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OBJECTIVE: To investigate the relationship between mutated genes and clinical features in patients with essential thrombocythemia (ET). METHODS: The clinical data of 69 patients with ET from October 2018 to March 2022 were retrospectively analyzed. According to driver mutation type, patients were divided into JAK2 group, CALR group and triple-negative group. The sex, age, cardiovascular risk factors, thrombosis, splenomegaly, routine blood test and coagulation status of patients in three groups were analyzed. RESULTS: Among 69 ET patients, 46 cases were associated with JAK2 mutation, 14 cases with CALR mutation, 8 cases with triple-negative mutation, and one with MPL gene mutation. There were no significant differences in age and sex among the three groups (P >0.05). The highest thrombotic rate was 26.09% (12/46) in JAK2 group, then 12.5% (1/8) in triple-negative group, while no thrombotic events occurred in CALR group. The incidence of splenomegaly was the highest in JAK2 group (34.78%), while no splenomegaly occurred in triple-negative group. The white blood cell (WBC) count in JAK2 group was (9.00±4.86)×109/L, which was significantly higher than (6.03±2.32)×109/L in CALR group (P <0.05). The hemoglobin (Hb) and hematocrit (HCT) in JAK2 group were (148.42±18.79) g/L and (0.44±0.06)%, respectively, which were both significantly higher than (131.00±15.17) g/L and (0.39±0.05)% in triple-negative group (P <0.05). The platelet (PLT) in JAK2 group was (584.17±175.77)×109/L, which was significantly lower than (703.07±225.60)×109/L in CALR group (P <0.05). The fibrinogen (Fg) in JAK2 and triple-negative group were (2.64±0.69) g/L and (3.05±0.77) g/L, respectively, which were both significantly higher than (2.24±0.47) g/L in CALR group (P <0.05, P <0.01). The activated partial thromboplastin time (APTT) in triple-negative group was (28.61±1.99) s, which was significantly decreased compared with (31.45±3.35) s in CALR group (P <0.05). CONCLUSIONS: There are differences in blood cell count and coagulation status among ET patients with different driver gene mutations. Among ET patients, JAK2 mutation is most common. Compared with CALR group, the thrombotic rate, WBC and Fg significantly increase in JAK2 group, while PLT decrease. Compared with triple-negative group, the incidence of splenomegaly and HCT significantly increase. Compared with CALR group, Fg significantly increases but APTT decreases in triple-negative group.
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Trombocitemia Essencial , Trombose , Humanos , Calreticulina/genética , Janus Quinase 2/genética , Mutação , Estudos Retrospectivos , Esplenomegalia/complicações , Trombocitemia Essencial/genética , Trombocitemia Essencial/complicaçõesRESUMO
Buyang Huanwu Decoction (BYHW) contains chemical components such as ligustrazine, oxypaeoniflora, chlorogenic acid, and others. To explore the neuroprotective effect and potential target protein of BYHW in cerebral infarction (CI). A double-blind, randomized controlled trial was established and patients with CI were divided into the BYHW group (n = 35) and the control group (n = 30). To evaluate the efficacy by TCM syndrome score and clinical indicators, and to explore the changes of serum proteins by proteomics technology, so as to explore the mechanism of BYHW and potential target proteins. The study found that compared with the control group, the TCM syndrome score, including Deficiency of Vital Energy (DVE), Blood Stasis (BS), and NIHSS in the BYHW group decreased significantly (p < 0.05), and the Barthel Index (BI) score was significantly higher. A total of 99 differential regulatory proteins were identified by proteomics, which act on lipids and atherosclerosis, complement and coagulation cascade, and TNF-α signaling pathway. In addition, Elisa verified the results of proteomics and found that BYHW can reduce the neurological impairments focus on IL-1ß, IL-6, TNF-α, MCP-1, MMP-9, and PAI-1. Significance: In this study, quantitative proteomics was used in combination with liquid chromatography-mass spectrometry (LC-MS/MS) to study the therapeutic effect of BYHW on cerebral infarction (CI) and potential changes in serum proteomics. In addition, the public proteomics database was used for bioinformatics analysis, and Elisa experiment verified the results of proteomics, further clarifying the potential protection mechanism of BYHW on CI.
