The autologous bone marrow mononuclear cell transplantation by intracoronary route treat patients with severe heart failure after myocardial infarction

Objective To investigate the chronic effects of intracoronary autologous bone marrow mononuclear cell (BM-MNCs) transplantation in patients with refractory heart failure (RIHF) after myocardial infarction. Methods Thirty patients with RIHF (LVEF<40%) were enrolled in this nonrandomized study, autologous BM-MNCs (5.0±0.7)×107 were transplanted with via infarct-related coronary artery in 16 patients and 14 patients received     

Interleukin-27 enhances the production of tumour necrosis factor-α and interferon-γ by bone marrow T lymphocytes in aplastic anaemia

Aplastic anaemia (AA) is considered as an immune-mediated bone marrow failure syndrome. The mechanism is involved with a variety of immune molecules including interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α) and interleukins (ILs). IL-27 is a novel member of the IL-12 family, which mediates T cell response and enhances the production of IFN-γ. However, little is known about the role of IL-27 in the development of AA. This study investigated the role of IL-27 and its receptor IL-27R in the pathogenesis of AA. Both the mRNA expression of IL-27/IL-27R subunits in the bone marrow mononuclear cells (BMMNCs) and the levels of IL-27 in the marrow plasma in AA were found to be higher than in controls. Increased IL-27 correlated with the disease severity of AA. Subsequently, we stimulated marrow T lymphocytes with recombinant human (rh)IL-27 and found that rhIL-27 enhanced the production of TNF-α and IFN-γ in both CD4(+) and CD8(+) T lymphocytes from AA patients. We also detected increased TNF-α and IFN-γ in the supernatants of BMMNCs from AA patients after IL-27 stimulation. In conclusion, our data suggest that elevated IL-27 and IL-27-induced TNF-α and IFN-γ overproduction might be involved in the pathogenesis of AA.     

Expression of interferon-γ and tumor necrosis factor-α in bone marrow T cells and their levels in bone marrow plasma in patients with aplastic anemia

Immune-mediated stem cell damage has been postulated to be responsible for disease initiation and progression in aplastic anemia (AA). It is hypothesized that T lymphocytes play a major role in destroying the bone marrow (BM) stem cells of AA patients by infiltrating the BM and secreting excessive levels of anti-hematopoietic cytokines, interferon-gamma (IFN-), and tumor necrosis factor-alpha (TNF-). We undertook this study to assess the pathogenic significance of anti-hematopoietic cytokines such as IFN- and TNF- in BM T cells and plasma of AA patients. Significantly elevated levels of IFN- and TNF- were found in the BM plasma of AA patients compared to controls (p=0.05 and 0.006, respectively). Intracellular IFN- and not TNF- in BM CD3⁺ T cells of AA patients was significantly higher compared to controls (p=0.04 and p=0.2, respectively). A follow-up analysis of expression of these cytokines in BM T cells and their levels in BM plasma in five AA patients before and 180 days (6 months) after antithymocyte globulin (ATG) and cyclosporin A (CsA) therapy showed a decline 180 days after therapy compared to pre-therapy. We thus conclude that increased production of both IFN- and TNF- in the BM may contribute to disease pathogenesis in AA and ATG therapy may induce hematological remission by suppressing the elevated levels of IFN- and TNF- in AA BM.     

Synergy of inhibition of DNA synthesis in human bone marrow by azidothymidine plus deficiency of folate and/or vitamin B12?

The effect of azidothymidine (Zidovudine, AZT) on pyrimidine (thymidine, deoxyuridine, and thymidine triphosphate) incorporation into DNA in folate- and/or vitamin B12-deficient and normal human bone marrow cells was studied to investigate whether such vitamin deficiency affects susceptibility to AZT-induced hematologic toxicity. Bone marrow cells from 12 patients were studied: 5 had folate and/or vitamin B12 deficiency; 7 controls included 5 with anemia related to chronic disease and 2 with iron deficiency. At 0.2 microM AZT (3 hr, 37 degrees C), the approximate pharmacologic serum trough level, pyrimidine incorporation into DNA was suppressed by 12 to 19% in folate- and/or vitamin B12-deficient cells and by 16 to 23% in normal cells. At 2.0 microM AZT (3 hr, 37 degrees C), the approximate pharmacologic serum peak level, this was suppressed by 15 to 40% in folate- and/or vitamin B12-deficient cells and by 32 to 47% in controls. Deoxyuridine incorporation into DNA was inhibited significantly greater than thymidine at 2.0 microM AZT (3 hr, 37 degrees C) in both groups. Inhibition of deoxyuridine incorporation was not reversed with methyltetrahydrofolate or vitamin B12. There tended to be less striking suppression by AZT of deoxyuridine incorporation into DNA in bone marrow cells from vitamin B12-deficient patients, which was made more striking by adding vitamin B12. This suggests that some of what passes for "AZT damage" to bone marrow cells may in fact be coincident deficiency of vitamin B12. AZT inhibition of DNA synthesis in 3 hr bone marrow cultures is relatively consistent in a variety of hematologic disorders. As approximately two-thirds of AIDS patients appear to be in negative balance with respect to folate and/or vitamin B12, the fact that AZT-induced inhibition of pyrimidine incorporation into DNA is occurring in cells which may be megaloblastic, i.e., in a state of impaired DNA synthesis, suggests that these cells may be more susceptible to AZT toxicity. The data also support the notion that AZT inhibition results predominantly from termination of DNA chain elongation. Whether folate or vitamin B12 supplementation may partially overcome apparent "AZT inhibition" of DNA synthesis (hematologic toxicity) and whether the benefit of such therapy exceeds the risk will require further study.     

