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1.
J Cell Physiol ; 237(9): 3554-3564, 2022 09.
Article in English | MEDLINE | ID: mdl-35696549

ABSTRACT

Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by fat accumulation and chronic inflammation in the liver. Dynein light chain of 8 kDa (LC8) was identified previously as an inhibitor of nuclear factor kappa B (NF-κB), a key regulator of inflammation, however, its role in NASH remains unknown. In this study, we investigated whether LC8 can alleviate NASH using a mouse model of methionine and choline-deficient (MCD) diet-induced NASH and examined the underlying mechanism. LC8 transgenic (Tg) mice showed lower hepatic steatosis and less progression of NASH, including hepatic inflammation and fibrosis, compared to wild-type (WT) mice after consuming an MCD diet. The hepatic expression of lipogenic genes was lower, while that of lipolytic genes was greater in LC8 Tg mice than WT mice, which might be associated with resistance of LC8 Tg mice to hepatic steatosis. Consumption of an MCD diet caused oxidative stress, IκBα phosphorylation, and subsequent p65 liberation from IκBα and nuclear translocation, resulting in induction of proinflammatory cytokines and chemokines. However, these effects of MCD diet were reduced by LC8 overexpression. Collectively, these results suggest that LC8 alleviates MCD diet-induced NASH by inhibiting NF-κB through binding to IκBα to interfere with IκBα phosphorylation and by reducing oxidative stress via scavenging reactive oxygen species. Thus, boosting intracellular LC8 could be a potential therapeutic strategy for patients with NASH.


Subject(s)
Dyneins , NF-kappa B , Non-alcoholic Fatty Liver Disease , Oxidative Stress , Animals , Choline/metabolism , Cytoplasmic Dyneins , Diet , Disease Models, Animal , Dyneins/genetics , Dyneins/metabolism , Inflammation/metabolism , Liver/metabolism , Liver/pathology , Methionine/metabolism , Mice , Mice, Inbred C57BL , NF-KappaB Inhibitor alpha/metabolism , NF-kappa B/metabolism , Non-alcoholic Fatty Liver Disease/genetics
2.
J Cell Physiol ; 236(12): 8239-8252, 2021 12.
Article in English | MEDLINE | ID: mdl-34192358

ABSTRACT

Many bone diseases such as osteoporosis and periodontitis are caused by hyperactivation of osteoclasts. Calcium (Ca2+ ) signals are crucial for osteoclast differentiation and function. Thus, the blockade of Ca2+ signaling may be a strategy for regulating osteoclast activity and has clinical implications. Flunarizine (FN) is a Ca2+ channel antagonist that has been used for reducing migraines. However, the role of FN in osteoclast differentiation and function remains unknown. Here, we investigated whether FN regulates osteoclastogenesis and elucidated the molecular mechanism. FN inhibited osteoclast differentiation along with decreased expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), and attenuated osteoclast maturation and bone resorption. FN inhibition of osteoclast differentiation was restored by ectopic expression of constitutively active NFATc1. FN reduced calcium oscillations and its inhibition of osteoclast differentiation and resorption function was reversed by ionomycin, an ionophore that binds Ca2+ . FN also inhibited Ca2+ /calmodulin-dependent protein kinase IV (CaMKIV) and calcineurin leading to a decrease in the cAMP-responsive element-binding protein-dependent cFos and peroxisome proliferator-activated receptor-γ coactivator 1ß expression, and NFATc1 nuclear translocation. These results indicate that FN inhibits osteoclastogenesis via regulating CaMKIV and calcineurin as a Ca2+ channel blocker. In addition, FN-induced apoptosis in osteoclasts and promoted osteogenesis. Furthermore, FN protected lipopolysaccharide- and ovariectomy-induced bone destruction in mouse models, suggesting that it has therapeutic potential for treating inflammatory bone diseases and postmenopausal osteoporosis.


Subject(s)
Calcium Signaling/drug effects , Flunarizine/antagonists & inhibitors , Osteoclasts/drug effects , Osteogenesis/drug effects , Animals , Bone Resorption/drug therapy , Bone Resorption/metabolism , Calcineurin/metabolism , Cell Differentiation/drug effects , Flunarizine/metabolism , Humans , NFATC Transcription Factors/drug effects , NFATC Transcription Factors/metabolism , Osteoclasts/metabolism , Osteogenesis/physiology , Osteoporosis/drug therapy , Osteoporosis/metabolism , RANK Ligand/metabolism
3.
J Cell Physiol ; 236(3): 1854-1865, 2021 03.
Article in English | MEDLINE | ID: mdl-32700766

ABSTRACT

Cinchonine (CN) has been known to exert antimalarial, antiplatelet, and antiobesity effects. It was also recently reported to inhibit transforming growth factor ß-activated kinase 1 (TAK1) and protein kinase B (AKT) through binding to tumor necrosis factor receptor-associated factor 6 (TRAF6). However, its role in bone metabolism remains largely unknown. Here, we showed that CN inhibits osteoclast differentiation with decreased expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key determinant of osteoclastogenesis. Immunoblot and quantitative real-time polymerase chain reaction analysis as well as the reporter assay revealed that CN inhibits nuclear factor-κB and activator protein-1 by regulating TAK1. CN also attenuated the activation of AKT, cyclic AMP response element-binding protein, and peroxisome proliferator-activated receptor-γ coactivator 1ß (PGC1ß), an essential regulator of mitochondrial biogenesis. Collectively, these results suggested that CN may inhibit TRAF6-mediated TAK1 and AKT activation, which leads to downregulation of NFATc1 and PGC1ß resulting in the suppression of osteoclast differentiation. Interestingly, CN not only inhibited the maturation and resorption function of differentiated osteoclasts but also promoted osteoblast differentiation. Furthermore, CN protected lipopolysaccharide- and ovariectomy-induced bone destruction in mouse models, suggesting its therapeutic potential for treating inflammation-induced bone diseases and postmenopausal osteoporosis.


Subject(s)
Cell Differentiation , Cinchona Alkaloids/pharmacology , Osteoclasts/cytology , Osteoclasts/metabolism , Osteogenesis , Proto-Oncogene Proteins c-akt/metabolism , Animals , Bone Resorption/metabolism , Bone Resorption/pathology , Cell Differentiation/drug effects , Cinchona Alkaloids/chemistry , Cyclic AMP Response Element-Binding Protein/metabolism , Gene Expression Regulation/drug effects , Humans , Inflammation/pathology , Lipopolysaccharides , MAP Kinase Kinase Kinases/metabolism , Male , Mice , Mice, Inbred C57BL , Models, Biological , NF-kappa B/metabolism , NFATC Transcription Factors/metabolism , Nuclear Proteins/metabolism , Osteoclasts/drug effects , Osteogenesis/drug effects , Ovariectomy , RANK Ligand/pharmacology , RAW 264.7 Cells , Transcription Factor AP-1/metabolism , Transcription Factors/metabolism
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