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Aging Aug 2019This study determined whether or not benign prostatic hyperplasia (BPH) induced by a high-fat diet (HFD) is involved in inflammatory responses, apoptosis, and the signal...
This study determined whether or not benign prostatic hyperplasia (BPH) induced by a high-fat diet (HFD) is involved in inflammatory responses, apoptosis, and the signal transducer and activator of transcription (STAT3)/nuclear factor-kappa B (NF-κB)- and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress pathways. Forty rats were divided into four groups: control; HFD; testosterone; and HFD+testosterone. Hematoxylin and eosin (HE) staining was used to assess histologic changes. An enzyme-linked immunosorbent assay and Western blot analysis were used to detect levels of related proteins. Compared with the control group, the prostate levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), transforming growth factor-β1 (TGF-β1), and monocyte chemotactic protein-1 (MCP-1) were significantly increased, while the levels of glutathione peroxidase (GSH-Px), glutathione reductase (GR), glutathione (GSH), and superoxide dismutase (SOD) were decreased. The TNF-κB, Bcl-2, and caspase-3 levels were increased, while the Bax level was markedly decreased. The cytoplasmic expression of STAT3 and NF-κB was increased, while the nuclear expression of Nrf2 was markedly decreased compared with the control group. In summary, our results demonstrated that a long-term HFD might cause changes in inflammatory responses, apoptosis, and oxidative stress, thus contributing to prostatic hyperplasia. The underlying mechanisms might be related to the STAT3/NF-κB- and Nrf2-mediated oxidative stress pathway.
Topics: Animals; Apoptosis; Diet, High-Fat; Inflammation; Male; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Prostate; Prostatic Hyperplasia; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Signal Transduction; Testosterone
PubMed: 31412319
DOI: 10.18632/aging.102138 -
Frontline Gastroenterology 2021Peripheral cytopaenias and dyspoiesis are common in cirrhosis; however, the prevalence of dyspoiesis and its contribution in cirrhosis-related cytopaenias has not been...
BACKGROUND AND AIM
Peripheral cytopaenias and dyspoiesis are common in cirrhosis; however, the prevalence of dyspoiesis and its contribution in cirrhosis-related cytopaenias has not been studied. We aimed to study the bone marrow (BM) dyspoiesis and its impact on peripheral blood cell counts and refractory anaemia in patients with cirrhosis.
PATIENTS AND METHODS
We reviewed all the BM aspirates and biopsies of cirrhotic cases, done from 2011 to 2018 for clinical indications. Dyspoiesis was considered if >5% of the precursor cells of any of the three lineages showed dyspoietic changes. Primary haematological or non-haematological malignancies, chronic kidney disease, drug intake, acute and chronic hepatitis and granulomatous disease were excluded.
RESULTS
Of 608 these, 82 cases (13.5%) showed dyspoiesis in the BM precursors. There was no difference in age (p=0.16), gender (p=0.58) and spleen size (p=0.35) in cases with or without dyspoiesis. Majority of the cases had dyspoiesis in erythroid series (62, 75.6%) and megakaryocytes (15, 18.2%). Dyspoiesis was more prominent in alcoholics 44 cases (53.6%) and autoimmune diseases 13 cases (15.8%). Erythroid hyperplasia (47.7±14.4 vs 40±11.1; p<0.001) was more in cases with dyserythropoiesis, indicating ineffective erythropoiesis. Patients with dyspoiesis had lower haemoglobin (7.5±1.9 vs 9.3±2.2 g/dL, p<0.001). 54 (8.07%) had refractory anaemia with dyspoiesis present in 48 (88.8%) (p<0.01). Dyspoiesis was independently associated with refractory anaemia when adjusted for age, gender, aetiology and liver disease severity.
CONCLUSIONS
BM dyspoiesis, especially dyserythropoiesis, is associated with severe refractory anaemia in patients with cirrhosis and requires new therapeutic approaches.
