Tetrandrine Inhibits Proinflammatory Cytokines, iNOS and COX-2 Expression in Human Monocytic Cells

Wu, Shu-Jing; Ng, Lean‐Teik

doi:10.1248/bpb.30.59

Cited by 51 publications

(36 citation statements)

References 31 publications

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“…36,37) Recent studies have demonstrated that tetrandrine can inhibit NF-κB activation by suppression of IκBα degradation, and consequently it inhibits the production of proinflammatory cytokines. 34,[38][39][40][41] Therefore, we examined the anti-osteoporotic and anti-osteoclastogenic effects of tetrandrine. In the present study, we demonstrate for the first time that tetrandrine significantly ameliorates the decrease of bone mass in sciatic-neurectomized mice by inhibiting osteoclast differentiation.…”

Section: -7)mentioning

confidence: 99%

Tetrandrine Prevents Bone Loss in Sciatic-Neurectomized Mice and Inhibits Receptor Activator of Nuclear Factor κB Ligand-Induced Osteoclast Differentiation

Takahashi

Tonami

Tachibana

et al. 2012

Biological & Pharmaceutical Bulletin

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One of the mediators of osteoclast differentiation is receptor activator of nuclear factor κB ligand (RANKL), which is produced by osteoblasts. Binding of RANKL to its receptor, RANK, activates several signaling pathways, including those involving mitogen-activated protein kinases (MAPKs), nuclear factor κB (NF-κB), nuclear factor of activated T cells c1 (NFATc1) and Ca 2 -calcineurin. In the present study, we found that tetrandrine, a bisbenzylisoquinoline alkaloid extracted from the root of Stephania tetrandra S. MOORE, significantly ameliorated the decrease of bone mass in sciatic-neurectomized osteoporosis model mice. It appears that tetrandrine acts directly on osteoclast precursors, since tetrandrine inhibited osteoclast differentiation not only in mouse bone marrow cells, but also in monocultures of murine macrophage RAW 264.7 cells without osteoblasts. Tetrandrine suppressed RANKL-induced amplification of NFATc1, a master regulator of osteoclast differentiation. However, it did not affect other signaling molecules such as MAPKs and NF-κB. These results suggest that tetrandrine is a candidate for the treatment of bone-destructive diseases, or at least a suitable lead compound for further development.Key words tetrandrine; osteoporosis; osteoclast; receptor activator of nuclear factor κB ligand; nuclear factor of activated T cell c1Bone remodeling is a physiological process that involves resorption of bone by osteoclasts and synthesis of bone matrix by osteoblasts.1) A relative increase of bone resorption over bone formation can result in osteoporosis, one of the most prevalent diseases in the aged population.2,3) Osteoclasts are known to be formed by the fusion of hematopoietic cells of the monocyte-macrophage lineage during the early stage of the differentiation process.4) Terminal differentiation in this lineage is characterized by acquisition of mature phenotypic markers, such as expression of tartrate-resistant acid phosphatase (TRAP), calcitonin receptor, matrix metalloproteinase 9 (MMP9), and cathepsin K, as well as morphological conversion into large multinucleated cells and formation of resorption lacunae on bone. 5-7)The essential signaling molecules for osteoclast differentiation include receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), and both of them are produced by osteoblasts. 8)RANKL induces the signaling essential for precursor cells to differentiate into osteoclasts, 9) whereas M-CSF provides the survival signal for these cells.10) RANKL binding to RANK, a receptor of RANKL that is expressed in osteoclast precursors, mediates the biological effects of RANKL and leads to the recruitment of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which in turn results in the activation of the downstream signaling pathway, including nuclear factor κB (NF-κB), c-Jun N-terminal protein kinase (JNK), p38, extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase/AKT. [11][12][13][14] RANKL activation of JNK ph...

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Section: -7)mentioning

confidence: 99%

Tetrandrine Prevents Bone Loss in Sciatic-Neurectomized Mice and Inhibits Receptor Activator of Nuclear Factor κB Ligand-Induced Osteoclast Differentiation

Takahashi

Tonami

Tachibana

et al. 2012

Biological & Pharmaceutical Bulletin

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“…20,21) Hence, we consider the increased release of IL-10 in mice treated with 10-fold-diluted Pairogen and their macrophages to be due to reduction in TNF-α and IL-6 production. Although several antioxidants have been reported to interfere early in inflammatory responses by blocking or modifying the signal transduction of cytokines, [33][34][35] administration of 10-fold-diluted Pairogen just before or just after R. aurantiacus infection did not show any effects on cytokine expression and the development of inflammation in mice (data not shown).…”

Section: Discussionmentioning

confidence: 91%

Ferrous Ferric Chloride Downregulates the Inflammatory Response to <i>Rhodococcus aurantiacus</i> Infection in Mice

