Immune status of people living in the Tande-Tande sub-village (Indonesia), an area with high indoor radon concentration.

On Earth, there are significant variations in terms of exposure to naturally occurring radiation among different areas. Radon, a naturally-occurring radioactive gas that is the primary cause of lung cancer in nonsmokers and the second most prevalent cause among smokers, poses a considerable risk. Indoor radon, in particular, constitutes the most substantial source of natural radiation to which individuals are exposed. This study assessed the immune status of a population chronically exposed to high indoor radon concentration in Indonesia. Fifty-seven subjects from the Tande-Tande sub-village (high indoor radon concentration area) were compared to fifty-three participants living in the Topoyo village (low concentration area). We contrasted the immunological conditions of these two populations by measuring levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-4 (IL-4), and IL-10 in serum. Moreover, we also measured levels of the nuclear factor kappa B (NF-κB), superoxide dismutase (SOD), glutathione peroxidase (GPX), and protein kinase B in its phosphorylated (pAkt) and non-phosphorylated form (Akt) in peripheral blood mononuclear cells (PBMCs) of a subset of participants (31 from each population). TNF-α, IFN-γ, and IL-4 levels in Tande-Tande sub-village inhabitants were significantly lower than those in the control group living in the Topoyo village (p = 0.001, p = 0.017, and p = 0.002). The concentration of IL-10 also tended to be lower in people living in the high indoor radon concentration area, but it did not differ significantly between Tande-Tande sub-village inhabitants and Topoyo inhabitants (p = 0.106). Protein levels of NF-κB, pAkt, and Akt in Tande-Tande sub-village inhabitants also did not differ significantly between Tande-Tande sub-village inhabitants and Topoyo inhabitants (p = 0.234, p = 0.210, and p = 0.657). Similarly, activities of SOD and GPX did not differ significantly between the two populations (p = 0.569 and p = 0.949). Overall, despite their chronic exposure to high indoor radon concentrations, our study revealed no increase in the levels of TNF-α, IFN-γ, IL-10, IL-4, SOD, and GPX in the inhabitants of Tande-Tande sub-village compared with people living in the Topoyo village. Furthermore, our study demonstrated no activation in the Akt pathway, as indicated by the pAkt/Akt ratio observed in PBMC lysates of individuals residing in the Tande-Tande sub-village.

DAP3 Is Involved in Modulation of Cellular Radiation Response by RIG-I-Like Receptor Agonist in Human Lung Adenocarcinoma Cells.

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) mediate anti-viral response through mitochondria. In addition, RLR activation induces anti-tumor effects on various cancers. We previously reported that the RLR agonist Poly(I:C)-HMW/LyoVec™ (Poly(I:C)) enhanced radiosensitivity and that cotreatment with Poly(I:C) and ionizing radiation (IR) more than additively increased cell death in lung adenocarcinoma cells, indicating that Poly(I:C) modulates the cellular radiation response. However, it remains unclear how mitochondria are involved in the modulation of this response. Here, we investigated the involvement of mitochondrial dynamics and mitochondrial ribosome protein death-associated protein 3 (DAP3) in the modulation of cellular radiation response by Poly(I:C) in A549 and H1299 human lung adenocarcinoma cell lines. Western blotting revealed that Poly(I:C) decreased the expression of mitochondrial dynamics-related proteins and DAP3. In addition, siRNA experiments showed that DAP3, and not mitochondrial dynamics, is involved in the resistance of lung adenocarcinoma cells to IR-induced cell death. Finally, we revealed that a more-than-additive effect of cotreatment with Poly(I:C) and IR on increasing cell death was diluted by DAP3-knockdown because of an increase in cell death induced by IR alone. Together, our findings suggest that RLR agonist Poly(I:C) modulates the cellular radiation response of lung adenocarcinoma cells by downregulating DAP3 expression.

Regulation of Antioxidant Stress-Responsive Transcription Factor Nrf2 Target Gene in the Reduction of Radiation Damage by the Thrombocytopenia Drug Romiplostim.

