Cadmium contributes to cardiac metabolic disruption by activating endothelial HIF1A-GLUT1 axis.

Cadmium (Cd) is an environmental risk factor of cardiovascular diseases. Researchers have found that Cd exposure causes energy metabolic disorders in the heart decades ago. However, the underlying molecular mechanisms are still elusive. In this study, male C57BL/6 J mice were exposed to cadmium chloride (CdCl2) through drinking water for 4 weeks. We found that exposure to CdCl2 increased glucose uptake and utilization, and disrupted normal metabolisms in the heart. In vitro studies showed that CdCl2 specifically increased endothelial glucose uptake without affecting cardiomyocytic glucose uptake and endothelial fatty acid uptake. The glucose transporter 1 (GLUT1) as well as its transcription factor HIF1A was significantly increased after CdCl2 treatment in endothelial cells. Further investigations found that CdCl2 treatment upregulated HIF1A expression by inhibiting its degradation through ubiquitin-proteasome pathway, thereby promoted its transcriptional activation of SLC2A1. Administration of HIF1A small molecule inhibitor echinomycin and A-485 reversed CdCl2-mediated increase of glucose uptake in endothelial cells. In accordance with this, intravenous injection of echinomycin effectively ameliorated CdCl2-mediated metabolic disruptions in the heart. Our study uncovered the molecular mechanisms of Cd in contributing cardiac metabolic disruption by inhibiting HIF1A degradation and increasing GLUT1 transcriptional expression. Inhibition of HIF1A could be a potential strategy to ameliorate Cd-mediated cardiac metabolic disorders and Cd-related cardiovascular diseases.

Characterizing the dynamic learning process: Implications of a quantitative analysis.

Understanding the neural mechanisms involved in learning processes is crucial for unraveling the complexities of behavior and cognition. Sudden change from the untrained level to the fully-learned level is a pivotal feature of instrumental learning. However, the concept of change point and suitable methods to conveniently analyze the characteristics of sudden change in groups remain elusive, which might hinder a fuller understanding of the neural mechanism underlying dynamic leaning process. In the current study, we investigated the learning processes of mice that were trained in an aversive instrumental learning task, and introduced a novel strategy to analyze behavioral variations in instrumental learning, leading to improved clarity on the concept of sudden change and enabling comprehensive group analysis. By applying this novel strategy, we examined the effects of cocaine and a cannabinoid receptor agonist on instrumental learning. Intriguingly, our analysis revealed significant differences in timing and occurrence of sudden changes that were previously overlooked using traditional analysis. Overall, our research advances understanding of behavioral variation during instrumental learning and the interplay between learning behaviors and neurotransmitter systems, contributing to a deeper comprehension of learning processes and informing future investigations and therapeutic interventions.

Parthenolide inhibits the proliferation and migration of cervical cancer cells via FAK/GSK3ß pathway.

PURPOSE: Cervical cancer (CC) ranks as the fourth most prevalent malignancy among women worldwide, necessitating effective therapeutic interventions to mitigate its detrimental impact on both physical and mental health. Parthenolide (PTL), a natural product of the sesquiterpene lactone derived from Feverfew leaves, has exhibited promising anti-tumor properties in previous studies; however, its precise effects and underlying molecular mechanisms in CC remain elusive. METHODS: In this work, we investigated the effect of PTL on the proliferation and migration of CC cells. Western blot analysis and Reverse transcription­quantitative PCR were used for mechanistic elucidation. RESULTS: Our findings indicated that PTL substantially inhibited the proliferation of HeLa and SiHa CC cell lines in a dose- and time-dependent manner. Moreover, PTL significantly suppressed the migration of CC cells by down-regulating the expression of vascular endothelial growth factor (VEGF), metastasis-associated protein 1 (MTA1), and transforming growth factor-ß1 (TGF-ß1). Mechanistically, PTL blocked the phosphorylation of focal adhesion kinase (FAK) and glycogen synthase kinase-3ß (GSK3ß) induced by epidermal growth factor (EGF). Further investigations revealed that PTL suppressed the proliferation of CC cells by inhibiting the EGF-mediated phosphorylation of the FAK/GSK3ß signaling pathway. CONCLUSION: Taken together, the present in vitro results suggest that PTL may inhibit the proliferation and migration of CC cells through down-regulating the FAK/GSK3ß signaling pathway, providing new insights for the application of PTL in the treatment of CC.

