While Strychnos nux-vomica L. has long been used for the treatment of cancer, its pharmacological mechanism remains vague. Herein, we have used network pharmacology to predict active ingredients and potential targets of Strychnos nux-vomica L. in treating multiple myeloma. The results showed that 60 known targets of the Strychnos nux-vomica L. were also targets for multiple myeloma, including 14 of these putative targets were observed to be major hubs in terms of topological importance. Additionally, the results of pathway enrichment analysis indicated that targets of Strychnos nux-vomica L. in treating multiple myeloma were mainly clustered into multiple biological processes that activate several signaling pathways that include the PI3K-Akt, p38-MAPK, Ras/Raf, MEK, and ERK pathways. This implies that these were also involved in the underlying mechanisms of Strychnos nux-vomica L. on multiple myeloma. These data successfully explain the potential effects of Strychnos nux-vomica L. for multiple myeloma treatment via the molecular mechanisms predicted by network pharmacology. Moreover, our present data might shed light on the further clinical application of Strychnos nux-vomica L. in treating multiple myeloma.
The transcriptional repressor Gfi1 regulates the expression of genes important for survival, proliferation and differentiation of hematopoietic cells. Gfi1 deficient mice are severely neutropenic and accumulate ill-defined CD11b(+)GR1(int) myeloid cells. Here we show that Gfi1 expression levels determine mono- or granulocytic lineage choice in precursor cells. In addition, we identify CD48 as a cell surface marker which enables a better definition of monocytes and granulocytes in mouse bone marrow. Using the CD48/Gr1/Gfi1 marker combination we can show that the CD11b(+)GR1(int) cells accumulating in Gfi1 deficient mice are monocytes and not granulocyte precursors. Expression of CD48, Gr1 and Gfi1 define different bone marrow subpopulations that are either committed to the granulocytic lineage, or bipotential precursors of granulocytes or monocytes. Finally, a comparison of genes differentially expressed between murine Gfi1 high granulocytic precursors and mature granulocytes with gene expression changes from human myeloblasts versus neutrophils show a strong resemblance of human and mouse differentiation pathways. This underlines the value of the markers CD48 and Gfi1 identified here to study human and murine granulo-monocytic differentiation.
The antitumor enzyme L‑asparaginase (L‑Asp) has commonly been used for the treatment of acute lymphoblastic leukemia. However, the effects of L‑Asp on acute myeloid leukemia (AML) and their underlying mechanisms have not been fully elucidated. In the present study, the effects of L‑Asp on cell proliferation and apoptosis were investigated using the AML cell lines U937, HL‑60 and KG‑1a. The effects of combining L‑Asp with mitoxantrone (MIT) and cytarabine (Ara‑c) were also analyzed. The combination of MIT and Ara‑C is known as MA therapy, and is a widely used therapeutic regimen for the treatment of elderly patients with refractory AML. When applied alone, L‑Asp inhibited cell proliferation and induced apoptosis in each of the cell lines tested. Furthermore, the combined use of L‑Asp with MA therapy further potentiated the inhibition of cell proliferation while increasing the induction of apoptosis. These findings provide evidence for the potential antitumor effect of L‑Asp in AML, and indicate that improved efficacy maybe achieved by combining L‑Asp with MIT and Ara‑c. This combination may provide a promising new therapeutic strategy for the treatment of AML.
Mitochondrial dysfunction has been linked to many diseases including organ degeneration and cancer. Mesenchymal stem cells/stromal cells (MSCs) provide a valuable source for stem cell-based therapy and represent an emerging therapeutic approach for tissue regeneration. Increasing evidence suggests that MSCs can directly donate mitochondria to recover from cell injury and rescue mitochondrial damage-provoked tissue degeneration. Meanwhile, cancer cells and cancer stromal cells also cross-talk through mitochondrial exchange to regulate cancer metastasis. This review summarizes the research on MSCs and their mitochondrial transfer. It provides an overview of the biology, function, niches and signaling that play a role in tissue repair. It also highlights the pathologies of cancer growth and metastasis linked to mitochondrial exchange between cancer cells and surrounding stromal cells. It becomes evident that the function of MSC mitochondrial transfer is a double-edged sword. MSC mitochondrial transfer may be a pharmaceutical target for tissue repair and cancer therapy.
