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Reactive oxygen species and neuroepithelial interactions during wound healing
Published in David M. Gardiner, Regenerative Engineering and Developmental Biology, 2017
A hallmark of wound repair in vertebrates is the regeneration of cutaneous sensory axons into the wounded area. In rats, Dorsal root ganglion (DRG) axons were found to hyperinnervate the wound, and this hyperinnervation pattern persisted up to 12 weeks after injury (Reynolds and Fitzgerald 1995). Most of our current knowledge about the molecular mechanisms leading to somatosensory axon regeneration stems from rodent studies in which axotomies were performed. During an axotomy, either the brachial or sciatic nerve is exposed via an incision made into the limb, and axons are subsequently severed via nerve crush or transection. These injuries result in the disconnection of the distal axonal portion from the cell body, and the distal axon subsequently undergoes rapid degeneration. This process was originally identified by Augustus Volney Waller in 1850 and is defined by a stereotypic sequence of events leading to fragmentation, degradation, and clearance of axon debris. Nerve injury by axotomy triggers the release of two calcium waves at the injury site: a fast wave and a slow wave. These waves propagate along the proximal axon toward the soma. The fast wave leads to the release of internal calcium stores from the endoplasmic reticulum, which promotes nuclear export of histone deacetylase (HDAC5) in the soma (Cho et al. 2013). This primes the chromatin for transcription via acetylation (Ac) of histone 3 (H3). A second calcium wave stimulates local protein translation. One pathway involves importin-mediated retrograde transport of nuclear localization sequence (NLS)-containing transcription factors into the nucleus, which activate the expression of downstream genes. In addition, dual leucine zipper kinase (DLK-1) is locally translated, which leads to retrograde STAT3 transport into the soma. This process also involves Jun N-terminal kinase (JNK), leading to activation of C-JUN and activating transcription factor-3 (ATF3) (Rishal and Fainzilber 2014).
Nuclear targeting peptide-modified, DOX-loaded, PHBV nanoparticles enhance drug efficacy by targeting to Saos-2 cell nuclear membranes
Published in Journal of Biomaterials Science, Polymer Edition, 2018
Ayla Şahin, Gozde Eke, Arda Buyuksungur, Nesrin Hasirci, Vasif Hasirci
The nucleus is separated from the rest of cytoplasm by the double membrane structure of the nuclear envelope (NE) which constitutes a major barrier and the main rate limiting step in the transport of drugs into the nucleus [6,10]. The NE contains nuclear pore complexes (NPC) which are channels that allow the passive diffusion of small molecules (ca. 9 nm in diameter) or transport of larger molecules (ca. 39 nm in diameter) in an energy dependent manner [4]. The transfer of drugs through the energy dependent pathway into the nucleus is mediated by homologous proteins called importins. This transfer mechanism is divided into two steps. In the first step, importin α binds to Nuclear Localization Signal (NLS), which is a special oligopeptide, and importin β binds to the cytoplasmic filaments that bring the target molecule to the nuclear pore. In the second step, importin α is transported through the nuclear pore into the nucleus together with its cargo [11].
Nonviral gene delivery using PAMAM dendrimer conjugated with the nuclear localization signal peptide derived from human papillomavirus type 11 E2 protein
Published in Journal of Biomaterials Science, Polymer Edition, 2021
Jeil Lee, Yong-Eun Kwon, Jaegi Kim, Dong Woon Kim, Hwanuk Guim, Jehyeong Yeon, Jin-Cheol Kim, Joon Sig Choi
Therapeutic genes must be delivered to the nuclear region for successful gene therapy. However, nonviral vectors have difficulties in selectively delivering DNA molecules into the nuclear region, limiting their application in genetic medicine. Nonviral gene delivery is inhibited by membranous barriers; one of these, the nuclear envelope, consists of two lipid bilayer membranes and a nuclear pore complex (NPC), limiting the entry of molecules larger than 9 nm. NLS is a tag sequence that enables the transport of proteins from the cytoplasm to the nuclear region and permits the active transport of molecules up to 39 nm [29]. Since the size of the cationic polymer/pCN-Luci polyplexes was too large to directly penetrate the NPC pores, we hypothesized that PAMAM derivatives conjugated with NLS peptides/pCN-Luci polyplexes would be localized in the perinuclear region because of their size, and subsequently delivered to the nuclear region when the nuclear envelope disappears during mitosis. In our previous study, polyplexes of PAMAM derivatives conjugated with NLS peptides and pCN-Luci showed high transfection efficiency and perinuclear localization. A series of experiments and previous findings indicate that each factor, such as enhanced cellular uptake and proton-buffering capacity, affects the transfection efficiency of PAMAM derivatives modified with NLS peptides, which showed a lower proton-buffering capacity than PEI 25 kDa [17–19]. If proton-buffering capacity was the main reason for the increased transfection efficiency, PAMAM derivatives modified with NLS peptides should have a buffering capacity similar to that of PEI (25 kDa). Therefore, the improved transfection efficiency of RKRAR- and RKRARH-PAMAM G2 may be a product of the combined effects of these three factors.
The cationic (calcium and lead) and enzyme conundrum
Published in Journal of Toxicology and Environmental Health, Part B, 2018
Jane Kasten-Jolly, David A. Lawrence
It is now evident that PKC isozymes have specific functions within the nucleus and translocation of specific isozymes to the nucleus is tissue and stimulus dependent, as reviewed by Lim et al. (2015). For example, stimuli that promote differentiation of HL-60 cells prompt DAG production in the nucleus by phospholipase D and induce PKCα to translocate to the nucleus, whereas, stimuli that promote proliferation prompt PKCβII to translocate to the nuclei. The most common means of proteins to translocate in and out of the cell nucleus is via nuclear localization signals (NLS) found as part of their amino acid sequence composition. Classical NLS motifs can be either monopartite or bipartite. Isoforms of PKC do not have the canonical NLS motif, but display a nuclear targeting motif that is similar to the classical NLS bipartite motif. Specific PKC isoform translocation to the nucleus might be dependent on the cell stimuli and the isoform’s nuclear targeting motif. Once in the nucleus, PKC isoforms directly influence gene transcription through phospho-modification of histones, RNA polymerase II, and transcription factors, Fos and CREB. Phosphorylation of histones by nuclear PKCδ has been associated with apoptosis of cells undergoing cellular stress. In addition to the cytosolic role of PKCθ in T-cell activation, the isozyme influences transcription in the nucleus by phosphorylating proteins that cause epigenetic modification of histones, such as histone demethylases. Another function of PKCθ in the nucleus is to directly promote transcription of IL-2 by its involvement in phosphorylation and binding of CREB to the IL-2 promoter. In macrophages, induction by IFN-γ leads to STAT1 phosphorylation by PKCδ resulting in the gene transcription of the class II transactivator protein (CIITA), while in B-cells PKCδ promotes the transcription of CIITA through phosphorylation of CREB. In non-immune system cells PKCα, PKCβI, and PKCβII were found to produce phosphorylation of H3T6, thereby blocking H3K4 demethylation. In breast cancer cells PKCβI was detected as part of a regulatory complex for the regulation of ERα gene transcription.