BackgroundDiabetic neuropathy is a common neuropathy associated with paresthaesia and pain. The mechanisms underlying the painful conditions are not well understood. The aim of this study is to investigate the participation of purinergic P2X3 receptors in painful diabetic neuropathy.ResultsDiabetes was induced by an intraperitoneal injection of streptozotocin (STZ). We showed that mechanical allodynia was induced two weeks after a STZ injection and lasted for at least another seven weeks. The mechanical allodynia was significantly attenuated by peripheral administration of the P2X receptor antagonists, PPADS or TNP-ATP. DiI was subcutaneously injected into the rat hindpaw to label hindpaw-innervated dorsal root ganglion (DRG) neurons. ATP activated fast-inactivating P2X3 receptor-mediated currents in the labeled DRG neurons were studied. ATP responses in STZ-treated rats were ~2-fold larger than those in control rats. Furthermore, the expression of P2X3 receptor proteins in the plasma membrane of L4-6 DRGs of STZ rats was significantly enhanced while the total expression of P2X3 receptors remained unaltered.ConclusionsThese results indicate that a large enhancement of P2X3 receptor activity and an increase in the membrane expression of P2X3 receptors contribute to the development of chronic pain in STZ-induced diabetic rats and suggest a possible target for the treatment of diabetic neuropathic pain.
DNA double-strand breaks (DSBs) are the major lethal lesion induced by ionizing radiation (IR). RAD51-dependent homologous recombination (HR) is one of the most important pathways in DSB repair and genome integrity maintenance. However, the mechanism of HR regulation by RAD51 remains unclear. To understand the mechanism of RAD51-dependent HR, we searched for interacting partners of RAD51 by a proteomics analysis and identified lamin B1 in human cells. Lamins are nuclear lamina proteins that play important roles in the structural organization of the nucleus and the regulation of chromosome functions. Immunoblotting analyses revealed that siRNA-mediated lamin B1 depletion repressed the DNA damage-dependent increase of RAD51 after IR. The repression was abolished by the proteasome inhibitor MG132, suggesting that lamin B1 stabilizes RAD51 by preventing proteasome-mediated degradation in cells with IR-induced DNA damage. We also showed that lamin B1 depletion repressed RAD51 focus formation and decreased the survival rates after IR. On the basis of these results, we propose that lamin B1 promotes DSB repair and cell survival by maintaining the RAD51 protein levels for HR upon DSB induction after IR.-Liu, N.-A., Sun, J., Kono, K., Horikoshi, Y., Ikura, T., Tong, X., Haraguchi, T., Tashiro, S. Regulation of homologous recombinational repair by lamin B1 in radiation-induced DNA damage. FASEB J. 29, 2514-2525 (2015). www.fasebj.org Key Words: B-type lamins • nuclear envelope • progeria syndrome • RAD51 • recombinational DNA repair AMONG THE VARIOUS TYPES of DNA damage induced by ionizing radiation (IR), double-strand breaks (DSBs) are regarded as the most serious impairment leading to cell death. In mammalian cells, DSBs are repaired mainly by 1 of 2 genetically distinct processes, nonhomologous end joining and homologous recombination (HR) (1). HR is a process that requires the presence of a homologous DNA region to serve as a template for accurate repair (2). RAD51, a recA homolog that forms helical filaments, binds to single-strand DNA, thus promoting recombinational repair (3, 4). RAD51 knockout mice usually die at an early stage of embryogenesis, and cells lacking functional RAD51 often exhibit chromosome breaks and cell-cycle arrest (5, 6). RAD51-defective animals and cells are both sensitive to IR. On the other hand, RAD51 overexpression in different organisms and cell types apparently increases genomic instability by stimulating aberrant recombination between short repetitive elements (7,8). These findings indicate that RAD51 is a critical protein in HR repair and cell survival. Interestingly, RAD51 has been shown to form nuclear foci at sites containing DSBs (9, 10). However, the mechanisms that regulate the RAD51 protein levels and its focus formation in response to DNA damage remain unclear.Higher-order nuclear architectures, including the nuclear lamina, are considered to be essential for the proper regulation of DNA metabolism, including gene activation and silencing, as well as DNA replication and ...
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The intrinsic earth magnetic field (geomagnetic field, GMF) provides an essential environmental condition for most living organisms to adapt the solar cycle by rhythmically synchronizing physiological and behavioral processes. However, hypomagnetic field (HMF) of outer space, the Moon, and the Mars differs much from GMF, which poses a critical problem to astronauts during long-term interplanetary missions. Multiple experimental works have been devoted to the HMF effects on circadian rhythm and found that HMF perturbs circadian rhythms and profoundly contributes to health problems such as sleep disorders, altered metabolic as well as neurological diseases. By systemizing the latest progress on interdisciplinary cooperation between magnetobiology and chronobiology, this review sheds light on the health effects of HMF on circadian rhythms by elaborating the underlying circadian clock machinery and molecular processes.
Aneuploidy is a hallmark of genomic instability that leads to tumor initiation, progression, and metastasis. CDC20, Bub1, and Bub3 form the mitosis checkpoint complex (MCC) that binds the anaphase-promoting complex or cyclosome (APC/C), a crucial factor of the spindle assembly checkpoint (SAC), to ensure the bi-directional attachment and proper segregation of all sister chromosomes. However, just how MCC is regulated to ensure normal mitosis during cellular division remains unclear. In the present study, we demonstrated that LNC CRYBG3, an ionizing radiation-inducible long noncoding RNA, directly binds with Bub3 and interrupts its interaction with CDC20 to result in aneuploidy. The 261–317 (S3) residual of the LNC CRYBG3 sequence is critical for its interaction with Bub3 protein. Overexpression of LNC CRYBG3 leads to aneuploidy and promotes tumorigenesis and metastasis of lung cancer cells, implying that LNC CRYBG3 is a novel oncogene. These findings provide a novel mechanistic basis for the pathogenesis of NSCLC after exposure to ionizing radiation as well as a potential target for the diagnosis, treatment, and prognosis of an often fatal disease.
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