- Benzoquinone, a leukemogenic metabolite of benzene, catalytically inhibits the protein tyrosine phosphatase PTPN2 and alters STAT1 signaling. [Journal Article]
- JBJ Biol Chem 2019 Jun 27
- Protein tyrosine phosphatase, non-receptor type 2 (PTPN2) is mainly expressed in hematopoietic cells where it negatively regulates growth factor and cytokine signaling. PTPN2 is an important regulato…
Protein tyrosine phosphatase, non-receptor type 2 (PTPN2) is mainly expressed in hematopoietic cells where it negatively regulates growth factor and cytokine signaling. PTPN2 is an important regulator of hematopoiesis and immune/inflammatory responses, as evidenced by loss of function mutations of PTPN2 in leukemia and lymphoma and knockout mice studies. Benzene (BZ) is an environmental chemical that causes hematological malignancies, and its hematotoxicity arises from its bioactivation in the bone marrow to electrophilic metabolites, notably 1,4-benzoquinone (BQ), a major hematotoxic benzene metabolite. Although the molecular bases for benzene-induced leukemia are not well understood, it has been suggested that benzene metabolites alter topoisomerases II function and thereby significantly contribute to leukemogenesis. However, several studies indicate that benzene and its hematotoxic metabolites may also promote the leukemogenic process by reacting with other targets and pathways. Interestingly, alterations of cell-signaling pathways, such as Janus kinase (JAK)/signal transducer and activator of transcription (STAT), have been proposed to contribute to benzene-induced malignant blood diseases. We show here that 1,4-benzoquinone directly impairs PTPN2 activity. Mechanistic and kinetic experiments with purified human PTPN2 indicated that this impairment results from the irreversible formation (kinact = 645 M-1s-1) of a covalent 1,4-benzoquinone adduct at the catalytic cysteine residue of the enzyme. Accordingly, cell experiments revealed that 1,4-benzoquinone exposure irreversibly inhibits cellular PTPN2 and concomitantly increases tyrosine phosphorylation of STAT1 and expression of STAT1-regulated genes. Our results provide molecular and cellular evidence that 1,4-benzoquinone covalently modifies key signaling enzymes, implicating it in benzene-induced malignant blood diseases.
- The effect of subchronic oral exposure to zearalenone on hematologic and biochemical analytes, and the blood redox status of adult rabbit bucks. [Journal Article]
- VCVet Clin Pathol 2019; 48(2):328-334
- CONCLUSIONS: Under the present experimental conditions, ZEN affected some of the clinicopathologic analytes of adult rabbit bucks; these changes were mostly indicative of mild hepatocellular damage and dysfunction, inflammatory and/or allergic responses, and renal tubular damage. A ZEN dose of 50 μg/kg body weight did not seem to affect the blood redox status of bucks, as evaluated by the ROM concentrations.
- Thrombotic microangiopathy in hematotoxic snakebites and its impact on the prognosis: an entity often overlooked. [Journal Article]
- JTJ Thromb Thrombolysis 2019 Apr 26
- Snakebite associated thrombotic microangiopathy (TMA) is a spectrum of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury (AKI). We carried out thi…
Snakebite associated thrombotic microangiopathy (TMA) is a spectrum of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury (AKI). We carried out this study to find out the prevalence of TMA in hematotoxic snake envenomation and to analyze its impact on the clinical outcome of patients. Retrospective data were collected from the medical records, hospital and lab information system after institutional ethics committee approval. Hematotoxic snake bite patients were categorized into Group 1 (with TMA) and Group 2 (without TMA). Chi square test, Mann-Whitney 'U' test and Odd's ratio (OR) were used for statistical analysis. Out of 331 snakebite cases admitted, 202 (64.33%) were hematotoxic envenomation with a mean age of 42.26 ± 15.61. Majority were males with a male to female ratio of 2.01:1. Lower limb was the most common site of bite (59.9%). The prevalence of coagulopathy, TMA and AKI observed was 56.4, 18.8 and 37.6% respectively. AKI had a significant risk of undergoing hemodialysis when it was associated with TMA (r = 0.635, OR = 19.3182, P < 0.0001). Higher number of patients in Group 1 received more blood products (r = 0.406, OR = 8.525, P < 0.0001). Prolonged hospital stay (17.25 ± 12.23 vs. 8.86 ± 7.18 days, P < 0.0001) and higher complication rates were (33.33% vs. 11.4%, P < 0.0048) observed in patients with TMA. Snakebite associated TMA has a significant impact on the prognosis and understanding the pathophysiology of this entity will help to formulate guidelines.