Ionizing radiation induces severe oxidative stress, resulting in individual death by acute radiation syndrome. The nuclear factor-erythroid-2-related factor 2 (Nrf2) plays an important role in the antioxidant response pathway. Recently, romiplostim (RP), an idiopathic thrombocytopenic purpura therapeutic drug, was reported to completely rescue mice exposed to lethal total-body irradiation (TBI). However, the details underlying the mechanism for reducing radiation damage remain largely unknown. To elucidate the involvement of the master redox regulator Nrf2 in the radio-mitigative efficacy of RP on TBI-induced oxidative stress, expression of Nrf2 target genes in hematopoietic tissues such as bone marrow, spleen, and lung from mice treated with RP for three consecutive days after 7 Gy of X-ray TBI was analyzed. RP promoted the recovery of bone marrow cells from day 10 and the significant up-regulation of reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) dehydrogenase quinone 1 (Nqo1), glutamate-cysteine ligase catalytic subunit (Gclc) and glutamate-cysteine ligase modifier subunit (Gclm) was observed compared to the TBI mice. RP also promoted the recovery of splenic cells on day 18, and the significant up-regulation of Nqo1, Gclc and Gclm in spleen both on day 10 and 18 and Nqo1 and Gclm in lung on day 10 was observed compared to the TBI mice. The present study suggests that the radio-mitigative effects of RP indicates on the activation of Nrf2 target genes involved in redox regulation and the antioxidative function, especially Nqo1, Gclc and Gclm. It is indicating the importance of these genes in the maintenance of biological homeostasis in response to radiation-induced oxidative stress.

Relationship between the Regulation of Caspase-8-Mediated Apoptosis and Radioresistance in Human THP-1-Derived Macrophages.

Radiosensitivity varies depending on the cell type; highly differentiated cells typically exhibit greater radioresistance. We recently demonstrated that human macrophages derived from THP-1 monocytic cells, which lack TP53, are highly resistant to radiation-induced apoptosis compared with undifferentiated THP-1 cells. However, the mechanisms by which THP-1 cells acquire radioresistance during differentiation remain unknown. Herein, we investigated the mechanisms by which THP-1-derived macrophages develop p53-independent radioresistance by analyzing DNA damage responses and apoptotic pathways. Analysis of γ-H2AX foci, which indicates the formation of DNA double-strand breaks (DSB), suggested that a capacity to repair DSB of macrophages is comparable to that of radiosensitive THP-1 cells. Furthermore, treatment with inhibitors against DSB repair-related proteins failed to enhance radiation-induced apoptosis in THP-1-derrived macrophages. Analysis of the apoptotic pathways showed that radiosensitive THP-1 cells undergo apoptosis through the caspase-8/caspase-3 cascade after irradiation, whereas this was not observed in the macrophages. Caspase-8 protein expression was lower in macrophages than in THP-1 cells, whereas mRNA expressions were comparable between both cell types. Co-treatment with a proteasome inhibitor and ionizing radiation effectively induced apoptosis in macrophages in a caspase-8-dependent manner. Results suggest that the regulation of caspase-8-mediated apoptosis during differentiation plays a role in the p53-independent radioresistance of THP-1-derived macrophages.

p53-independent structure-activity relationships of 3-ring mesogenic compounds' activity as cytotoxic effects against human non-small cell lung cancer lines.

BACKGROUND: We recently demonstrated the cytotoxicity of liquid crystal precursors (hereafter referred to as "mesogenic compounds") in the human non-small cell lung cancer (NSCLC) cell line A549 which carry wild-type p53. p53 mutations are observed in 50 % of NSCLC and contribute to their resistance to chemotherapy. To develop more effective and cancer-specific agents, in this study, we investigated the structure-activity relationships of mesogenic compounds with cytotoxic effects against multiple NSCLC cells. METHODS: The pharmacological effects of mesogenic compounds were examined in human NSCLC cells (A549, LU99, EBC-1, and H1299) and normal WI-38 human fibroblast. Analyses of the cell cycle, cell-death induction, and capsases expression were performed. RESULTS: The 3-ring compounds possessing terminal alkyl and hydroxyl groups (compounds C1-C5) showed cytotoxicity in NSCLC cells regardless of the p53 status. The compounds C1 and C3, which possess a pyrimidine at the center of the core, induced G2/M arrest, while the compounds without a pyrimidine (C2, C4, and C5) caused G1 arrest; all compounds produced caspase-mediated cell death. These events occurred in a p53-independent manner. Furthermore, it was suggested that compounds induced cell death through p53-independent DNA damage-signaling pathway. Compounds C2, C4, and C5 did not show strong cytotoxicity in WI-38 cells, whereas C1 and C3 did. However, the cytotoxicity of compound C1 against WI-38 cells was improved by modulating the terminal alkyl chain lengths of the compound. CONCLUSIONS: We showed the p53-indepdent structure-activity relationships of mesogenic compounds related to the cytotoxic effects. These structure-activity relationships will be helpful in the development of more effective and cancer-specific agents.