Interferon-γ mediates the immunosuppression of bone marrow mesenchymal stem cells on T-lymphocytes in vitro

Objectives: In the present study, we first confirmed the suppressive function of MSCs in allogeneic T cell proliferation and then examined the underlying mechanisms for MSCs’ immunomodulation and the role of the pro-in?ammatory cytokine interferon (IFN)-γ.

Methods: Human MSCs were cultured in the presence or absence of IFN-γ. The expression level of prostaglandin E₂ (PGE₂), hepatocyte growth factor (HGF), transforming growth factor (TGF)-β₁ and indoleamine 2,3-dioxygenase (IDO) by MSCs were measured. T lymphocytes were isolated from peripheral blood of healthy donors and then induced to proliferate under the stimulation of anti-human CD3 mAb and anti-human CD28 mAb. In the presence of MSCs, T cell proliferation was examined by BrdU incorporation. In addition, PGE₂, HGF, TGF-β₁, Kynurenine, recombinant human IFN-γ and anti-IFN-γ mAb were added and cell proliferation was examined.

Results: Compared to the controls (MSCs alone), MSCs cocultured with IFN-γ expressed significantly higher concentrations of PGE₂, HGF and TGF-β₁. The mRNA level of IDO was remarkably increased. Human bone marrow-derived MSCs alone notably suppressed T lymphocytes proliferation in vitro. Addition of exogenous IFN-γ did not ablate the immunosuppressive effects of MSCs. Addition of anti-IFN-γ mAb partially restored suppression of T cell proliferation by MSCs.

Conclusions: Human MSCs constitutively expressed immunosuppressive levels of PGE₂, HGF and TGF-β₁. The proinflammatory cytokine IFN-γ exhibited synergistic effects with MSCs on immunosuppression, possibly by up-regulating PGE₂, HGF and TGF-β₁ in MSCs and inducting MSCs expression of IDO, involved in tryptophan catabolism.     

Identification of Flt3⁺CD150⁻ myeloid progenitors in adult mouse bone marrow that harbor T lymphoid developmental potential

Common myeloid progenitors (CMPs) were first identified as progenitors that were restricted to myeloid and erythroid lineages. However, it was recently demonstrated that expression of both lymphoid- and myeloid-related genes could be detected in myeloid progenitors. Furthermore, these progenitors were able to give rise to T and B lymphocytes, in addition to myeloid cells. Yet, it was not known whether these progenitors were multipotent at the clonogenic level or there existed heterogeneity within these progenitors with different lineage potential. Here we report that previously defined CMPs possess T-lineage potential, and that this is exclusively found in the Flt3(+)CD150(-) subset of CMPs at the clonal level. In contrast, we did not detect B-lineage potential in CMP subsets. Therefore, these Flt3(+)CD150(-) myeloid progenitors were T/myeloid potent. Yet, Flt3(+)CD150(-) myeloid progenitors are not likely to efficiently traffic to the thymus and contribute to thymopoiesis under normal conditions because of the lack of CCR7 and CCR9 expression. Interestingly, both Flt3(+)CD150(-) and Flt3(-)CD150(-) myeloid progenitors are susceptible to Notch1-mediated T-cell acute lymphoblastic leukemia (T-ALL). Hence, gain-of-function Notch1 mutations occurring in developing myeloid progenitors, in addition to known T-lineage progenitors, could lead to T-ALL oncogenesis.     

Melatonin attenuates kainic acid-induced neurotoxicity in mouse hippocampus via inhibition of autophagy and α-synuclein aggregation

