Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells.

Relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia-initiating stem cells (LICs) that are typically not targeted by most existing therapies. Using a murine AML model, human AML cell lines, and patient samples, we show that AML LICs are sensitive to endogenous and exogenous cyclopentenone prostaglandin-J (CyPG), Δ12-PGJ2, and 15d-PGJ2, which are increased upon dietary selenium supplementation via the cyclooxygenase-hematopoietic PGD synthase pathway. CyPGs are endogenous ligands for peroxisome proliferator-activated receptor gamma and GPR44 (CRTH2; PTGDR2). Deletion of GPR44 in a mouse model of AML exacerbated the disease suggesting that GPR44 activation mediates selenium-mediated apoptosis of LICs. Transcriptomic analysis of GPR44-/- LICs indicated that GPR44 activation by CyPGs suppressed KRAS-mediated MAPK and PI3K/AKT/mTOR signaling pathways, to enhance apoptosis. Our studies show the role of GPR44, providing mechanistic underpinnings of the chemopreventive and chemotherapeutic properties of selenium and CyPGs in AML.

Avoiding "COVID Blindness": Advocating Cognitive Bias Teaching in the Context of COVID-19.

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Nitric oxide regulates metabolism in murine stress erythroid progenitors to promote recovery during inflammatory anemia.

Inflammation skews bone marrow hematopoiesis increasing the production of myeloid effector cells at the expense of steady-state erythropoiesis. A compensatory stress erythropoiesis response is induced to maintain homeostasis until inflammation is resolved. In contrast to steady-state erythroid progenitors, stress erythroid progenitors (SEPs) utilize signals induced by inflammatory stimuli. However, the mechanistic basis for this is not clear. Here we reveal a nitric oxide (NO)-dependent regulatory network underlying two stages of stress erythropoiesis, namely proliferation, and the transition to differentiation. In the proliferative stage, immature SEPs and cells in the niche increased expression of inducible nitric oxide synthase ( Nos2 or iNOS ) to generate NO. Increased NO rewires SEP metabolism to increase anabolic pathways, which drive the biosynthesis of nucleotides, amino acids and other intermediates needed for cell division. This NO-dependent metabolism promotes cell proliferation while also inhibiting erythroid differentiation leading to the amplification of a large population of non-committed progenitors. The transition of these progenitors to differentiation is mediated by the activation of nuclear factor erythroid 2-related factor 2 (Nfe2l2 or Nrf2). Nrf2 acts as an anti-inflammatory regulator that decreases NO production, which removes the NO-dependent erythroid inhibition and allows for differentiation. These data provide a paradigm for how alterations in metabolism allow inflammatory signals to amplify immature progenitors prior to differentiation. Key points: Nitric-oxide (NO) dependent signaling favors an anabolic metabolism that promotes proliferation and inhibits differentiation.Activation of Nfe2l2 (Nrf2) decreases NO production allowing erythroid differentiation.

Should Medical Students Be Overprotected? A Survey from China and Review About the Roles of Medical Student Under the COVID-19.

Objective: The impact of COVID-19 continues to this day, there are many disputes about how medical students should be managed and diverse arrangements were adopted by medical schools around all over the world. The purpose of this study was to discuss the risks and benefits of medical student participation in healthcare in the context of COVID-19. Methods: An online cross-sectional survey was distributed to 300 Medical students undergoing standardized training program (STP) in China-Japan Union Hospital of Jilin University. The survey included questions about basic demographic characteristics, roles and mental state of interns during the pandemic, comments on the University's management of medical students. Data were processed using SPSS 25.0 statistical analysis software, the comparison between two groups of data was performed using t-test; the non-normally distributed variables were analyzed using Mann-Whitney U-test, differences between groups were compared using chi-square test for analysis. p < 0.05 was considered statistically significant. Results: A total of 191 students completed the survey (response rate 63.67%). The epidemic had a significant psychological impact on students, but most of them believed that participation in clinical work under voluntary, precise protective measures and strict supervision were benefit for their future. Older, married, female, and salaried students are more willing to engage in pandemic-related activities. The biggest challenge of working under the pandemic focused on high working pressure and insufficient protection, the biggest harvest was getting knowledge and accumulating experience. Conclusion: Circumstances, cultures, outbreaks and strategies for coping with COVID-19 varied around the world. Medical students do not need to be overprotected, participation in pandemic work in an optimized system is acceptable and beneficial to their career plan. Medical education should focus on improving the social status of infectious diseases and cultivating future doctors with awareness of epidemic prevention and control.

