ABSTRACT
Osteoclasts (OCs) play an essential role in bone destruction in patients with multiple myeloma (MM). Bortezomib can ameliorate bone destruction in patients with MM, but advanced MM often resists bortezomib. We studied the molecular mechanisms of bortezomib tolerance in MM. The expression of the MM-related genes in newly diagnosed patients with MM and normal donors were studied. C-C motif chemokine ligand 3 (CCL3) is a cytokine involved in the differentiation of OCs, and its expression is closely related to APRIL (a proliferation-inducing ligand). We found that bortezomib treatment inhibited APRIL and CCL3. But the heme oxygenase-1 (HO-1) activator hemin attenuated the inhibitory effects of bortezomib on APRIL and CCL3. We induced mononuclear cells to differentiate into OCs, and the enzyme-linked immunosorbent assay showed that the more OCs differentiated, the higher the levels CCL3 secretions detected. Animal experiments showed that hemin promoted MM cell infiltration in mice. The weight and survival rate of tumor mice were associated with HO-1 expression. Immunohistochemical staining showed that HO-1, APRIL, and CCL3 staining were positively stained in the tumor infiltrating sites. Then, MM cells were transfected with L-HO-1/si-HO-1 expression vectors and cultured with an nuclear factor (NF)-kappa B (κB) pathway inhibitor, QNZ. The results showed that HO-1 was the upstream gene of APRIL, NF-κB, and CCL3. We showed that HO-1 could attenuate the inhibitory effect of bortezomib against the APRIL-NF-κB-CCL3 signaling pathways in MM cells, and the tolerance of MM cells to bortezomib and the promotion of bone destruction are related to HO-1.
ABSTRACT
Dimeric cyclophosphazanes [{P(µ-NR)}2(µ-NR)]2 [R = (t)Bu ( 1) and iPr ( 3)] were oxidized with elemental selenium. During these reactions an unexpected CN bond cleavage and NH bond formation occurred. Compound 1 produced P4(µ-N(t)Bu)3(µ-NH)3Se4 ( 2) where three tBu groups were lost in the form of isobutylene. In contrast, during the oxidation of the less sterically hindered 3, the resulting product, P4(µ-N(i)Pr)5(µ-NH)Se4 ( 4), showed only one substituent loss. Theoretical studies confirmed the steric nature of the driving force underlying the different outcomes.
ABSTRACT
Two important neurotransmitters, serotonin (5-hydroxytryptamine, 5-HT) and neuropeptide Y (NPY), have been confirmed to be involved in food intake regulation. To clarify whether the cerebellum participates in modulation of food intake through these two neurotransmitters, we investigated the distribution and expression levels of 5-HT and NPY in cerebellum of the duck. Our results showed that 5-HT and NPY were distributed only at the Purkinje cell layer of the duck cerebellum. Moreover, the expression level of 5-HT in fasted (4 h) and tryptophan (100-200 mg/kg)-treated ducks was significantly higher than that in control animals (P<0.01), whereas the expression of NPY was significantly decreased (P<0.01). Therefore, our results indicated that inhibitory regulation of food intake respectively increased and decreased cerebellar 5-HT and NPY in the duck.