Phase-separated super-enhancers confer an innate radioresistance on genomic DNA.

Recently, biomolecular condensates formed through liquid-liquid phase separation have been widely reported to regulate key intracellular processes involved in cell biology and pathogenesis. BRD4 is a nuclear protein instrumental to the establishment of phase-separated super-enhancers (SEs) to direct the transcription of important genes. We previously observed that protein droplets of BRD4 became hydrophobic as their size increase, implying an ability of SEs to limit the ionization of water molecules by irradiation. Here, we aim to establish if SEs confer radiation resistance in cancer cells. We established an in vitro DNA damage assay that measures the effect of radicals provoked by the Fenton reaction on DNA integrity. This revealed that DNA damage was markedly reduced when BRD4 underwent phase separation with DNA. Accordingly, co-focal imaging analyses revealed that SE foci and DNA damage foci are mutually exclusive in irradiated cells. Lastly, we observed that the radioresistance of cancer cells was significantly reduced when irradiation was combined with ARV-771, a BRD4 de-stabilizer. Our data revealed the existence of innately radioresistant genomic regions driven by phase separation in cancer cells. The disruption of these phase-separated components enfolding genomic DNA may represent a novel strategy to augment the effects of radiotherapy.

Radiosensitivity of human haematopoietic stem/progenitor cells.

The haematopoietic system is regenerative tissue with a high proliferative potential; therefore, haematopoietic stem cells (HSCs) are sensitive to extracellular oxidative stress caused by radiation and chemotherapeutic agents. An understanding of this issue can help predict haematopoietic recovery from radiation exposure as well as the extent of radiation damage to the haematopoietic system. In the present study, the radiosensitivity of human lineage-committed myeloid haematopoietic stem/progenitor cells (HSPCs), including colony-forming unit-granulocyte macrophage, burst-forming unit-erythroid and colony-forming unit-granulocyte-erythroid-macrophage-megakaryocyte cells, which are contained in adult individual peripheral blood (PB) and fetus/neonate placental/umbilical cord blood (CB), were studied. The PB of 59 healthy individual blood donors and the CB of 42 neonates were investigated in the present study. HSPCs prepared from PB and CB were exposed to 0.5 or 2 Gy x-irradiation. The results showed that large individual differences exist in the surviving fraction of cells. In the case of adult PB, a statistically significant negative correlation was observed between the surviving fraction observed at a dose of 0.5 Gy and the age of the blood donors; however, none of these correlations were observed after 2 Gy x-irradiation. In addition, seasonal and gender variation were observed in the surviving fraction of CB HSPCs. The present results suggest that there are large individual differences in the surviving fraction of HSPCs contained in both adult PB and fetus/neonate CB. In addition, some factors, including the gender, age and season of birth, affect the radiosensitivity of HSPCs, especially with a relatively low-dose exposure.

Relationship between obesity and serum reactive oxygen metabolites in adolescents.

