PHF6 loss reduces leukemia stem cell activity in an acute myeloid leukemia mouse model.

Acute myeloid leukemia (AML) is a malignant hematologic disease caused by gene mutations and genomic rearrangements in hematologic progenitors. The PHF6 (PHD finger protein 6) gene is highly conserved and located on the X chromosome in humans and mice. We found that PHF6 was highly expressed in AML cells with MLL rearrangement and was related to the shortened survival time of AML patients. In our study, we knocked out the Phf6 gene at different disease stages in the AML mice model. Moreover, we knocked down PHF6 by shRNA in two AML cell lines and examined the cell growth, apoptosis, and cell cycle. We found that PHF6 deletion significantly inhibited the proliferation of leukemic cells and prolonged the survival time of AML mice. Interestingly, the deletion of PHF6 at a later stage of the disease displayed a better anti-leukemia effect. The expressions of genes related to cell differentiation were increased, while genes that inhibit cell differentiation were decreased with PHF6 knockout. It is very important to analyze the maintenance role of PHF6 in AML, which is different from its tumor-suppressing function in T-cell acute lymphoblastic leukemia (T-ALL). Our study showed that inhibiting PHF6 expression may be a potential therapeutic strategy targeting AML patients.

BCL10 correlates with bad prognosis and immune infiltration of tumor microenvironment in hepatocellular carcinoma.

It has been reported that B-cell CLL-lymphoma 10 (BCL10) serves as an oncogene in cervical cancer. However, the roles of BCL10 in hepatocellular carcinoma (HCC), especially involved in immune infiltration remain not clear. This study aims to explore the relationship between BCL10 and the prognosis and clinical significance, and immune infiltration in HCC. The expression of BCL10 was analyzed between HCC samples and non-tumor samples in the multiple datasets. In addition, the prognostic values of BCL10 and its methylation in HCC were also investigated. The clinical significance of BCL10 has also been explored. Furthermore, the correlation between BCL10 and immune infiltration in HCC microenvironment was assessed. Finally, the biological behaviors of BCL10 in HCC were verified by cell function experiments. It was found that the expression levels of BCL10 were increased in HCC patients in multiple datasets. Moreover, the increased BCL10 and its reduced methylation were associated with the poor survival. BCL10 was significantly associated with immune infiltration. When BCL10 was knocked down in HCC cells, their proliferation ability was significantly inhibited, their migration was significantly decreased, their apoptosis was significantly increased, and AKT signaling pathway was inhibited. In conclusion, BCL10 is a potential prognostic and diagnostic biomarker related to immune infiltration in HCC microenvironment.

Noise Suppression for GPR Data Based on SVD of Window-Length-Optimized Hankel Matrix.

Ground-penetrating radar (GPR) is an effective tool for subsurface detection. Due to the influence of the environment and equipment, the echoes of GPR contain significant noise. In order to suppress noise for GPR data, a method based on singular value decomposition (SVD) of a window-length-optimized Hankel matrix is proposed in this paper. First, SVD is applied to decompose the Hankel matrix of the original data, and the fourth root of the fourth central moment of singular values is used to optimize the window length of the Hankel matrix. Then, the difference spectrum of singular values is used to construct a threshold, which is used to distinguish between components of effective signals and components of noise. Finally, the Hankel matrix is reconstructed with singular values corresponding to effective signals to suppress noise, and the denoised data are recovered from the reconstructed Hankel matrix. The effectiveness of the proposed method is verified with both synthetic and field measurements. The experimental results show that the proposed method can effectively improve noise removal performance under different detection scenarios.

Evaluation of the effects of preconditioning regimens on hepatic veno-occlusive disease in mice after hematopoietic stem cell transplantation.

