RESUMEN
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.
RESUMEN
Iron overload (IO) caused by frequent blood transfusion in hematological diseases has become a major concern. In this study, up-regulation of heme oxygenase-1 (HO-1), a protector against oxidative stress, was observed in bone marrow mesenchymal stem cells (BMMSCs) at the early stage of IO and had favorable prognosis in an IO mouse model. Given that the protective role of HO-1 in IO damage of BMMSCs was still unknown, the mechanism was explored in vitro and in vivo. BMMSCs were transfected with HO-1/siHO-1 in vitro, and the mouse model was established to further evaluate the effect of HO-1 on IO in vivo. As a result, HO-1 decreased the apoptotic rate of BMMSCs with IO through reducing intracellular reactive oxygen species (ROS) but increasing IL-10 secretion. In addition, IL-10 was mediated by HO-1 via the ERK pathway. Intracellular iron was down-regulated by hepcidin depending on IL-10. In conclusion, HO-1 protects BMMSCs from ROS by secreting IL-10 upon iron overload.
Asunto(s)
Células de la Médula Ósea/efectos de los fármacos , Hemo-Oxigenasa 1/fisiología , Interleucina-10/metabolismo , Sobrecarga de Hierro , Hierro/toxicidad , Proteínas de la Membrana/fisiología , Células Madre Mesenquimatosas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Animales , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Citoprotección/efectos de los fármacos , Citoprotección/genética , Células HEK293 , Hemo-Oxigenasa 1/genética , Humanos , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/prevención & control , Masculino , Proteínas de la Membrana/genética , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Transfección , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: The incidence of superior vena cava syndrome has been increasing in hemodialysis patients with the widespread use of dialysis catheters. Although endovascular intervention remains the primary choice for treatment, the long-term patency rate is not optimistic. Occlusive lesions are often encountered that cannot be opened using this intervention. Therefore, we chose to present this case involving a pericardial patch used to reconstruct the superior vena cava in the treatment of catheter-associated chronic superior vena cava occlusion. METHODS: Here, we report a case of facial swelling and severe bilateral pleural effusion secondary to superior vena cava occlusion in a 41-year-old woman. An endovascular venous intervention was attempted initially but failed. Finally, we adopted a procedure using the pericardium as a patch to reconstruct the superior vena cava, maintaining most of the original anatomical structure. RESULTS: This patient's facial swelling and bilateral pleural effusion disappeared after the operation. In addition, her symptoms of coughing and dyspnea were relieved. The Brescia-Cimino fistula in her left forearm functioned well. CONCLUSION: The use of a pericardial patch to reconstruct the superior vena cava is a reliable approach in patients who are not candidates for endovascular treatment.