In this study, the protective effect of melatonin on kainic acid (KA)-induced neurotoxicity involving autophagy and α-synuclein aggregation was investigated in the hippocampus of C57/BL6 mice. Our data showed that intraperitoneal injection of KA (20 mg/kg) increased LC3-II levels (a hallmark protein of autophagy) and reduced mitochondrial DNA content and cytochrome c oxidase levels (a protein marker of mitochondria). Atg7 siRNA transfection prevented KA-induced LC3-II elevations and mitochondria loss. Furthermore, Atg7 siRNA attenuated KA-induced activation of caspases 3/12 (biomarkers of apoptosis) and hippocampal neuronal loss, suggesting a pro-apoptotic role of autophagy in the KA-induced neurotoxicity. Nevertheless, KA-induced α-synuclein aggregation was not affected in the Atg7 siRNA-transfected hippocampus. The neuroprotective effect of melatonin (50 mg/kg) orally administered 1 hr prior to KA injection was studied. Melatonin was found to inhibit KA-induced autophagy-lysosomal activation by reducing KA-induced increases in LC3-II, lysosomal-associated membrane protein 2 (a biomarker of lysosomes) and cathepsin B (a lysosomal cysteine protease). Subsequently, KA-induced mitochondria loss was prevented in the melatonin-treated mice. At the same time, melatonin reduced KA-increased HO-1 levels and α-synuclein aggregation. Our immunoprecipitation study showed that melatonin enhanced ubiquitination of α-synuclein monomers and aggregates. The anti-apoptotic effect of melatonin was demonstrated by attenuating KA-induced DNA fragmentation, activation of caspases 3/12, and neuronal loss. Taken together, our study suggests that KA-induced neurotoxicity may be mediated by autophagy and α-synuclein aggregation. Moreover, melatonin may exert its neuroprotection via inhibiting KA-induced autophagy and a subsequent mitochondrial loss as well as reducing α-synuclein aggregation by enhancing α-synuclein ubiquitination in the CNS.     

Impact of β2 integrin deficiency on mouse natural killer cell development and function

Natural killer (NK) cells are innate immune cells that express members of the leukocyte β2 integrin family in humans and mice. These CD11/CD18 heterodimers play critical roles in leukocyte trafficking, immune synapse formation, and costimulation. The cell-surface expression of one of these integrins, CD11b/CD18, is also recognized as a major marker of mouse NK-cell maturation, but its function on NK cells has been largely ignored. Using N-ethyl-N-nitrosourea (ENU) mutagenesis, we generated a mouse carrying an A → T transverse mutation in the Itgb2 gene, resulting in a mutation that prevented the cell-surface expression of CD18 and its associated CD11a, CD11b, and CD11c proteins. We show that β2 integrin-deficient NK cells have a hyporesponsive phenotype in vitro, and present an alteration of their in vivo developmental program characterized by a selective accumulation of c-kit(+) cells. NK-cell missing-self recognition was partially altered in vivo, whereas the early immune response to mouse cytomegalovirus (MCMV) infection occurred normally in CD18-deficient mice. Therefore, β2 integrins are required for optimal NK-cell maturation, but this deficiency is partial and can be bypassed during MCMV infection, highlighting the robustness of antiviral protective responses.     

Combined treatment with TRAIL and PPARγ ligands overcomes chemoresistance of ovarian cancer cell lines

Purpose  

Ovarian cancer accounts for the highest mortality among all gynecological cancers, mainly due to the fast developing chemoresistance. The death ligand TRAIL induces apoptosis and is able to sensitize tumor cells to cytostatic drugs without affecting physiological tissue. Combined treatment of TRAIL and the antidiabetic acting PPARγ ligands was shown to induce apoptosis synergistically in different ovarian cancer cell lines.     

Durable remission of Sézary syndrome after unrelated bone marrow transplantation by reduced-intensity conditioning

A 22-year-old Japanese man was diagnosed with Sézary syndrome with large cell transformation. His skin lesions persisted after treatment with 7 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), psoralen and ultraviolet light A, and total skin electron beam irradiation. He subsequently underwent allogeneic bone marrow transplantation by reduced-intensity conditioning from a human leukocyte antigen-identical unrelated donor. He developed grade II of acute graft-versus-host disease and extensive-type chronic graft-versus-host disease. He has no signs of disease 36 months after the transplantation. The prognosis of patients with advanced stage of mycosis fungoides or Sézary syndrome is very poor. Allogeneic hematopoietic stem cell transplantation, especially by reduced-intensity conditioning, is expected to become a curative treatment option, and graft-versus-tumor effect might play a critical role for sustained remission.     

TRIM11 promotes cell proliferation of non‐small cell lung cancer through the inhibition of ferroptosis by AMPK

Lung cancer is one of the leading causes of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent type. This study investigates the role of TRIM11 gene in NSCLC and its underlying mechanism. NSCLC patients were recruited from our hospital and showed upregulated TRIM11 mRNA and protein expressions. Patients with high TRIM11 expression had lower survival rates. TRIM11 gene was found to promote cell proliferation and reduce ROS-induced ferroptosis in NSCLC. Additionally, TRIM11 gene induced AMPK expression and its regulation affected TRIM11's effects on cell proliferation and ferroptosis in NSCLC. IP analysis revealed that TRIM11 protein interacted with AMPK protein in NSCLC. These data confirmed that TRIM11 promotes cell proliferation and reduces ROS-induced ferroptosis in NSCLC through AMPK. Hence, TRIM11 is a potential target for the treatment of NSCLC and other cancers.