Intra-Peritoneal Transplantation for Generating Acute Myeloid Leukemia in Mice.

There is an unmet need for novel therapies to treat acute myeloid leukemia (AML) and the associated relapse that involves persistent leukemia stem cells (LSCs). An experimental AML rodent model to test therapies based on successfully transplanting these cells via retro-orbital injections in recipient mice is fraught with challenges. The aim of this study was to develop an easy, reliable, and consistent method to generate a robust murine model of AML using an intra-peritoneal route. In the present protocol, bone marrow cells were transduced with a retrovirus expressing human MLL-AF9 fusion oncoprotein. The efficiency of lineage negative (Lin-) and Lin-Sca-1+c-Kit+ (LSK) populations as donor LSCs in the development of primary AML was tested, and intra-peritoneal injection was adopted as a new method to generate AML. Comparison between intra-peritoneal and retro-orbital injections was done in serial transplantations to compare and contrast the two methods. Both Lin- and LSK cells transduced with human MLL-AF9 virus engrafted well in the bone marrow and spleen of recipients, leading to a full-blown AML. The intra-peritoneal injection of donor cells established AML in recipients upon serial transplantation, and the infiltration of AML cells was detected in the blood, bone marrow, spleen, and liver of recipients by flow cytometry, qPCR, and histological analyses. Thus, intra-peritoneal injection is an efficient method of AML induction using serial transplantation of donor leukemic cells.

Interleukin-4 treatment reduces leukemia burden in acute myeloid leukemia.

Interleukin-4 (IL-4) is a signature cytokine pivotal in Type 2 helper T cell (Th2) immune response, particularly in allergy and hypersensitivity. Interestingly, IL-4 increases endogenous levels of prostaglandin D2 (PGD2 ) and its metabolites, Δ12 -prostaglandin J2 (Δ12 -PGJ2 ) and 15-deoxy-Δ12,14 -prostaglandin J2 (15d-PGJ2 ), collectively called cyclopentenone PGs (CyPGs). However, the therapeutic role of IL-4 in hematologic malignancies remains unclear. Here, we employed a murine model of acute myeloid leukemia (AML), where human MLL-AF9 fusion oncoprotein was expressed in hematopoietic progenitor cells, to test the effect of IL-4 treatment in vivo. Daily intraperitoneal treatment with IL-4 at 60 µg/kg/d significantly alleviated the severity of AML, as seen by decreased leukemia-initiating cells (LICs). The effect of IL-4 was mediated, in part, by the enhanced expression of hematopoietic- PGD2  synthase (H-PGDS) to effect endogenous production of CyPGs, through autocrine and paracrine signaling mechanisms. Similar results were seen with patient-derived AML cells cultured ex vivo with IL-4. Use of GW9662, a peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, suggested endogenous CyPGs-PPARγ axis mediated p53-dependent apoptosis of LICs by IL-4. Taken together, our results reveal a beneficial role of IL-4 treatment in AML suggesting a potential therapeutic regimen worthy of clinical trials in patients with AML.

Taxifolin ameliorates sepsis-induced lung capillary leak through inhibiting the JAK/STAT3 pathway.

