RAPSYN-mediated neddylation of BCR-ABL alternatively determines the fate of Philadelphia chromosome-positive leukemia.

Philadelphia chromosome-positive (Ph+) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved remarkable success in prolonging patient survival, intolerance, relapse, and TKI resistance remain serious issues for patients with Ph+ leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph+ leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast to in vivo ineffectiveness of PROTAC-based degraders, depletion of RAPSYN expression, or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph+ leukemia.

Chronic myeloid leukemia (CML for short) accounts for about 15% of all blood cancers diagnosed in adults in the United States. The condition is characterized by the overproduction of immature immune cells that interfere with proper blood function. It is linked to a gene recombination (a type of mutation) that leads to white blood cells producing an abnormal 'BCR-ABL' enzyme which is always switched on. In turn, this overactive protein causes the cells to live longer and divide uncontrollably. Some of the most effective drugs available to control the disease today work by blocking the activity of BCR-ABL. Yet certain patients can become resistant to these treatments over time, causing them to relapse. Other approaches are therefore needed to manage this disease; in particular, a promising avenue of research consists in exploring whether it is possible to reduce the amount of the enzyme present in diseased cells. As part of this effort, Zhao, Dai, Li, Zhang et al. focused on RAPSYN, a scaffolding protein previously unknown in CML cells. In other tissues, it has recently been shown to participate in neddylation ­ a process by which proteins receive certain chemical 'tags' that change the way they behave. The experiments revealed that, compared to healthy volunteers, RAPSYN was present at much higher levels in the white blood cells of CML patients. Experimentally lowering the amount of RAPSYN in CML cells led these to divide less quickly ­ both in a dish and when injected in mice, while also being linked to decreased levels of BCR-ABL. Additional biochemical experiments indicated that RAPSYN sticks with BCR-ABL to add chemical 'tags' that protect the abnormal protein against degradation, therefore increasing its overall levels. Finally, the team showed that SRC, an enzyme often dysregulated in emerging cancers, can activate RAPSYN's ability to conduct neddylation; such mechanism could promote BCR-ABL stabilization and, in turn, disease progression. Taken together, these experiments indicate a new way by which BCR-ABL levels are controlled. Future studies should investigate whether RAPSYN also stabilizes BCR-ABL in patients whose leukemias have become resistant to existing drugs. Eventually, RAPSYN may offer a new target for overcoming drug-resistance in CML patients.

Adsorption of lithium ions from aqueous solution by magnetic aluminum-based adsorbents.

Magnetic aluminum-based adsorbents (MLDHs) were prepared with a coprecipitation method and used to separate lithium ions from the aqueous solutions. In static adsorption experiment, the adsorption capacity of MLDHs for lithium ions reached 8.22 mg/g. In a mixed solution of various metal ions, the adsorbents exhibited higher selectivity for lithium ions. Kinetic studies indicated that the adsorption process conformed to a pseudo-second-order model. The experimental data were fitted with nonlinear regression using commonly used adsorption isotherms. It was found that the adsorption isotherm process could be described by the Langmuir model. In addition, the thermodynamic parameters revealed that the adsorption of lithium was a spontaneous endothermic process.

Structural design and performance study of primitive triply periodic minimal surfaces Ti6Al4V biomimetic scaffold.

This paper comprehensively evaluated the static mechanical compressive properties, permeability, and cell adhesion effect on the inner wall of the Primitive triply periodic minimal surface Ti6Al4V bionic scaffolds with different axial diameter ratios through numerical simulation and experiments. The results show that when the axial diameter ratio is 1:2, the elastic modulus of the scaffold is about 1.25 and the yield strength is about 1.36. The scaffold's longitudinal and transverse mechanical properties align with human bone tissue. Its permeability is also better than that of circular pores. The scaffold with an axial diameter ratio of 1:3 has the best permeability, ranging from 1.28e-8 to 1.60e-8 m2, which is more conducive to the adsorption of cells on the inner wall of the scaffold. These results show that the scaffold structure with an axial diameter ratio of not 1:1 has more advantages than the ordinary uniform scaffold structure with an axial diameter ratio of 1:1. This is of great significance to the optimal design of scaffold.

Study on the influence of an underground low-light environment on human safety behavior.

