BSA-stabilized selenium nanoparticles ameliorate intracerebral hemorrhage's-like pathology by inhibiting ferroptosis-mediated neurotoxicology via Nrf2/GPX4 axis activation.

Intracerebral hemorrhage (ICH) is a prevalent hemorrhagic cerebrovascular emergency. Alleviating neurological damage in the early stages of ICH is critical for enhancing patient prognosis and survival rate. A novel form of cell death called ferroptosis is intimately linked to hemorrhage-induced brain tissue injury. Although studies have demonstrated the significant preventive impact of bovine serum albumin-stabilized selenium nanoparticles (BSA-SeNPs) against disorders connected to the neurological system, the neuroprotective effect on the hemorrhage stroke and the mechanism remain unknown. Therefore, based on the favorable biocompatibility of BSA-SeNPs, h-ICH (hippocampus-intracerebral hemorrhage) model was constructed to perform BSA-SeNPs therapy. As expected, these BSA-SeNPs could effectively improve the cognitive deficits and ameliorate the damage of hippocampal neuron. Furthermore, BSA-SeNPs reverse the morphology of mitochondria and enhanced the mitochondrial function, evidenced by mitochondrial respiration function (OCR) and mitochondrial membrane potential (MMP). Mechanistically, BSA-SeNPs could efficiently activate the Nrf2 to enhance the expression of antioxidant GPX4 at mRNA and protein levels, and further inhibit lipid peroxidation production in erastin-induced ferroptotic damages. Taken together, this study not only sheds light on the clinical application of BSA-SeNPs, but also provides its newly theoretical support for the strategy of the intervention and treatment of neurological impairment following ICH.

Pivotal Role of GSTO2 in Ferroptotic Neuronal Injury After Intracerebral Hemorrhage.

Previous research has found that an adaptive response to ferroptosis involving glutathione peroxidase 4 (GPX4) is triggered after intracerebral hemorrhage. However, little is known about the mechanisms underlying adaptive responses to ferroptosis. To explore the mechanisms underlying adaptive responses to ferroptosis after intracerebral hemorrhage, we used hemin-treated HT22 cells to mimic brain injury after hemorrhagic stroke in vitro to evaluate the antioxidant enzymes and performed bioinformatics analysis based on the mRNA sequencing data. Further, we determined the expression of GSTO2 in hemin-treated hippocampal neurons and in a mouse model of hippocampus-intracerebral hemorrhage (h-ICH) by using Western blot. After hemin treatment, the antioxidant enzymes GPX4, Nrf2, and glutathione (GSH) were upregulated, suggesting that an adaptive response to ferroptosis was triggered. Furthermore, we performed mRNA sequencing to explore the underlying mechanism, and the results showed that 2234 genes were differentially expressed. Among these, ten genes related to ferroptosis (Acsl1, Ftl1, Gclc, Gclm, Hmox1, Map1lc3b, Slc7a11, Slc40a1, Tfrc, and Slc39a14) were altered after hemin treatment. In addition, analysis of the data retrieved from the GO database for the ten targeted genes showed that 20 items on biological processes, 17 items on cellular components, and 19 items on molecular functions were significantly enriched. Based on the GO data, we performed GSEA and found that the glutathione metabolic process was significantly enriched in the hemin phenotype. Notably, the expression of glutathione S-transferase omega (GSTO2), which is involved in glutathione metabolism, was decreased after hemin treatment, and overexpression of Gsto2 decreased lipid reactive oxygen species level in hemin-exposed HT22 cells. In addition, the expression of GSTO2 was also decreased in a mouse model of hippocampus-intracerebral hemorrhage (h-ICH). The decreased expression of GSTO2 in the glutathione metabolic process may be involved in ferroptotic neuronal injury following hemorrhagic stroke.

Ferroptosis-related NFE2L2 and NOX4 Genes are Potential Risk Prognostic Biomarkers and Correlated with Immunogenic Features in Glioma.

