesis , Isoquinolines/pharmacology , Matrix Metalloproteinase 9/biosynthesis , Breast Neoplasms/enzymology , Cell Movement/drug effects , Cyclooxygenase 2/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Heme Oxygenase-1/biosynthesis , Heme Oxygenase-1/genetics , Humans , MCF-7 Cells , Matrix Metalloproteinase 9/genetics , Neoplasm Invasiveness , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , RNA, Messenger/biosynthesis , RNA, Small Interfering , Signal Transduction , Tetradecanoylphorbol Acetate , Tissue Inhibitor of Metalloproteinase-1/biosynthesis , Tissue Inhibitor of Metalloproteinase-2/biosynthesis , Transcription Factor AP-1/biosynthesis , Transcription Factor RelA/biosynthesis
16.
Int J Oncol ; 44(1): 309-18, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24173318

ABSTRACT

Halofuginone (HF) is extracted from Dichroa febrifuga, a plant used in traditional medicine. We report that the HF extract inhibits the growth of breast cancer cells and induces the generation of reactive oxygen species (ROS) and apoptosis, an important feature of potential anticancer agents. In addition, HF significantly reduces the migration and invasion of MCF-7 and MDA-MB-231 human breast cancer cells after 12-O-tetraecanoylphorbol-13-acetate (TPA) stimulation. As matrix metalloproteinase-9 plays a critical role in tumor metastasis, we analyzed its expression with the HF extract treatment. Western blot analysis and gelatin zymography showed that HF suppresses MMP-9 expression and activity concentration-dependently. HF also decreases the nuclear protein levels of nuclear factor kappa B (NF-κB) and c-fos (AP-1), critical transcription factors regulating MMP-9 expression through binding the MMP-9 promoter region. Luciferase assays showed that HF decreases TPA-induced MMP-9 promoter binding activities of NF-κB and AP-1. Taken together, these are the first results indicating that halofuginone may represent a promising new agent for breast cancer chemotherapy.


Subject(s)
Apoptosis/drug effects , Breast Neoplasms/drug therapy , Matrix Metalloproteinase 9/biosynthesis , Piperidines/administration & dosage , Quinazolinones/administration & dosage , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Movement/drug effects , Cell Proliferation/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells , Matrix Metalloproteinase 9/genetics , NF-kappa B/biosynthesis , Proto-Oncogene Proteins c-akt/biosynthesis , Transcription Factor AP-1/genetics
17.
Zhonghua Jie He He Hu Xi Za Zhi ; 36(8): 563-6, 2013 Aug.
Article in Chinese | MEDLINE | ID: mdl-24252730

ABSTRACT

OBJECTIVE: To improve understanding of the clinical characteristics and diagnosis of allergic bronchopulmonary mycosis (ABPM). METHODS: We retrospectively analyzed the clinical data, including clinical symptoms, laboratory tests, pulmonary function tests and chest CT imaging of 95 asthmatic patients with positive serum mycosis-specific IgE from January 2010 to September 2012 in Zhongshan Hospital Affiliated to Fudan University. RESULTS: Of the 95 patients, 59 cases met the diagnostic criteria of ABPM. There were 34 males and 25 females, with a mean age of (53 ± 4) years and a duration of asthma for (21 ± 4) years. Thirty-six cases showed mycosis hypersensitivity (MH). There were 10 males and 26 females, with a mean age of (46 ± 6) years and a duration of asthma for (16 ± 5) years. Clinical symptoms such as wheeze (52 vs 21, χ(2) = 11.159, P = 0.001), cough (54 vs 27, χ(2) = 4.859, P = 0.030) and expectoration (43 vs 9, χ(2) = 25.731, P = 0.000) were more common in the ABPM group compared to the MH group.In the ABPM group, 58 were A. fumigatus-specific IgE antibody positive, 34 Penicillium-specific IgE antibody positive and 1 only Penicillium-specific IgE antibody positive.While in the MH group, 15 were A.fumigatus-specific IgE antibody positive, 24 Penicillium-specific IgE antibody positive and 17 only Penicillium-specific IgE antibody positive.In the ABPM group, the percentage of positive fumigatus-specific IgE antibody was higher (58 vs 15, χ(2) = 24.500, P = 0.000), while the percentages of dermatophagoides pteronyssinus(21 vs 20, χ(2) = 3.632, P = 0.045) and Dermatophagoides farinae(17 vs 21, χ(2) = 8.118, P = 0.004) were lower. Total serum IgE [(4395 ± 1437) IU/ml vs (276 ± 133) IU/ml, T = 4.384, P = 0.000], peripheral eosinophil percentage[(12.56 ± 1.20)% vs (1.30 ± 0.15)%, t = 8.175, P = 0.000] and count [(2.09 ± 0.43)×10(9)/L vs (0.19 ± 0.04)×10(9)/L, t = 7.032, P = 0.000] were higher in the ABPM group as compared to the MH group.FEV1% slightly declined in the ABPM group [(70.2 ± 2.3)% vs (78.3 ± 3.2%)%, t = 2.011, P = 0.038].Forty-one cases (69.50%) had central bronchiectasis and 18 (30.50%) had mucus plugs in the ABPM group. Chest CT scan was normal in the MH group. CONCLUSIONS: ABPM is common in asthmatic patients but has long been underestimated and misdiagnosed.Efforts need to be intensified to improve the awareness among clinicians for early diagnosis and treatment of the disease.