PubMed: 33489067
DOI: 10.1136/flgastro-2019-101350 -
Nutrients Nov 2011Vitamin E consists of eight different variants: α-, β-, γ-, and δ-tocopherols (saturated phytyl tail) and α-, β-, γ-, and δ-tocotrienols (unsaturated phytyl... (Review)
Review
Vitamin E consists of eight different variants: α-, β-, γ-, and δ-tocopherols (saturated phytyl tail) and α-, β-, γ-, and δ-tocotrienols (unsaturated phytyl tail). Cancer prevention studies with vitamin E have primarily utilized the variant α-tocopherol. To no avail, a majority of these studies focused on variant α-tocopherol with inconsistent results. However, γ-tocopherol, and more recently δ-tocopherol, have shown greater ability to reduce inflammation, cell proliferation, and tumor burden. Recent results have shown that γ-enriched mixed tocopherols inhibit the development of mammary hyperplasia and tumorigenesis in animal models. In this review, we discuss the possible differences between the variant forms, molecular targets, and cancer-preventive effects of tocopherols. We recommend that a γ-enriched mixture, γ- and δ-tocopherol, but not α-tocopherol, are promising agents for breast cancer prevention and warrant further investigation.
Topics: Apoptosis; Breast Neoplasms; Cell Proliferation; Cyclooxygenase 2; ErbB Receptors; Female; Humans; NF-E2-Related Factor 2; PPAR gamma; Receptors, Estrogen; Tocopherols; Vitamin E; alpha-Tocopherol; gamma-Tocopherol
PubMed: 22254089
DOI: 10.3390/nu3110962 -
Pediatrics and Neonatology Nov 2022Unlike in adults, there is no consensus on management and diagnosis of polycythemia in children. This study aims to evaluate the diagnosis and verify the algorithm in...
BACKGROUND
Unlike in adults, there is no consensus on management and diagnosis of polycythemia in children. This study aims to evaluate the diagnosis and verify the algorithm in children with polycythemia.
METHODS
Seventy-nine children with polycythemia were followed-up in our pediatric hematology-oncology clinic between December 15, 2019, and July 15, 2021. After eliminating secondary causes (hypoxia, pulmonary, cardiac diseases), we checked for genetic mutations, including congenital erythrocytosis gene panel (JAK, EPOR, EPAS1, EGNL1, HBB, HBA, BPGM, and VHL). We also compared parameters for secondary and idiopathic polycythemia groups.
RESULTS
Of the 79 children, thirty-five had secondary polycythemia (hypoxia, pulmonary, cardiac diseases), and one was diagnosed with a novel likely pathogenic mutation c.2089C > G; p.Pro697Ala in exon 13 of EPAS1 gene. Others (n = 35) had persistent and idiopathic polycythemia. Here, we compared the idiopathic and secondary cases. We found that the ratio of family history of polycythemia (n = 4 (9.5%) vs 0%, respectively) was higher in the second group (p = 0.009). In addition, the mean age (14.7 ± 3.52 vs 13.4 ± 4.67 respectively) (p = 0.042) and the ratio of erythroid hyperplasia in bone marrow [n = 3 (8.6%) vs 0% respectively] (p = 0.003) was higher in the idiopathic polycythemia group, compared to secondary polycythemia patients.
CONCLUSION
Finding the genetic defect in polycythemia is a significant issue. Due to being a rarity in children, the first line JAK mutation analysis should be performed in selected cases. This study is the first description of a Turkish patient with EPAS1 p.Pro697Ala mutation, thereby expanding our knowledge about the clinical features of the disease. However, new investigations are required to confirm its function.
Topics: Child; Humans; Heart Diseases; Hypoxia; Mutation; Polycythemia; Adolescent; Basic Helix-Loop-Helix Transcription Factors
PubMed: 36002380
DOI: 10.1016/j.pedneo.2022.06.006 -
Experimental and Therapeutic Medicine Aug 2018The present study investigated the expression and clinical significance of kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid-2-related factor-2...
