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•Plasmalogens (Pls) can inhibit NO production in microglial cells.•Pls inhibit NF-kB, p38MAPK and JNK pathways.•PUFA-Pls is more effective than oleic acid (monounsaturated fatty ...acid)-Pls.
The special lipids plasmalogens (Pls) were reported to be reduced in the neurodegenerative brains such as Alzheimer’s disease where a marked increase of glial activation is often observed. We previously found that a reduction of brain Pls can enhance the glial activation in murine brains. However, the detailed role of Pls in the prevention of glial activation was mostly elusive. Here we report that the Pls, extracted from scallop (sPls), significantly inhibited the inducible form of nitric oxide synthase (NOS2) and the production of NO in LPS (lipopolysaccharide)-activated microglial cells. We also observed that the polyunsaturated docosahexaenoic acid (DHA)-containing Pls but not the monounsaturated oleic acid-containing Pls attenuated the NOS2 induction. In addition, sPls blocked the activation of nuclear factor (NF)-kB and mitogen-activated protein kinases (MAPKs) e.g., JNK and p38 MAPK, thereby attenuated the nuclear translocation of NF-kB subunit, p65, and activator protein-1 (AP-1) proteins (c-Fos and c-Jun). Interestingly, LPS treatments suppressed the expression of Pls synthesizing enzymes, glycerone phosphate O-acyltransferase (GNPAT) and alkylglycerone phosphate synthase (AGPS) in the microglial cells by the p38MAPK and JNK pathways. Furthermore, the knockdown of GNPAT and AGPS genes by sh-RNAs accelerated the LPS-induced activation of p38MAPK and JNK, resulting in the increased production of NO. These findings suggested that a decrease of brain Pls can activate the NF-kB, p38MAPK and JNK pathways to induce a prolonged microglial activation which may downplay the neuroprotective events in the brains of neurodegenerative diseases.
Prospective isolation of hematopoietic stem and progenitor cells has identified the lineal relationships among all blood-cell types and has allowed their developmental mechanisms to be assayed at the ...single-cell level. These isolated cell populations are used to elucidate the molecular mechanism of lineage fate decision and of its plasticity directly by stage-specific enforcement or repression of lineage-instructive signaling in purified cells. With an emphasis on the myeloid lineage, this review summarizes current concepts and controversies regarding adult murine hematopoietic development and discusses the potential mechanisms, operated by single or by multiple transcription factors, of myeloid lineage fate decision.
A novel anti-cytomegalovirus (CMV) agent, letermovir (LMV), could reportedly improve the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) recipients because of its high potential ...to prevent CMV reactivation. Therefore, 685 Japanese allo-HCT recipients, of whom ~80% had a high risk of CMV reactivation, were retrospectively analyzed to assess the impacts of prophylactic LMV on the incidence of clinically significant CMV (csCMV) infection as well as their transplant outcome. By comparing 114 patients who received LMV prophylaxis for a median 92 days to 571 patients without prophylaxis, we observed that prophylactic LMV could significantly (1) reduce the 180-day cumulative incidence of csCMV infection (44.7 vs. 72.4%, p < 0.001), (2) delay the median time until initiation of CMV antigenemia-guided preemptive therapy (90 vs. 36 days, p < 0.001), (3) shorten the duration of anti-CMV preemptive treatment (21 vs. 25 days, p = 0.006), and (4) improve the overall survival rate at 180 days after transplant (80.4 vs. 73.0%, p = 0.033) with a trend of lower non-relapse mortality (8.9 vs. 14.9%, p = 0.052). Our findings demonstrate that prophylactic LMV treatment is highly effective in preventing the development of csCMV infection and ultimately reduces transplant-related mortality.
Mycobacteria possess various immunomodulatory molecules on the cell wall. Mannose-capped lipoarabinomannan (Man-LAM), a major lipoglycan of Mycobacterium tuberculosis, has long been known to have ...both inhibitory and stimulatory effects on host immunity. However, the direct Man-LAM receptor that explains its pleiotropic activities has not been clearly identified. Here, we report that a C-type lectin receptor Dectin-2 (gene symbol Clec4n) is a direct receptor for Man-LAM. Man-LAM activated bone-marrow-derived dendritic cells (BMDCs) to produce pro- and anti-inflammatory cytokines, whereas it was completely abrogated in Clec4n–/– BMDCs. Man-LAM promoted antigen-specific T cell responses through Dectin-2 on DCs. Furthermore, Man-LAM induced experimental autoimmune encephalitis (EAE) as an adjuvant in mice, whereas Clec4n–/– mice were resistant. Upon mycobacterial infection, Clec4n–/– mice showed augmented lung pathology. These results demonstrate that Dectin-2 contributes to host immunity against mycobacterial infection through the recognition of Man-LAM.
