Uncovering the effect of low-frequency static magnetic field on tendon-derived cells: from mechanosensing to tenogenesis

Magnetotherapy has been receiving increased attention as an attractive strategy for modulating cell physiology directly at the site of injury, thereby providing the medical community with a safe and non- invasive therapy. Yet, how magnetic eld in uences tendon cells both at the cellular and molecular levels remains unclear. Thus, the in uence of a low-frequency static magnetic eld (2 Hz, 350 mT) on human tendon-derived cells was studied using di erent exposure times (4 and 8 h; short-term studies) and di erent regimens of exposure to an 8h-period of magnetic stimulation (continuous, every 24 h or every 48 h; long-term studies). Herein, 8 h stimulation in short-term studies signi cantly upregulated the expression of tendon-associated genes SCX, COL1A1, TNC and DCN (p < 0.05) and altered intracellular Ca2+ levels (p < 0.05). Additionally, every 24 h regimen of stimulation signi cantly upregulated COL1A1, COL3A1 and TNC at day 14 in comparison to control (p < 0.05), whereas continuous exposure di erentially regulated the release of the immunomodulatory cytokines IL-1β and IL-10 (p < 0.001) but only at day 7 in comparison to controls. Altogether, these results provide new insights on how low-frequency static magnetic eld ne-tune the behaviour of tendon cells according to the magnetic settings used, which we foresee to represent an interesting candidate to guide tendon regeneration.info:eu-repo/semantics/publishedVersio

Potential biological role of poly (ADP-ribose) polymerase (PARP) in male gametes

Maintaining the integrity of sperm DNA is vital to reproduction and male fertility. Sperm contain a number of molecules and pathways for the repair of base excision, base mismatches and DNA strand breaks. The presence of Poly (ADP-ribose) polymerase (PARP), a DNA repair enzyme, and its homologues has recently been shown in male germ cells, specifically during stage VII of spermatogenesis. High PARP expression has been reported in mature spermatozoa and in proven fertile men. Whenever there are strand breaks in sperm DNA due to oxidative stress, chromatin remodeling or cell death, PARP is activated. However, the cleavage of PARP by caspase-3 inactivates it and inhibits PARP's DNA-repairing abilities. Therefore, cleaved PARP (cPARP) may be considered a marker of apoptosis. The presence of higher levels of cPARP in sperm of infertile men adds a new proof for the correlation between apoptosis and male infertility. This review describes the possible biological significance of PARP in mammalian cells with the focus on male reproduction. The review elaborates on the role played by PARP during spermatogenesis, sperm maturation in ejaculated spermatozoa and the potential role of PARP as new marker of sperm damage. PARP could provide new strategies to preserve fertility in cancer patients subjected to genotoxic stresses and may be a key to better male reproductive health

Rescue of platinum-damaged oocytes from programmed cell death through inactivation of the p53 family signaling network

Non-proliferating oocytes within avascular regions of the ovary are exquisitely susceptible to chemotherapy. Early menopause and sterility are unintended consequences of chemotherapy, and efforts to understand the oocyte apoptotic pathway may provide new targets for mitigating this outcome. Recently, the c-Abl kinase inhibitor imatinib mesylate (imatinib) has become the focus of research as a fertoprotective drug against cisplatin. However, the mechanism by which imatinib protects oocytes is not fully understood, and reports of the drug's efficacy have been contradictory. Using in vitro culture and subrenal grafting of mouse ovaries, we demonstrated that imatinib inhibits the cisplatin-induced apoptosis of oocytes within primordial follicles. We found that, before apoptosis, cisplatin induces c-Abl and TAp73 expression in the oocyte. Oocytes undergoing apoptosis showed downregulation of TAp63 and upregulation of Bax. While imatinib was unable to block cisplatin-induced DNA damage and damage response, such as the upregulation of p53, imatinib inhibited the cisplatin-induced nuclear accumulation of c-Abl/TAp73 and the subsequent downregulation of TAp63 and upregulation of Bax, thereby abrogating oocyte cell death. Surprisingly, the conditional deletion of Trp63, but not ΔNp63, in oocytes inhibited apoptosis, as well as the accumulation of c-Abl and TAp73 caused by cisplatin. These data suggest that TAp63 is the master regulator of cisplatin-induced oocyte death. The expression kinetics of TAp63, c-Abl and TAp73 suggest that cisplatin activates TAp63-dependent expression of c-Abl and TAp73 and, in turn, the activation of TAp73 by c-Abl-induced BAX expression. Our findings indicate that imatinib protects oocytes from cisplatin-induced cell death by inhibiting c-Abl kinase, which would otherwise activate TAp73-BAX-mediated apoptosis. Thus, imatinib and other c-Abl kinase inhibitors provide an intriguing new way to halt cisplatin-induced oocyte death in early follicles and perhaps conserve the endocrine function of the ovary against chemotherapy.Cell Death and Differentiation advance online publication, 19 April 2013; doi:10.1038/cdd.2013.31

The emerging roles of YAP and TAZ in cancer

Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the major downstream effectors of the Hippo pathway, which regulates tissue homeostasis, organ size, regeneration and tumorigenesis. In this Progress article, we summarize the current understanding of the biological functions of YAP and TAZ, and how the regulation of these two proteins can be disrupted in cancer. We also highlight recent findings on their expanding role in cancer progression and describe the potential of these targets for therapeutic intervention