OBJECTIVES: Various cross-sectional studies have revealed a significant positive relationship between systemic oxidative stress and obesity-related indices such as body mass index (BMI, kg/m²). However, little is known of the role of oxidative stress during adolescence. The aim of this study was to determine the association between obesity and serum reactive oxygen metabolites (ROM) in adolescents. METHOD: A total of 595 healthy junior high school students from northern Japan were enrolled in the study. Oxidative stress was evaluated by measuring serum levels of ROM. Obesity indices included BMI and percentage body fat (PBF). The analyses were stratified by sex and controlled for age and menarche. Partial correlation coefficients and analysis of covariance were also analyzed. RESULTS: In female students, ROM levels increased with increasing BMI and PBF. Therefore, ROM levels were significantly higher in the underweight group than in the BMI-classified overweight-obese (P < 0.001) and normal weight groups (P < 0.05). ROM levels were significantly higher in the high PBF group than in the underweight (P < 0.05) and normal groups (P < 0.001). CONCLUSION: The results of this study show that, regardless of menarche, obesity indicators such as BMI and PBF are correlated with the level of oxidative stress in female adolescents.

[A continuous 4-year evaluation of medical informatics education in a graduate school of health sciences using a questionnaire survey].

The purpose of this study was to identify the level of awareness among undergraduate students regarding medical informatics and to ascertain whether educational training has progressed with time in the Department of Health Sciences at Hirosaki University, Japan, which is a co-medical staff training institution that conducts a 4-year university course in medical informatics. The university accepts students who have completed the 3rd grade of medical licensing tests and who have attended the medical informatics lectures for 4 years (2007-2010). The ratio of first sight terminology percentage in any given fiscal year in all the 30 terminology categories varied widely from 0% to 80%, but the trend in various categories did not vary between fiscal years. The terminology of informatics under medical technology students obtained high scores of 52.5-77.3% after attending courses, which was higher compared with students from other classes. On the other hand, student nurses and occupational therapy students obtained 0-44.2%. Each class scored a high percentage of correct answers in the medical information-related terminology. Among the radiology students who attended the classes, the percentage of correct answers in categories of "digital imaging and communication in medicine" and "picture archiving and communication system" were lower than other medical terminology categories. These results reflect the gaps in educational curriculum of 1st and 2nd grades of medical licensing tests.

The Acute Radiation Syndrome-Mitigator Romiplostim and Secreted Extracellular Vesicles Improved Survival in Mice Acutely Exposed to Myelosuppressive Doses of Ionizing Radiation.

In cases of accidental high-dose total-body irradiation (TBI), acute radiation syndrome (ARS) can cause death. We reported that the thrombopoietin receptor agonist romiplostim (RP) has the potential to completely rescue mice exposed to lethal TBI. Extracellular vesicles (EVs) are involved in cell-to-cell communication, and the mechanism of RP action may be related to EVs that reflect the radio-mitigative information. We investigated the radio-mitigative effects of EVs on mice with severe ARS. C57BL/6 mice exposed to lethal TBI were treated with RP, and the EVs were isolated from the serum and intraperitoneally injected into other mice with severe ARS. The 30-day survival rate of lethal TBI mice drastically improved by 50-100% with the administration of EVs in the sera collected weekly from the mice in which radiation damage was alleviated and mortality was avoided by the administration of RP. Four responsive miRNAs, namely, miR-144-5p, miR-3620-5p, miR-6354, and miR-7686-5p showed significant expression changes in an array analysis. In particular, miR-144-5p was expressed only in the EVs of RP-treated TBI mice. Specific EVs may exist in the circulating blood of mice that escaped mortality with an ARS mitigator, and their membrane surface and endogenous molecules may be the key to the survival of mice with severe ARS.

Prediction of hub genes and key pathways associated with the radiation response of human hematopoietic stem/progenitor cells using integrated bioinformatics methods.

Hematopoietic stem cells (HSCs) are indispensable for the maintenance of the entire blood program through cytokine response. However, HSCs have high radiosensitivity, which is often a problem during radiation therapy and nuclear accidents. Although our previous study has reported that the combination cytokine treatment (interleukin-3, stem cell factor, and thrombopoietin) improves the survival of human hematopoietic stem/progenitor cells (HSPCs) after radiation, the mechanism by which cytokines contribute to the survival of HSPCs is largely unclear. To address this issue, the present study characterized the effect of cytokines on the radiation-induced gene expression profile of human CD34+ HSPCs and explored the hub genes that play key pathways associated with the radiation response using a cDNA microarray, a protein-protein interaction-MCODE module analysis and Cytohubba plugin tool in Cytoscape. This study identified 2,733 differentially expressed genes (DEGs) and five hub genes (TOP2A, EZH2, HSPA8, GART, HDAC1) in response to radiation in only the presence of cytokines. Furthermore, functional enrichment analysis found that hub genes and top DEGs based on fold change were enriched in the chromosome organization and organelle organization. The present findings may help predict the radiation response and improve our understanding of this response of human HSPCs.