Severe graft-versus-host disease post allogeneic hematopoietic stem cell transplantation due to loss of HLA heterozygosity in recipient lymphocytes after full graft rejection.

Germ cell tumors complicated by hematological malignancy (HM) are a rare clinical phenomenon. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially effective therapy, but graft-versus-host disease (GVHD) is a life-threatening complication. We report a case of a 13-year-old female patient diagnosed with germ cell tumors followed by acute lymphoblastic leukemia. After chemotherapy, she received allo-HSCT and her chimerism rate decreased rapidly to near zero by 6 months without evidence of HM recurrence. However, she developed severe, multiorgan GVHD-like manifestations. DNA analysis revealed the pathogenesis of GVHD to be loss of HLA heterozygosity in recipient hematopoietic cells.

ß­adrenergic receptor activation promotes the proliferation of HepG2 cells via the ERK1/2/CREB pathways.

Primary liver cancer is one of the most frequently diagnosed malignant tumors seen in clinics, and typically exhibits aggressive invasive behaviors, a poor prognosis, and is associated with high mortality rates. Long-term stress exposure causes norepinephrine (NE) release and activates the ß-Adrenergic receptor (ß-AR), which in turn exacerbates the occurrence and development of different types of cancers; however, the molecular mechanisms of ß-AR in liver cancer are not fully understood. In the present study, reverse transcription (RT)-PCR and RT-quantitative PCR showed that ß-AR expression was upregulated in human liver cancer cells (HepG2) compared with normal liver cells (LO2). Moreover, NE treatment promoted the growth of HepG2 cells, which could be blocked by propranolol, a ß-AR antagonist. Notably, NE had no significant effect on the migration and epithelial-mesenchymal transition in HepG2 cells. Further experiments revealed that NE increased the phosphorylation levels of the extracellular signal-regulated kinase 1/2 (ERK1/2) and cyclic adenosine monophosphate response element-binding protein (CREB), while inhibition of ERK1/2 and CREB activation significantly blocked NE-induced cell proliferation. In summary, the findings of the present study suggested that ß-adrenergic receptor activation promoted the proliferation of HepG2 cells through ERK1/2/CREB signaling pathways.

Cucurbitacin E inhibits the proliferation of glioblastoma cells via FAK/AKT/GSK3ß pathway.

Glioblastoma (GBM) is the most common primary intracranial tumor in the brain with high growth rate and high mortality rate. Cucurbitacin E (CUE), a tetracyclic triterpene compound derived from species of the genus Cucurbita, has been demonstrated to display significant antitumor effects on various malignancies. In the present study, the effects of CUE on GBM and its underlying molecular mechanisms were explored. The data revealed that CUE inhibited the proliferation of the GBM cell lines U87­MG and U251­MG in a dose­ and time­dependent manner. Mechanistically, CUE reduced the phosphorylation of focal adhesion kinase (FAK), protein kinase B (AKT), and glycogen synthase kinase­3ß (GSK3ß) at both basal and epidermal growth factor (EGF)­induced levels. Moreover, CUE inhibited the proliferation of U87­MG and U251­MG cells by blocking EGF­induced phosphorylation of the FAK, AKT and GSK3ß. Subsequently, CUE reduced the expression of cyclinD1 and cyclinB1. Collectively, these results indicated that CUE inhibited the proliferation of U87­MG and U251­MG cells by suppressing the FAK/AKT/GSK3ß signaling pathway, which also suggested that CUE has potential application in treating GBM.