- Ultraviolet A-induced hematotoxic and genotoxic potential in Nile tilapia Oreochromis niloticus. [Journal Article]
- PPPhotochem Photobiol Sci 2019 Jun 12; 18(6):1495-1502
- Fish as an aquatic organism could be harmed by various levels of solar ultraviolet radiation (UVA). The present study aimed to characterize UVA (20, 60 and 180 min for 3 days) irradiation-induced hem…
Fish as an aquatic organism could be harmed by various levels of solar ultraviolet radiation (UVA). The present study aimed to characterize UVA (20, 60 and 180 min for 3 days) irradiation-induced hematological and biochemical changes in Oreochromis niloticus. Hematological parameters such as the red blood cell (RBC) count, hemoglobin (Hb) level and hematocrit (Hct) value were significantly (p < 0.05) reduced in fish exposed to different doses of UVA. Also, the leukocyte (WBC) count was significantly reduced (p < 0.05). However, the differential counts of WBCs - lymphocytes, eosinophils and monocytes - increased significantly in the exposed fish compared to the control fish. Many morphological and genotoxic alterations in erythrocytes were observed in the present work. The glucose level showed a significant decrease, but cholesterol and triglycerides showed a significant increase after exposure to UVA. Total protein levels of the fish showed a significant increase (p < 0.05) in the exposed groups. Also, concentrations of urea and creatinine increased significantly as fish were exposed to increasing UVA radiation, compared to the control fish. Finally, the activities of alanine aminotransferase (ALT, U l-1) and aspartate aminotransferase (AST, U l-1) exhibited a significant increase (p < 0.05) with increasing UVA doses.
- Role of therapeutic plasma exchange in snake bite associated thrombotic microangiopathy-A case report with review of literature. [Case Reports]
- JCJ Clin Apher 2019 Feb 19
- Post snake bite renal failure due to thrombotic microangiopathy (TMA) is often overlooked and not considered as a separate entity while managing the patient. This case report highlights the efficacy …
Post snake bite renal failure due to thrombotic microangiopathy (TMA) is often overlooked and not considered as a separate entity while managing the patient. This case report highlights the efficacy of Therapeutic Plasma Exchange in managing the post envenomation TMA. Anti-snake venom was administered following severe hematotoxic envenomation, but later on developed acute kidney injury and hence hemodialysis was done for 2 days without much improvement. On third day of bite, diagnosis of TMA was made from microangiopathic hemolytic picture in peripheral blood smear, thrombocytopenia and renal failure. Therapeutic plasma exchange with human albumin solution was started on a daily basis and after 3 cycles, patient's condition improved as shown by the laboratory parameters. Though this entity is not well defined, the supporting evidence is found in few reports of published literature. Hence, we propose plasma exchange as an adjunctive therapeutic option in post snake TMA.
- Human exposure to mercury and its hematological effects: a systematic review. [Journal Article]
- CSCad Saude Publica 2019 Feb 11; 35(2):e00091618
- Mercury is a metal found in the environment from natural and anthropogenic sources. It is highly toxic to ecosystems and living beings. Most human exposures come from ingestion of contaminated seafoo…
Mercury is a metal found in the environment from natural and anthropogenic sources. It is highly toxic to ecosystems and living beings. Most human exposures come from ingestion of contaminated seafood, outgassing from dental amalgam or occupational exposure (e.g. gold mining), among other cases. Large populations are exposed to mercury, making it a very important issue from the public health perspective. Adverse health effects are commonly seen in the nervous system, but every organ is a potential target, such as the bone marrow. The main goal of this study was to assess the available evidence on human exposure to mercury and its hematological effects. A search strategy was constructed, including key terms (MeSH, text word and equivalents) for querying 2 repositories of master dissertation and PhD thesis (Fiocruz/ARCA and University of São Paulo) and 4 different electronic databases: BVS/LILACS, MEDLINE/PubMed, Scopus and TOXLINE/NIH, for articles published from 1950 to February 2018. There was no language restriction and a tool (EPHPP) was used to assess the quality of included studies. According to pre-established criteria, 80 studies were retrieved, all of them observational (48 case reports, 24 cross-sectional, 6 case series and 2 cohorts), comprising 9,284 people. Despite the fact that most exposed ones (6,012) had normal blood cell count and mercury hematological effects did not seem very usual (1,914 cases: 14 severe and 29 deaths), three studies reported association (β) for anemia, lymphopenia, neutrophilia and basophilia. We concluded that the gathered information pointed to mercury hematotoxic effects, some of them may be serious and even fatal.