DAP3-mediated cell cycle regulation and its association with radioresistance in human lung adenocarcinoma cell lines.

Mitochondria play important roles in the cellular response to various types of stress, including that triggered by ionizing radiation. We have previously reported that the mitochondrial ribosomal protein death-associated protein 3 (DAP3) regulates the radioresistance of human lung adenocarcinoma (LUAD) cell lines A549 and H1299. However, the underlying mechanism of this regulation remains to be elucidated. To this end, we have herein investigated the role of DAP3 in the cell cycle regulation after irradiation. Notably, the DAP3 knockdown attenuated the radiation-induced increase of the G2/M cell population. Furthermore, western blotting analysis has revealed that the DAP3 knockdown decreased the expression of proteins related to the G2/M arrest, such as those of the phosphorylated cdc2 (Tyr15) and the phosphorylated checkpoint kinase 1 (Ser296), in irradiated A549 cells and H1299 cells. Moreover, by using a chk1 inhibitor, we were able to demonstrate that chk1 is involved in the radiation-induced G2/M arrest in both A549 and H1299 cells. Notably, the chk1 inhibitor was able to enhance the radiosensitivity of H1299 cells, while both chk1 inhibitor-abolished G2 arrest and inhibition of chk2-mediated events such as downregulation of radiation-induced p21 expression were required for enhancing radiosensitivity of A549 cells. Collectively, our findings reveal a novel role of DAP3 to regulate G2/M arrest through pchk1 in irradiated LUAD cells and suggest that chk1-mediated G2/M arrest regulates the radioresistance of H1299 cells, whereas both the chk1-mediated G2/M arrest and the chk2-mediated events contribute to the radioresistance of A549 cells.

Cytotoxic Activity of Unique Synthesized Five-membered Heterocyclic Compounds Coordinated with Tiopronin Monovalent.

BACKGROUND: We recently synthesized a compound in which 5-mercapto-1-methyltetrazole (MM4) was coordinated to tiopronin monovalent (TPN-Au(I)) and reported its cytotoxic activity against human leukemia cells in vitro. OBJECTIVE: We further synthesized other heterocyclic compounds coordinated with TPN-Au(I) and assessed their cytotoxic activity against hepatocellular carcinoma HepG2 and lung cancer cell line H1299 in vitro. METHODS: Seven kinds of compounds were synthesized by introducing a five-membered heterocyclic compound into TPN-Au(I). The number of viable cells was counted by a trypan blue dye exclusion assay. Fluorescence conjugated-Annexin V and propidium iodide were used for the apoptosis analysis. RESULTS: Seven compounds were successfully synthesized. Among these compounds, TPN-Au(I)-MTZ (3- mercapto-1,2,4-triazole), TPN-Au(I)-MMT (2-mercapto-5-methyl-1,3,4-thiadiazole), and TPN-Au(I)-MMTT (2-mercapto-5-methylthio-1,3,4-thiadiazole) effectively suppressed the proliferation and induced apoptosis in HepG2 cells. In addition, TPN-Au(I)-MMTT and TPN-Au(I)-MMT also showed effective cytotoxicity against H1299 cells. CONCLUSION: The present results showed that introduction of some five-membered heterocyclic compounds, especially MMT and MMTT, to TPN-Au(I) improved the cytotoxicity against solid cancer cells.

Chromosome aberrations, micronucleus frequency, and catalase concentration in a population chronically exposed to high levels of radon.