Refractory hepatosplenic T-cell lymphoma was successfully treated with salvage allogeneic hematopoietic stem cell transplantation combined with enhanced myeloablative preconditioning.

This study aims to evaluate the clinical benefit of salvage allogeneic hematopoietic stem cell transplantation (allo-HSCT) in combination with enhanced myeloablative preconditioning in the treatment of refractory liver and spleen T-cell lymphomas. A retrospective analysis was performed on three patients (with refractory liver and spleen T-cell lymphomas) who have been treated with salvage allo-HSCT combined with enhanced myeloablative preconditioning. One of three patients had a liver biopsy; the other two underwent bone marrow analysis using morphology, immunology, cytogenetics, and molecular biology. All three patients were resistant to chemotherapy and with a high tumor load, so a new total body irradiation/splenic region irradiation/GEM/CLAG/ATG preconditioning regimen was conducted and followed with salvage HSCT. Two patients received haploidentical-donor hematopoietic stem cell transplants, and one received an unrelated full-donor hematopoietic stem cell transplant. The three patients survived disease-free until May 2021. Clinically, hepatosplenic T-cell lymphoma (HSTCL) is rare, with a poor prognosis and chemotherapy response. Based on the present study's encouraging clinical results, salvage allo-HSCT in conjunction with an enhanced myeloablative preconditioning regiment may be an effective and safe treatment for HSTCL.

Dihydroartemisinin protects blood-brain barrier permeability during sepsis by inhibiting the transcription factor SNAI1.

Blood-brain barrier (BBB) injury is involved in the pathogenesis of sepsis-associated encephalopathy. In this study, we used dihydroartemisinin (DHA), a derivative of artemisinin, to treat a cecal ligation and puncture (CLP)-induced mouse sepsis model and a tumour necrosis factor α (TNF-α)-stimulated human cerebral microvessel endothelial cells (hCMEC)/D3 cell line. We found that DHA decreased BBB permeability and increased the expression of the tight junction protein occludin (OCLN) in the CLP model. In hCMEC/D3 cells, DHA decreased TNF-α-induced hyperpermeability and increased the expression of OCLN. DHA also repressed SNAI1 expression in the CLP mouse model and in TNF-α-stimulated hCMEC/D3 cells. These data suggest that DHA protects BBB permeability during sepsis by stimulating the expression of OCLN, by downregulating the expression of the SNAI1 transcription factor.

Sinensetin suppresses angiogenesis in liver cancer by targeting the VEGF/VEGFR2/AKT signaling pathway.

Sinensetin (SIN) is a polymethoxy flavone primarily present in citrus fruits. This compound has demonstrated anticancer activity. However, the underlying mechanism of its action has not been fully understood. The present study investigated the impact of SIN on angiogenesis in a liver cancer model. In a murine xenograft tumor model, SIN inhibited the growth of HepG2/C3A human liver hepatoma cell-derived tumors and reduced the expression levels of platelet/endothelial cell adhesion molecule-1 and VEGF. In HepG2/C3A cells, SIN repressed VEGF expression by downregulating hypoxia-inducible factor expression. In cultured human umbilical vein endothelial cells, SIN increased apoptosis and repressed migration and tube formation. In addition, SIN decreased the phosphorylation of VEGFR2 and inhibited the AKT signaling pathway. Molecular docking demonstrated that the VEGFR2 core domain effectively combined with SIN at various important residues. Collectively, these data suggested that SIN inhibited liver cancer angiogenesis by regulating VEGF/VEGFR2/AKT signaling.

Two cases of acute lymphoid leukemia patients with loss of heterozygosity in HLA region before transplantation.