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•Dectin-2 recognizes mycobacterial Man-LAM•Man-LAM induces both pro- and anti-inflammatory cytokine production through Dectin-2•IL-10 production during mycobacterial infection is abrogated in Clec4n−/− DCs•Man-LAM induces EAE as an adjuvant through Dectin-2-FcRγ signaling axis
Mycobacterial lipoarabinomannan is a well-known immunomodulatory component. Yamasaki and colleagues demonstrate that Dectin-2 is a direct receptor for this lipoglycan.
Microtubule targeting agents (MTAs) such as taxanes are broadly used for the treatment of patients with cancer. Although MTAs are not effective for treatment of colorectal cancer (CRC), preclinical ...studies suggest that a subset of patients with CRC, especially those with cancers harboring the BRAF mutation, could benefit from such agents. However, two MTAs, eribulin (Eri) and vinorelbine, have shown limited clinical efficacy. Here, we report that insulin‐like growth factor 1 receptor (IGF‐1R) signaling is involved in Eri resistance. Using CRC cell lines, we showed that Eri induces activation and subsequent translocation of IGF‐1R to the nucleus. When the activation and/or nuclear translocation of IGF‐1R was inhibited, Eri induced DNA damage and enhanced G2/M arrest. In a xenograft model using the Eri‐resistant SW480 cell line, the combination of Eri and the IGF‐1R inhibitor linsitinib suppressed tumor growth more efficiently than either single agent. Thus, our results indicated that combination dosing with Eri and an IGF‐1R inhibitor could overcome Eri resistance and offer a therapeutic opportunity in CRC.
Nuclear translocation of IGF‐1R in SW480 following exposure to eribulin revealed by immunofluorescent staining. Nuclear translocation of IGF‐1R was not observed when exposed to the combination of eribulin and IGF‐1R inhibitor.
Cellular differentiation is regulated through activation and repression of defined transcription factors. A hallmark of differentiation is a pronounced change in cell shape, which is determined by ...dynamics of the actin cytoskeleton. Here we show that regulation of the transcriptional coactivator MKL1 (megakaryoblastic leukemia 1) by actin cytoskeleton dynamics drives adipocyte differentiation mediated by peroxisome proliferator-activated receptor γ (PPARγ), a master transcriptional regulator of adipogenesis. Induction of adipocyte differentiation results in disruption of actin stress fibres through downregulation of RhoA-ROCK signalling. The consequent rapid increase in monomeric G-actin leads to the interaction of G-actin with MKL1, which prevents nuclear translocation of MKL1 and allows expression of PPARγ followed by adipogenic differentiation. Moreover, we found that MKL1 and PPARγ act in a mutually antagonistic manner in the adipocytic differentiation programme. Our findings thus provide new mechanistic insight into the relation between the dynamics of cell shape and transcriptional regulation during cellular differentiation.
Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. Here we identified T cell immunoglobulin mucin-3 (TIM-3) as a surface ...molecule expressed on LSCs in most types of AML except for acute promyelocytic leukemia, but not on normal hematopoietic stem cells (HSCs). TIM-3
+ but not TIM-3
− AML cells reconstituted human AML in immunodeficient mice, suggesting that the TIM-3
+ population contains most, if not all, of functional LSCs. We established an anti-human TIM-3 mouse IgG2a antibody having complement-dependent and antibody-dependent cellular cytotoxic activities. This antibody did not harm reconstitution of normal human HSCs, but blocked engraftment of AML after xenotransplantation. Furthermore, when it is administered into mice grafted with human AML, this treatment dramatically diminished their leukemic burden and eliminated LSCs capable of reconstituting human AML in secondary recipients. These data suggest that TIM-3 is one of the promising targets to eradicate AML LSCs.
► TIM-3 is highly expressed in stem cells in AML of most FAB types except for M3 ► TIM-3 is not expressed in normal hematopoietic stem cells ► TIM-3 killing antibody treatment could eradicate human AML in a xenograft model ► Targeting TIM-3 could be a practical approach for human AML treatment
Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by human T-cell leukemia/lymphoma virus type 1 (HTLV-1). ATLL occurs in approximately 3%-5% of HTLV-1 carriers during ...their lifetime and follows a heterogeneous clinical course. The Shimoyama classification has been frequently used for treatment decisions in ATLL patients, and antiviral therapy has been reportedly promising, particularly in patients with indolent type ATLL; however, the prognosis continues to be dismal for patients with aggressive-type ATLL. Recent efforts to improve treatment outcomes have been focused on the development of prognostic stratification and improved dosage, timing, and combination of therapeutic modalities, such as antiviral therapy, chemotherapy, allogeneic hematopoietic stem cell transplantation, and molecular targeted therapy.
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