MicroRNA‐21 and programmed cell death 4 (PDCD4), a downstream target of miR‐21, mediate diverse physiological responses. Here we demonstrate that globular adiponectin (gAcrp) modulates expression of miR‐21 and PDCD4 in RAW 264.7 macrophages. These effects were abrogated by inhibitors of ERK1/2, JNK or NF‐κB. Conditioned media collected from gAcrp‐stimulated RAW 264.7 macrophages caused similar effects as direct gAcrp treatment, showing the paracrine effect of gAcrp. These data indicate that gAcrp modulates the miR‐21/PDCD4 axis through the ERK and JNK/NF‐κB pathways in RAW 264.7 macrophages and further suggest that the miR‐21/PDCD4 axis may be a novel target mediating adiponectin‐induced biological responses.
Leptin, a hormone predominantly produced in adipose tissue, induces growth of cancer cells via inhibition of apoptosis and/or induction of the cell cycle progression. Previous studies demonstrated that estrogen receptor signaling plays an important role in the growth of breast cancer cells. Similarly, autophagy induction by leptin plays a critical role in the growth cancer cells. However, the role of estrogen receptor signaling in relation to leptin‐induced autophagy activation, mediating the growth of breast cancer cells, has not been explored yet. In this study, we examined the role of estrogen receptor signaling in leptin‐induced autophagy activation, which mediates the growth of breast cancer cells, and the potential underlying mechanisms. In this study, we found that leptin significantly induced the growth and proliferation of estrogen receptor positive breast cancer cells (MCF‐7), whereas no significant effects were observed in estrogen receptor negative breast cancer cells (MDA‐MB‐231). Furthermore, leptin‐induced growth of MCF‐7 cells was significantly inhibited by pretreatment with tamoxifen, a selective estrogen receptor modulator, and gene silencing of estrogen receptor alpha, indicating that estrogen receptor signaling plays an important role in leptin‐induced growth of MCF‐7 cells. Moreover, pretreatment with tamoxifen and gene silencing of estrogen receptor alpha significantly suppressed leptin‐induced increase in the expression of autophagy‐related genes, including microtubule‐associated protein light chain 3‐II (LC3 II), Atg5, beclin‐1, and autophagosome formation and induction of autophagic flux, indicating the critical role of estrogen receptor signaling in leptin‐induced autophagy activation in MCF‐7 cells. In addition, leptin‐induced growth of MCF‐7 cells was significantly inhibited, on pretreatment with 3‐Methyladenine (3‐MA), a pharmacological inhibitor of autophagy, implicating the role of leptin‐induced autophagy activation in the growth of breast cancer cells. Moreover, leptin‐induced phosphorylation of AMPK was significantly inhibited by tamoxifen pretreatment and leptin‐induced FoxO3A expression was significantly suppressed by pretreatment with Compound C, a pharmacological inhibitor of AMPK, indicating that estrogen receptor signaling modulates AMPK/FoxO3A axis, which has been shown to play a critical role in leptin‐induced autophagy induction, in breast cancer cells. Based on these data, it can be concluded that estrogen receptor signaling plays a critical role in leptin‐induced autophagy activation via modulation of AMPK/FoxO3A axis in breast cancer cells.
Obesity has been known to negatively modulate the life-span and immunosuppressive potential of mesenchymal stromal cells (MSC). However, it remains unclear what drives the compromised potency of obese MSC. In this study, we examined the involvement of adiponectin, an adipose tissue-derived hormone, in obesity-induced impaired therapeutic function of MSC. Diet-induced obesity leads to a decrease in serum adiponectin, accompanied by impairment of survival and immunomodulatory effects of adipose-derived MSC (ADSC). Interestingly, priming with globular adiponectin (gAcrp) improved the immunomodulatory potential of obese ADSC. Similar effects were also observed in lean ADSC. In addition, gAcrp potentiated the therapeutic effectiveness of ADSC in a mouse model of DSS-induced colitis. Mechanistically, while obesity inhibited the glycolytic capacity of MSC, gAcrp treatment induced a metabolic shift toward glycolysis through activation of adiponectin receptor type 1/p38 MAPK/hypoxia inducible factor-1
Chromanone-containing compounds have been reported to possess several important biological activities. As a part of our continuing effort for discovering potent anti-inflammatory agents, a series of halogen-containing 3-benzylidenechroman-4-ones (1–15) were synthesized, and evaluated for their inhibitory effect on lipopolysaccharide (LPS)-stimulated reactive oxygen species (ROS) production in RAW 264.7 macrophages. Compounds 4 and 10 exhibited significant inhibitory activity (IC50 = 5.09 ± 1.27 and 5.11 ± 0.51 μM, respectively) against LPS-stimulated ROS production in RAW 264.7 macrophages.
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