Leukemia is a complex disease in which mutations and other genomic and epigenomic abnormalities play a role in both its initiation and progression. Acute lymphoid leukemia (ALL) patients with loss of heterozygosity (LOH) in the HLA region before transplantation have been described rarely. In this report, we described two ALL cases with LOH encompassing the HLA, wholly or partly. HLA molecular typing was performed on peripheral blood (PB) and somatic cell. Simultaneously, we performed whole-exome sequencing. Typing results on PB samples collected during blast crisis demonstrated complete or partial homozygosity at the -A, -B, -C, -DR, and -DQ loci. Two somatic samples demonstrated heterozygosity at all loci. LOH at the HLA gene locus may significantly influence the donor search, resulting in misidentification of homozygous donors. We recommend confirming the patients' HLA typing with hematological malignancies when homozygosity is detected at any locus by using somatic samples or alternatively from PB when remission is achieved.

Galectin-9 and PSMB8 overexpression predict unfavorable prognosis in patients with AML.

Acute myeloid leukemia (AML) is a deadly heterogeneous hematologic malignancy. Despite the well-characterized genetic characteristics and new promising targeted therapies for AML, the clinical outcome remains suboptimal. Galectin-9 (Gal-9) is a good potential target due to its immunosuppressive capacity in inflammatory processes. In our study, we firstly performed a wide range of integrated bioinformatical approach to assess the importance of Gal-9 by analyzing the expression, potential function and prognostic impact in AML. The results indicated that Gal-9 is overexpressed in AML cells, especially when relapse after hematopoietic stem cell transplantation (HSCT) and predicts poor prognosis. Co-expression analysis showed Gal-9 has a strong positive correlation with proteasome subunit beta type-8 (PSMB8), which was also highly expressed in AML with poor prognosis, implying a synergy in cell survival, cell signaling and the development of AML. In summary, we have confirmed the overexpression of Gal-9 and its partner PSMB8 in AML and validated their importance as prognostic factors. We propose that Gal-9 and PSMB8 could be a promising molecular target for treatment of AML and may provide more combined treatment options, especially in patients with relapse after HSCT.

Dihydroartemisinin inhibits endothelial cell migration via the TGF-ß1/ALK5/SMAD2 signaling pathway.

Anti-angiogenesis therapy is a novel treatment method for malignant tumors. Endothelial cell (EC) migration is an important part of angiogenesis. Dihydroartemisinin (DHA) exhibits strong anti-angiogenic and anti-EC migration effects; however, the underlying molecular mechanisms are yet to be elucidated. The TGF-ß1/activin receptor-like kinase 5 (ALK5)/SMAD2 signaling pathway serves an important role in the regulation of migration. The present study aimed to explore the effects of DHA treatment on EC migration and the TGF-ß1/ALK5/SMAD2 signaling pathway. The effects of DHA on human umbilical vein EC migration were assessed using wound healing and Transwell assays. The effects of DHA on the TGF-ß1/ALK5/SMAD2 signaling pathway were detected using western blotting. DHA exhibited an inhibitory effect on EC migration in the wound healing and Transwell assays. DHA treatment upregulated the expression levels of ALK5 and increased the phosphorylation of SMAD2 in ECs. SB431542 rescued the inhibitory effect of DHA during EC migration. DHA inhibited EC migration via the TGF-ß1/ALK5/SMAD2-dependent signaling pathway, and DHA may be a novel drug for the treatment of patients with malignant tumors.

[Characteristic of 8p11 Myeloproliferative Syndrome with Rare Phenotype].