Subject(s)
Aspergillosis, Allergic Bronchopulmonary/diagnosis , Asthma/diagnosis , Immunoglobulin E/blood , Adolescent , Adult , Aged , Aged, 80 and over , Allergens/immunology , Aspergillosis, Allergic Bronchopulmonary/diagnostic imaging , Aspergillosis, Allergic Bronchopulmonary/immunology , Aspergillus fumigatus/immunology , Asthma/diagnostic imaging , Asthma/immunology , Biomarkers/blood , Eosinophils/immunology , Female , Humans , Immunoglobulin E/immunology , Male , Middle Aged , Respiratory Function Tests , Retrospective Studies , Tomography, X-Ray Computed , Young Adult
18.
Environ Toxicol Pharmacol ; 35(2): 335-46, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23395777

ABSTRACT

Extracts of Acanthopanax senticosus, a traditional herb commonly found in Northeastern Asia, are used for treating neurodegenerative disorders such as ischemia and depression. However, the mechanisms of its neuroinflammatory and cytoprotective effects have not been investigated. We examined the mechanism of A. senticosus activity in anti-neuroinflammatory and neuroprotective processes. HO-1 is an inducible enzyme present in most cell lines. ASE increased HO-1 expression, which reduced LPS-induced nitric oxide/ROS production in BV2 cells. Moreover, the induction of HO-1 expression protected cells against glutamate-induced neuronal cell death. Activation of the p38-CREB pathway and translocation of Nrf2 are strongly involved in ASE-induced HO-1 expression. Our results showed that ASE-induced HO-1 expression through the p38-CREB pathway plays an important role in the generation of anti-neuroinflammatory and neuroprotective responses. ASE also increases the translocation of Nrf2 to regulate HO-1 expression. Furthermore, our results indicate that ASE serves as a potential therapeutic agent for neuronal disorders.


Subject(s)
Eleutherococcus/chemistry , Heme Oxygenase-1/metabolism , Hippocampus/drug effects , Membrane Proteins/metabolism , Microglia/drug effects , Neuroprotective Agents/pharmacology , Plant Extracts/pharmacology , Animals , Cell Death/drug effects , Cell Line/drug effects , Cyclic AMP Response Element-Binding Protein/metabolism , Drug Evaluation, Preclinical , Glutamic Acid/adverse effects , Hippocampus/cytology , Hippocampus/metabolism , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Lipopolysaccharides/pharmacology , Mice , Microglia/cytology , Microglia/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Neurotoxicity Syndromes/drug therapy , Neurotoxicity Syndromes/etiology , Nitric Oxide/metabolism , Plants, Medicinal/chemistry , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects
19.
Int J Mol Med ; 30(6): 1512-20, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22992724