PURPOSE: To deepen our knowledge on the effects of high levels of indoor radon exposure, we assessed the frequencies of unstable and stable chromosome aberrations and micronucleus (MN), as well as the concentration of an endogenous antioxidant (catalase, CAT), in blood samples of individuals chronically exposed to high indoor radon concentrations in Indonesia (Tande-Tande sub-village, Mamuju, West Sulawesi). Moreover, we also investigated the occurrence of a radio-adaptive response (RAR) in Tande-Tande sub-village inhabitants using the G2 MN assay. MATERIALS AND METHODS: The frequencies of dicentric (DC), acentric (AF), ring (R), and translocation (Tr) chromosomes in Tande-Tande inhabitants were compared to those in people living in a reference area with low levels of indoor radon levels (Topoyo village, Indonesia). The number of MN per 1000 binucleated cells (BNC) and CAT concentration per total protein was quantified and compared between groups. Lastly, we irradiated (2 Gy) phytohemagglutinin-stimulated samples in vitro and measured the frequency of MN to verify the occurrence of a RAR in Tande-Tande sub-village inhabitants. RESULTS AND CONCLUSION: The frequencies of DC, AF, and Tr did not differ between Tande-Tande inhabitants and control subjects (p = 0.350, 0.521, 0.597). The frequency of MN in Tande-Tande inhabitants was significantly lower than that in the control group (p = 0.006). Similarly, CAT concentration in Tande-Tande inhabitants was also significantly lower than that in the control population (p < 0.001). Significant negative correlations were identified for MN number and CAT concentration versus indoor radon concentration, annual effective dose, or cumulative dose both within groups and when all data were analyzed together. Our findings indicate that, despite the high indoor radon levels, Tande-Tande inhabitants are not under oxidative stress, since this group had lower CAT concentration and MN frequency than those in the control group. The negative correlation between MN frequency and indoor radon concentration, annual effective dose, and cumulative dose suggests the occurrence of an RAR phenomenon in Tande-Tande sub-village inhabitants. This interpretation is also supported by the results of the G2 MN assay, which revealed lower MN frequencies after in vitro irradiation of samples from Tande-Tande sub-village inhabitants than those in samples from the control group (p = 0.0069, for cumulative MN frequency; p = 0.0146, for radiation-induced MN only).

Development of an Automatic Chronological Record Creation System Using Voice AI to Facilitate Information Aggregation and Sharing in the Event of a Disaster.

OBJECTIVE: In the event of a disaster, the chain of command and communication of each relevant agency is important. In this study, a chronological record creation system using voice AI (V-CRS) was developed, and an experiment was conducted to determine whether the obtained information could be quickly and easily summarized in chronological order. METHODS: After a lecture by Japanese Disaster Medical Assistant (DMAT) Team members and 8 medical clerks on how to use the developed tool, a comparison experiment was conducted between manual input and V-CRS utilization of the time to compile disaster information. RESULTS: Results proved that V-CRS can collect information gathered at headquarters more quickly than handwriting. It was also suggested that even medical clerks who have never been trained to record information during disasters could record information at the same speed as trained DMAT personnel. CONCLUSION: V-CRS can transcribe audio information even in situations where technical terms and physical units must be recorded, such as radiation disasters. It has been proven that anyone can quickly organize information using this method, to some extent.

Functional properties of synthetic N-acyl-L-homoserine lactone analogs of quorum-sensing gram-negative bacteria on the growth of human oral squamous carcinoma cells.

Quorum sensing is defined as the ability of microorganisms to sense their population density via the release of signaling molecules composed of acyl-homoserine lactone (AHL), which is a type of autoinducer (AI). Previous structure-activity relationship (SAR) studies demonstrated that the 3-oxo group, homoserine lactone of L-form, and long acyl side chain have crucial roles in apoptosis induction. Various types of synthetic AI analogs of Pseudomonas aeruginosa were prepared, and SAR study was conducted to determine their effects against human oral squamous carcinoma cells derived from gingival carcinoma Ca9-22 cells and tongue cancer SAS cells. Not only the antiproliferative potential but also the radiation-sensitizing effects against these cells were examined. It was found that antiproliferative activity partly depended on HSL structure and acyl side chain length. Moreover, a few compounds, compound 5 and 87, showed antiproliferative effects against both Ca9-22 and SAS cells, and also induced radiation-sensitizing effects against Ca9-22 cells. Compound 5 alone induced apoptotic cell death accompanied by sub-G1 phase accumulation in cell cycle and caspase-3 activation, and radiation-sensitizing effects of compound 5 could be attributed to enhanced apoptosis induction. In contrast, there were no remarkable alterations in cell cycle distribution in Ca9-22 treated with compound 87 alone or in combination. However, both compounds lack 3-oxo and their acyl side chain lengths are not necessarily long. This SAR study demonstrated that HSL analogs, which lacked the recommended characteristics for apoptosis induction clearly showed antiproliferative and radiation-sensitizing activity in Ca9-22 cells.