BACKGROUND: As a systemic inflammatory reaction, sepsis is associated with various organ dysfunctions. The capillary leakage and the imbalance between T helper 17 and regulatory T (Th17/Treg) cells are associated with sepsis-induced lung injury. Taxifolin (TXL) has been found to play a vital role in regulating this diverse disease. However, the detailed functioning and mechanism of TXL in regulating sepsis-induced lung capillary leak remain elusive. METHODS: Balb/c mice were used to establish sepsis-induced lung injury model through administration of lipopolysaccharide (LPS). The structure of lung tissues was observed by using hematoxylin & eosin staining. Protein level and total cells in bronchoalveolar lavage fluid (BALF) were measured by bicinchoninic acid (BCA) protein assay kit and hematimetry assay, respectively. Quantitative real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were employed to detect the level of inflammatory cytokines. The content of Th17 and Treg cells were measured by flow cytometry analysis. Western blot assay was used to determine the protein level of retinoid-related orphan receptor-γt (RORγt), Forkhead box P3 (Foxp3), Janus kinase 2 (JAK2), phospho(p)-JAK2, signal transducer and activator of transcription 3 (STAT3), and phospho(p)-STAT3. RESULTS: Taxifolin effectively prolonged the survival period of sepsis mice and alleviated LPS-induced lung injury in a dose-dependent manner. Moreover, TXL reduced LPS-induced increase in protein levels and T cell content in BALF, and effectively restored the wet:dry ratio of lung tissue and tissue permeability. Treating with TXL notably inhibited the production of pro-inflammatory cytokines induced by sepsis and influenced the balance between Th17 and Treg cells. Furthermore, TXL treatment suppressed the activation of JAK/STAT3 signaling pathway in a dose-dependent manner. CONCLUSION: Our findings revealed that TXL alleviated sepsis-induced capillary leak in the lungs of mice by regulating JAK/STAT3 signaling pathway.

Selegiline Protects Against Lipopolysaccharide (LPS)-Induced Impairment of the Blood-Brain Barrier Through Regulating the NF-κB/MLCK/p-MLC Signaling Pathway.

Disruption of the blood-brain barrier (BBB) is an important hallmark of sepsis-associated encephalopathy (SAE). Selegiline, a selective and irreversible inhibitor of monoamine oxidase type B, has been applied for the treatment of nervous disorders. In this study, we aimed to investigate whether selegiline has a protective capacity in the impairment of the BBB in both in vivo and in vitro experiments. In a sepsis mouse model, administration of selegiline ameliorated lipopolysaccharide (LPS)-induced impairment of BBB integrity. Additionally, treatment with selegiline increased the expression of the tight junction protein junctional adhesion molecule A (JAM-A) against LPS. Also, we found that selegiline inhibited the production of the proinflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1ß. In an in vitro experimental model, bEnd.3 brain endothelial cells were exposed to LPS. Results indicate that stimulation with LPS significantly increased the permeability of bEnd.3 cells and reduced the expression of JAM-A, both of which were rescued by treatment with selegiline. Additionally, selegiline prevented the activation of the NF-κB/MLCK/p-MLC signaling pathway in LPS-challenged bEnd.3 cells. These results indicate that selegiline exerted a protective effect on BBB dysfunction, which might be attributed to the inhibition of the NF-κB/MLCK/p-MLC signaling pathway. These findings provide a basis for further research into the neuroprotective mechanism of selegiline.

The Essential Role of Selenoproteins in the Resolution of Citrobacter rodentium-Induced Intestinal Inflammation.

