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J Ethnopharmacol ; : 113965, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33639205


ETHNOPHARMACOLOGICAL RELEVANCE: Danggui Buxue Decoction (DBD) as a traditional Chinese medicine (TCM) has been widely used to treat blood deficiency. With the immune regulation and hematopoietic effect, DBD improved the quality of life in non-small-cell lung cancer (NSCLC) patients. We previously reported that DBD sensitized the response of NSCLC to Gemcitabine (Gem); however, the synergism and attenuation mechanism on the combination of Gem and DBD has not yet been elucidated. AIM OF THE STUDY: To investigate the mechanisms of DBD in enhancing the anticancer activity of Gem and alleviating Gem-induced myelosuppression. MATERIALS AND METHODS: A549 nude mice model was established to study the effect on the combination of Gem and DBD. The organ indices, peripheral blood cells and the hematopoiesis-related cytokines were analyzed in Gem-induced myelosuppressive mice. Then we studied the whole process from Gem-induced bone marrow suppression to self-healing, and the mechanism of DBD's attenuation by the experiments of bone marrow nucleated cells (BMNCs). RESULTS: There were an enhanced anticancer effect and an improvement of hematopoietic function by combining of Gem and DBD in A549 nude mice model. DBD regulated Hu antigen R (HuR), deoxycytidine kinase (dCK) and nuclear factor erythroid 2-related factor (Nrf2), increased the expression of thrombopoietin (TPO) and granulocyte-macrophage colony stimulating factor (GM-CSF). For Gem-induced myelosuppressive mice, DBD improved the number of peripheral blood cells and the levels of hematopoiesis-related cytokines. Moreover, DBD was observed to reduce deoxyribonucleic acid (DNA) content at the G1 phase, promoted BMNCs proliferation and up-regulated cycle-related proteins. CONCLUSIONS: The results indicated that DBD not only improved the sensitivity of Gem but also alleviated Gem-induced myelosuppression. This study may provide a pharmacological basis for the combination of DBD and Gem in clinical application.

Artigo em Inglês | MEDLINE | ID: mdl-33360677


Topical tazarotene combined with clindamycin phosphate can significantly improve the adherence and outcomes for the treatment of acne vulgaris than monotherapy, a novel tazarotene (0.05%)/clindamycin phosphate (1.2%) cream is thus developed. However, the pharmacokinetics and potential interaction of tazarotene and clindamycin phosphate in skin when formulated together remain unknown, which should be investigated to assess this novel cream. In the present work, a sensitive and rapid LC-MS/MS method for simultaneous determination of tazarotene, clindamycin phosphate and their active metabolites tazarotenic acid, clindamycin in Bama mini-pig skin was developed and reported for the first time. After pretreatment of the skin samples, the analytes were well separated on a Hypersil BDS C8 column (4.6 × 100 mm, 2.4 µm) using 0.2% (v/v) formic acid-0.1% (w/v) ammonium acetate water solution and acetonitrile as mobile phase in linear gradient elution. Quantification of tazarotene, clindamycin phosphate and their active metabolites tazarotenic acid, clindamycin was conducted under positive electrospray ionization mode using multiple reactions monitoring detection. The LC-MS/MS method was fully validated and then applied to the dermal pharmacokinetic study of the tazarotene/clindamycin phosphate cream. According to the obtained results, tazarotene and clindamycin phosphate did not have any drug-drug interaction when they were formulated together in the cream for topical application. Their absorption and metabolism features in the skin were also characterized, which can support the clinical medication regimen of tazarotene/clindamycin phosphate cream.

J Pharm Biomed Anal ; : 113784, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33280996


Chinese herbal drugs are often combined with chemotherapy drugs for the treatment of cancers. However, the combination administrations often do not have scientifically sound bases established on full preclinical and clinical investigations. A commonly used anti-colon-cancer herb-drug pair, irinotecan (CPT-11) hydrochloride injection and Kang'ai (KA) injection was taken as an example to investigate the possible pharmacokinetic interactions between Chinese herbal drugs and chemotherapy injections to determine the potential adverse drug reactions (ADRs). Rats were randomly divided into three groups and received 20 mg/kg CPT-11 injection 15 min after administration of 4 mL/kg saline for the CPT-11 single administration group and 4 mL/kg KA injection for the separated co-administration group, respectively. In the pre-mixed co-administration group, rats received a mixture of 20 mg/kg CPT-11 injection and 4 mL/kg KA injection. Blood samples were collected at 10 pre-determined time points between 0 and 24 h. The tissue samples were collected at 5 and 8 min after the injections, respectively. A reliable LC-MS/MS method was established for the simultaneous determination of CPT-11 and its metabolites, SN-38, SN-38 G and APC in the rat plasma and tissue samples, after full confirmation of two injections chemical and stability compatibilities. Compared to the C0 (5129 ± 757 ng/mL) and AUC0-t (7858 ± 1307 ng h/mL) of CPT-11 in the CPT-11 single administration group, the C0 (4574 ± 371 ng/mL) and AUC0-t (8779 ± 601 ng h/mL) after the separated co-administration remained unchanged, but the pre-mixed co-administration resulted with a significant increased C0 (29,454 ± 12,080 ng/mL) and AUC0-t (15,539 ± 5165 ng h/mL) (p < 0.05). Since the exposures of CPT-11 in most tissues in the pre-mixed co-administration group were dramatically lower than the separated co-administration group, the increased CPT-11 plasma concentration may be produced by the delayed tissue distribution because of the encapsulation by the components contained in KA injection, such as polysaccharides. Similar differences were also found in its metabolite, SN-38 G. There are obvious herb-drug interactions between CPT-11 injection and KA injection after the pre-mixed co-administration. The resulting excessive CPT-11 in the plasma may lead to many serious ADRs. Therefore, the full evaluation of herb-drug interactions is necessary and inappropriate combinations should be avoided.