- Hematological and immunological impairment following in-utero and postnatal exposure to aluminum sulfate in female offspring of albino rats. [Journal Article]
- IIImmunopharmacol Immunotoxicol 2019; 41(1):40-47
- CONCLUSIONS: Perinatal AS exposure caused mostly non-linear dose-dependent hematotoxicity and immunological impairment especially for the acquired immunity either cellular or humoral. Further studies can examine the immunotoxic effect of Al on male offspring during different stages of immune development.
- Utility of Clot Waveform Analysis in Russell's Viper Bite Victims with Hematotoxicity. [Journal Article]
- JEJ Emerg Trauma Shock 2018 Jul-Sep; 11(3):211-216
- CONCLUSIONS: CWA showed changes which provided information earlier than the conventional coagulation studies in the snakebite victims studied. While aPTT or WBCT reflects clotting time, CWA conveys the dynamic process of clot formation and stabilization. CWA may reveal disorders of clotting in snakebite victims before the conventional tests become abnormal. Future research should assess the speed and accuracy of the test in diagnosing hemotoxic envenomation and its potential role in guiding antivenom therapy.
- Effects of the food additives sodium acid pyrophosphate, sodium acetate, and citric acid on hemato-immunological pathological biomarkers in rats: Relation to PPAR-α, PPAR-γ and tnfα signaling pathway. [Journal Article]
- ETEnviron Toxicol Pharmacol 2018; 62:98-106
- The food additives sodium acid pyrophosphate (SAPP), sodium acetate (SA), and citric acid (CA) were evaluated for their hemato-immunotoxic effects. Forty adult Sprague-Dawley rats were distributed in…
The food additives sodium acid pyrophosphate (SAPP), sodium acetate (SA), and citric acid (CA) were evaluated for their hemato-immunotoxic effects. Forty adult Sprague-Dawley rats were distributed into four groups and were orally administered water, SAPP (12.6 mg/kg), CA (180 mg/kg), or SA (13.5 mg /kg) daily for 90 days. Erythrogram and leukogram profiles were evaluated. The levels of lysozyme, nitric oxide, immunoglobulin, and phagocytic activity were measured. Histologic and immunohistochemical evaluations of splenic tissues were performed. Changes in the mRNA expression levels of peroxisome proliferator-activated receptor α and γ (PPAR-α and PPAR-γ), and tumor necrosis factor α (TNF-α) genes were assessed. A significant leukopenic condition was observed with SAPP, while CA induced marked leukocytosis, and SA showed a lymphocytosis condition. Both the innate and humoral parameters were significantly depressed. Various pathological lesions were observed, including diffuse hyperplasia of the red pulp, depletion of the white pulp, and capsular and parenchymal fibrosis. A marked decrease in CD3 T-lymphocyte and CD20 B-lymphocyte immunolabeling in rats treated with SAPP and SA was evident. Marked downregulation of PPAR-α and PPAR-γ together with upregulation of TNF-α was recorded. These results indicate that high doses of SAPP, SA and CA exert hematotoxic and immunotoxic effects with long-term exposure.
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- Functional Assays of Hematopoietic Stem Cells in Toxicology Research. [Journal Article]
- MMMethods Mol Biol 2018; 1803:317-333
- The hematopoietic stem cell is the foundational cell of the entire blood and immune system and as such is particularly sensitive to toxicological insults. While this review will identify some of the …
The hematopoietic stem cell is the foundational cell of the entire blood and immune system and as such is particularly sensitive to toxicological insults. While this review will identify some of the classes of chemicals known to be hematotoxic, most of the discussion will focus on the strengths and weaknesses of various hematological assays used in toxicology research. Furthermore, protocols for isolating both human and murine hematopoietic stem cells are described. Methodologies are also described for various culture systems useful for testing the impacts of potential toxicants on hematopoietic stem cells both in vivo and in vitro.