Enteropathogenic Escherichia coli (EPEC) leads to adverse colonic inflammation associated with poor resolution of inflammation and loss of epithelial integrity. Micronutrient trace element selenium (Se) is incorporated into selenoproteins as the 21st amino acid, selenocysteine (Sec). Previous studies have shown that such an incorporation of Sec into the selenoproteome is key for the anti-inflammatory functions of Se in macrophages and other immune cells. An intriguing mechanism underlying the anti-inflammatory and pro-resolving effects of Se stems from the ability of selenoproteins to skew arachidonic acid metabolism from pro-inflammatory mediators, prostaglandin E2 (PGE2) toward anti-inflammatory mediators derived from PGD2, such as 15-deoxy-Δ12, 14- prostaglandin J2 (15d-PGJ2), via eicosanoid class switching of bioactive lipids. The impact of Se and such an eicosanoid-class switching mechanism was tested in an enteric infection model of gut inflammation by C. rodentium, a murine equivalent of EPEC. C57BL/6 mice deficient in Se (Se-D) experienced higher mortality when compared to those on Se adequate (0.08 ppm Se) and Se supplemented (0.4 ppm Se) diets following infection. Decreased survival was associated with decreased group 3 innate lymphoid cells (ILC3s) and T helper 17 (Th17) cells in colonic lamina propria of Se-D mice along with deceased expression of epithelial barrier protein Zo-1. Inhibition of metabolic inactivation of PGE2 by 15-prostaglandin dehydrogenase blocked the Se-dependent increase in ILC3 and Th17 cells in addition to reducing epithelial barrier integrity, as seen by increased systemic levels of FITC-dextran following oral administration; while 15d-PGJ2 administration in Se-D mice alleviated the effects by increasing ILC3 and Th17 cells. Mice lacking selenoproteins in monocyte/macrophages via the conditional deletion of the tRNA[Sec] showed increased mortality post infection. Our studies indicate a crucial role for dietary Se in the protection against inflammation following enteric infection via immune mechanisms involving epithelial barrier integrity.

Epo receptor signaling in macrophages alters the splenic niche to promote erythroid differentiation.

Anemic stress induces stress erythropoiesis, which rapidly generates new erythrocytes to restore tissue oxygenation. Stress erythropoiesis is best understood in mice where it is extramedullary and occurs primarily in the spleen. However, both human and mouse stress erythropoiesis use signals and progenitor cells that are distinct from steady-state erythropoiesis. Immature stress erythroid progenitors (SEPs) are derived from short-term hematopoietic stem cells. Although the SEPs are capable of self-renewal, they are erythroid restricted. Inflammation and anemic stress induce the rapid proliferation of SEPs, but they do not differentiate until serum erythropoietin (Epo) levels increase. Here we show that rather than directly regulating SEPs, Epo promotes this transition from proliferation to differentiation by acting on macrophages in the splenic niche. During the proliferative stage, macrophages produce canonical Wnt ligands that promote proliferation and inhibit differentiation. Epo/Stat5-dependent signaling induces the production of bioactive lipid mediators in macrophages. Increased production of prostaglandin J2 (PGJ2) activates peroxisome proliferator-activated receptor γ (PPARγ)-dependent repression of Wnt expression, whereas increased production of prostaglandin E2 (PGE2) promotes the differentiation of SEPs.

Xuebijing Injection Alleviates Pam3CSK4-Induced Inflammatory Response and Protects Mice From Sepsis Caused by Methicillin-Resistant Staphylococcus aureus.

