scholarly journals Hematological Findings in Non-Treated and γ-Irradiated Mice Deficient for MIC-1/GDF15

2018 ◽  
pp. 623-636
Author(s):  
M. HOFER ◽  
Z. HOFEROVÁ ◽  
J. REMŠÍK ◽  
M. NOVÁKOVÁ ◽  
J. PROCHÁZKOVÁ ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Hematological Parameters ◽  
Blood Platelet ◽  
Dependent Manner ◽  
Distribution Width ◽  
Knock Out ◽  
Pathological Conditions ◽  
Platelet Size ◽  
Radiation Induced

Several members of the TGF-ß family are known to effectively regulate the fate of hematopoietic progenitor cells in a complex and context-dependent manner. Growth differentiation factor-15 (GDF15) is a divergent member of the TGF-ß family. This stress-induced cytokine has been proposed to possess immunomodulatory functions and its high expression is often associated with progression of a variety of pathological conditions. GDF15 is also induced by chemotherapy and irradiation. Very few fundamental studies have been published regarding the effect of GDF15 in hematopoiesis. In this study, we analyzed the hematological status of untreated and γ-irradiated mice deficient for GDF15 as a result of genetic knock-out (KO), in order to clarify the regulatory role of GDF15 in hematopoiesis. Significant differences between GDF15 KO mice and their pertinent WT controls were found in the parameters of blood monocyte numbers, blood platelet size, and distribution width, as well as in the values of bone marrow granulocyte/macrophage progenitor cells. Different tendencies of some hematological parameters in the GDF15 KO mice in normal conditions and those under exposure of the mice to ionizing radiation were registered. These findings are discussed in the context of the GDF15 gene function and its lack under conditions of radiation-induced damage.

scholarly journals Effect of genetic variants in FAS and let-7a on radiation-induced intestinal toxicity in the treatment of prostate cancer

2021 ◽  
Author(s):  
Honglei Guo ◽  
Feng Yuan ◽  
Yancui Zhu ◽  
Ling He
Keyword(s):  
Prostate Cancer ◽  
Dependent Manner ◽  
Intestinal Toxicity ◽  
Rectal Volume ◽  
Obvious Association ◽  
Radiation Induced ◽  
Computational Analyses ◽  
Putative Marker ◽  
Dose Dependent

IntroductionThe present study aimed to explore the effects of pri-let-7a-1 rs10739971 and FAS-670 rs1800682 polymorphisms on the pathogenesis of radiation induced intestinal toxicity in prostate cancer (PC) patients.Material and methods380 PC patients with or without signs of intestinal toxicity were enrolled to study the effects of let-7a rs10739971 and FAS-670 rs1800682 polymorphisms on rectal volume and the risk of intestinal toxicity. In addition, real-time PCR, Western-blot analysis, immunohistochemistry, luciferase assays and computational analyses were performed to explore the mechanism underlying the role of let-7a rs10739971 polymorphism in radiation induced intestinal toxicity.ResultsThe let-7a rs10739971 polymorphism but not the FAS-670 rs1800682 polymorphism was closely related to the risk of radiation induced intestinal toxicity featured by a high rectal volume. In addition, there was no obvious association between the rectal volume and the genotype and allele frequencies of FAS -670 rs1800682 and Pri-let-7a-1 rs10739971 polymorphisms. The GG genotype of let-7a rs10739971 polymorphism reduced let-7a expression but enhanced FAS expression. In addition, the intestinal toxicity (-) group showed a much higher level of let-7a and a much lower level of FAS than the intestinal toxicity (+) group. FAS was a virtual target gene of let-7a, which decreased FAS protein expression in a dose-dependent manner.ConclusionsThe GG genotype of pri-let-7a-1 rs10739971 polymorphism could increase the risk of radiation induced intestinal toxicity in PC patients. Therefore, the pri-let-7a-1 rs10739971 polymorphism could be used as a putative marker to predict the risk of intestinal toxicity in PC patients undergoing radiotherapy.