Objective. This study aimed to research the impact that a coal mine lighting environment has on human safety behavior in an underground coal mine. Methods. We built a coal mine lighting simulation experiment system including both general lighting and local lighting divided into six different illumination gradients (0, 10, 30, 50, 75 and 100 lx) to test and analyze the effects of general illumination gradients on human fatigue, attention, reaction and eye-hand coordination with SPSS version 22.0. Results. Illuminance has a significant effect on human fatigue, attention, reaction ability and eye-hand coordination ability. Specifically, human fatigue is negatively correlated and the other indicators are positively correlated with the increase of illuminance. Notably, attention distribution ability seems to be most significantly influenced by illuminance according to this study, followed by human fatigue, reaction and eye-hand coordination ability. Conclusion. The results of the study indicate that illumination of the general lighting environment is expected to be controlled at a gradient of at least 50-75 lx or above in the coal mine environment where there is both general lighting and local lighting to reduce the incidence of accidents.

Lighting for work: a study on the effect of underground low-light environment on miners' physiology.

Low-light environment affects human physiology, psychology, and behavior. It causes errors in work and increases accidents. In this study, we built a coal mine lighting simulation experiment system. The system not only includes an experimental environment simulation system and a physiological indicator test system, but also adds a miners' working simulation system. We aim to study the effect of different illumination levels (0lx, 10lx, 50lx, 100lx, and 200lx) on three indicators: heart rate, electrodermal activity, and respiration. The results show illuminance has a significant negative correlation with all the above three indicators. Heart rate seems to be most significantly affected by illuminance, and it changes significantly from the normal level (200lx) at 50lx. By contrast, the respiratory rate and electrodermal activity change significantly at 10lx. When the illuminance is 50~100lx, all the three indicators return to the normal level. The results suggest that coal mine illumination should be around 50~100lx. When the minimum illumination is less than 10lx, accidents tend to increase.

How to analyse the injury based on 24Model: a case study of coal mine gas explosion injury.

BACKGROUND: Coal mine gas explosion injury has caused mass casualties, which have resulted in widespread concern. METHODS: In order to prevent gas explosion injury in coal mine, 24Model is proposed to analyse the risk in this paper. 24Model is a human-oriented and organisation-oriented risk analysis method. Based on the 24Model, we propose a general procedure for analysing the causes of injury within the organisation. RESULTS: A coal mine gas explosion case was analysed using the 24Model and the proposed analysis method, and the evolution of injury and the interaction of various causes was showed, and 6 unsafe conditions, 25 unsafe acts, 13 safety knowledge, 13 safety management systems and 13 safety cultures were obtained. CONCLUSION: Case analysis results show that by using the 24Model and analysis method the proposed effect can help employees to clearly see the evolution and identify the causes of the injury, to better understand the logical relationship with the causes of the injury, improve the effectiveness of training and effectively prevent similar injury. The case study provides a practical procedure for injury investigation and analysis, and thus, preventive measures can be made according to the various causations at different levels.

Study on mechanical properties and permeability of elliptical porous scaffold based on the SLM manufactured medical Ti6Al4V.

In this paper, we take the elliptical pore structure which is similar to the microstructure of cancellous bone as the research object, four groups of bone scaffolds were designed from the perspective of pore size, porosity and pore distribution. The size of the all scaffolds were uniformly designed as 10 × 10 × 12 mm. Four groups of model samples were prepared by selective laser melting (SLM) and Ti6Al4V materials. The statics performance of the scaffolds was comprehensively evaluated by mechanical compression simulation and mechanical compression test, the manufacturing error of the scaffold samples were evaluated by scanning electron microscope (SEM), and the permeability of the scaffolds were predicted and evaluated by simulation analysis of computational fluid dynamics (CFD). The results show that the different distribution of porosity, pore size and pores of the elliptical scaffold have a certain influence on the mechanical properties and permeability of the scaffold, and the reasonable size and angle distribution of the elliptical pore can match the mechanical properties and permeability of the elliptical pore scaffold with human cancellous bone, which has great potential for research and application in the field of artificial bone scaffold.

A simulation experiment study to examine the effects of noise on miners' safety behavior in underground coal mines.