A leading cause of death worldwide is sepsis that develops as a dysregulated immune response to infection. Serious infection caused by methicillin-resistant Staphylococcus aureus (MRSA) increases the difficulty of treatment in septic patients. Host-directed therapy (HDT) is an emerging approach to bacterial infections. Xuebijing injection (XBJ), a commercialized injectable prescription from traditional Chinese medicine, has been used as adjuvant therapy for sepsis with a history of 15 years. Whether it plays a protective role in severe infection caused by antibiotic-resistant bacteria is still unknown. In this study, XBJ significantly improved the survival of MRSA-induced sepsis mice. In MRSA-infected mouse model, XBJ down-regulated the expression of inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, MCP-1, MIP-2, and IL-10 in sera. Besides that, it decreased the bacterial load in spleens, livers, and alleviated tissue damage of lung, liver, and kidney. The combination of XBJ with vancomycin or dexamethasone exhibited a better down-regulatory role of the inflammatory response. Then, the protective mechanism of XBJ was further investigated. XBJ inhibited heat-killed MRSA-induced IL-6 and TNF-α production in mouse macrophages. XBJ also decreased Pam3CSK4 (a synthetic tripalmitoylated lipopeptide mimicking bacterial lipoproteins)-stimulated expression of IL-6, TNF-α, IL-1ß, IL-12, etc. in mouse macrophages. Furthermore, XBJ down-regulated the activation of NF-κB, MAPK, and PI3K/Akt pathways in Pam3CSK4-stimulated mouse macrophages. In conclusion, our findings demonstrated that XBJ played a protective role in MRSA-challenged mice and down-regulated the inflammatory response and the activation of signaling pathways initiated by Pam3CSK4. It enlarged the clinical application of XBJ in the treatment of severe bacterial infection, e.g. caused by MRSA.

Crth2 receptor signaling down-regulates lipopolysaccharide-induced NF-κB activation in murine macrophages via changes in intracellular calcium.

Prostaglandin D2 and its cyclopentenone metabolites [cyclopentenone prostaglandins (CyPGs)], Δ12prostaglandin J2 and 15-deoxy-Δ12,14-prostaglandin J2, act through 2 GPCRs, d-type prostanoid 1 and the chemoattractant receptor homologous molecule expressed on type 2 T-helper cells (Crth2). In addition to its role in allergy and asthma, the role of Crth2 in the resolution of inflammation, to mediate the proresolving functions of endogenous CyPGs, is not well understood. We investigated the regulation of LPS or zymosan-induced inflammatory response by signals from the Crth2 receptor in macrophages that lack Crth2 expression [knockout (KO)]. Increased expression of proinflammatory genes, including Tnf-α, was observed in Crth2 KO cells. Targeting the endogenous biosynthetic pathway of CyPGs with indomethacin or HQL79, which inhibit cyclooxygenases or hematopoietic prostaglandin D synthase, respectively, or use of Crth2 antagonists recapitulated the proinflammatory phenotype as in Crth2 KO cells. Ligand-dependent activation of Crth2 by 13,14-dihydro-15-keto-prostaglandin D2 increased Ca2+ influx through store-operated Ca2+ entry (SOCE) accompanied by the up-regulation of stromal interaction molecule 1 and calcium release-activated calcium modulator 1 expression, suggesting that the proresolution effects of CyPG-dependent activation of SOCE could be mediated by Crth2 during inflammation. Interestingly, Crth2 signaling down-regulated the Ca2+-regulated heat stable protein 1 that stabilizes Tnf-α mRNA via the increased expression of microRNA 155 to dampen inflammatory responses triggered through the TNF-α-NF-κB axis. In summary, these studies present a novel regulatory role for Crth2 during inflammatory response in macrophages.-Diwakar, B. T., Yoast, R., Nettleford, S., Qian, F., Lee, T.-J., Berry, S., Huffnagle, I., Rossi, R. M., Trebak, M., Paulson, R. F., Prabhu, K. S. Crth2 receptor signaling down-regulates lipopolysaccharide-induced NF-κB activation in murine macrophages via changes in intracellular calcium.

Shengjiang Powder ameliorates myocardial injury in septic rats by downregulating the phosphorylation of P38-MAPK.