J Comp Neurol ; 476(3): 301-11, 2004 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-15269972


Dopaminergic (DA) neurons in the substantia nigra (SN) and ventral tegmental area (VTA) of the midbrain project to the dorsolateral caudate/putamen and to the ventromedially located nucleus accumbens, respectively, establishing the mesostriatal and the mesolimbic pathways. Disruptions in this system have been implicated in Parkinson's disease, drug addiction, schizophrenia, and attention deficit hyperactivity disorder. However, progress in our understanding has been hindered by a lack of knowledge of how these pathways develop. In this study, different retrograde tracers, placed into the dorsolateral caudate/putamen and the nucleus accumbens, were used to analyze the development of the dopaminergic pathways. In embryonic day 15 mouse embryos, both SN and VTA neurons, as well as their fibers, were doubly labeled by striatal injections into the dorsolateral and ventromedial striatum. However, by birth, the SN DA neurons were labeled exclusively by DiA placed in the dorsolateral striatum, and the VTA DA neurons were labeled only by DiI injected into the ventromedial striatum. These data suggest that initial projections from midbrain DA neurons target nonspecifically to both the dorsolateral striatum and the nucleus accumbens. Later during development, the separate mesostriatal and mesolimbic pathways differentiate through the selective elimination of mistargeted collaterals.

Envelhecimento/fisiologia , Neostriado/crescimento & desenvolvimento , Vias Neurais/citologia , Neurônios/citologia , Área Tegmentar Ventral/crescimento & desenvolvimento , Envelhecimento/patologia , Animais , Transporte Axonal , Núcleo Caudado/citologia , Núcleo Caudado/crescimento & desenvolvimento , Núcleo Caudado/metabolismo , Diferenciação Celular , Dopamina/metabolismo , Feminino , Corantes Fluorescentes , Mesencéfalo/anatomia & histologia , Mesencéfalo/crescimento & desenvolvimento , Mesencéfalo/metabolismo , Camundongos , Camundongos Endogâmicos , Neostriado/citologia , Neostriado/metabolismo , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/metabolismo , Neurônios/metabolismo , Gravidez , Putamen/anatomia & histologia , Putamen/crescimento & desenvolvimento , Putamen/metabolismo , Substância Negra/citologia , Substância Negra/crescimento & desenvolvimento , Substância Negra/metabolismo , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/metabolismo
J Neurosci ; 23(34): 10963-70, 2003 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-14645492


The A-class of the erythropoietin-producing hepatocellular carcinoma cell-derived (EphA) tyrosine kinase receptors and their ligands, the A-ephrins, play critical roles in the specification of topographic axon projection maps during development. In this study, the role of the EphA subfamily in callosal projections was investigated using transgenic mice expressing a kinase deletion mutant of EphA5. In approximately half of these transgenic mice, cerebral cortical neurons in various cortical regions (primary and secondary somatosensory cortices and frontal as well as visual areas) failed to project to the contralateral cortex. When commissural axons were examined with DiI labeling, few callosal fibers were found to traverse the midline in both the adult and neonatal transgenic mice. This defect in callosal development correlates with the expression of the transgene, because neurons in the superficial layers of the motor cortex, where transgene expression is low, show normal contralateral projection through the corpus callosum. In addition, multiple EphA receptors are expressed in callosal neurons and ephrin-A5 stimulates neurite outgrowth of callosal neurons in vitro. The midline glia structures important for callosal axon midline crossing appear normal in the transgenic mice, suggesting that the defects are unrelated to defective guidance structures at the midline. These observations suggest critical functions for EphA receptor in establishing callosal connections during brain development.

Agenesia do Corpo Caloso , Malformações do Sistema Nervoso/genética , Receptores da Família Eph/biossíntese , Receptores da Família Eph/genética , Animais , Axônios/patologia , Córtex Cerebral/patologia , Corpo Caloso/patologia , Expressão Gênica , Hibridização In Situ , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Malformações do Sistema Nervoso/patologia , Neuritos/patologia , Neurônios/patologia , RNA Mensageiro/metabolismo , Transgenes