The present study investigated the expression and clinical significance of kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid-2-related factor-2 (Nrf2) expression in diffuse large B-cell lymphoma (DLBCL). These proteins were detected by immunohistochemistry in 39 DLBCL cases and 17 cases of reactive lymph node hyperplasia, and their association with the clinicopathological features of DLBCL patients was analyzed. In DLBCL, the percentage of cells with positive staining for Keap1 and Nrf2 was 46.2 and 35.9%, respectively, which was significantly higher than that in reactive lymph node hyperplasia (17.7 and 5.9%, respectively). There was no correlation between Keap1 and Nrf2 expression according to a Spearman rank correlation analysis (r=0.272; P>0.05). Keap1 and Nrf2 expression was associated with the international prognostic index and Ann-Arbor clinical stage (P<0.05), and Keap1 and Nrf2 expression was higher in DLBCL patients with stage III-IV (68.4 and 52.6%, respectively) compared with in those with stage I-II (25.0 and 20.0%, respectively). The aberrant expression of Keap1 and Nrf2 in DLBCL suggests that these factors may have crucial roles in the development and progression of the disease, and may therefore be used as prognostic indicators.
PubMed: 30112024
DOI: 10.3892/etm.2018.6208 -
Journal of the Mechanical Behavior of... Aug 2015Individuals with sickle cell disease often experience acute and chronic bone pain due to occlusive events within the tissue vasculature that result in ischemia,...
Individuals with sickle cell disease often experience acute and chronic bone pain due to occlusive events within the tissue vasculature that result in ischemia, necrosis, and organ degeneration. Macroscopically, sickle bone is identified in clinical radiographs by its reduced mineral density, widening of the marrow cavity, and thinning of the cortical bone due to the elevated erythroid hyperplasia accompanying the disease. However, the microstructural architecture of sickle bone and its role in mechanical functionality is largely unknown. This study utilized micro-CT and biomechanical testing to determine the relationship between the bone morphology, tissue mineral density, and trabecular and cortical microarchitecture of 10- and 21-week-old femurs from transgenic sickle male mice and littermates with sickle trait, as well as a wild-type control. While bone tissue mineral density did not vary among the genotypes at either age, variation in bone microstructure were observed. At 10 weeks, healthy and trait mice exhibited similar morphology within the cortical and trabecular bone, while sickle mice exhibited highly connected trabeculae. Within older femurs, sickle and trait specimens displayed significantly fewer trabeculae, and the remaining trabeculae had a more deteriorated geometry based on the structure model index. Thinning of the cortical region in sickle femurs contributed to the displayed flexibility with a significantly lower elastic modulus than the controls at both 10- and 21-weeks old. Wild-type and trait femurs generally demonstrated similar mechanical properties; however, trait femurs had a significantly higher modulus than sickle and wild-type control at 21-weeks. Overall, these data indicate that the progressive damage to the microvasculature caused by sickle cell disease, results in deleterious structural changes in the bone tissue׳s microarchitecture and mechanics.
Topics: Anemia, Sickle Cell; Animals; Biomechanical Phenomena; Bone Density; Disease Models, Animal; Elastic Modulus; Femur; Male; Mice; Weight-Bearing; X-Ray Microtomography
PubMed: 25957113
DOI: 10.1016/j.jmbbm.2015.04.019 -
Journal of Gastrointestinal Oncology Dec 2020Crocin, an active constituent of saffron, has anticancer activity. In this study, we investigated the relationship of Crocin with human gastric epithelial cells induced...
BACKGROUND
Crocin, an active constituent of saffron, has anticancer activity. In this study, we investigated the relationship of Crocin with human gastric epithelial cells induced by 1-methyl-3-nitroso-1-nitroguanidine (MNNG), and explored the underlying mechanism.
METHODS
, the animal growth and atypical hyperplasia were observed in Sprague-Dawley rats. A cell model was established by treating the human gastric mucosa epithelial cell line GES-1 with MNNG. The effects of Crocin on proliferation, cell cycle, apoptosis, and epithelial-mesenchymal transition (EMT) in GES-1 cells were analyzed using Cell Counting Kit-8, colony formation, flow cytometry, and Transwell assay, respectively. Western blot was used to explore the potential mechanism..
RESULTS
The gastric mucosa of animal model deteriorated obviously, the weight growth rate slowed down, and the atypical hyperplasia of gastric mucosa increased. The GES-1 cells had characteristics of malignant cells such as proliferation, apoptosis, and metastasis ability. It was found that Crocin suppressed the cell proliferation, increased apoptosis, and blocked the cycle arrest in G0/G1 phase simultaneously. Furthermore, Crocin negatively regulated the invasion ability of MNNG-treated GES-1 cells and EMT process. Crocin also increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), decreased TAZ in MNNG-treated GES-1 cells. Interestingly, Crocin regulated the expression of TAZ and yes-associated protein (YAP) by increasing Nrf2 level, as well as their upstream targets, mercaptopyruvate sulfurtransferase (MST) and large tumor suppressor (LATS).