BACKGROUND: Noise pollution in coal mines is of great concern. Personal injuries directly or indirectly related to noise occur from time to time. Its effects impact the health and safety of coal mine workers. This study aimed to identify if and how the level of noise impacts miners' safety behavior in underground coal mines. METHODS: In order to study the influence of noise on miners in the mining industry, we built a coal mine noise simulation experiment system, and set the noise test level at 50 dB ~ 120 dB according to the actual working environment at well. We divided the noise gradient into 8 categories and conducted 93 experiments, in which we aim to test miners' attention distribution, fatigue, and reaction under each level, and the experimental results were analyzed by SPSS22.0 software. RESULTS: The results show that the increase of environmental noise level will have an impact on the attention, reaction, and fatigue. The noise is positively related to the fatigue, the noise is negatively related to the attention and reaction. In the noise environment, the sensitivity of the personnel to optic stimuli is higher than that to acoustic stimuli. The test indicators of attention, fatigue, and reaction will change significantly, when the noise level is greater than 70 ~ 80 dB. CONCLUSIONS: From the perspective of accident prevention, the noise level can be controlled within the range of less than 70 ~ 80 dB, which can control the occurrence of accidents to a certain extent.

Optimization of extraction flavonoids from Exocarpium Citri Grandis and evaluation its hypoglycemic and hypolipidemic activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Exocarpium Citri Grandis (ECG; Huajuhong in Chinese) is a precious traditional Chinese medicine with a history of hundreds of years in China. It has been demonstrated to possess numerous pharmacological properties, including antitussive, expectorant, anti-inflammatory, hypoglycemic, and hypolipidemic. However, no in-depth report exists on the hypoglycemic and hypolipidemic properties of ECG. AIM OF THE STUDY: This study aimed to evaluate the hypoglycemic and hypolipidemic properties of ECG flavonoids extract in vitro and in vivo so as to lay the foundation for further researches in this field. MATERIALS AND METHODS: Total flavonoids (TF) and naringin were separately extracted from ECG, and the components of TF were identified by HPLC-MS. The antioxidant capacities of TF and naringin were determined by 2,2,1-diphenyl-1-picrylhydrazyl (DPPH)-free radical scavenging tests, and digestive enzymes activity inhibition assays in vitro in order to evaluate their hypoglycemic properties. Furthermore, diabetic mice experiments were performed to assess the hypoglycemic and hypolipidemic properties of TF and naringin in vivo. RESULTS: Five compounds were identified from TF, including naringin, rhoifolin, poncirin, bergaptol, and naringenin. The half maximal inhibitory concentration (IC50) of TF and naringin to DPPH-free radicals were 0.269 and 1.946 mg/mL, respectively. TF and naringin demonstrated a certain inhibitory effect on α-glucosidase and a weaker inhibitory effect on α-amylase. The results of animal experiments showed that TF and naringin had no significant effect on the blood glucose levels, but they could lead to significant (p < 0.05 or p < 0.01) increase in the serum insulin level and high-density lipoprotein cholesterol (HDL-C) levels with concomitant reduction in the total cholesterol (TC), total triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels in diabetic mice. In addition, TF and naringin could reduce the liver index of diabetic mice (p < 0.01) and reduce the kidney index at low doses (p < 0.05). CONCLUSIONS: Our study revealed that the hypoglycemic and hypolipidemic activities of TF is mainly derived from naringin, and other active ingredients in TF also have the effects of alleviating oxidative stress, inhibiting digestive enzyme activity and reducing blood lipids. Our results thus provide a scientific basis for the application of ECG in antidiabetic treatment.

Preparation and characterization of a novel colorimetric indicator film based on gelatin/polyvinyl alcohol incorporating mulberry anthocyanin extracts for monitoring fish freshness.

