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Results for “Colony-Stimulating Factors”

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PubMed1977

The isolation and characterization of a colony stimulating factor from human lung.

Serum-free conditioned medium from human lung obtained at autopsy provides a rich source of colony stimulating factor which stimulates granulocytic and macrophagic colony growth in both mouse and human bone marrow. The appearance of the factor is enhanced by endotoxin and inhibited by either puromycin or actinomycin D. Human lung colony stimulating factor is stable at the pH range of 6.5-10 and temperature of 56 degrees C for 30 min. It is resistant to trypsin and neuraminidase but is sensitive to subtilisin, chymotrypsin and periodate. It shows heterogeneity on Sephadex gel filtration with two activity peaks having molecular weight of 200 000 and 40 000, respectively. Upon gel electrophoresis, human lung colony stimulating factor migrates in the alpha-globulin post-albumin region. Using the combination procedures of hydroxyapatite chromatography and preparative polyacrylamide gel electrophoresis a 600-fold purification was achieved with a final specific activity of 6-10(5) units per mg protein. The purified colony stimulating factor is very labile; however, the activity can be stabilized by the addition of gelatin or bovine serum albumin at the concentration of 0.1% and 0.2 mg/ml, respectively.

Chromatography↗
PubMed1978

Is granulopoietic activity (GA) in vivo comparable to colony stimulating factor (CSF)?

Human sera after column chromatography on Sephadex G-200 were tested for Granulopoietic Activity (GA) in vivo and Colony Stimulating Factor (CSF) in vitro. We have found that GA after chromatography is distributed in three peaks but CSF only in one peak with high activity, and evident activity in volume 135 ml. This activities are in good agreement with two peaks of GA. We assume that GA and CSF after this chromatographic procedure is free from lipoproteins inhibitors. The obtained results are briefly discussed.

Animals↗
PubMed2026

ARL6IP1 Inhibits Breast Cancer Tumor Progression by Targeting OLFM4 to Regulate Glycolysis.

INTRODUCTION: ARL6IP1 has been linked to cancer progression, but its precise role in BC, particularly in metabolism and its interaction with an OLFM4, remains unclear. AIMS: This study aimed to investigate the role of ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1) in breast cancer (BC) cell behavior and metabolism and explore its interaction with an olfactomedin-4 (OLFM4) as a potential therapeutic target. OBJECTIVE: The objective of this study was to determine the effects of ARL6IP1 knockdown on BC cell proliferation, invasion, migration, apoptosis, oxidative stress, and glycolysis. Additionally, this study also explored the interaction between ARL6IP1 and OLFM4 and their combined role in BC progression and metabolism. METHODS: Key gene modules in the GSE73540 dataset were identified through weighted gene co-expression network analysis (WGCNA). Three BC-related datasets (GSE73540, GSE22820, and GSE36295) and The Cancer Genome Atlas (TCGA) were applied for additional examination of differentially expressed genes (DEGs). Intersection analysis selected ARL6IP1 as a hub gene for prognostic analysis. In vitro experiments investigated how ARL6IP1 knockdown influences BC cell proliferation, invasion, migration, apoptosis, epithelial-mesenchymal transition (EMT), oxidative stress, and glycolysis. The connection between ARL6IP1 and an OLFM4 was confirmed using Co-immunoprecipitation (Co-IP), and their roles in BC tumor progression and glycolysis were evaluated. RESULTS: ARL6IP1 was elevated in BC datasets and linked with poor BC prognosis. Experiments demonstrated that knockdown of ARL6IP1 significantly reduced BC cell growth while promoting apoptosis and oxidative stress. Besides, ARL6IP1 knockdown reduced glycolysis, as manifested by decreased extracellular acidification rate (ECAR), glucose consumption, adenosine triphosphate (ATP) levels, and lactate production while increasing mitochondrial respiration (OCR). Co-IP validated the connection between ARL6IP1 and OLFM4, and OLFM4 overexpression partially counteracted the suppression of glycolysis and cell behavior resulting from ARL6IP1 knockdown. CONCLUSION: ARL6IP1 is a critical regulator of BC progression, influencing glycolysis, mitochondrial function, and key cellular behaviors. Targeting the ARL6IP1-OLFM4 axis offers a promising therapeutic strategy for managing BC.