CONCLUSIONS
Crocin protected against MNNG-induced malignant transformation through the Nrf2/Hippo signaling pathway, which might be a drug candidate for clinical gastric cancer management.
PubMed: 33456997
DOI: 10.21037/jgo-20-406 -
Free Radical Biology & Medicine Nov 2015Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates the basal and stress-inducible expression of a battery of genes encoding key components of the... (Review)
Review
Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease.
UNLABELLED
Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates the basal and stress-inducible expression of a battery of genes encoding key components of the glutathione-based and thioredoxin-based antioxidant systems, as well as aldo-keto reductase, glutathione S-transferase, and
NAD(P)H
quinone oxidoreductase-1 drug-metabolizing isoenzymes along with multidrug-resistance-associated efflux pumps. It therefore plays a pivotal role in both intrinsic resistance and cellular adaptation to reactive oxygen species (ROS) and xenobiotics. Activation of Nrf2 can, however, serve as a double-edged sword because some of the genes it induces may contribute to chemical carcinogenesis by promoting futile redox cycling of polycyclic aromatic hydrocarbon metabolites or confer resistance to chemotherapeutic drugs by increasing the expression of efflux pumps, suggesting its cytoprotective effects will vary in a context-specific fashion. In addition to cytoprotection, Nrf2 also controls genes involved in intermediary metabolism, positively regulating those involved in NADPH generation, purine biosynthesis, and the β-oxidation of fatty acids, while suppressing those involved in lipogenesis and gluconeogenesis. Nrf2 is subject to regulation at multiple levels. Its ability to orchestrate adaptation to oxidants and electrophiles is due principally to stress-stimulated modification of thiols within one of its repressors, the Kelch-like ECH-associated protein 1 (Keap1), which is present in the cullin-3 RING ubiquitin ligase (CRL) complex CRLKeap1. Thus modification of Cys residues in Keap1 blocks CRLKeap1 activity, allowing newly translated Nrf2 to accumulate rapidly and induce its target genes. The ability of Keap1 to repress Nrf2 can be attenuated by p62/sequestosome-1 in a mechanistic target of rapamycin complex 1 (mTORC1)-dependent manner, thereby allowing refeeding after fasting to increase Nrf2-target gene expression. In parallel with repression by Keap1, Nrf2 is also repressed by β-transducin repeat-containing protein (β-TrCP), present in the Skp1-cullin-1-F-box protein (SCF) ubiquitin ligase complex SCFβ-TrCP. The ability of SCFβ-TrCP to suppress Nrf2 activity is itself enhanced by prior phosphorylation of the transcription factor by glycogen synthase kinase-3 (GSK-3) through formation of a DSGIS-containing phosphodegron. However, formation of the phosphodegron in Nrf2 by GSK-3 is inhibited by stimuli that activate protein kinase B (PKB)/Akt. In particular, PKB/Akt activity can be increased by phosphoinositide 3-kinase and mTORC2, thereby providing an explanation of why antioxidant-responsive element-driven genes are induced by growth factors and nutrients. Thus Nrf2 activity is tightly controlled via CRLKeap1 and SCFβ-TrCP by oxidative stress and energy-based signals, allowing it to mediate adaptive responses that restore redox homeostasis and modulate intermediary metabolism. Based on the fact that Nrf2 influences multiple biochemical pathways in both positive and negative ways, it is likely its dose-response curve, in terms of susceptibility to certain degenerative disease, is U-shaped. Specifically, too little Nrf2 activity will lead to loss of cytoprotection, diminished antioxidant capacity, and lowered β-oxidation of fatty acids, while conversely also exhibiting heightened sensitivity to ROS-based signaling that involves receptor tyrosine kinases and apoptosis signal-regulating kinase-1. By contrast, too much Nrf2 activity disturbs the homeostatic balance in favor of reduction, and so may have deleterious consequences including overproduction of reduced glutathione and NADPH, the blunting of ROS-based signal transduction, epithelial cell hyperplasia, and failure of certain cell types to differentiate correctly. We discuss the basis of a putative U-shaped Nrf2 dose-response curve in terms of potentially competing processes relevant to different stages of tumorigenesis.