scholarly journals Autophagy in endocrine tumors

2015 ◽  
Vol 22 (4) ◽  
pp. R205-R218 ◽  
Author(s):  
Andrea Weckman ◽  
Fabio Rotondo ◽  
Antonio Di Ieva ◽  
Luis V Syro ◽  
Henriett Butz ◽  
...  
Keyword(s):  
Treatment Efficacy ◽  
Endocrine Tumors ◽  
Dependent Manner ◽  
Endocrine Glands ◽  
Cell Type ◽  
Pathological Conditions ◽  
Tumor Survival ◽  
Different Types ◽  
Intracellular Process

Autophagy is an important intracellular process involving the degradation of cytoplasmic components. It is involved in both physiological and pathological conditions, including cancer. The role of autophagy in cancer is described as a ‘double-edged sword,’ a term that reflects its known participation in tumor suppression, tumor survival and tumor cell proliferation. Available research regarding autophagy in endocrine cancer supports this concept. Autophagy shows promise as a novel therapeutic target in different types of endocrine cancer, inhibiting or increasing treatment efficacy in a context- and cell-type-dependent manner. At present, however, there is very little research concerning autophagy in endocrine tumors. No research was reported connecting autophagy to some of the tumors of the endocrine glands such as the pancreas and ovary. This review aims to elucidate the roles of autophagy in different types of endocrine cancer and highlight the need for increased research in the field.

scholarly journals Sall4-Gli3 system in early limb progenitors is essential for the development of limb skeletal elements

2015 ◽  
Vol 112 (16) ◽  
pp. 5075-5080 ◽  
Author(s):  
Ryutaro Akiyama ◽  
Hiroko Kawakami ◽  
Julia Wong ◽  
Isao Oishi ◽  
Ryuichi Nishinakamura ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Sonic Hedgehog ◽  
Limb Development ◽  
Critical Role ◽  
Dependent Manner ◽  
Skeletal Element ◽  
Proximal Development ◽  
Limb Outgrowth ◽  
Common Regulator

Limb skeletal elements originate from the limb progenitor cells, which undergo expansion and patterning to develop each skeletal element. Posterior-distal skeletal elements, such as the ulna/fibula and posterior digits develop in a Sonic hedgehog (Shh)-dependent manner. However, it is poorly understood how anterior-proximal elements, such as the humerus/femur, the radius/tibia and the anterior digits, are developed. Here we show that the zinc finger factors Sall4 and Gli3 cooperate for proper development of the anterior-proximal skeletal elements and also function upstream of Shh-dependent posterior skeletal element development. Conditional inactivation of Sall4 in the mesoderm before limb outgrowth caused severe defects in the anterior-proximal skeletal elements in the hindlimb. We found that Gli3 expression is reduced in Sall4 mutant hindlimbs, but not in forelimbs. This reduction caused posteriorization of nascent hindlimb buds, which is correlated with a loss of anterior digits. In proximal development, Sall4 integrates Gli3 and the Plzf-Hox system, in addition to proliferative expansion of cells in the mesenchymal core of nascent hindlimb buds. Whereas forelimbs developed normally in Sall4 mutants, further genetic analysis identified that the Sall4-Gli3 system is a common regulator of the early limb progenitor cells in both forelimbs and hindlimbs. The Sall4-Gli3 system also functions upstream of the Shh-expressing ZPA and the Fgf8-expressing AER in fore- and hindlimbs. Therefore, our study identified a critical role of the Sall4-Gli3 system at the early steps of limb development for proper development of the appendicular skeletal elements.

scholarly journals Transcriptional landscape of myogenesis from human pluripotent stem cells reveals a key role of TWIST1 in maintenance of skeletal muscle progenitors

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
In Young Choi ◽  
Hotae Lim ◽  
Hyeon Jin Cho ◽  
Yohan Oh ◽  
Bin-Kuan Chou ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Progenitor Cells ◽  
Pluripotent Stem Cells ◽  
Expression Profiles ◽  
Human Pluripotent Stem Cells ◽  
Knock Out ◽  
Muscle Progenitor Cells ◽  
Transcriptional Landscape