Humans↗
PubMed2026

LncRNA HOTAIR contributes to cigarette smoke-induced pro-inflammatory responses in human airway epithelial cells.

Inhalation of cigarette smoke (CS) is the primary risk factor for chronic obstructive pulmonary disease (COPD), inducing epigenetic changes in the airway epithelium, including dysregulation of long-noncoding RNAs (lncRNAs). LncRNA homeobox gene transcript antisense RNA (HOTAIR) regulates chromatin remodeling and has been implicated in CS-induced malignant transformation. We hypothesized that HOTAIR expression is altered in COPD, leading to airway epithelial abnormalities. HOTAIR expression and overall survival were studied in The Cancer Genome Atlas (TCGA) database. Airway epithelial cells (AECs) were isolated from transplanted lungs of 11 patients with COPD, tracheobronchial tissue of 9 non-COPD donors, and bronchial brushings of ex-smokers with/without COPD (n = 6/group). HOTAIR expression, histone modifications, and production of proinflammatory cytokines (CXCL8 and GM-CSF) were assessed in the absence/presence of CS extract (CSE) and HOTAIR-polycomb inhibitor AQB. High HOTAIR expression correlated with poor overall survival in cancer patients with COPD, but not those without. Although HOTAIR expression was not significantly different between AECs from controls and subjects with COPD at baseline, it was significantly increased by 20% CSE only in COPD-derived AECs. CSE significantly decreased H3K4me3 levels in COPD-derived AECs, but not those from controls. AQB reduced baseline H3K27me3 levels in both groups, with a stronger effect in control-derived AECs. In addition, it reduced H3K4me3 levels in the presence of CSE in both groups. Finally, although AQB significantly suppressed CSE-induced production of GM-CSF and CXCL8 in control AECs, it failed to do so in COPD. Together, these findings suggest that COPD-derived AECs are more susceptible to CSE-induced HOTAIR upregulation, which may have a proinflammatory effect that cannot be inhibited by AQB.NEW & NOTEWORTHY COPD-derived AECs exhibit higher susceptibility to CSE-induced HOTAIR upregulation. CSE induces distinct histone modification patterns (H3K4me3) specifically in COPD-derived AECs. HOTAIR is essential for mediating CSE-induced proinflammatory responses in AECs.

Humans↗
PubMed1976

Cellular subclasses in human leukemic hemopoiesis.

Cellular organization and communication in leukemic hemopoiesis may be compared with its counterpart in normal hemopoiesis. Results obtained using cell culture methods have provided some support for the view that leukemic hemopoiesis, like normla hemopoiesis, may involve 3 levels of differentiation: leukemic stem cells, committed leukemic progenitors, and more mature cells. Evidence is also beginning to emerge that leukemic populations may be regulated by messages from the environment in a manner analogous to normal hemopoiesis. The apparent similarities between leukemic and normal hemopoiesis raise, the possibility that the target cell for leukemic transformation is the normal pluripotent stem cell. The development of culture methods for the production of leukovirus-like particles from human leukemic cells provides a possible first step toward the direct identification of leukemic target cells.

Anemia, Sideroblastic↗
PubMed1978

Co-regulation of type C RNA virus production and cell differentiation in myeloid leukemic cells.