ABSTRACT

Recent evidence indicates that microglial activation and hippocampal damage may play important roles in neurodegenerative diseases, including Alzheimer's disease. Bambusae Caulis in Taeniam has been used as a folk remedy for the treatment of hypertension and cardiovascular disease in China and Korea. In this study, the mechanism responsible for the neuroprotective and anti-neuroinflammatory effects of Bambusae Caulis in Taeniam ethyl acetate fraction (BCE) was investigated. Heme oxygenase-1 (HO-1) is an inducible enzyme expressed in response to various inflammatory stimuli. Due to its role in the anti-inflammatory signaling pathway, the expression and modulation of HO-1 are important. In this study, the neuroprotective and anti-neuroinflammatory effects of BCE were examined using the murine microglial BV2 and hippocampal HT22 cells. We demonstrated that the administration of BCE provided neuroprotective effects against glutamate-induced cytotoxicity in HT22 cells through the HO-1 and nuclear erythroid-2 related factor 2 (Nrf-2) signaling pathways. We also reported that BCE inhibited lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and that the presence of selective inhibitors of HO-1 (SnPP) resulted in the inhibition of BCE-mediated anti-inflammatory activity in BV2 microglial cells. BCE was shown to induce HO-1 expression as well as the nuclear translocation of Nrf-2 in both microglial and hippocampal cells. These findings revealed the potential therapeutic mechanisms of BCE in neurodegenerative diseases, suggesting that HO-1 and Nrf-2 signaling may play important roles in the mediation of its neuroprotective and anti-neuroinflammatory effects.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Bambusa/chemistry , Drugs, Chinese Herbal/pharmacology , Microglia/drug effects , Neuroprotective Agents/pharmacology , Alzheimer Disease/drug therapy , Animals , Cell Line , Cell Survival/drug effects , Cytokines/metabolism , Cytokines/pharmacology , Cytokines/physiology , Enzyme Induction/drug effects , Glutamic Acid/pharmacology , Glutamic Acid/physiology , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism , Hippocampus/cytology , Inflammation Mediators/metabolism , Lipopolysaccharides/pharmacology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Microglia/immunology , Microglia/physiology , NF-E2-Related Factor 2/physiology , Neurons/drug effects , Neurons/immunology , Neurons/physiology , Nitrites/metabolism , Protein Transport , Reactive Oxygen Species/metabolism , Transcriptional Activation/drug effects
20.
Int Immunopharmacol ; 14(1): 13-20, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22728094

ABSTRACT

Amyloid ß (Aß) induces the production of neuroinflammatory molecules, which may contribute to the pathogenesis of numerous neurodegenerative diseases. Therefore, suppression of neuroinflammatory molecules could be developed as a therapeutic method. Aromatic (ar)-turmerone, turmeric oil isolated from Curcuma longa, has long been used in Southeast Asia as both a remedy and a food. In this study, we investigated the anti-inflammatory effects of ar-turmerone in BV2 microglial cells. Aß-stimulated microglial cells were tested for the expression and activation of MMP-9, iNOS, and COX-2, the production of proinflammatory cytokines, chemokines, and ROS, as well as the underlying signaling pathways. Ar-turmerone significantly suppressed Aß-induced expression and activation of MMP-9, iNOS, and COX-2, but not MMP-2. Ar-turmerone also reduced TNF-α, IL-1ß, IL-6, and MCP-1 production in Aß-stimulated microglial cells. Further, ar-turmerone markedly inhibited the production of ROS. Impaired translocation and activation of NF-κB were observed in Aß-stimulated microglial cells exposed to ar-turmerone. Furthermore, ar-turmerone inhibited the phosphorylation and degradation of IκB-α as well as the phosphorylation of JNK and p38 MAPK. These results suggest that ar-turmerone impaired the Aß-induced inflammatory response of microglial cells by inhibiting the NF-κB, JNK, and p38 MAPK signaling pathways. Lastly, ar-turmerone protected hippocampal HT-22 cells from indirect neuronal toxicity induced by activated microglial cells. These novel findings provide new insights into the development of ar-turmerone as a therapeutic agent for the treatment of neurodegenerative disorders.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Ketones/pharmacology , Microglia/drug effects , Neurodegenerative Diseases/drug therapy , Sesquiterpenes/pharmacology , Amyloid beta-Peptides/immunology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Cell Line, Transformed , Cholinergic Neurons/pathology , Curcuma/chemistry , Cytokines/metabolism , Cytoprotection/drug effects , Humans , Inflammation Mediators/metabolism , MAP Kinase Kinase 4/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Microglia/immunology , NF-kappa B/metabolism , Neurodegenerative Diseases/immunology , Oxidative Stress/drug effects , Plant Oils/chemistry , Signal Transduction/drug effects , Signal Transduction/immunology , p38 Mitogen-Activated Protein Kinases/metabolism
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