Effects and Mechanisms of Exogenous Electromagnetic Field on Bone Cells: A Review.

Osteoporosis, fractures, and other bone diseases or injuries represent serious health problems in modern society. A variety of treatments including drugs, surgeries, physical therapies, etc. have been used to prevent or delay the progression of these diseases/injuries with limited effects. Electromagnetic field (EMF) has been used to non-invasively treat bone diseases, such as fracture and osteoporosis, for many years. However, because a variety of cellular and molecular events can be affected by EMF with various parameters, the precise bioeffects and underlying mechanisms of specific EMF on bone cells are still obscure. Here, we summarize the common therapeutic parameters (frequency and intensity) of major types of EMF used to treat bone cells taken from 32 papers we selected from the PubMed database published in English from 1991 to 2018. Briefly, pulse EMF promotes the proliferation of osteoblasts when its frequency is 7.5-15 Hz or 50-75 Hz and the intensity is 0.40-1.55 mT or 3.8-4 mT. Sinusoidal EMF, with 0.9-4.8 mT and 45-60 Hz, and static magnetic field with 0.1-0.4 mT or 400 mT, can promote osteoblast differentiation and maturation. Finally, we summarize the latest advances on the molecular signaling pathways influenced by EMF in osteoblasts and osteoclasts. A variety of molecules such as adenosine receptors, calcium channels, BMP2, Notch, Wnt1, etc., can be influenced by EMF in osteoblasts. For osteoclasts, EMF affects RANK, NF-κB, MAPK, etc. We speculate that EMF with different frequencies and intensities exert distinct bioeffects on specific bone cells. More high-quality work is required to explore the detailed effects and underlying mechanisms of EMF on bone cells/skeleton to optimize the application of EMF on bone diseases/injuries. Bioelectromagnetics. 2020;41:263-278 © 2020 Bioelectromagnetics Society.

Activation of Adenosine 2A receptor inhibits neutrophil apoptosis in an autophagy-dependent manner in mice with systemic inflammatory response syndrome.

Systemic inflammatory response syndrome (SIRS) is an overwhelming whole body inflammation caused by infectious diseases or sterile insults. Neutrophils are the dominant participants during inflammation, and their survival and death determine the initiation as well as resolution of SIRS. Apoptosis and autophagy are two fundamental cellular processes that modulating cell fate, but their correlation and regulators in neutrophils under SIRS condition have not been elucidated. In this study, we demonstrated that high dose of LPS induced both apoptosis and autophagy of neutrophils in a mouse SIRS model and LPS-stimulated neutrophils in vitro. Moreover, we found that the adenosine 2A receptor (A2AR), a known anti-inflammatory G protein-coupled receptor (GPCR), could inhibit LPS-induced neutrophil apoptosis by suppressing the LPS-induced autophagy. Activation of A2AR suppressed LPS-induced autophagy by inhibiting the ROS-JNK pathway as well as promoting GPCR ßϒ subunit-AKT signaling. The A2AR-inhibited autophagy suppressed apoptosis of neutrophils by blocking caspase8, caspase3 and PARP signaling. These findings not only increase our understandings of neutrophils' fate and function in response to systemic inflammation, but also identify a novel anti-inflammatory role of A2AR in modulating neutrophils' survival during inflammation.

Sorafenib sensitizes (-)-gossypol-induced growth suppression in androgen-independent prostate cancer cells via Mcl-1 inhibition and Bak activation.

The natural BH3-mimetic (-)-gossypol shows promising efficacy in ongoing phase II/III clinical trials for human prostate cancer. Here, we show for the first time, that treatment with (-)-gossypol and multikinase inhibitor sorafenib synergistically suppresses the growth of androgen-independent prostate cancer cells (AI-PC) in vitro and in vivo. Our data suggest that sorafenib attenuates (-)-gossypol-induced Mcl-1 upregulation in AI-PCs. In this way, it serves as a potent chemosensitizer to affect cell death. Interestingly, (-)-gossypol and sorafenib induce cell death via two distinct pathways among different AI-PCs; DU145 cells via apoptosis and PC-3 via autophagy. The appointed death pathway may depend on the level of proapoptotic protein Bak, although the level of antiapoptotic protein Bcl-2 plays some role in it. DU145 cells with high Bak level prefer apoptosis induction, whereas PC-3 cells with low Bak prefer the induction of autophagy. Furthermore, inhibiting nondominant death pathways, that is, autophagy in DU145 and apoptosis in PC-3, enhances cell killing by (-)-gossypol/sorafenib combination therapy. Ultimately, our data expose a new action for sorafenib as an enhancer of (-)-gossypol-induced cell growth suppression and reveal a novel cell death mode by Bak activation manners in AI-PCs. These new insights may facilitate the rational design of clinical trials by selecting patients most likely to benefit from the Bcl-2-targeted molecular therapy.