Topics: Animals; Carcinogenesis; Humans; NF-E2-Related Factor 2; Oxidation-Reduction; Oxidative Stress; Signal Transduction
PubMed: 26122708
DOI: 10.1016/j.freeradbiomed.2015.06.021 -
Archives of Pathology & Laboratory... Apr 2020Detailed diagnostic features of acute myeloid leukemia in Down syndrome are lacking, leading to potential misdiagnoses as standard acute myeloid leukemia occurring in...
CONTEXT.—
Detailed diagnostic features of acute myeloid leukemia in Down syndrome are lacking, leading to potential misdiagnoses as standard acute myeloid leukemia occurring in patients with Down syndrome.
OBJECTIVE.—
To evaluate diagnostic features of acute myeloid leukemia and myelodysplastic syndrome in patients with Down syndrome.
DESIGN.—
Diagnostic bone marrow samples from 163 patients enrolled in the Children's Oncology Group study AAML0431 were evaluated by using central morphologic review and institutional immunophenotyping. Results were compared to overall survival, event-free survival, mutation status, cytogenetics, and minimal residual disease results.
RESULTS.—
Sixty myelodysplastic syndrome and 103 acute myeloid leukemia samples were reviewed. Both had distinctive features compared to those of patients without Down syndrome. They showed megakaryocytic and erythroid but little myeloid dysplasia, and marked megakaryocytic hyperplasia with unusual megakaryocyte morphology. In acute myeloid leukemia cases, megakaryoblastic differentiation of blasts was most common (54 of 103, 52%); other cases showed erythroblastic (11 of 103, 11%), mixed erythroid/megakaryoblastic (20 of 103, 19%), or no differentiation (10 of 103, 10%). Myelodysplastic syndrome and acute myeloid leukemia cases had similar event-free survival and overall survival. Leukemic subgroups showed interesting, but not statistically significant, trends for survival and minimal residual disease. Cases with institutional diagnoses of French American British M1-5 morphology showed typical features of Down syndrome disease, with survival approaching that of other cases.
CONCLUSIONS.—
Myelodysplastic syndrome and acute myeloid leukemia in Down syndrome display features that allow discrimination from standard cases of disease. These distinctions are important for treatment decisions, and for understanding disease pathogenesis. We propose specific diagnostic criteria for Down syndrome-related subtypes of acute myeloid leukemia and myelodysplastic syndrome.
Topics: Child; Down Syndrome; Female; Humans; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes
PubMed: 31429606
DOI: 10.5858/arpa.2018-0526-OA -
Blood Advances Jan 2022VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is caused by somatic mutations in UBA1 and is identified by a genotype-driven method. This...
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is caused by somatic mutations in UBA1 and is identified by a genotype-driven method. This condition affects unrelated men with adultonset inflammatory syndromes in association with hematologic manifestations of peripheral cytopenia and bone marrow myeloid dysplasia. Although bone marrow vacuolization restricted to myeloid and erythroid precursors has been identified in patients with VEXAS, the detailed clinical and histopathological features of peripheral blood and bone marrows remain unclear. The current case report describes the characteristic hematologic findings in patients with VEXAS, including macrocytic anemia, thrombocytopenia, marked hypercellular bone marrow with granulocytic hyperplasia, megaloblastic changes in erythroid precursors, and the absence of hematogones in addition to prominent vacuoles in myeloid and erythroid precursor cells. Characterizing the clinical and hematologic features helps to raise awareness and improve diagnosis of this novel, rare, but potentially underrecognized disease. Prompt diagnosis expands the general knowledgeable and understanding of this disease, and optimal management may prevent patients from developing complications related to this refractory inflammatory syndrome and improve the overall clinical outcome.
Topics: Humans; Male; Mutation; Myelodysplastic Syndromes; Myeloproliferative Disorders; Neoplasms; Ubiquitin-Activating Enzymes
PubMed: 34649277
DOI: 10.1182/bloodadvances.2021005243