Mouse myeloid leukemic cells which differ in their competence to be induced to differentiate by the normal macrophage- and granulocyte-inducing protein MGI have been used to study the relationship between type C RNA virus production and myeloid cell differentiation. Clones which can be induced by MGI to form Fc and C3 rosettes, to synthesize and secrete lysozyme and to differentiate to mature macrophages and granulocytes (MGI+D+) were induced by MGI to produce higher amounts of type C virus. Clones (MGI+D-) that were less inducible by MGI for Fc and C3 rosettes and lysozyme and were not induced to from mature cells were also less inducible higher virus production. In both types of clones, the increased virus production induced by MGI preceded the induction of rosettes and lysozyme. Clones that were not induced by MGI for rosettes or lysozyme (MGI-D-) showed little or no enhancement of virus production. MGI did not affect virus production in erythroleukemic cells, and erythropoietin did not affect virus production in the myeloid leukemic cells. Dexamethasone, lipopolysaccharide, dimethylsulfoxide and low concentrations of actinomycin D can induce some differentiation-associated properties in some of the clones. With these compounds, there was also a direct relationship between the enhancement of virus production and induction of differentiation-associated properties. Virus released from the three types of clones before or after treatment with MGI or dexamethasone was identified as N-tropic. The enhancement of virus production, as measured by reverse transcriptase activity, was accompanied by an increase in the amount of the viral protein p30, and interferon, which idd not inhibit the induction of differentiation in the myeloid leukemic cells, also did not prevent the increase in the amount of p30. After the early enhancement of virus production associated with the induction of differentiation, a shut-off of virus production occurred in the mature cells induced by MGI in MGI+D+ clones, whereas clones that did not differentiate to mature cells continued to produce virus. The results indicate that enhancement of virus production appears to be an early step in the induction of differentiation. Once induction has occurred, the lack of virus production in the mature cells suggest that a subsequent shut-off of virus production may be required for the completion of differentiation to mature cells. This relationship between cell differentiation and virus production suggests that type C virus has a regulatory role in myeloid cell differentiation.

Animals↗
PubMed1976

Human preleukaemia cell culture studies in sideroblastic anaemia.

Cell structure abnormalties are found in acute leukaemia and preleukaemic states. Studies on bone marrow cells and peripheral leucocytes of 4 patients with idiopathic acquired sideroblastic anaemia showed patterns in cell culture similar to those reported in acute leukaemia: 2 of these patients later developed leukaemia. Other patients with idiopathic, secondary or congenital sideroblastosis showed no such cell culture abnormalities, and none developed leukaemia. Studies such as this suggest that cell culture methods detect altered cellular function preceding overt leukaemia and that these abnormal findings may be helpful in the evaluation of patient groups with an increased incidence of leukaemia.

Anemia, Sideroblastic↗
PubMed2026

Randomized phase 2 trial of CPX-351 vs. CLAG-M (cladribine, cytarabine, G-CSF, and mitoxantrone) for medically unfit adults with acute myeloid leukemia or other high-grade myeloid neoplasms.

Even with new drugs available, how best to treat unfit adults with acute myeloid leukemia (AML) remains uncertain. In a previous trial in such patients, we found high-dose cytarabine-based therapy with CLAG-M yielded higher response rates but no more toxicity than lower-intensity therapy with dose-attenuated CLAG-M. Here, we conducted a single-institution phase 2 trial (NCT04195945) randomizing 60 adults with untreated AML and medical unfitness with Treatment-Related Mortality (TRM) score of ≥13.1 (68% with ECOG performance status 3-4) 1:1 to standard-dose CPX-351 or CLAG-M. Primary endpoint was 3-month overall survival (OS); key secondary endpoints included overall response rate, rate of measurable residual disease (MRD) negativity, toxicity/mortality rates, and survival estimates. Only CLAG-M met the primary endpoint of ≥63% 3-month OS (70% vs. 60%; P = 0.41), and CLAG-M therapy was associated with a non-significantly higher complete remission (CR) plus CR with incomplete hematologic recovery rate (73% vs. 47%, P = 0.064). Nonetheless, there was no statistically significant difference in relapse-free survival following CLAG-M vs. CPX-351 (median 37.6 vs. 19.9 months; P = 0.80) or OS (median 10.5 vs. 5.8 months; P = 0.76). In patients with proliferative disease, however, OS following CLAG-M was longer (median 18.5 vs. 3.9 months; P = 0.02) suggesting a role for intensive therapy in this patient subset.

Adult↗
PubMed2026

Human iPSC-derived alveolar macrophages reveal macrophage subtype functions of itaconate in M. tuberculosis defense.

Mycobacterium tuberculosis (Mtb) survives within multiple macrophage populations during infection, including alveolar macrophages (AMs) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1-mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to Mtb infection. The role of itaconate in human macrophages is less clear, and it is unknown whether itaconate mediates distinct effects in macrophage subtypes. Here, we investigated the role of itaconate in macrophages derived from human induced pluripotent stem cells (iPSCs), induced by either GM-CSF to resemble AMs (AM-like cells, hereafter ipAM-Ls) or M-CSF to resemble monocyte-derived macrophages (MDM-like cells, hereafter ipMDM-Ls). Both human macrophage types produced substantially less itaconate than mouse macrophages, and ipAM-Ls produced 4-fold less itaconate than ipMDM-Ls. Surprisingly, ACOD1-deficient ipAM-Ls, but not ipMDM-Ls, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb-induced inflammatory response in ipMDM-Ls, but not ipAM-Ls, affecting both the type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to tuberculosis, with distinct roles in different macrophage subsets. These results also show that genetically tractable iPSC-derived macrophages are a useful model to dissect cellular host-pathogen interactions in human macrophages.