Sepsis is the systemic inflammatory response caused by infection. Cardiac dysfunction is an acknowledged result of sepsis. Shengjiang Powder, a prescribed traditional Chinese medicine, showed anti-infection and antipyretic functions in our previous study. In this study, we established a septic rat model via cecal ligation puncture (CLP) to evaluate the effects of Shengjiang Powder on sepsis and the involvement of P38 mitogen activated protein kinase (P38-MAPK) signaling. The 10 main ingredients of Shengjiang Powder were identified by LC-MS. The results of this study indicated that Shengjiang Powder at a concentration of 3.0 g/kg with SB203580 (an inhibitor of P38-MAPK) could improve myocardial injury, ameliorate the histopathological abnormalities, decrease apoptosis and upregulate proliferating cell nuclear antigen (PCNA) levels in myocardial tissues. Further, cytokine mRNA expression levels (tumor necrosis factor - alpha, TNF-α and interleukin 6, IL-6) were decreased by Shengjiang Powder and SB203580 in the myocardial tissues. Furthermore, the p-P38 protein level in myocardial tissues was upregulated in septic rats but decreased upon treatment with Shengjiang Powder and SB203580; however, the relative protein level of P38 showed no significant changes. Collectively, Shengjiang Powder showed a myocardial protective effect on rats with CLP-induced sepsis.

Selenium and selenoproteins in prostanoid metabolism and immunity.

Selenium (Se) is an essential trace element that functions in the form of the 21st amino acid, selenocysteine (Sec) in a defined set of proteins. Se deficiency is associated with pathological conditions in humans and animals, where incorporation of Sec into selenoproteins is reduced along with their expression and catalytic activity. Supplementation of Se-deficient population with Se has shown health benefits suggesting the importance of Se in physiology. An interesting paradigm to explain, in part, the health benefits of Se stems from the observations that selenoprotein-dependent modulation of inflammation and efficient resolution of inflammation relies on mechanisms involving a group of bioactive lipid mediators, prostanoids, which orchestrate a concerted action toward maintenance and restoration of homeostatic immune responses. Such an effect involves the interaction of various immune cells with these lipid mediators where cellular redox gatekeeper functions of selenoproteins further aid in not only dampening inflammation, but also initiating an effective and active resolution process. Here we have summarized the current literature on the multifaceted roles of Se/selenoproteins in the regulation of these bioactive lipid mediators and their immunomodulatory effects.

Exposure to nickel oxide nanoparticles induces pulmonary inflammation through NLRP3 inflammasome activation in rats.

With recent advances in the manufacture and application of nickel oxide nanoparticles (NiONPs), concerns about their adverse effects on the respiratory system are increasing. However, the underlying cellular and molecular mechanisms of NiONP-induced pulmonary toxicity remain unclear. In this study, we focused on the impacts of NiONPs on pulmonary inflammation and investigated whether the NLRP3 inflammasome is involved in NiONP-induced pulmonary inflammation and injury. NiONP suspensions were administered by single intratracheal instillation to rats, and inflammatory responses were evaluated at 3 days, 7 days, or 28 days after treatment. NiONP exposure resulted in sustained pulmonary inflammation accompanied by inflammatory cell infiltration, alveolar proteinosis, and cytokine secretion. Expression of Nlrp3 was markedly upregulated by the NiONPs, which was accompanied by overexpression of the active form of caspase-1 (p20) and interleukin (IL)-1ß secretion in vivo. NiONP-induced IL-1ß secretion was partially prevented by co-treatment with a caspase-1 inhibitor in macrophages. Moreover, siRNA-mediated Nlrp3 knockdown completely attenuated NiONP-induced cytokine release and caspase-1 activity in macrophages in vitro. In addition, NiONP-induced NLRP3 inflammasome activation requires particle uptake and reactive oxygen species production. Collectively, our findings suggest that the NLRP3 inflammasome participates in NiONP-induced pulmonary inflammation and offer new strategies to combat the pulmonary toxicity induced by NiONPs.

50 Hz electromagnetic field exposure promotes proliferation and cytokine production of bone marrow mesenchymal stem cells.

