Neuroinflammation is a major component in the transition to and perpetuation of neuropathic pain states. Spinal neuroinflammation involves activation of TLR4, localized to enlarged, cholesterol-enriched lipid rafts, designated here as inflammarafts. Conditional deletion of cholesterol transporters ABCA1 and ABCG1 in microglia, leading to inflammaraft formation, induced tactile allodynia in naive mice. The apoA-I binding protein (AIBP) facilitated cholesterol depletion from inflammarafts and reversed neuropathic pain in a model of chemotherapy-induced peripheral neuropathy (CIPN) in wild-type mice, but AIBP failed to reverse allodynia in mice with ABCA1/ABCG1–deficient microglia, suggesting a cholesterol-dependent mechanism. An AIBP mutant lacking the TLR4-binding domain did not bind microglia or reverse CIPN allodynia. The long-lasting therapeutic effect of a single AIBP dose in CIPN was associated with anti-inflammatory and cholesterol metabolism reprogramming and reduced accumulation of lipid droplets in microglia. These results suggest a cholesterol-driven mechanism of regulation of neuropathic pain by controlling the TLR4 inflammarafts and gene expression program in microglia and blocking the perpetuation of neuroinflammation.
Dendropsophini is the most species-rich tribe within Hylidae with 234 described species. Although cytogenetic information is sparse, chromosome numbers and morphology have been considered as an important character system for systematic inferences in this group. Using a diversity of standard and molecular techniques, we describe the previously unknown karyotypes of the genera Xenohyla, Scarthyla and Sphaenorhynchus and provide new information on Dendropsophus and Lysapsus. Our results reveal significant karyotype diversity among Dendropsophini, with diploid chromosome numbers ranging from 2n = 22 in S. goinorum, 2n = 24 in Lysapsus, Scinax, Xenohyla, and almost all species of Sphaenorhynchus and Pseudis, 2n = 26 in S.carneus, 2n = 28 in P.cardosoi, to 2n = 30 in all known Dendropsophus species. Although nucleolar organizer regions (NORs) and C-banding patterns show a high degree of variability, NOR positions in 2n = 22, 24 and 28 karyotypes and C-banding patterns in Lysapsus and Pseudis are informative cytological markers. Interstitial telomeric sequences reveal a diploid number reduction from 24 to 22 in Scarthyla by a chromosome fusion event. The diploid number of X.truncata corroborates the character state of 2n = 30 as a synapomorphy of Dendropsophus.
Current treatments for chronic pain rely largely on opioids despite their substantial side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in NaV1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between NaV subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of NaV1.7 in primary afferents via epigenome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)–dCas9 and zinc finger proteins at the spinal level as a potential treatment for chronic pain. Toward this end, we first optimized the efficiency of NaV1.7 repression in vitro in Neuro2A cells and then, by the lumbar intrathecal route, delivered both epigenome engineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain, and BzATP-induced pain. Our results show effective repression of NaV1.7 in lumbar dorsal root ganglia, reduced thermal hyperalgesia in the inflammatory state, decreased tactile allodynia in the neuropathic state, and no changes in normal motor function in mice. We anticipate that this long-lasting analgesia via targeted in vivo epigenetic repression of NaV1.7 methodology we dub pain LATER, might have therapeutic potential in management of persistent pain states.
Recebido para publicação em 12/12/2008Aceito para publicação em 07/03/2009 RESUMO Células-tronco são caracterizadas por seu estado indiferenciado e seu alto poder de autorrenovação através de divisões assimétricas. Sob a infl uência de determinados sinais biológicos, elas podem se diferenciar em células fenotipicamente distintas de seus precursores. São divididas em dois grandes grupos de acordo com o local de seu isolamento: embrionárias, que são as células retiradas da camada celular interna do blastocisto; e adultas, que são aquelas encontradas em diversos locais de tecidos pós-natais. As células-tronco mesenquimais, por sua vez, formam um grupo heterogêneo de células adultas multipotentes, capazes de originar tecidos mesenquimais: ósseo, adiposo e cartilaginoso, sendo encontradas tanto em tecidos fetais quanto em adultos. O líquido amniótico humano, um fl uido complexo e dinâmico que envolve o feto durante a gestação, contém uma variedade de célu-las esfoliadas do embrião em sua composição. Procedimentos bem estabelecidos de isolamento, crescimento e expansão das células do líquido amniótico podem proporcionar uma fonte alternativa de células-tronco mesenquimais com diversas aplicações biomédicas.Palavras-Chaves: Células-tronco mesenquimais. Líquido amniótico. Terapia celular. ABSTRACTStem cells are characterized by their undifferentiated state and their high capacity of self renewal through asymmetric divisions. Under the infl uence of certain biological signals they can differentiate into specialized cells phenotypically different from their precursors. They are divided into to their place of origin: embryonic
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