Ferroptosis is a newfound mode of regulated cell death that may have potential to associate with prognostic or diagnostic factors in glioma. In this research, 5 genes related to glioma were screened through the FerrDb database, and we analyzed the combination between genes and glioma of survival and prognosis via TCGA, GEPIA, TIMER, and other databases. Survival curve and prognostic analysis showed that the overexpression of NFE2L2 and NOX4, respectively, has a remarkable link with a worse prognosis in glioma. Then, the association between the expression of the two genes and tumor-infiltrating immune cells level was explored based on the GSCA, and the immunity of NFE2L2 and NOX4 based on the TISIDB database was also investigated. In glioma, especially GBM, there is a strong association between gene expression and immune infiltration, even in macrophages, nTreg, and Th2 cells, which play immunosuppressive functions in TME. In conclusion, these results indicate that NFE2L2 and NOX4 could be risk prognosis biomarkers in glioma, and they bound up with immune infiltration and tumor immunity in tumorigenesis.

FDG PET/CT of Primary Breast Lymphoma in a Man.

ABSTRACT: Primary lymphoma of the male breast is extremely rare. We describe FDG PET/CT findings in a man with primary breast lymphoma in his right breast. The breast tumor showed intense FDG uptake mimicking breast carcinoma.

[Antitumor effect of baicalin on rat brain glioma].

OBJECTIVE: To investigate the therapeutic mechanism of baicalin on rat brain glioma. METHODS: Deep brain glioma models were established by injection of glioma cell line C6 cells into the brain of Wistar rats. The rats at 7 days after modeling were randomly divided into tumor control group (0.9% NaCl solution 30 mg×kg(-1)×d(-1) gavage)and experimental groups. The experimental rats was divided into 3 groups: low dose group (50 mg×kg(-1)×d(-1)), middle dose group (100 mg×kg(-1)×d(-1)) and high dose group (200 mg×kg(-1)×d(-1)), given the baicalin by gavage. Pathological and electron microscopic changes were observed. The expressions of p53 and Bcl-2 were determined by immunohistochemistry, and the changes of MRI, the average survival time and body weight of the rats in each group after treatments were analyzed. RESULTS: Compared with the control group, the tumor diameter and volume of high dose group rats before sacrifice were significantly reduced (P < 0.01), and the survival time was significantly prolonged (P < 0.01). Immunohistochemistry revealed strong positive expression rate of mutant p53 (84.47 ± 3.74)% and moderately positive rate (47.28 ± 2.38)% in the control group, significantly higher than that in the negative group (12.91 ± 1.07)% (P < 0.01). The positive rate of mutant p53 of the high dose group was (46.42 ± 2.19)%, significantly lower than that of the control group (84.47 ± 3.74)% (P < 0.01). The expression rate of Bcl-2 in the control group was strongly positive (86.51 ± 4.17)% and moderate positive (48.19 ± 2.11)%, significantly higher than that of the negative group (10.36 ± 1.43)% (P < 0.01). Electron microscopy revealed that baicalin caused damages of the cell nuclei and organelles in the gliomas. CONCLUSIONS: Baicalin has significant inhibitory effect on glioma in vivo, and its mechanism may be related to cell apoptosis induced by down-regulated expression of mutant p53, but not related with Bcl-2 expression.

The CD133+ subpopulation of the SW982 human synovial sarcoma cell line exhibits cancer stem-like characteristics.