OBJECTIVE: To investigate the effects of extremely low frequency electromagnetic field (ELF-EMF) on the proliferation and cytokine production of mesenchymal stem cells (MSC) and the effects of mesenchymal stem cell conditioned medium (MSC-CM) on the proliferation and migration of macrophagocytes (RAW264.7). METHODS: Bone marrow derived-mesenchymal stem cells (rBMSC) were isolated from rats, cultured and randomly divided into two groups: SHAM group (absence of electromagnetic field exposure) and EMF group. Cells in EMF group were exposed to ELF-EMF (50 Hz, 1 mT, 4 h/d) under sXc-ELF. Mouse mesenchymal stem cells (mMSC) were exposed to EMF for 3 days. RESULTS: The cell viability, DNA synthesis and proportion of cells in S phase in EMF group increased markedly when compared with SHAM group (P<0.05). When compared with SHAM group, the mRNA expressions of M-CSF and SCF increased markedly at 2 days after EMF exposure (P<0.05), the mRNA expressions of SCF, M-CSF, TPO, LIF, IL-11 and IL-7 increased dramatically, but the mRNA expressions of IL-6, SDF-1, IFN-γ and TNF-α remained unchanged (P>0.05) in mMSCs at 3 days after EMF exposure. In EMF group, the viability of RAW264.7 after MSC-CM treatment increased markedly as compared to SHAM group (P<0.05), and the ability to migrate of RAW264.7 after MSC-CM treatment in EMF group also increased significantly when compared with SHAM group (P<0.05). CONCLUSION: EMF is able to promote the proliferation of rBMSCs, up-regulate the expressions of hematopoietic growth factors in rBMSC and mMSC and increase the mMSC induced proliferation and migration of RAW264.7.

Prognostic factors of lymphoma patients after autologous stem cell transplantation.

UNLABELLED: BacKGROUND: Hematopoietic stem cell transplantation (HSCT) is considered to be a cure for lymphoma. However, factors related to its prognosis remain unclear. MATERIAL AND METHODS: Eighty patients diagnosed with lymphoma and treated with autologous HSCT (Auto HSCT) were recruited. The primary endpoints included overall survival (OS) and progression-free survival (PFS). RESULTS: After a median follow-up of 37.9 months, the 3-year OS was 75%. Univariate analysis showed age (P=0.020), elevated lactate dehydrogenase (LDH) (P=0.031), international prognostic index (IPI) (P=0.015), Eastern Cooperative Oncology Group (ECOG) (P=0.048), bone marrow involvement (P=0.038), and time to neutrophil recovery (P=0.043) were prognostic factors of lymphoma. Multivariate analysis revealed IPI (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.09-2.34, P=0.016) and time to neutrophil recovery (HR 2.69, 95% CI 1.02-7.07, P=0.045) were independent factors correlated with OS. CONCLUSIONS: IPI and neutrophil recovery are recommendatory predictors for lymphoma patients after Auto HSCT.

NiO nanoparticles induce apoptosis through repressing SIRT1 in human bronchial epithelial cells.

With application of nano-sized nickel-containing particles (Nano-Ni) expanding, the health concerns about their adverse effects on the pulmonary system are increasing. However, the mechanisms for the pulmonary toxicity of these materials remain unclear. In the present study, we focused on the impacts of NiO nanoparticles (NiONPs) on sirtuin1 (SIRT1), a NAD-dependent deacetylase, and investigated whether SIRT1 was involved in NiONPs-induced apoptosis. Although the NiONPs tended to agglomerate in fluid medium, they still entered into the human bronchial epithelial cells (BEAS-2B) and released Ni(2+) inside the cells. NiONPs at doses of 5, 10, and 20µg/cm(2) inhibited the cell viability. NiONPs' produced cytotoxicity was demonstrated through an apoptotic process, indicated by increased numbers of Annexin V positive cells and caspase-3 activation. The expression of SIRT1 was markedly down-regulated by the NiONPs, accompanied by the hyperacetylation of p53 (tumor protein 53) and overexpression of Bax (Bcl-2-associated X protein). However, overexpression of SIRT1 through resveratrol treatment or transfection clearly attenuated the NiONPs-induced apoptosis and activation of p53 and Bax. Our results suggest that the repression of SIRT1 may underlie the NiONPs-induced apoptosis via p53 hyperacetylation and subsequent Bax activation. Because SIRT1 participates in multiple biologic processes by deacetylation of dozens of substrates, this knowledge of the impact of NiONPs on SIRT1 may lead to an improved understanding of the toxic mechanisms of Nano-Ni and provide a molecular target to antagonize Nano-Ni toxicity.