Generation of skeletal muscle cells with human pluripotent stem cells (hPSCs) opens new avenues for deciphering essential, but poorly understood aspects of transcriptional regulation in human myogenic specification. In this study, we characterized the transcriptional landscape of distinct human myogenic stages, including OCT4::EGFP+ pluripotent stem cells, MSGN1::EGFP+ presomite cells, PAX7::EGFP+ skeletal muscle progenitor cells, MYOG::EGFP+ myoblasts, and multinucleated myotubes. We defined signature gene expression profiles from each isolated cell population with unbiased clustering analysis, which provided unique insights into the transcriptional dynamics of human myogenesis from undifferentiated hPSCs to fully differentiated myotubes. Using a knock-out strategy, we identified TWIST1 as a critical factor in maintenance of human PAX7::EGFP+ putative skeletal muscle progenitor cells. Our data revealed a new role of TWIST1 in human skeletal muscle progenitors, and we have established a foundation to identify transcriptional regulations of human myogenic ontogeny (online database can be accessed in http://www.myogenesis.net/).

scholarly journals Hepatic progenitor cells promote the repair of schistosomiasis liver injury by inhibiting IL-33 secretion in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Beibei Zhang ◽  
Xiaoying Wu ◽  
Jing Li ◽  
An Ning ◽  
Bo Zhang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Progenitor Cells ◽  
Normal Liver ◽  
Protective Role ◽  
Dependent Manner ◽  
Hepatic Progenitor Cells ◽  
Wild Type ◽  
Mice Model

Abstract Background Hepatic schistosomiasis, a chronic liver injury induced by long-term Schistosoma japonicum (S. japonicum) infection, is characterized by egg granulomas and fibrotic pathology. Hepatic progenitor cells (HPCs), which are nearly absent or quiescent in normal liver, play vital roles in chronic and severe liver injury. But their role in the progression of liver injury during infection remains unknown. Methods In this study, the hepatic egg granulomas, fibrosis and proliferation of HPCs were analyzed in the mice model of S. japonicum infection at different infectious stages. For validating the role of HPCs in hepatic injury, tumor necrosis factor-like-weak inducer of apoptosis (TWEAK) and TWEAK blocking antibody were used to manipulate the proliferation of HPCs in wild-type and IL-33−/− mice infected with S. japonicum. Results We found that the proliferation of HPCs was accompanied by inflammatory granulomas and fibrosis formation. HPCs expansion promoted liver regeneration and inhibited inflammatory egg granulomas, as well as the deposition of fibrotic collagen. Interestingly, the expression of IL-33 was negatively associated with HPCs’ expansion. There were no obvious differences of liver injury caused by infection between wild-type and IL-33−/− mice with HPCs’ expansion. However, liver injury was more attenuated in IL-33−/− mice than wild-type mice when the proliferation of HPCs was inhibited by anti-TWEAK. Conclusions Our data uncovered a protective role of HPCs in hepatic schistosomiasis in an IL-33-dependent manner, which might provide a promising progenitor cell therapy for hepatic schistosomiasis.

HEMATOLOGICAL PROFILE OF RATS ADMINISTERED WITH PROPOLIS FOLLOWING ANTITUBERCULOSIS DRUGS INDUCED TOXICITY

2018 ◽  
Vol 24 (2) ◽  
Author(s):  
NISHA SAHU ◽  
HEMESHWER KUMAR CHANDRA ◽  
GITA MISHRA ◽  
SATENDRA KUMAR NIRALA ◽  
MONIKA BHADAURIA
Keyword(s):  
Hematological Parameters ◽  
Blood Parameters ◽  
Positive Control ◽  
Blood Parameter ◽  
Dependent Manner ◽  
Distribution Width ◽  
Antituberculosis Drugs ◽  
Hematological Indices ◽  
Propolis Extract ◽  
Therapeutic Choice