Several soft tissues sarcomas have been reported to contain cancer stem-like cells (CSCs) or tumor-initiating cells, based on their ability to initiate and sustain tumor growth. However, these cells have not yet been identified in the human synovial sarcoma cell line SW982. CD133, a surface glycoprotein specific to stem and progenitor cells, has been described as a CSC marker in different tumor types. In the present study, we identified a CSC subpopulation in SW982 cells using the CD133 cell surface marker. CD133-positive (CD133(+)) cells were identified in SW982 cells (8.59%); these cells showed an increased ability to form spherical colonies and could self-renew in serum-starved culture conditions, compared to CD133-negative (CD133(-)) cells. Real-time PCR analysis of stemness genes revealed that the CD133+ subpopulation expresses higher levels of Bmi1, c-Myc, Nanog, Oct3/4 and Sox2. CD133(+) cells showed increased resistance to cisplatin (CDDP) and doxorubicin (DXR), possibly due to upregulation of the ABCG2 drug transporter gene. In vivo studies revealed that the CD133(+) subpopulation is highly tumorigenic. These findings indicate that CD133(+) SW982 cells have characteristics similar to CSCs. This discovery may lead to the development of novel therapies that specifically target CD133(+) synovial sarcoma CSCs.

Four common polymorphisms in microRNAs and the risk of adult glioma in a Chinese case-control study.

Emerging evidence has shown that microRNAs (miRNAs) participate in human carcinogenesis as tumor suppressors or oncogenes. It has been suggested that four common single nucleotide polymorphisms (SNPs; miR-146aG > C, 149C > T, 196a2C > T, and 499A > G) are associated with susceptibility to numerous malignancies. However, published results are inconsistent and inclusive. To further investigate the role of these loci, we examined the association of the miRNA polymorphisms with the risk of gliomas in a Han population in northeastern China. Both miR-146aG > C and 196a2C > T showed allelic differences between glioma patients and healthy controls in the studied population, with an OR of 1.30 (P = 0.0006) and an odds ratio (OR) of 1.25 (P = 0.003), respectively. Logistic regression analysis also revealed that the 146aG > C and 196a2C > T wild-type homozygous carriers had an increased glioma risk compared to the variant carriers. Besides, in pairwise comparisons two SNP combinations were associated with the risk of glioma. Among others, carriers of both homozygous risk genotypes, i.e., 146aGG and 196a2CC were associated with a nearly 4-fold increased risk of glioma (OR = 3.77, P = 1.3 × 10(-4)). Overall, glioma risk increased with increasing numbers of risk variant alleles. These results suggest that the miR-146aG > C and 196a2C > T might influence the risk of developing glioma in a northeastern Han Chinese population.

Genetic polymorphisms in the DNA repair gene XRCC1 and susceptibility to glioma in a Han population in northeastern China: a case-control study.

BACKGROUND: Several single nucleotide polymorphisms (SNPs) in the X-ray cross-complementing group 1 (XRCC1) gene have been shown to influence DNA repair and to modify cancer susceptibility. To investigate the role of these loci further, we examined the association of three XRCC1 polymorphisms with the risk of gliomas in a Han population in northeastern China. METHODS: Using a PCR-RFLP method, XRCC1 Arg194Trp, Arg280His and Arg399Gln were genotyped in 624 glioma patients and 580 healthy controls. RESULTS: Significant differences in the distribution of the Arg399Gln allele were detected between glioma patients and healthy controls by a logistic regression analysis (OR=1.35, 95%CI 1.17-1.68, P=0.001). Our data also revealed that the Arg399Gln variant (allele A) carriers had an increased glioma risk compared to the wild-type (allele G) homozygous carriers (OR=1.40, 95%CI 1.12-1.76, P=0.003). CONCLUSIONS: These results suggest that the XRCC1 Arg399Gln might influence the risk of developing glioma in a Han population in northeastern Chinese.

[Treatment of hematopathy by tiaohe ganpi recipe in assisting the hematopoietic stem cell transplantation].