OBJECTIVE: To deeply understand the clinical manifestation, laboratory examination characteristics, diagnosis and treatment of an eight p11 myeloproliferative syndrome (EMS) with rare phenotypes. METHODS: The clinical and laboratory characteristics and the process of allogeneic hematopoietic stem cell transplantation (allo-HSCT) were summarized in 1 rare EMS case involving T/B/myeloid cells. Meanwhile, 2 similar cases in the previous literature were also discussed. RESULTS: The bone marrow examination indicated that the patient with B-cell acute lymphocytic leukemia. The lymph node biopsy showed that the patient was T lymphoblastic/myeloid lymphoma. The 8p11 abnormality was found by the examination of bone marrow chromosomes. The RT-PCR examination showed that the BCR-ABL fused gene was negtive. The FGFR1 breakage was found by using the FISH with FGFR1 probe in lymph node. The Mutation of FMNL3, NBPF1 and RUNX1 genes was found by using the whole exome sequencing. The patient received allo-HSCT under CR2. By the follow-up till to September 2019, the patient survived without the above-mentioned disease. CONCLUSION: EMS manifest as neoplasms involving T-lineage, B-lineage, and myeloid-lineage simultaneously is extremely rare. Although the FGFR1 gene-targeted therapy can be conducted, allo-HSCT should be actively considered.

Clostridium perfringens sepsis in three patients with acute leukemia and review of the literature.

In this study, we aimed to improve understanding of the clinical manifestations, laboratory findings, and risk factors of Clostridium perfringens sepsis in patients with acute leukemia and to analyze treatment strategies for improving prognosis. We analyzed clinical manifestations, laboratory data, diagnosis, and treatment strategies in three cases of C. perfringens sepsis in patients with acute leukemia. We also reviewed and analyzed the relevant literature, incorporating our findings into the discussion. All three patients developed septic shock with neutropenia following chemotherapy. Analysis of blood samples confirmed the presence of C. perfringens, and two patients had fulminant intravascular hemolysis and developed multiple organ dysfunction syndrome. Two patients survived and one died despite timely and full-dose antibacterial treatments, blood purification, and noninvasive positive pressure ventilation. Overall, our findings showed that C. perfringens sepsis is rare in patients with acute leukemia but progresses rapidly. A high mortality rate was observed, and patients often experienced refractory shock and intravascular hemolysis. This demonstrates the importance of early detection and diagnosis. Multimodal treatments, including fluid resuscitation, antibiotics, organ support, and blood purification, are essential for success.

Dihydroartemisinin inhibits the expression of von Willebrand factor by downregulation of transcription factor ERG in endothelial cells.

Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has effective antitumor and anti-inflammatory actions. von Willebrand factor (vWF), a large multifunctional glycoprotein, has a prominent function in hemostasis and is a key factor in thrombus formation. In addition, vWF has been regarded as a prospective biomarker for the diagnosis of endothelial dysfunction. In our experiment, we observed that 25 µM DHA specifically downregulated the expression of vWF mRNA and protein in human umbilical vein endothelial cells (HUVECs). Further investigations demonstrated that this DHA-decreased vWF expression was mediated by the transcription factor ERG and not GATA3. Luciferase activity assay confirmed that DHA regulated the ERG binding with the -56 ETS-binding motif on the human vWF promoter. Thus, the -56 ETS motif on the vWF promoter region regulates the expression of vWF gene which is induced by DHA. Taken together, we proved that DHA decreased the vWF transcription through the downregulation of ERG in HUVECs. As vWF plays a key role in vascular homeostasis, our findings suggest a new role of DHA in vascular diseases.

Erg mediates downregulation of claudin-5 in the brain endothelium of a murine experimental model of cerebral malaria.

Cerebral malaria (CM) is a severe complication with brain vascular hyperpermeability. Claudin-5 is the major component of tight junctions. To investigate the expression of claudin-5 in CM, we established a murine experimental cerebral malaria (ECM) model and an in vitro model by treating murine brain endothelial cells (bEnd3) with plasma from ECM mice. Expression of claudin-5 and the ETS transcription factor Erg was reduced in the brain endothelium of ECM mice. In bEnd3 cells exposed to ECM plasma, decreased expression of claudin-5 and Erg, and increased permeability were observed. Silencing of Erg significantly reduced Cldn5 expression. ChIP assays indicated that Erg binds to the -813 ETS motif of the murine Cldn5 gene promoter, and the binding is decreased by treatment with ECM plasma.