Pre-conditioning regimens before hematopoietic stem cell transplantation (HSCT), such as total body irradiation (TBI) or busulfan/cyclophosphamide (BU/CY), are associated with hepatic veno-occlusive disease (HVOD). However, the mechanism of these regimens on hepatic veno-occlusive disease remains unclear. The aim of this study is to evaluate the effect of TBI or BU/CY on HVOD in mice after HSCT. Mice received TBI or BU/CY followed by HSCT. Analysis of liver pathology and function, and platelet aggregation were performed. Both these regimens caused damage to liver sinusoid endothelial cells, leading to loss of normal structural integrity of liver sinusoid, abnormal liver function, fibrin deposition, inflammatory cells infiltration and platelet aggregation. No differences of liver function in these regimens were observed. Increased hepatic lipid droplets, mitochondrial swelling and higher incidence of HVOD were observed in BU/CY. In conclusion, both TBI and BU/CY caused damage to liver sinusoid endothelial cells and occurrence of HVOD with higher incidence for BU/CY. Meanwhile, inflammation and platelet activation was also observed, suggesting targeting them maybe beneficial in the prophylaxis of HVOD.

Endothelial Robo4 suppresses endothelial-to-mesenchymal transition induced by irradiation and improves hematopoietic reconstitution.

Bone marrow ablation is routinely performed before hematopoietic stem cell transplantation (HSCT). Hematopoietic stem and progenitor cells (HSPCs) require a stable bone marrow microenvironment to expand and refill the peripheral blood cell pool after ablation. Roundabout guidance receptor 4 (Robo4) is a transmembrane protein exclusive to endothelial cells and is vital in preserving vascular integrity. Hence, the hypothesis is that Robo4 maintains the integrity of bone marrow endothelial cells following radiotherapy. We created an endothelial cell injury model with γ-radiation before Robo4 gene manipulation using lentiviral-mediated RNAi and gene overexpression techniques. We demonstrate that Robo4 and specific mesenchymal proteins (Fibronectin, Vimentin, αSma, and S100A4) are upregulated in endothelial cells exposed to irradiation (IR). We found that Robo4 depletion increases the expression of endoglin (CD105), an auxiliary receptor for the transforming growth factor (TGF-ß) family of proteins, and promotes endothelial-to-mesenchymal transition (End-MT) through activation of both the canonical (Smad) and non-canonical (AKT/NF-κB) signaling pathways to facilitate Snail1 activation and its nuclear translocation. Endothelial Robo4 overexpression stimulates the expression of immunoglobulin-like adhesion molecules (ICAM-1 and VCAM-1) and alleviates irradiation-induced End-MT. Our coculture model showed that transcriptional downregulation of endothelial Robo4 reduces HSPC proliferation and increases HSC quiescence and apoptosis. However, Robo4 overexpression mitigated the damaged endothelium's suppressive effects on HSC proliferation and differentiation. These findings indicate that by controlling End-MT, Robo4 preserves microvascular integrity after radiation preconditioning, protects endothelial function, and lessens the inhibitory effect of damaged endothelium on hematopoietic reconstitution.

Macrophage depletion damages hematopoiesis partially through inhibition of cell homing and expansion after hematopoietic cell transplantation.

Bone marrow macrophages (Mφ) are essential components of the bone marrow niche that regulate the function of hematopoietic stem cells. Poor graft function and inhibition of hematopoietic production can result from abnormal macrophage function; however, the underlying mechanism is unclear. Clodronate liposomes (Clo-Lip) have been used widely to deplete macrophages and study their functions. Our previous results showed that Clod-Lip-mediated clearance of macrophages plays a vital role in regulating hematopoietic reconstruction after allogeneic hematopoietic cell transplantation (HCT). In this study, using an isogenic hematopoietic stem cell transplantation model, we found that Clod-Lip-mediated clearance of macrophages suppressed hematopoietic reconstruction by inhibiting the homing process of hematopoietic cells. We also demonstrated that macrophage depletion inhibited the direct supportive effect of macrophages on hematopoietic stem and progenitor cells and erythroid differentiation but promoted the production of megakaryocytic progenitors ex vivo. We showed that macrophages increase CD49e expression on hematopoietic stem and progenitor cells (HSPCs). However, CD49e inhibitors did not support the proliferative effect of macrophages on hematopoietic cells. In contrast, macrophage E-selectin/ intercellular cell adhesion molecule-1 (ICAM-1) may be involved in directly regulating HSPCs. In conclusion, macrophage depletion with Clo-Lip partially disrupts bone marrow hematopoiesis after HCT by impeding donor cell homing and macrophage-HSPCs interactions.