Cross regulation between hypoxia-inducible transcription factor-1α (HIF-1α) and transforming growth factor (TGF)-ß1 mediates nickel oxide nanoparticles (NiONPs)-induced pulmonary fibrosis.

Numerous analyses including in vivo and in vitro experiments have demonstrated that inhalation exposure of NiONPs can result in pulmonary fibrosis. However, the potential mechanisms of this pathological process remain elusive. Here, we investigate the role of HIF-1α and TGF-ß1 in NiONPs-induced pulmonary fibrosis with a focus on the interplay of the above two proteins. In vivo, male Sprague&Dawley rats were exposed to NiONPs and pulmonary fibrosis was demonstrated using H&E staining and immunochemistry of αSMA. In vitro, NiONPs contributed to cell proliferation and increased expressions of collagen-1 and αSMA in human fetal lung fibroblasts. Both HIF-1α and TGF-ß1 were upregulated by NiONPs treatment. Inhibition of HIF-1α reduced TGF-ß1 expression and downregulation of TGF-ß1 reduced HIF-1α protein level. Mechanism investigation revealed that TGF-ß1 affects nuclear translocation activity of HIF-1α. Taken together, these finding provide evidence that HIF-1α and TGF-ß1 act in synergy to foster NiONPs-induced pulmonary fibrosis, and the cross talk between them is a pivotal mechanism of pulmonary fibrosis.

Co-transplantation with mesenchymal stem cells expressing a SDF-1/HOXB4 fusion protein markedly improves hematopoietic stem cell engraftment and hematogenesis in irradiated mice.

INTRODUCTION: Mesenchymal stem cells (MSCs) contribute to the engraftment of transplanted hematopoietic stem cells (HSCs). MSCs also accelerate hematological recovery by secreting SDF-1 and enabling HSCs to enter the bone marrow (BM) via the SDF-1/CXCR4 axis. HOXB4 has been shown to stimulate HSC self-renewal. In this study, we examined whether SDF-1 and HOXB4 expression in MSCs co-transplanted with HSCs could synergistically improve hematopoietic recovery in irradiated mice. METHODS: Using recombinant adenoviruses, we generated genetically modified BM-MSCs that expressed SDF-1, HOXB4, and an SDF-1/HOXB4 fusion gene. We then co-transplanted these modified MSCs with HSCs and investigated blood cell counts, BM cellularity, degree of human HSC engraftment, and survival rate in irradiated mice. RESULTS: We found that co-culturing the SDF-1/HOXB4 fusion gene-modified MSCs (SDF-1/HOXB4-MSCs) and human umbilical cord blood CD34(+) cells significantly improved HSC cell expansion in vitro. More importantly, co-transplantation of CD34(+) cells and SDF-1/HOXB4-MSCs markedly increased the hematopoietic potential of irradiated mice as evidenced by the rapid recovery of WBC, PLT and HGB levels in peripheral blood and of BM cellularity. Co-transplantation also markedly improved engraftment of human CD45(+) cells in mouse BM. CONCLUSIONS: Our study demonstrates that SDF-1/HOXB4-MSCs markedly accelerate hematopoietic recovery and significantly improve survival among mice treated with a lethal dose of irradiation. Therefore, SDF-1/HOXB4-MSCs could have therapeutic value by improving the efficacy of clinical transplantations in patients with defective hematopoiesis.