RESUMEN
Paclitaxel, a microtubule-stabilizing chemotherapy drug, can cause severe paclitaxel-induced peripheral neuropathic pain (PIPNP). The roles of transient receptor potential (TRP) ion channel vanilloid 1 (TRPV1, a nociceptor and heat sensor) and melastatin 8 (TRPM8, a cold sensor) in PIPNP remain controversial. In this study, Western blotting, immunofluorescence staining, and calcium imaging revealed that the expression and functional activity of TRPV1 were upregulated in rat dorsal root ganglion (DRG) neurons in PIPNP. Behavioral assessments using the von Frey and brush tests demonstrated that mechanical hyperalgesia in PIPNP was significantly inhibited by intraperitoneal or intrathecal administration of the TRPV1 antagonist capsazepine, indicating that TRPV1 played a key role in PIPNP. Conversely, the expression of TRPM8 protein decreased and its channel activity was reduced in DRG neurons. Furthermore, activation of TRPM8 via topical application of menthol or intrathecal injection of WS-12 attenuated the mechanical pain. Mechanistically, the TRPV1 activity triggered by capsaicin (a TRPV1 agonist) was reduced after menthol application in cultured DRG neurons, especially in the paclitaxel-treated group. These findings showed that upregulation of TRPV1 and inhibition of TRPM8 are involved in the generation of PIPNP, and they suggested that inhibition of TRPV1 function in DRG neurons via activation of TRPM8 might underlie the analgesic effects of menthol.
Asunto(s)
Ganglios Espinales , Neuralgia , Paclitaxel , Ratas Sprague-Dawley , Canales Catiónicos TRPM , Canales Catiónicos TRPV , Animales , Paclitaxel/efectos adversos , Paclitaxel/farmacología , Canales Catiónicos TRPM/metabolismo , Canales Catiónicos TRPV/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Ratas , Neuralgia/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/inducido químicamente , Masculino , Hiperalgesia/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Capsaicina/farmacología , Capsaicina/análogos & derivados , Neuronas/metabolismo , Neuronas/efectos de los fármacosRESUMEN
Tumor metastasis is a key factor affecting the life of patients with malignant tumors. For the past hundred years, scientists have focused on how to kill cancer cells and inhibit their metastasis in vivo, but few breakthroughs have been made. Here we hypothesized a novel mode for cancer metastasis. We show that the phagocytosis of apoptotic tumor cells by macrophages leads to their polarization into the M2 phenotype, and that the expression of stem cell related as well as drug resistance related genes was induced. Therefore, it appears that M2 macrophages have "defected" and have been transformed into the initial "metastatic cancer cells", and thus are the source, at least in part, of the distal tissue tumor metastasis. This assumption is supported by the presence of fused cells with characteristics of both macrophage and tumor cell observed in the peripheral blood and ascites of patients with ovarian cancer. By eliminating the expression of CD206 in M2 macrophages using siRNA, we show that the growth and metastasis of tumors was suppressed using both in vitro cell line and with experimental in vivo mouse models. In summary, we show that M2 macrophages in the blood circulation underwent a "change of loyalty" to become "cancer cells" that transformed into distal tissue metastasis, which could be suppressed by the knockdown of CD206 expression.
RESUMEN
Two new difluoroboron ß-carbonyl cyclic ketonate complexes C2B and DC2B were investigated using several spectroscopic methods. Relative to the absorption spectra, the fluorescence spectra were more affected by the polarity of the solvent. Also, compound C2B showed a more pronounced Stokes' shift after solvent polarity increased. Transient absorption measurements then demonstrated the relaxation behaviour of the excited state compound molecule. The kinetic results showed that the excited state C2B in tetrahydrofuran (THF) can return from the intramolecular charge-transfer (ICT) state and the initial excited state to the ground state. The kinetic relaxation pathway after THF was replaced by dimethyl sulfoxide became single. When the carbazole unit was introduced, DC2B also exhibited an ICT state but there was no significant difference in the excited state relaxation path after solvent polarity was changed. The results indicated that C2B is more susceptible to solvent polarity regulation. The global fit results revealed that an increase in the solvent polarity prolonged the lifetime of the ICT state of compound C2B and had the opposite effect on compound DC2B. These results provide guidance for understanding the relationship between solvent polarity and the designing and synthesizing advanced compound materials.
Asunto(s)
Compuestos de Boro/química , Carbazoles/química , Furanos/química , Cetonas/química , Compuestos de Boro/síntesis química , Cetonas/síntesis química , Fenómenos Ópticos , Solventes/química , Espectrometría de FluorescenciaRESUMEN
We had reported that neural stem cells from human fetal striatum (hsNSCs) expressed neural stem cell markers, and were capable of differentiation into neurons, astrocytes, and oligodendrocytes in vitro. To examine multipotency of hsNSCs, some experiments of transgerm layer differentiation in vitro were carried out. Our data indicated that hsNSCs could also generate osteocytes, adipocytes, and hepatocyte-like cells in vitro. Meanwhile, we injected hsNSCs into murine blastocysts at embryonic day 3.5 of gestation. Microinjection of hsNSCs led to the generation of chimeric embryos. Embryos at embryonic day 3.5 of gestation were shown to contribute to the hsNSC-derived cells by PCR-southern blot of 17alphamod, a special method to discover human cells from animals. Analysis of the donor distribution in different tissues showed that donor-derived cells seeded to various tissues. The cellular nature of the human donor cells in chimeric tissues is, however, currently unknown, and further work will be done to identify what differentiated phenotypes have developed from the human cells.