We investigated the antitumor effect and mechanism of hematoporphyrin monomethyl ether-mediated photodynamic therapy (HMME-PDT) in sarcomas. Intracellular uptake of HMME by osteosarcoma cells (LM8 and K7) was time- and dose-dependent, while this was not observed for myoblast cells (C2C12) and fibroblast cells (NIH/3T3). HMME-PDT markedly inhibited the proliferation of sarcoma cell lines (LM8, MG63, Saos-2, SW1353, TC71, and RD) (P<0.05), and the killing effect was improved with increased HMME concentration and energy intensity. Flow cytometry analysis revealed that LM8, MG63, and Saos-2 cells underwent apoptosis after treatment with HMME-PDT. Additionally, apoptosis was induced after HMME-PDT in a three-dimensional culture of osteosarcoma cells. Hoechst 33342 staining confirmed apoptosis. Cell death caused by PDT was rescued by an irreversible inhibitor (Z-VAD-FMK) of caspase. However, cell viability was not markedly decreased compared with the HMME-PDT group. Expression levels of caspase-1, caspase-3, caspase-6, caspase-9, and poly (ADP-ribose) polymerase (PARP) proteins were markedly up-regulated in the treatment groups and increased with HMME concentration as determined by western blot analysis. In vivo, tumor volume markedly decreased at 7-16 days post-PDT. Hematoxylin and eosin staining revealed widespread necrotic and infiltrative inflammatory cells in the HMME-PDT group. Immunohistochemistry analysis also showed that caspase-1, caspase-3, caspase-6, caspase-9, and PARP proteins were significantly increased in the HMME-PDT group. These results indicate that HMME-PDT has a potent killing effect on osteosarcoma cells in vitro and significantly inhibits tumor growth in vivo, which is associated with the caspase-dependent pathway.
This study will provide evidence-based medical evidence in the application of infliximab for pediatric rheumatology.
Methods
The 45 cases of this study were allocated to treatment group and control group. The treatment group was divided into JIA and JAS subgroup. the disease of them were all in active stage.If the patients took methotrexate (MTX) before enrolling group, the dose must be stabile in 10-15mg/m2 per week for at least 3 months. A small dose of non-steroidal anti-inflammatory drugs (NSAID) was allowed. The test group received MTX combined with infliximab intravenous infusion (JIA group: 3 mg kg–1; JAS group: 5 mg kg–1); the control group received MTX combined an equal volume of placebo intravenous infusion. The cases of JIA group were injected at 0 weeks, 2 weeks, 6 weeks, 14 weeks, 22 weeks, 30 weeks, and the JAS group were injected at 0 weeks, 2 weeks, 6 weeks, 12 weeks, 18 weeks, 24 weeks. Observe the efficacy at each time point and evaluate whether there were significant differences between treatment and control groups so as to judge whether infliximab could reduce disease activity more effectively and durably.
Results
The treatment groups included 12 JIA cases and 7 JAS cases while the control group included 18 JIA cases and 8 JAS cases. A total number of 45 cases achieved the injection. The ACR30 improvement rate of JIA treatment group after two weeks was 66.7%, while the control group was 27.7% (P=0.035). The ACR30 and ACR50 improvement rate of JIA treatment group after 30 weeks were 91.7% and 75%; while the control group was 61.1% (P=0.099) and 22.2% (P=0.004). The ASAS 20 response rate of JAS treatment group after two weeks was 85.7%, which was far higher than 25%, the rate of the control group (P=0.04). The ASAS 20 response rate in the treatment group at the endpoint was 100%, while the rate of control group was 37.5% (P=0.07). The recorded adverse reaction in the process of drug use was visible. 3 children merged with respiratory tract infection. An old JIA children merged with chest distress and polypnea 5 minutes later after the second time intravenous infliximab and the symptoms were disappeared after drug withdrawal. One JIA case of penicillin anaphylaxis appeared with systemic wheal -like rash during the 4th injection, and the rash subsided one hour later with the oral phenergan treatment. Tuberculosis, severe infections and tumors were not found in the Short-term observation.
Conclusions
This study shows that MTX combined with infliximab can quickly alleviate joint pain and reduce inflammatory markers compared with single MTX in the treatment of juvenile idiopathic arthritis and juvenile ankylosing spondylitis. The significant difference is more obvious in juvenile ankylosing spondylitis treatment. This study also provides data to support the point that the use of infliximab in children is of good safety. The allergy incidence is even lower than the same type of adult reports. The statistically significant differences did not appear in part of the control study considering that it needed a larger sample to support. The long-term efficacy and safety of infliximab require a large sample and long-term follow-up study.
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