HDAC6 Enhances Endoglin Expression through Deacetylation of Transcription Factor SP1, Potentiating BMP9-Induced Angiogenesis.

Histone deacetylase 6 (HDAC6) plays a crucial role in the acetylation of non-histone proteins and is notably implicated in angiogenesis, though its underlying mechanisms were previously not fully understood. This study conducted transcriptomic and proteomic analyses on vascular endothelial cells with HDAC6 knockdown, identifying endoglin (ENG) as a key downstream protein regulated by HDAC6. This protein is vital for maintaining vascular integrity and plays a complex role in angiogenesis, particularly in its interaction with bone morphogenetic protein 9 (BMP9). In experiments using human umbilical vein endothelial cells (HUVECs), the pro-angiogenic effects of BMP9 were observed, which diminished following the knockdown of HDAC6 and ENG. Western blot analysis revealed that BMP9 treatment increased SMAD1/5/9 phosphorylation, a process hindered by HDAC6 knockdown, correlating with reduced ENG expression. Mechanistically, our study indicates that HDAC6 modulates ENG transcription by influencing promoter activity, leading to increased acetylation of transcription factor SP1 and consequently altering its transcriptional activity. Additionally, the study delves into the structural role of HDAC6, particularly its CD2 domain, in regulating SP1 acetylation and subsequently ENG expression. In conclusion, the present study underscores the critical function of HDAC6 in modulating SP1 acetylation and ENG expression, thereby significantly affecting BMP9-mediated angiogenesis. This finding highlights the potential of HDAC6 as a therapeutic target in angiogenesis-related processes.

Responsiveness to Platelet Transfusions in Pediatric Patients with Thrombocytopenia: Incidence, Clinical Variables.

BACKGROUND: Refractoriness to platelet transfusion has not been adequately studied in pediatric patients with thrombocytopenia. Our objectives were: (1) to describe the practice of platelet transfusion in pediatric patients with thrombocytopenia of various etiologies; (2) to assess the responsiveness to platelet transfusions and clinical variables affecting platelet transfusions response; and (3) to evaluate incidence of PTR. METHODS: A retrospective study included pediatric patients with thrombocytopenia admitted to a tertiary children's hospital who received ≥ 1 platelet transfusion during hospitalization. Responsiveness was measured by corrected count increment (CCI), poor platelet transfusion response (PPTR), and platelet transfusion refractoriness (PTR). RESULTS: A total of 334 patients were eligible for the study and received 1,164 transfusions, with a median of 2 (IQR: 1 - 5) platelet transfusions. Patients admitted with hematologic malignancies had the highest median number of platelet transfusions (5, IQR: 4 - 10). The median CCI of 1,164 platelet post-transfusions was 17.0 (IQR: 9.4 - 24.6) and the incidence of PPTR was 11.9%. Patients admitted with ITP had the lowest median CCI (7.6, IQR: 1.0 - 12.5) and the highest incidence of PPTR (36.4%, 8/22). Older age of platelet components, low doses of platelet transfusion, increasing number of platelet transfusions (≥ 5), splenomegaly, bleeding, DIC, shock, ECMO supported, and HLA antibody-positive were independent risk factors for PPTR. Finally, the incidence of PTR was 11.4%. CONCLUSIONS: Practical experience of clinicians regarding the use of apheresis platelets in pediatric patients is determined. Highlight that PTR is not a low probability event when apheresis platelets are received in pediatric patients.

Hydrogen sulfide functions as a micro-modulator bound at the copper active site of Cu/Zn-SOD to regulate the catalytic activity of the enzyme.

The present study examines whether there is a mechanism beyond the current concept of post-translational modifications to regulate the function of a protein. A small gas molecule, hydrogen sulfide (H2S), was found to bind at active-site copper of Cu/Zn-SOD using a series of methods including radiolabeled binding assay, X-ray absorption near-edge structure (XANES), and crystallography. Such an H2S binding enhanced the electrostatic forces to guide the negatively charged substrate superoxide radicals to the catalytic copper ion, changed the geometry and energy of the frontier molecular orbitals of the active site, and subsequently facilitated the transfer of an electron from the superoxide radical to the catalytic copper ion and the breakage of the copper-His61 bridge. The physiological relevance of such an H2S effect was also examined in both in vitro and in vivo models where the cardioprotective effects of H2S were dependent on Cu/Zn-SOD.

[Clinical and laboratory characteristics of juvenile myelomonocytic leukemia].

OBJECTIVE: To study the clinical and laboratory characteristics of juvenile myelomonocytic leukemia (JMML). METHODS: The clinical characteristics and laboratory results were retrospectively analyzed in 10 children with newly diagnosed JMML. They were compared with those of 28 children with myelodysplastic syndrome (MDS) and 44 children with chronic myeloid leukemia (CML). RESULTS: Compared with the children with CML or MDS, the children with JMML had significantly higher rates of skin rashes, ecchymosis, and lymphadenectasis, a significantly lower serum cholinesterase (ChE) level, and a significantly higher fetal hemoglobin level (P<0.05). The white blood cell count of children with JMML was significantly higher than that of children with MDS, but significantly lower than that of children with CML (P<0.05). In addition, the myeloid/erythroid ratio and rate of dyshaematopoiesis were significantly lower in children with JMML than those in children with CML or MDS. The children with JMML had a significantly higher expression of mature monocyte marker CD14 than those with CML or MDS (P<0.05). The levels of myeloid markers CD33, CD11b, CD13, and CD15 in children with JMML were significantly higher than those in children with MDS, but significantly lower than those in children with CML (P<0.05). The levels of CD2 and CD7 in children with JMML were higher than those in children with CML, but lower than those in children with MDS (P<0.05). CONCLUSIONS: Skin rashes, ecchymosis, lymphadenectasis, and ChE reduction are more common in children with JMML than in those with CML or MDS, while dyshaematopoiesis is less common. In addition, CD14 level increases significantly in children with JMML.