OBJECTIVE: To observe the clinical efficacy and the survival of hematopathy patients by Tiaohe Ganpi Recipe (TGR) in assisting the hematopoietic stem cell transplantation (HSCT), thus finding out new thinking ways and methods for Chinese medicine in intervening HSCT. METHODS: Twenty-seven hematopathy patients scheduled to receive HSCT were randomly assigned to two groups, thirteen in the control group and fourteen in the treatment group. They were treated with the conventional treatment of HSCT, but TGR was additionally given to patients in the treatment group during the whole course. All patients were followed up till December 31, 2009 (with the median follow-up time of twenty-five months). The hemopoietic rebuilding time, the implantation state, the therapy correlated mortality, the recurrence rate, preconditioning correlated complications, and graft-versus-host disease (GVHD), the survival time, the survival probability, and so on in the two groups were observed and compared. RESULTS: Better results were obtained in the treatment group in the survival time (41.6 +/- 6.5 months vs. 21.0 +/- 5.9 months), the survival probability (78.6% vs. 30.8%), the 1-3-year cumulative interval survival rate (80.8% vs. 46.2%, 69.3% vs. 34.6%, and 69.3% vs. 34.6%, respectively), the therapy correlated mortality (0 vs. 30.8%), and the death risk (all P < 0.05). As time went by, the cumulative survival rate decreased and the death risk increased gradually in both groups. There was insignificant difference in the hemopoietic rebuilding time (17.9 +/- 7. 9 days vs. 18.1 +/- 6.8 days), the implantation state, the occurrence rate of preconditioning correlated complications (14.3% vs. 23.1%), GVHD occurrence, and the recurrence rate (21.4% vs. 23.1%, P > 0.05). CONCLUSION: TGR could lower the therapy correlated mortality, prolong the survival time, and improve the cumulative survival rate in the HSCT treatment of hematopathy patients, playing efficacy enhancing and toxicity reducing effect.

HIF-1 prevents the overproduction of mitochondrial ROS after cytokine stimulation through induction of PDK-1.

Excessive reactive oxygen species (ROS) are toxic to hematopoietic cells. The majority of cellular ROS are derived from mitochondria and glucose metabolism, and cytokines stimulate this process. During hypoxia, hypoxia inducible factor-1 (HIF-1) attenuates hypoxia-induced mitochondrial ROS production through the induction of pyruvate dehydrogenase kinase-1 (PDK-1). Previously, we found that thrombopoietin (TPO) induces the generation of mitochondrial ROS. Interestingly, the TPO-induced production of mitochondrial ROS promotes the activation of HIF-1. Based on these findings, we speculated that TPO-activated HIF-1 functions as a feedback mechanism to block the overproduction of ROS following TPO stimulation. We found that TPO induces the expression of PDK-1 in a TPO-dependent cell line, UT-7/TPO, in a HIF-1-dependent manner. Inhibition of either HIF-1 or PDK-1 resulted in the increased production of ROS following TPO stimulation. Our observations suggest that HIF-1 functions as a ROS sensor to prevent the overproduction of mitochondrial ROS following cytokine stimulation.

Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan.

Abnormal activation of hypoxia-inducible factor-1 (HIF-1), one of the most important transcription factors for the adaptation of cells to hypoxia, is frequently observed in numerous types of solid tumors. Dysregulation of HIF-1 induces tumor angiogenesis and enhances the expression of anti-apoptotic proteins and glycolysis-associated enzymes in cancer cells, which in turn leads to the promotion of tumor growth. In the present study, we examined the pathophysiologic role of HIF-1 in multiple myeloma. Furthermore, we explored the possibility that HIF-1 may be a molecular target for myeloma therapy. We identified constitutive expression of the hypoxia-inducible factor-1 alpha (HIF-1alpha)-subunit in established myeloma cell lines and in primary myeloma cells. Treatment with insulin-like growth factor-1 (IGF-1) significantly increased HIF-1alpha expression through activation of the AKT and mitogen-activated protein kinase signaling pathways. Inhibition of HIF-1 function either by echinomycin, a specific HIF-1 inhibitor, or a siRNA against HIF-1alpha resulted in enhanced sensitivity to melphalan in myeloma cells. This inhibition of HIF-1 also reversed the protective effect of IGF-1 on melphalan-induced apoptosis. Inhibition of HIF-1 drastically reduced both basal and IGF-1-induced expression of survivin, one of the most important anti-apoptotic proteins in myeloma cells. We conclude that HIF-1 inhibition may be an attractive therapeutic strategy for multiple myeloma.