Longitudinal follow-up reveals occurrence of successive Cryptosporidium bovis and Cryptosporidium ryanae infections by different subtype families in dairy cattle.

Cryptosporidium bovis and Cryptosporidium ryanae are common species causing cryptosporidiosis in cattle. Data accumulated thus far indicate that the infection patterns of the two species could be different between areas with and without Cryptosporidium parvum. To better understand the infection dynamics of these two species, cross-sectional and longitudinal studies of Cryptosporidium spp. were conducted using genotyping and subtyping tools. In the cross-sectional survey, analysis of 634 faecal samples from two farms identified only C. bovis and C. ryanae in pre-weaned calves. Two birth cohorts of 61 and 78 calves were followed longitudinally over a 12 month period, which revealed the shedding of C. bovis oocysts started at 1-2 weeks of age and peaked initially at 6-8 weeks of age. Altogether calves experienced four infections by six subtype families of C. bovis, with each infection caused by different subtype families. In contrast, the shedding of C. ryanae oocysts started at 2-4 weeks of age, and the two infections were caused by different subtype families. The cumulative incidence of C. bovis infection was 100% (58/58, 32/32) on both farms, compared with 84.4-98.3% (27/32 and 57/58) for C. ryanae infection. Overall, the mean duration of oocyst shedding in the cohort studies was 3.8-4.0 weeks for C. bovis compared with 2.1 weeks for C. ryanae. The oocyst shedding intensity was high (mean oocysts per gram of faeces was over 105) during the first infection with each species but became significantly lower in the later infections. Cryptosporidium ryanae was associated with the occurrence of diarrhea on one farm, while C. bovis was not. The data indicate that there is an early occurrence of C. bovis and C. ryanae in pre-weaned calves with high infection intensity in the absence of C. parvum. Calves infected with the same Cryptosporidium sp. multiple times could be associated with the presence of subtype-specific immunity.

Multi-Omics Analysis of the Tumor Microenvironment in Liver Metastasis of Colorectal Cancer Identified FJX1 as a Novel Biomarker.

Colorectal cancer incidence and mortality have increased in recent years, with more than half of patients who died of colorectal cancer developing liver metastases. Consequently, colorectal cancer liver metastasis is the focus of clinical treatment, as well as being the most difficult. The primary target genes related to colorectal cancer liver metastasis were via bioinformatics analysis. First, five prognosis-related genes, CTAG1A, CSTL1, FJX1, IER5L, and KLHL35, were identified through screening, and the prognosis of the CSTL1, FJX1, IER5L, and KLHL35 high expression group was considerably poorer than that of the low expression group. Furthermore, the clinical correlation analysis revealed that in distinct pathological stages T, N, and M, the mRNA expression levels of CSTL1, IER5L, and KLHL35 were higher than in normal tissues. Finally, a correlation study of the above genes and clinical manifestations revealed that FJX1 was strongly linked to colorectal cancer liver metastasis. FJX1 is thought to affect chromogenic modification enzymes, the Notch signaling system, cell senescence, and other signaling pathways, according to KEGG enrichment analysis. FJX1 may be a critical target in colorectal cancer metastasis, and thus has the potential as a new biomarker to predict and treat colorectal cancer liver metastases.

Methylation Drives SLC2A1 Transcription and Ferroptosis Process Decreasing Autophagy Pressure in Colon Cancer.

