Bupleurum Polysaccharides Attenuates Lipopolysaccharide-Induced Inflammation via Modulating Toll-Like Receptor 4 Signaling

Wu, Jiang; Zhang, Yunyi; Guo, Li; Li, Hong; Chen, Daofeng

doi:10.1371/journal.pone.0078051

Cited by 38 publications

(20 citation statements)

References 40 publications

(56 reference statements)

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“…Moreover, the increase of TRAF6 by TNF-α and IL-1β was very rapid (15 min). In agreement with our results, Wu et al showed that TRAF6 was significantly increased at 15 min after incubation with lipopolysaccharides in macrophages [51]. The rapid induction of TRAF6 may be attributed to translational regulation, which needs to be investigated in the future.…”

Section: Discussionsupporting

confidence: 92%

TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling

Jiang

Cao

et al. 2014

Pain

125

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The proinflammatory cytokines TNF-α and IL-1β have been strongly implicated in the pathogenesis of neuropathic pain, but the intracellular signaling of these cytokines in glial cells are not fully understood. Tumor necrosis factor receptor associated factor 6 (TRAF6) plays a key role in signal transduction in the TNF receptor superfamily and the interleukin-1 receptor superfamily. In this study, we investigated the role of TRAF6 in neuropathic pain in mice following spinal nerve ligation (SNL). SNL induced persistent TRAF6 upregulation in the spinal cord. Interestingly, TRAF6 was mainly colocalized with the astrocytic marker GFAP on SNL day 10 and partially expressed in microglia on SNL day 3. In cultured astrocytes, TRAF6 was up-regulated after exposure to TNF-α or IL-1β. TNF-α or IL-1β also increased CCL2 expression, which was suppressed by both siRNA and shRNA targeting TRAF6. TRAF6 siRNA treatment also inhibited the phosphorylation of c-Jun N-terminal kinase (JNK) in astrocytes induced by TNF-α or IL-1β. JNK inhibitor D-NKI-1 dose-dependently decreased IL-1β-induced CCL2 expression. Moreover, spinal injection of TRAF6 siRNA decreased intrathecal TNF-α-or IL-1β-induced allodynia and hyperalgesia. Spinal TRAF6 inhibition via TRAF6 siRNA, shRNA lentivirus, or antisense oligodeoxynucleotides partially reversed SNL-induced neuropathic pain and spinal CCL2 expression. Finally, intrathecal injection of TNF-α-activated astrocytes induced mechanical allodynia, which was attenuated by pretreatment of astrocytes with TRAF6 siRNA. Taken together, the results suggest that TRAF6, upregulated in spinal cord astrocytes in the late phase after nerve injury, maintains neuropathic pain by integrating TNF-α and IL-1β signaling and activating the JNK/CCL2 pathway in astrocytes.

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Section: Discussionsupporting

confidence: 92%

TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling

Jiang

Cao

et al. 2014

Pain

125

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“…reported by other compounds, such as inosine, 14 bupleurum polysaccharides, 21 proxylin A, 22 and quercetin, 23 and by other pyrrol compounds, such as T-686, an inhibitor of plasminogen activator inhibitor-1 that was associated with a mortality reduction in mice exposed to LPS. 24 However, none of those compounds had described any antiapoptotic activity in sepsisinduced lung injury.…”

Section: Inhibition Of Lps-induced Airway Cell Injury Ne Cabrera-benímentioning

confidence: 92%

Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates

Cabrera-Benítez

Pérez-Roth

Ramos-Nuez

et al. 2016

Laboratory Investigation

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Inflammation and apoptosis are crucial mechanisms for the development of the acute respiratory distress syndrome (ARDS). Currently, there is no specific pharmacological therapy for ARDS. We have evaluated the ability of a new family of 1,2,3,5-tetrasubstituted pyrrol compounds for attenuating lipopolysaccharide (LPS)-induced inflammation and apoptosis in an in vitro LPS-induced airway epithelial cell injury model based on the first steps of the development of sepsis-induced ARDS. Human alveolar A549 and human bronchial BEAS-2B cells were exposed to LPS, either alone or in combination with the pyrrol derivatives. Rhein and emodin, two representative compounds with proven activity against the effects of LPS, were used as reference compounds. The pyrrol compound that was termed DTA0118 had the strongest inhibitory activity and was selected as the lead compound to further explore its properties. Exposure to LPS caused an intense inflammatory response and apoptosis in both A549 and BEAS-2B cells. DTA0118 treatment downregulated Toll-like receptor-4 expression and upregulated nuclear factor-κB inhibitor-α expression in cells exposed to LPS. These anti-inflammatory effects were accompanied by a significantly lower secretion of interleukin-6 (IL-6), IL-8, and IL-1β. The observed antiapoptotic effect of DTA0118 was associated with the upregulation of antiapoptotic Bcl-2 and downregulation of proapoptotic Bax and active caspase-3 protein levels. Our findings demonstrate the potent anti-inflammatory and antiapoptotic properties of the pyrrol DTA0118 compound and suggest that it could be considered as a potential drug therapy for the acute phase of sepsis and septic ARDS. Further investigations are needed to examine and validate these mechanisms and effects in a clinically relevant animal model of sepsis and sepsis-induced ARDS.