Humans↗
PubMed2026

CRISPR screening identifies DTX4 governing alveolar macrophage cholesterol efflux in pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain incompletely defined. Here, through a genome-wide CRISPR screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify DTX4 as a pivotal regulator of cholesterol efflux in AMs. In mice, AAV-mediated silencing of DTX4 led to excessive AM lipid accumulation, exacerbated proteinosis, increased lung opacities, and deteriorated pulmonary function. Similarly, DTX4 depletion in primary AMs impaired cholesterol efflux and promoted intracellular lipid deposition. Conversely, AM-specific overexpression of DTX4 in the Csf2ra-/- PAP model markedly alleviated lipid accumulation, mitigated alveolar proteinosis, restored lung densities, and rescued pulmonary function. Mechanistically, DTX4 stabilizes the GM-CSF receptor via an E3-independent interaction to sustain JAK2/STAT5 signaling, which reciprocally maintains DTX4 transcription. This positive-feedback loop drives PPARγ expression, and its disruption in PAP impairs cholesterol efflux, a defect partially reversible by ectopic PPARγ expression. Collectively, our findings identify DTX4 as a central orchestrator of AM cholesterol efflux and surfactant homeostasis, positioning it as a promising therapeutic target for PAP.

Animals↗
PubMed1978

Macrophage colony development: properties of colony stimulating factors from murine embryo and pregnant uterus.

Extracts from embryonic and uterine tissue of mice, operationally defined as colony stimulating factor (CSF), promoted the growth of macrophage-granulocyte colonies in vitro. Uterine CSF focusses from pH 5.15 to 6.00 and embryonic CSF from pH 3.60 to 5.20, although both forms have similar biological activity. CSF is relatively resistant to denaturation but it is inactivated by periodate and dithiothreitol. Gel filtration indicates a molecular weight of 45,000 which is unchanged following treatment with insolubilized trypsin, a procedure which affords a useful purification (240-fold). Trypsin-sensitive material in CSF preparations modifies colonial form under certain conditions of culture, probably by increasing the motility of macrophages. Diaminoethane derivatives of CSF were prepared and retained biological activity at isoelectric points above pH 9.0. These derivatives may be covalently linked to Sepharose providing an insolubilized form of CSF to study interactions of CSF with the cell surface.

Animals↗
PubMed1975

Regulation of blood cell diferentiation.

The hemopoietic (blood forming) system contains pluripotent stem cells able to give rise to a variety of differentiated progeny, including erythrocytes, granulocytes, megakaryocytes, monocytes, macrophages, and possible other cell types. Although a good deal is known about cell lineage relationships in the hemopoietic system, only limited information is available about the mechanisms regulating the proliferation and differentiation of the stem cells and their progeny. An approach to this latter problem has been provided by the develoment of new techniques for the cultivation of hemopoietic cells in short-term cultures. In such cultures, the proliferation and differentiation of hemopoietic cells can be studied under controlled conditions. Two areas of investigation show particular promise: elucidation of the role of the cell surface membrane in regulation; and the possible development, through a detailed investigation of the properties of leukoviruses, of new methods for the genetic analysis of hemopoietic cells.

Animals↗
PubMed1979

Control factors of granulopoiesis in human serum.

The role of serum factors in the modulation of production of colony-stimulating activity (CSA) has been investigated. A factor has been described, and partially characterized, in human serum that has the capacity to stimulate increased synthesis and release of CSA by human mononuclear cells (MNC). MNC RNA and protein synthesis are required to demonstrate this effect of serum, but DNA synthesis and mitotic division are not required. The factor in serum resulting in this effect is a heat-labile protein with a molecular weight slightly greater than that of CSA.

Animals↗