Yimin

Tao²,

Kohanawa

et al. 2012

Biological & Pharmaceutical Bulletin

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The healthy drink Pairogen (Akatsuka Co., Mie, Japan) consists of 90% ferrous ferric chloride (FFC) water and 10% purified ingredients, including rice vinegar, Japanese apricot vinegar, apple vinegar, persimmon vinegar, vitamin B 2 , vitamin B 6 , vitamin C, glucose, fructose, citric acid, and malic acid.1,2) FFC is a special aqueous iron composed of a complex of ferrous chloride and ferric chloride and is known to participate in intracellular redox reactions.3,4) FFC water is obtained by immersing FFC ceramic beads (Akatsuka Co.) in water. Pairogen and FFC water are reported to influence multiple biological functions in living organisms. For example, Hasegawa et al. demonstrated that FFC water stimulates plant growth, particularly that of roots.5) The addition of either FFC water or Pairogen to a medium showed an equal effect on inducing the proliferation and differentiation of epidermal cells derived from both humans and mice.

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“…Tetrandrine (Tet), a natural product isolated from Stephania tetrandra, has been reported to be an anti-tumor and anti-inflammatory drug (1)(2)(3)(4)(5)(6)(7)(8). Previously, the present authors have demonstrated that Tet induces cell death in 11 cancer cell lines (1).…”

Section: Introductionmentioning

confidence: 84%

Tetrandrine triggers an alternative autophagy in DU145 cells

2017

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Abstract. Tetrandrine (Tet), a potent lysosomal inhibitor, blocks autophagic flux and induces cancer cell death. Previously, the present authors identified the prostate cancer cell line DU145 to exhibit high sensitivity towards Tet in 11 cancer cell lines. In the present study, autophagy in Tet-treated DU145 cells was investigated. Similar to other cell lines, such as PC-3 and 786-O cells, Tet neutralized the acidity of lysosome and blocked autophagy in DU145 cells. However, Tet failed to induce microtubule-associated protein 1 light chain 3 (LC3) conversion in DU145 cells. By contrast, it was observed by transmission electron microscopy that Tet induced an accumulation of autophagosomes in the cytoplasm. These contrasting results indicated that Tet triggered an LC3-independent autophagy in DU145 cells. Alkalizing lysosome with chloroquine enhanced Tet-induced cell death. The results of the present study indicated that detection of autophagy in tumor cells may assist in selecting lysosome inhibitors for chemotherapy treatment in prostate cancer. Introduction Tetrandrine (Tet), a natural product isolated fromStephania tetrandra, has been reported to be an anti-tumor and anti-inflammatory drug (1-8). Previously, the present authors have demonstrated that Tet induces cell death in 11 cancer cell lines (1). Tet directly neutralizes the lysosomal acidity, blocks the autophagic flux in the degradation step and causes energetic impairment, which eventually results in cell death (1). By contrast, Tet also acts as an autophagy agonist by inducing the synthesis of reactive oxygen species (3,4,9-11), indicating that Tet may function as a multi-target drug to regulate autophagy in cancer cells. Regardless of the Tet target, the present authors and other groups have previously consistently observed that Tet increases the number of autophagosomes, levels of microtubule-associated protein 1 light chain 3, type II (LC3-II) and the number of enhanced green fluorescent protein-LC3 puncta in cancer cells (1,3,9). DU145, a commonly used prostate cancer cell line for research, is different from PC-3 and LNCaP cells in terms of autophagy regulation (12). As alternative transcripts of autophagy related 5 (ATG5) lack one or two exons in DU145 cells, and this causes the autophagy pathway to be genetically impaired (12). By contrast, DU145 cells exhibited the highest sensitivity to Tet in all of the 11 cancer cell lines that were previously tested by the authors of the present study (1), implying that impairment in autophagy may increase Tet-induced cell death. In order to investigate the role of autophagy on Tet-induced cell death in DU145 cells, the ultrastructural changes following Tet treatment were observed by transmission electron microscopy (TEM). Notably, Tet treatment triggered an accumulation of autophagosomes in this cell line, indicating that alternative autophagy was involved. Materials and methodsTetrandrine and other reagents. Tet (Santa Cr uz Biotechnology, Inc., Dallas, TX, USA) was dissolved as previously described (1)....

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Tetrandrine Inhibits Proinflammatory Cytokines, iNOS and COX-2 Expression in Human Monocytic Cells

Cited by 51 publications

References 31 publications

Tetrandrine Prevents Bone Loss in Sciatic-Neurectomized Mice and Inhibits Receptor Activator of Nuclear Factor κB Ligand-Induced Osteoclast Differentiation

Tetrandrine Prevents Bone Loss in Sciatic-Neurectomized Mice and Inhibits Receptor Activator of Nuclear Factor κB Ligand-Induced Osteoclast Differentiation

Ferrous Ferric Chloride Downregulates the Inflammatory Response to <i>Rhodococcus aurantiacus</i> Infection in Mice

Tetrandrine triggers an alternative autophagy in DU145 cells

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