Colon cancer is a common malignant tumor in the digestive tract, with relatively high rates of morbidity and mortality. It is the third most common type of tumor in the world. The effective treatment of advanced colon cancer is limited, so it is particularly important to study the new pathogenesis of colon cancer. Ferroptosis is a nonapoptotic regulated cell death mode driven by iron-dependent lipid peroxidation, a process which has been discovered in recent years. Autophagy involves lysosomal degradation pathways that promote or prevent cell death. High levels of autophagy are associated with ferroptosis, but a clear association has not yet been made between ferroptosis and autophagy in colon cancer. Through the analysis of transcriptome expression profiling data in colon cancer, we obtained the common upregulated genes and downregulated genes by recording the intersection of the differentially expressed genes in each dataset. Solute Carrier Family 2 Member 1 (SLC2A1) was identified by combining autophagy genes obtained from GeneCards and ferroptosis genes obtained from FerrDb. In order to explore the clinical significance and prognostic value of SLC2A1, we utilized massive databases to conduct an in-depth exploration of the methylation of SLC2A1, and we also investigated the differences in immune infiltration between tumor and normal tissues. We found that there are abundant methylation sites in SLC2A1 and that the methylation of SLC2A1 is correlated with the immunosuppression of tumor tissue. We discovered that during the induction of environmental factors, the transcription and methylation levels of SLC2A1 were greatly increased, autophagy and ferroptosis were inhibited, and the immune system was defective, resulting in a poor prognosis for patients. These results suggest that the autophagy and ferroptosis-related gene SLC2A1 is involved in the tumor immune regulation of colon cancer, and SLC2A1 may become a new therapeutic target for colon cancer.

Homeostatic responses and growth of Leymus chinensis under incrementally increasing saline-alkali stress.

Despite considerable tolerance to salt and alkali stress, Leymus chinensis populations on the southwestern Songnen Plain in northern China are threatened by increasing soil salinity and alkalinity. To explore the species' responses to saline-alkali stress, we grew it in substrates with varying concentrations of nitrogen (N) and phosphorus (P) while applying varying levels of saline-alkali stress (increasing in 14-, 17- or 23 -day intervals). We measured the plants' contents of N and P, and the N:P ratio, and calculated their homeostasis indices (HN , HP and HN:P ) under each nutrient and saline-alkali stress treatment. The N content was found to be more sensitive to saline-alkali stress than the P content. The N and P contents were highest and the N:P ratio was stable at pH 8.4. At both pH 8.1 and 8.4, H N:P> H N > H P, but the indices and their relations differed at other pH values. Exposure to saline-alkali stress for the 14-day incremental interval had weaker effects on the plants. Rapid changes in salinity-alkalinity weakened both the positive effects of the weakly alkaline conditions (pH 7.5-8.4) and the negative effects of more strongly alkaline conditions (pH 8.7 or 9.3) on L. chinensis. When L. chinensis plants lack N, applying N fertilizer will be extremely efficient. The optimal concentrations of N and P appeared to be 16 and 1.2 mmol/L, respectively. When the L. chinensis plants were N- and P-limited, the specific growth rate correlated positively with N:P, when limited by N it correlated positively with the environmental N concentration, and when limited by P it was weakly positively correlated with the environmental P concentration.

Magnetoactive acoustic metamaterials based on nanoparticle-enhanced diaphragm.

Magnetoactive membrane-type acoustic metamaterials are fabricated by coating a layer of magnetic nanoparticles on the polyethylene (PE) membranes and their vibration characters are investigated experimentally. From our experiments, we discovered that, under different magnetic fields by varying the distance between a magnet and the membranes, such membranes exhibit tunable vibration eigenfrequencies (the shift towards lower frequencies), which is caused by the variation of the effective mass density and effective tension coefficient resulted from the second derivative of the magnetic field. The strong magnetic force between the layer of magnetic nanoparticles and the magnet enhances the eigenfrequency shift. A spring oscillator model is proposed and it agrees well with the experimental results. We also experimentally observed that the vibration radius, effective mass density, and effective tension coefficient of the membranes can enormously affect the eigenfrequencies of the membranes. We believe that this type of metamaterials may open up some potential applications for acoustic devices with turntable vibration properties.

Amelioration of glucose intolerance by the synthetic androstene HE3286: link to inflammatory pathways.