Antituberculosis drugs (ATD) used as standard drugs for the treatment of deadly disease tuberculosis, cause blood disorders. The present study was conducted to investigate the efficacy of propolis against ATD induced alteration in blood parameters in rats. Rats were administered with ATD for 8 weeks (3 days/week) followed by propolis at three different doses (100, 200 and 400 mg/kg) conjointly for 8 weeks (3 days/week) orally. Silymarin (50 mg/kg) was used as positive control in the study. After 8 weeks, animals were euthanized; blood was collected by retro-orbital sinus method for analysis of hematological parameters. The results of this study show a decrease in red blood cells, hemoglobin, hematocrit, mean corpuscular volume, red blood cell distribution width alongwith increase in the number of lymphocytes in ATD induced rats. Treatment with propolis extract encountered ATD induced blood parameter alteration which was evident by significant reversal in hematological indices towards control in a dose dependent manner. Thus, it can be concluded that propolis may be an agent of therapeutic choice in case of ATD induced hematological alterations.

Homeostatic Role of the Krüppel-Like Factor 4 (KLF4) in Proliferation and Differentiation of Primitive Hematopoietic Progenitor Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1497-1497 ◽  
Author(s):  
Chun Shik Park ◽  
Takeshi Yamada ◽  
H. Daniel Lacorazza
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Proliferative Potential ◽  
Dependent Manner ◽  
Hematopoietic Stem ◽  
Deficient Mice

Abstract Abstract 1497 Poster Board I-520 KLF4 is a tumor suppressor in the gastrointestinal tract known to induce cell cycle arrest in a cell context dependent manner. We recently reported that KLF4 maintains quiescence of T lymphocytes downstream of T-cell receptor signaling (Yamada et al., Nature Immunology, 2009). The role of KLF4 in reprogramming adult somatic cells into pluripotent stem cells along with Oct3/4, c-Myc and Sox2 suggests that KLF4 restricts proliferation of undifferentiated cells. In spite of a redundant role of KLF4 in fetal liver hematopoietic stem cells (HSC), its role in the maintenance of adult bone marrow HSCs has not been studied yet. To study the role of KLF4 in the hematopoietic system we used gain- and loss-of-function mouse models. Retroviral transfer of KLF4 into wild type bone marrow (BM) cells led to significant reduction of colony forming units (CFU) in methylcellulose cultures due to increased apoptosis and lower proliferation. Then, Mx1-Cre was used to induce deletion of Klf4-floxed mice by polyI:C administration. Analysis of peripheral blood cells up to 6-9 months post polyI:C administration showed significant reduction of monocytes, as previously reported, and expansion of CD8+CD44+ T cells due to their increased proliferative potential. BM cells from Klf4-deficient mice exhibited increased number of myeloid progenitor cells measured by flow cytometry (Lin-Sca-1-c-kit+FcRII/III+CD34+ cells), CFU and CFU-S8. Cytoablation with 5-fluorouracil (5-FU) showed lower nadir of peripheral white blood cells in Klf4-deficient mice compared to control mice. In spite of normal multilineage reconstitution in BM transplants experiments, competitive reconstitution with Klf4-deficient and normal BM cells resulted in reduced contribution of Klf4-deficient cells to peripheral blood, likely due to homing and proliferative differences. Collectively, our data shows that KLF4 has an important role in function of hematopoietic stem and progenitor cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Bone Marrow Macrophage Galectin-3 Regulates Platelet Production through Recognition of O-Glycans on Megakaryocytes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 409-409
Author(s):  
Melissa M Lee-Sundlov ◽  
Renata Grozovsky ◽  
Silvia Giannini ◽  
Martina McGrath ◽  
Haley E Ramsey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Antigen Expression ◽  
Blood Platelet ◽  
Activated Macrophages ◽  
Bone Marrow Macrophage ◽  
Platelet Production ◽  
Platelet Counts ◽  
Pathological Conditions ◽  
Galectin 3