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Proteômica , Fator de Necrose Tumoral alfa , Humanos , Cromatografia Líquida , Espectrometria de Massas em Tandem , Infarto Cerebral/tratamento farmacológicoRESUMO
Polycythemia vera (PV) is a malignant clonal hematological disease of hematopoietic stem cells characterized by the proliferation of peripheral blood cells, and JAK2 mutation is one of the main causes of PV peripheral blood cell proliferation. Abnormal cell metabolism is a new feature of malignant proliferation of tumor cells, but the role of metabolism in the pathogenesis and prognosis of PV remains unclear. We analyzed metabolic differences of peripheral blood sera between 32 PV patients and 20 healthy controls (HCs) by liquid chromatography-mass spectrometry (LC-MS) to investigate their relationship with cell proliferation and to screen for prognosis-related metabolic biomarkers. Compared to HC, 33 endogenous metabolites were significantly changed in PV and were involved in fatty acid metabolism, glucose metabolism, sphingolipid metabolism, and amino acid metabolism pathways. Among them, seven metabolites were closely associated with JAK2 mutations, 2 of which may contribute to the proliferation of peripheral blood cells in PV patients. A set of potential prognostic metabolic biomarkers containing four metabolites was identified by a receiver operating characteristic (ROC) curve according to the risk stratification of the PV patients and their combined AUC value of 0.952, with a sensitivity of 90.905% and specificity of 90.909% at the optimal cutoff point. Metabonomics is an important tool for the study of the pathogenesis of PV and the relationship between JAK2 gene mutation. Furthermore, the potential biomarkers of this study may provide a reference for the prognosis of PV.
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AbstractObjective: To analyze the DNA methylation gene mutations of myeloproliferative neoplasm (MPN), and preliminarily explore its clinical features. METHODS: Next-generation sequencing technology was used to detect 31 MPN-related genes in 105 cases of MPN patients ï¼»40 cases of polycythaemia vera (PV), 65 cases of essential thrombocythemia (ET)ï¼½, and to analyze the relationship between DNA methylation gene mutations and clinical features. RESULTS: 15 mutation types were detected in 105 patients (88 mutations in total), and the total mutation detection rate was 87.6% (92/105). A total of 23 mutations in 4 DNA methylation genes (TET2, DNMT3A, IDH1, IDH2) were detected in 22 patients. The mutation rate of DNA methylation genes was 21.0%, mainly in the form of double mutations, including JAK2 V617F and TET2 (n=10), JAK2 V617F and DNMT3A (n=4), CALR and TET2 (n=2), JAK2 V617F and IDH1 (n=1). Compared with MPN patients without DNA methylation gene mutations, the proportion of women with DNA methylation gene mutations and the white blood cell count (WBC) were significantly higher (P<0.05). Compared with MPN patients with triple-negative driver genes, the proportion of women with DNA methylation gene mutations, age, WBC, platelet count (PLT), and neutrophil-to-lymphocyte ratio (NLR) were significantly higher (P<0.05). The remaining difference was not statistically significant (P>0.05). The MPN10 score, the incidence of thrombotic events, and the proportion of medium-risk and high-risk patients with DNA methylation gene mutations were significantly higher than those of MPN patients without DNA methylation gene mutations (P<0.05). CONCLUSION: The mutation rate of DNA methylation genes was 21.0%, mainly coexisting in the form of double mutations. The proportion of women with DNA methylation gene mutations in MPN patients and WBC is high, the symptom load is heavy, the incidence of thrombosis is high, and the proportion of medium-high-risk patients is high, suggesting that their prognosis may be poor.
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Transtornos Mieloproliferativos , Policitemia Vera , Calreticulina/genética , Metilação de DNA , Feminino , Humanos , Janus Quinase 2/genética , Mutação , Transtornos Mieloproliferativos/genética , Policitemia Vera/genéticaRESUMO
DNA hypermethylation is an epigenetic modification that plays a critical role in the oncogenesis of myelodysplastic syndromes (MDS). Aberrant DNA methylation represses the transcription of promotors of tumor suppressor genes, inducing gene silencing. Realgar (α-As4S4) is a traditional medicine used for the treatment of various diseases in the ancient time. Realgar was reported to have efficacy for acute promyelocytic leukemia (APL). It has been demonstrated that realgar could efficiently reduce DNA hypermethylation of MDS. This review discusses the mechanisms of realgar on inhibiting DNA hypermethylation of MDS, as well as the species and metabolisms of arsenic in vivo.
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Arsenicais , Síndromes Mielodisplásicas , Arsenicais/farmacologia , Arsenicais/uso terapêutico , DNA , Metilação de DNA/genética , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , SulfetosRESUMO
Background: Acute myocardial infarction (AMI) is a common and life-threatening cardiovascular disease. However, there is a lack of pathology and drug studies on AMI within 20 min. Xueshuantong injection (XST) is mainly composed of Panax notoginseng saponins, which can dilate blood vessels and improve blood circulation, and is clinically used in the treatment of cardiovascular and cerebrovascular diseases. Purpose: The study aimed to investigate the protective mechanism of Xueshuantong injection against acute myocardial infarction within 20 min in rats by proteomic methods and molecular docking. Method: The male Sprague-Dawley rat acute myocardial infarction model was established by LAD ligation, and Xueshuantong injection (38 mg/kg) was injected into the caudal vein 15 min before surgery. Cardiac function evaluation, morphological observation, label-free quantitative proteomics, Western blotting analysis, molecular docking, and affinity measurement were applied in this study. Results: In a span of 20 min after acute myocardial infarction, the model group showed significant cardiac function impairment. Xueshuantong injection can significantly improve cardiac function and prevent pathological injury of myocardial tissue. A total of 117 vital differentially expressed proteins were identified by proteomic analysis, including 80 differentially expressed proteins (DEPs) in the sham group compared with model rats (Sham: model) and 43 DEPs in model rats compared with the Xueshuantong injection group (Model: XST). The treatment of Xueshuantong injection mainly involves "poly(A) RNA binding" and "cadherin binding involved in cell-cell adhesion." The differentially expressed levels of the pathways related to proteins Echdc2, Gcdh, Dlst, and Nampt, as well as 14-3-3 family proteins Ywhaz and Ywhab, could be quantitatively confirmed by WB. Molecular docking analysis and SPR analysis revealed that Ywhaz has a generally stable binding with five Xueshuantong injection components. Conclusion: Xueshuantong injection (XST) could protect rat myocardial function injury against AMI in 20 min. Echdc2, Ywhaz, Gcdh, Ywhab, Nampt, and Dlst play an essential role in this protective effect. In particular, Ywhaz might be the core target of Xueshuantong injection when treating acute myocardial infarction in the early stage. This study promoted the understanding of the protective mechanism of Xueshuantong injection in 20 min injury of acute myocardial infarction and contributed to the identification of possible targets of Xueshuantong injection.