Insulin resistance, the major metabolic abnormality underlying type 2 diabetes, is associated with chronic inflammation and heavy macrophage infiltration in white adipose tissue (WAT). The therapeutic properties of the synthetic adrenal steroid Delta(5)-androstene-17alpha-ethynyl-3beta,7beta,17beta-triol (HE3286) were characterized in metabolic disease models. Treatment of diabetic db/db mice with HE3286 suppressed progression to hyperglycemia and markedly improved glucose clearance. Similar effects were also observed in insulin-resistant, diet-induced obese C57BL/6J mice and genetically obese ob/ob mice. This effect appeared to be a consequence of reduced insulin resistance because HE3286 lowered blood insulin levels in db/db and ob/ob mice. Treatment with HE3286 was accompanied by suppressed expression of the prototype macrophage-attracting chemokine monocyte chemoattractant protein-1 in WAT, along with its cognate receptor C-C motif chemokine receptor-2. Exposure of mouse macrophages to HE3286 in vitro caused partial suppression of endotoxin (lipopolysaccharide)-induced nuclear factor kappa-B (NF-kappaB)-sensitive reporter gene expression, NF-kappaB nuclear translocation, and NF-kappaB/p65 serine phosphorylation. Proinflammatory kinases, including IkappaB kinase, c-Jun NH2-terminal kinase, and p38, were also inhibited by HE3286. In ligand competition experiments HE3286 did not bind to classical sex steroid or corticosteroid receptors, including androgen receptor (AR), progesterone receptor, estrogen receptor (ER) alpha or ERbeta, and glucocorticoid receptor (GR). Likewise, in cells expressing nuclear receptor-sensitive reporter genes HE3286 did not substantially stimulate transactivation of AR, ER, GR, or peroxisome proliferator-activated receptor (PPAR) alpha, PPARdelta, and PPARgamma. These findings indicate that HE3286 improves glucose homeostasis in diabetic and insulin-resistant mice and suggest that the observed therapeutic effects result from attenuation of proinflammatory pathways, independent of classic sex steroid receptors, corticosteroid receptors, or PPARs.

Preparation of 3D assembly of mono layered molybdenum disulfide nanotubules for rapid screening of carbamate pesticide diethofencarb.

The present work reports development of advanced nanosensor platform based on hierarchical 3D nanotubes assembled from MoS2 mono layers (3D MoS2NTs) for rapid and selective screening of well known carbamate fungicide, diethofencarb. The assembly of ultrathin MoS2 layers possessed mesopores and large specific surface area which enabled its potential implementation in electrode fabrication. Preparation of 3D MoS2NTs helped to avoid restacking and aggregation during its utilization as sensor material and manifested great sensing abilities towards electro-oxidation of diethofencarb. The LOD and LOQ for diethofencarb at 3D MoS2NTs/GCE were calculated as 0.32 ng µL-1 and 1.09 ng µL-1 in the concentration range of 1-55 ng µL-1 by square wave voltammetry (SWV) and further 0.63 ng µL-1 and 2.11 ng µL-1 in the concentration range of 1-35 ng µL-1 by differential pulse voltammetry (DPV). The developed 3D MoS2NTs nanosensor was successfully used to quantify diethofencarb in river water sample with satisfied recovery of 94.23%-105.46% justifying its analytical utility in pesticide screening. The study drives immense motivation towards sensing of hazardous pesticides using nanomaterials based advanced sensing devices for environmental monitoring.

Discovery of potent and orally available malonyl-CoA decarboxylase inhibitors as cardioprotective agents.

Discovery of 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamides as a new class of malonyl-coenzyme A decarboxylase (MCD) inhibitors is described. tert-Butyl 3-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamido)butanoate (5, CBM-301940) exhibited excellent potency and in vivo PK/ADME properties. It is the most powerful stimulant of glucose oxidation reported to date in isolated working rat hearts. Compound 5 improved the cardiac efficiency and function in a rat heart global ischemia/reperfusion model, suggesting MCD inhibitors may be useful for the treatment of ischemic heart diseases.

Busulfan and cyclosphamide induce liver inflammation through NLRP3 activation in mice after hematopoietic stem cell transplantation.