Abstract Bone marrow (BM) macrophages maintain both survival and retention of hematopoietic stem cells and regulate erythropoiesis. The role of macrophage lectins and glycans in thrombopoiesis remains unclear. We report a novel role for bone marrow macrophage galectin-3 in maintaining platelet counts, by phagocytosing megakaryocytes (MKs) expressing the Thomsen-Friedenreich (TF) antigen, which is often exposed under pathological conditions, such as cancer and malignancies. The TF antigen is a disaccharide presented in cryptic form on O-glycans and covered by a sialic acid moiety. The sialyltransferase ST3Gal1 transfers sialic acid onto the TF antigen. To investigate the role of O-glycans in thrombopoiesis, we generated mice with increased TF antigen in MKs by generating St3gal1loxP/PF4+ mice specifically lacking ST3Gal1 in the MK lineage. As expected, St3gal1loxP/PF4+ circulating platelets and BM MKs had increased TF antigen expression, compared to controls, as evidenced by peanut agglutinin (PNA) binding. Other blood cell lineages had no increase in TF antigen expression. St3gal1loxP/PF4+ mice developed mild thrombocytopenia, but surprisingly had virtually normal platelet clearance. BM MK colony forming units and in vitro proplatelet production were normal in St3gal1loxP/PF4+ mice, suggesting that extrinsic factors in the St3gal1loxP/PF4+BM environment affected platelet production. St3gal1loxP/PF4+ BM smears revealed increased hemophagocytosis, indicative of an increase in phagocytic macrophages. In vivo macrophage ablation by injection of clodronate-encapsulated liposomes significantly reduced the numbers of activated macrophages, thereby normalizing blood platelet counts and size. Flow cytometric phenotypic analysis of BM-derived macrophages showed an increased population of activated macrophages in St3gal1loxP/PF4+ mice, compared to controls, specifically macrophages with increased galectin-3 expression, a ligand for the TF antigen. Immunofluorescence staining of BM sections using a specific antibody towards the TF antigen showed that MK progenitors and pro-platelet-like structures expressed TF antigen in control BMs, which is significantly increased in St3gal1loxP/PF4+ mice and co-localized with galectin-3 expressing macrophages, supporting the notion that MK O-glycans and macrophage galectin-3 play a role in thrombopoiesis under steady state and pathological conditions. Consistent with this notion, galectin-3 deficient mice have slightly, but significantly increased blood platelet counts. We conclude that galactin-3 plays a minor role in normal thrombopoiesis. Activation of galectin-3 expressing macrophages by the MK TF antigen leads to MK phagocytosis, inhibition of platelet formation and thrombocytopenia. Disclosures No relevant conflicts of interest to declare.

The Routine Measurement of Platelet Size Using Sodium Citrate Alone as the Anticoagulant

1993 ◽  
Vol 70 (04) ◽  
pp. 687-690 ◽  
Author(s):  
P M W Bath
Keyword(s):  
Incubation Time ◽  
Sodium Citrate ◽  
Dependent Manner ◽  
High Concentration ◽  
Distribution Width ◽  
Routine Measurement ◽  
Platelet Size ◽  
Coefficients Of Variation ◽  
Important Marker ◽  
Made In

SummaryMean platelet volume (MPV), a measure of platelet size, is becoming recognised as an important marker of platelet function. However, platelets swell in edetic acid (EDTA), the Standard haematology anticoagulant, in a time-dependent manner making such measurements potentially unreliable. The effect of incubation time on MPV, and platelet distribution width (PDW), as measured in EDTA, low (1:9 volume/volume with blood) or high (1:4 v/v with blood) concentration sodium citrate was studied. MPV measured in high concentration sodium citrate did not change with time in contrast to MPV measured in either low concentration sodium citrate or EDTA which both increased in an inverse exponential fashion. MPV and PDW, measured in high concentration sodium citrate, had similar within-assay and between-assay coefficients of Variation as other platelet, red cell and white cell haematology variables measured in EDTA: MPV 1.4%, 2.1%; PDW 1.4%, 1.5%; MCV 0.4%, 0.7%; PC 3.1%, 6.1%; WCC 1.5%, 7.3%; Hb 2.1%, 2.4% respectively. MPV measured in EDTA and corrected for incubation time approximated to, but was higher than, the MPV measured in high concentration sodium citrate. PDW correlated inversely with platelet count (r = <0.415, 2p <0.001). MPV may be measured in sodium citrate (at 1:4 v/v with blood) alone with a better accuracy and reproducibility than similar measurements made in EDTA. Furthermore, such measurements are not influenced by incubation time, unlike for EDTA.

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