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BACKGROUND: Astrogliosis can result in astrocytes with hypertrophic morphology after injury, indicated by extended processes and swollen cell bodies. Lipocalin-2 (LCN2), a secreted glycoprotein belonging to the lipocalin superfamily, has been reported to play a detrimental role in ischaemic brains and neurodegenerative diseases. Sailuotong (SLT) capsule is a standardized three-herb preparation composed of ginseng, ginkgo, and saffron for the treatment of vascular dementia. Although recent clinical trials have demonstrated the beneficial effect of SLT on vascular dementia, its potential cellular mechanism has not been fully explored. METHODS: Male adult Sprague-Dawley (SD) rats were subjected to microsphere-embolized cerebral ischaemia. Immunostaining and Western blotting were performed to assess astrocytic reaction. Human astrocytes exposed to oxygen-glucose deprivation (OGD) were used to elucidate the effects of SLT-induced inflammation and astrocytic reaction. RESULTS: A memory recovery effect was found to be associated with the cerebral ischaemia-induced expression of inflammatory proteins and the suppression of LCN2 expression in the brain. Additionally, SLT reduced the astrocytic reaction, LCN2 expression, and the phosphorylation of STAT3 and JAK2. For in vitro experiments, OGD-induced expression of inflammation and LCN2 was also decreased in human astrocyte by the SLT treatment. Moreover, LCN2 overexpression significantly enhanced the above effects. SLT downregulated these effects that were enhanced by LCN2 overexpression. CONCLUSIONS: SLT mediates neuroinflammation, thereby protecting against ischaemic brain injury by inhibiting astrogliosis and suppressing neuroinflammation via the LCN2-JAK2/STAT3 pathway, providing a new idea for the treatment strategy of ischaemic stroke.
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Isquemia Encefálica/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Inflamação/tratamento farmacológico , Lipocalina-2/antagonistas & inibidores , Lipocalina-2/metabolismo , Memória/efeitos dos fármacos , Animais , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , TransfecçãoRESUMO
Background: Astrogliosis has the potential to lead to harmful effects, namely, neuroinflammation, and to interfere with synapse sprouting. Previous studies have suggested that Lipocalin-2 (LCN2) acts as a key target in regulating the reaction of astrocytes. However, the underlying molecular mechanism is not fully elucidated. In the present study, we examined the neuroprotective and anti-inflammatory effects of Ginkgo biloba extract (EGB), a well-known extract with potential immunoregulatory properties in the nervous system. Methods: Triphenyltetrazolium chloride staining, hematoxylin-eosin staining, electron microscopy, and neurological assessments were performed in a microsphere-embolized rat model. Human astrocytes exposed to oxygen glucose deprivation (OGD) were used for in vitro experiments. Inflammatory cytokines, multi-labeling immunofluorescence, and Western blotting were used to investigate the molecular mechanisms underlying the EGB-mediated anti-inflammatory effects in vivo and in vitro. Results: EGB markedly attenuated cerebral infarction and neuronal apoptosis, reduced the inflammatory cytokine level, and alleviated neurological deficiencies in cerebral ischemic rats. After surgery, EGB significantly inhibited astrocyte activation, reduced the phosphorylation of STAT3 and JAK2 and decreased LCN2 expression. In vitro, EGB blocked OGD-induced STAT3 activation and the generation of pro-inflammatory cytokines in human astrocytes, and these effects were significantly enhanced by LCN2 overexpression. EGB downregulated these effects enhanced by LCN2 overexpression. Conclusion: EGB is demonstrated to mediate neuroinflammation, which protects against ischemic brain injury by inhibiting astrogliosis and suppresses neuroinflammation via the LCN2-JAK2/STAT3 pathway, providing insight into a promising therapeutic strategy for ischemic stroke.