The aim of this study was to evaluate the role of NLRP3 inflammasome on BU/CY-induced liver inflammation in mice after HSCT. HSCT mice model was established through infusion of 5 × 10(6) bone marrow mononuclear cells after conditioned with BU/CY. On day 7, 14, 21 and 28 after HSCT, mice were sacrificed for analysis of liver inflammation, cytokine secretion, NLRP3 expression and caspase-1 activation as well as release of ATP and high-mobility group protein B1 (HMGB1). Furthermore, NLRP3 selective inhibitor (BAY 11-7082) was administrated into mice after HSCT to evaluate its effects on liver inflammation. Severe liver inflammation and damage with elevated secretion of IL-1ß and IL-18 were found in mice after HSCT. Meanwhile, elevated expressions of NLRP3 and caspase-1 activation in liver were found. In addition, increased release of ATP and HMGB1 were observed. Selective inhibition of NLRP3 decreased caspase-1 activation and secretion of IL-1ß and IL-18. Furthermore, NLRP3 inhibition also reduced infiltration of macrophages and neutrophils and improved liver function. In conclusion, NLRP3 was involved in BU/CY-induced liver inflammation after HSCT and selectively inhibited it ameliorated liver inflammation and improved liver function, suggesting targeting NLRP3 might be a new approach in the prophylaxis of liver inflammation after HSCT.

Gradient elution of organic acids on a beta-cyclodextrin column in the polar organic mode and its application to drug discovery.

A high performance liquid chromatographic method was developed that separated organic acids using the polar organic mode. The separation was obtained using a beta-cyclodextrin stationary phase with a mobile phase that was composed of acetonitrile/methanol/triethylamine (TEA)/acetic acid. The compounds were eluted under gradient conditions and the elution order depended on the number, type and position of the hydrogen bonding functional groups present in the molecule. Adjusting the acid to base ratio resulted in the biggest change in selectivity. In addition, increasing the methanol concentration decreased the retention times of the analytes, which had little effect on the selectivity. Using a certain set of conditions one could separate a large number of organic acids, which allowed these acids to be detected by UV and mass spectrometry. These conditions were used to evaluate the purity of potential pharmaceutical drug candidates that showed activity towards a kinase target vascular endothieal growth factor (Vegf). Each compound contained a carboxylic acid group that was critical to the activity. The method was able to give purity estimates of these samples, which were difficult to determine by other HPLC methods.

[The relationship between NLRP3 inflammsomes expression and liver damage after allogeneic hematopoietic stem cell transplantation in mice model].

OBJECTIVE: To explore the function of nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammsomes in liver damage after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: The study presented a murine (BALB/c-based) model of allo-HSCT. Chimera rate was measured by flow cytometry. The hematoxylin-eosin, Masson's trichrome, immunohistochemistry staining were used to observe the pathology changes in liver, then measured the degree of liver damage. Inflammation cells and NLRP3 were measured by Western blot, cytokines IL-1ß, IL-18 and NLRP3 related genes were tested with real-time quantitative polymerase chain reaction (q-PCR). RESULTS: Hematopoietic stem cells had been successfully transplanted, the chimera rate was geater than 97% on the 10th day. Liver damage occurred after allo-HSCT and suffered infiltration of inflammation cells, which reached the peak on day 15, then moved to moderate; the cytokines IL-1ß, IL-18 had the similar trend with liver injury, and reached the highest level on day 15, their mRNA expressions increased by (1.19 ± 0.40) fold and (1.64 ± 0.76) fold, respectively; Meanwhile, caspase-1 had the similar trend, its mRNA expression increased by (3.51 ± 0.46) fold on day 15; the inflammasomes NLRP1, NLRP3, NLRC4 and NLRP5 expressed in liver on day 15 of post-allo-HSCT, and NLRP3 inflammasome expressed highest among them. The mRNA and protein level of NLRP3 inflammasomes were kept with the serious degree of the liver damage, its mRNA expression increased by (2.91 ± 0.41) fold on day 15. CONCLUSION: NLRP3 inflammsome expressed in liver injury during allo-HSCT in mice, and may be one of the important factors contributed to liver injury.