Caspase-independent apoptosis induction of quorum-sensing autoinducer analogs against chronic myeloid leukemia K562.

Quorum sensing is defined as the ability of microorganisms to sense their population density via the release of signaling molecules called autoinducers (AIs). Various types of AI analogs were prepared and their antitumor properties against chronic myeloid leukemia (CML) K562 cells were investigated. Two AI analogs induced progressive apoptosis with JNK activation and p21 induction. In addition, this induction of apoptosis is not related to bcr-abl kinase, which sustains CML proliferation. However, the progression of apoptosis was not inhibited by a caspase family inhibitor. These results suggested that AI analogs could induce caspase-independent apoptosis in CML K562.

Suppressive effects of liquid crystal compounds on the growth of U937 human leukemic monocyte lymphoma cells.

BACKGROUND: The aim of this study was to evaluate the biological and pharmaceutical activities of 14 amphiphilic liquid-crystalline compounds (LCs), i.e, phenylpyrimidine derivatives possessing D-glucamine and cyanobiphenyl derivatives with a terminal hydroxyl unit. RESULTS: The cytotoxic properties of the LCs on the cell growth, cell cycle distribution, and cell signaling pathway of U937 human leukemic monocyte lymphoma cells were assessed by flow cytometry and western blot analysis. Some LCs showed cytostatic effects, suppressing cell growth via S-phase arrest and without apoptosis in U937 cells. To investigate the mechanisms of the LC-induced S-phase arrest, proteins relevant to cell cycle regulation were investigated by western blot analysis. The rate of LC-induced S-phase arrest was congruent with the decreased expression of MCM2, cyclin A, cyclin B, CDK2, phospho-CDK1 and Cdc25C. Observed changes in cell cycle distribution by LC treated might be caused by insufficient preparation for G2/M transition. Considering the structure of the LCs, the rod-like molecules displaying cytotoxicity against U937 cells possessed flexible spacers with no bulky polar group attached via the flexible spacer. CONCLUSIONS: Our results revealed that some LCs showed cytotoxic properties against non-solid type tumor human leukemic cells via LC-induced S-phase arrest and decreasing expression of several cell cycle related proteins.

Quality-assessments of characteristics of placental/umbilical cord blood associated with maternal age- and parity-related factor.

Umbilical cord blood (CB) has been widely used for unrelated allogeneic stem cell transplantation. It is important to determine the quality of CB units to avoid frequent problem of limited cell yields. However, no practical and/or optimum obstetric factors to predict them are yet available. This study analyzed the relationship between maternal/neonatal obstetric factors and the laboratory parameters of CB units to identify the optimum factors associated with a high yield of total nucleated cells (TNC). Primiparae in their early 30s may be one of the first selection criteria for CB donors to obtain higher yield of TNC.

Novel acridine-based N-acyl-homoserine lactone analogs induce endoreduplication in the human oral squamous carcinoma cell line SAS.

The cytotoxicity of novel acridine-based N-acyl-homoserine lactone (AHL) analogs was investigated on the human oral squamous carcinoma cell line SAS. One analog induced G2/M phase arrest at 5.3-10.6 µM and induced polyploidy at a higher dose (21.2 µM). Importantly, treatment of SAS cells with a combination of the AHL analog and the Jun N-terminal kinase (JNK) inhibitor, SP600125, prevented mitosis and induced polyploidy. The AHL analog synergized with X-irradiation to inhibit clonogenic survival of SAS cells; however, its radiosensitizing effects were relative to not X-irradiation-induced apoptosis but mitotic failure following enhanced expression of Aurora A and B. These results suggest that the active AHL analog showed growth-suppressive and radiosensitizing effects, which involve polyploidy followed by G2/M accumulation and atypical cell death in the SAS cell line.