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“…Thereafter, they were washed three times in PBS (5 min/wash) and incubated with a 1:200 dilution of secondary antibody (fluorescein isothiocyanate [FITC]-conjugated goat anti-mouse IgG) for 1 h at 37°C. The nuclei were stained using DAPI (0.25 g/ml; Life Technologies), and the staining was visualized using a confocal laser-scanning microscope (LSM510; Carl Zeiss, Gottingen, Germany) (26).…”

Section: Neutralization Of Lpsmentioning

confidence: 99%

Antimicrobial Peptide CMA3 Derived from the CA-MA Hybrid Peptide: Antibacterial and Anti-inflammatory Activities with Low Cytotoxicity and Mechanism of Action in Escherichia coli

Lee

Seo

Luchian

et al. 2016

Antimicrob Agents Chemother

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dCA-MA is a hybrid antimicrobial peptide (AMP) derived from two naturally occurring AMPs, cecropin A and magainin 2. CA-MA shows strong antimicrobial activity against Gram-negative and Gram-positive bacteria but also exhibits cytotoxicity toward mammalian cells. Our objective was to identify CA-MA analogues with reduced cytotoxicity by systematic replacement of amino acids with positively charged R groups (His and Lys), aliphatic R groups (Leu), or polar R groups (Glu). Among the CA-MA analogues studied (CMA1 to -6), CMA3 showed the strongest antimicrobial activity, including against drug-resistant Escherichia coli and Pseudomonas aeruginosa strains isolated from hospital patients. CMA3 appeared to act by inducing pore formation (toroidal model) in the bacterial membrane. In cytotoxicity assays, CMA3 showed little cytotoxicity toward human red blood cells (hRBCs) or HaCaT cells. Additionally, no fluorescence was released from small or giant unilamellar vesicles exposed to 60 M CMA3 for 80 s, whereas fluorescence was released within 35 s upon exposure to CA-MA. CMA3 also exerted strong lipopolysaccharide (LPS)-neutralizing activity in RAW 264.7 cells, and BALB/c mice exposed to LPS after infection by Escherichia coli showed improved survival after administration of one 0.5-mg/kg of body weight or 1-mg/kg dose of CMA3. Finally, in a mouse model of septic shock, CMA3 reduced the levels of proinflammatory factors, including both nitric oxide and white blood cells, and correspondingly reduced lung tissue damage. This study suggests that CMA3 is an antimicrobial/antiendotoxin peptide that could serve as the basis for the development of anti-inflammatory and/or antimicrobial agents with low cytotoxicity. W hen microorganisms infect vertebrate or invertebrate animals, the secretion of cytokines, chemokines, and other peptides is an important component of the animals' innate immune response (1, 2). Among those other peptides are antimicrobial peptides (AMPs), which play key roles in the innate immune responses of mammals, amphibians, and insects, among others (3, 4). Indeed, more than 2,300 different AMPs have been identified and isolated from a wide range of organisms, including bacteria (n ϭ 322), protozoa (n ϭ 6), fungi (n ϭ 12), plants (n ϭ 306), and animals (n ϭ 1,801). Most AMPs contain at least 10 amino acid residues, have a net charge ranging from Ϫ3 to ϩ20, and exhibit Ͻ60% hydrophobicity (5). Together, these features underlie the bactericidal activity of AMPs, enabling them to bind and form damaging pores in the membranes of Gram-negative and Gram-positive bacteria. To induce pore formation, AMPs have an ␣-helical structure and the ability to interact with anionic components of the cytoplasmic membrane, resulting in the formation of toroidal, carpet, or barrel stave pores (6). Additionally, many AMPs can potentially prevent septic shock via their antiendotoxic activity through electrostatic interaction with lipopolysaccharides (LPS) and lipoteichoic acid in the bacterial membrane (7-9).CA-MA is a hybrid AMP syn...

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Bupleurum Polysaccharides Attenuates Lipopolysaccharide-Induced Inflammation via Modulating Toll-Like Receptor 4 Signaling

Cited by 38 publications

References 40 publications

TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling

TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling

Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates

Antimicrobial Peptide CMA3 Derived from the CA-MA Hybrid Peptide: Antibacterial and Anti-inflammatory Activities with Low Cytotoxicity and Mechanism of Action in Escherichia coli

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