[Effect of endothelial progenitor cell on hematopoietic reconstitution in allogeneic hematopoietic stem cell transplantation mouse model].

OBJECTIVE: To examine the effects of endothelial progenitor cell (EPC) on hematopoietic reconstitution in allogeneic hematopoietic stem cell transplantation (allo-HSCT) mouse model. METHODS: Allo-HSCT mouse model was established with condition of BU/CY, in which C57BL/6 (H-2b) and BALB/c (H-2d) mice were used as donors and recipients respectively. Recipients were randomly divided into 4 groups: untreated group, BU/CY condition group, bone marrow transplantation (BMT) group and transplantation of BM cells combined with EPCs (combined transplantation) group. The pathological changes of BM cells following transplantation were dynamically observed. Changes of BM sinusoidal endothelium and angiogenesis were observed by MECA-32 antibody immunohistochemical staining. The proportion of intramedullary stem and progenitor cells and serum cytokines were analyzed by flow cytometry. The numbers of peripheral blood cells were also counted. RESULTS: (1) Injuries of BM hematopoietic tissue, sinusoidal endothelium and vascular were less severe in combined transplantation group than of BMT group. (2) EPC infusion significantly increased BM hematopoietic stem cells 21 days after transplantation. The percentage of BM hematopoietic stem cells in combined transplantation group peaked on day +14, which was higher than of BMT group (0.1743 vs 0.0787) (P<0.05). The continuously increased percentage of BM hematopoietic progenitor cells in combined transplantation group was significantly higher than in BMT group on day +21 (0.4550 vs 0.3905) (P<0.05). (3) The number of peripheral white blood cells in combined transplantation group was always higher than of BMT group, which reached the peak on day +14 (0.74×109/L to 0.47×109/L) (P<0.05). The peak number of peripheral blood platelets on day +14 in combined transplantation group was significantly higher than of group BMT (1228.9×109/L to 977.12×109/L) (P<0.05). CONCLUSION: Allo-HSCT combined with EPC infusion accelerated hematopoietic reconstitution compared with BMT alone in allo-HSCT mouse model.

Novel components of the human metabolome: the identification, characterization and anti-inflammatory activity of two 5-androstene tetrols.

Two natural 5-androstene steroid tetrols, androst-5-ene-3ß,7ß,16α,17ß-tetrol (HE3177) and androst-5-ene-3α,7ß,16α,17ß-tetrol (HE3413), were discovered in human plasma and urine. These compounds had significant aqueous solubility, did not bind or transactivate steroid-binding nuclear hormone receptors, and were not immunosuppressive in murine mixed-lymphocyte studies. Both compounds appear to be metabolic end products, as they were resistant to primary and secondary metabolism. Both were orally bioavailable, and were very well tolerated in a two-week dose-intensive toxicity study in mice. Anti-inflammatory properties were found with exogenous administration of these compounds in rodent disease models of multiple sclerosis, lung injury, chronic prostatitis, and colitis.

Oral treatment with HE3286 ameliorates disease in rodent models of rheumatoid arthritis.

HE3286 (17alpha-ethynyl-5-androstene-3beta, 7beta, 17beta-triol) is an orally bio-available synthetic derivative of naturally occurring androstene-3beta, 7beta, 17beta-triol. Our present data show that oral treatment with HE3286, favourably influenced the course of arthritis in the rat model of adjuvant-induced arthritis (reduced cumulative disease scores and paw edema), and in the mouse model of collagen antibody-induced arthritis (reduced clinical paw scores). Importantly, HE3286 was not immune suppressive in human mixed lymphocyte reaction or in animals challenged with Coxsackie B3 virus. HE3286 is currently in phase I/II clinical trials in rheumatoid arthritis and ulcerative colitis and these findings further strengthen the possibility that HE3286 may represent an effective anti-inflammatory agent useful for treating chronic inflammation with a more attractive safety profile than glucocorticoids or cyclooxygenase inhibitors.