This work aimed to develop a novel colorimetric indicator film for monitoring of food freshness based on gelatin/polyvinyl alcohol matrix incorporated with anthocyanin extracts from mulberry. The color of anthocyanin extracts solutions obviously changed from bright red to dark green in the pH range of 2.0-11.0. FTIR spectra and isothermal titration calorimetry showed that the anthocyanin extracts were successfully combined with gelatin/polyvinyl alcohol matrix by hydrogen binding and electrostatic interaction, which enhanced the stability of anthocyanin. The scanning electric microscopy showed that the compatibility between polyvinyl alcohol and gelatin were improved owing to the addition of anthocyanin extracts. With the anthocyanin extracts addition from 0 to 45 mg/100 mL mixed solution, the tensile strength decreased from 30.80 to 21.01 MPa and the elongation at break increased from 589.22% to 905.86%. The color response of film in buffer solution of different pH were in accordance with anthocyanin extracts solutions, and its color changes were clearly visible with naked eye. Finally, the film was evaluated by a test on monitoring fish spoilage, which presented visible color changes due to volatile nitrogenous compounds formed over time. These results showed that this developed film could be used as an effective method for the monitoring of food freshness.

Inclusion Complex of Exocarpium Citri Grandis Essential Oil with ß-Cyclodextrin: Characterization, Stability, and Antioxidant Activity.

The purpose of this study was to produce and characterize an inclusion complex between ß-cyclodextrin (ß-CD) and Exocarpium Citri Grandis essential oil (EEO), and to evaluate its antioxidant properties. The volatile compounds of EEO were characterized by gas chromatography-mass spectrometer. A comparison of the ß-CD, EEO, and the physical mixture with the inclusion complex revealed differences in their thermal stabilities and morphologies, which confirmed the formation of the ß-CD-EEO inclusion complex. Complexed with ß-CD, the ß-CD-EEO inclusion complex showed a higher stability and antioxidant activity when compared with physical mixture and EEO. Therefore, ß-CD can be used to form inclusion complexes with EEO to expand its potential applications in the food and drug industries. PRACTICAL APPLICATION: Exocarpium Citri Grandis is rich in essential oil and other ingredients. The optimized extraction, constituent composition, and encapsulation of EEO in ß-CD were investigated in this study. The results showed that the encapsulation process increased the antioxidant activity and stability of EEO, which provides both fundamental and practical knowledge for the application of EEO in the food and drug industries.

Dinuclear Lanthanide Complexes Based on a Schiff-base Ligand: Free Lattice Solvent Inducing the Single Molecule Magnet Behavior of Dy2 Compound.

Syntheses, crystal structures and magnetic properties are described for a series of seven-coordinate dinuclear lanthanide complexes of compositions Dy2 L2 (1) (H3 L=2-{[bis(2-hydroxy-3-ethoxybenzyl)(aminoethyl)amino]methyl}phenol) and Ln2 L2 ⋅MeCN (Ln=Dy (2), Sm (3), Eu (4), Gd (5), Tb (6), Ho (7)). The reaction of Dy(NO3 )3 ⋅6 H2 O with one equivalent of H3 L at 70 °C in DMF/EtOH under autogenous pressure gave compound 1. Complexes 2-7 were prepared by means of the same method as that used for 1, except DMF was replaced by MeCN as the reaction solvent and Dy(NO3 )3 ⋅6 H2 O was changed to the corresponding lanthanide salts. Complexes 1-7 possess the similar Ln2 cores bridged by µ2 -phenoxyl oxygen atoms. The slight difference between 1 and 2-7 arises from the existence of free MeCN molecule in 2-7. The purposeful introduction of solvent MeCN molecule changes the crystal system from triclinic for 1 to monoclinic for 2 and alters the Dy-O-Dy angles and Dy⋅⋅⋅Dy distances, consequentially resulting into dramatic influences on the magnetic properties of 1 and 2. Complex 1 shows no SMM character, while compound 2 with free MeCN molecule exhibits a field-induced slow magnetization relaxation behavior. Complete active space self-consistent field (CASSCF) calculations were performed on two Dy2 compounds to rationalize the observed difference in the magnetic behavior. Theoretical calculations reveal that the energy gap between the lowest two Kramers doublets of individual DyIII fragment for 2 is higher than those of 1 (1_a and 1_b). This conlusion is consistant with the experimental result that complex 2 exhibits better magnetic properties. This work proposes an ingenious strategy for inducing the SMM behavior in the Dy2 compounds.

Enhanced energy barriers triggered by magnetic anisotropy modulation via tuning the functional groups on the bridging ligands in Dy2 single-molecule magnets.

Two dinuclear dysprosium complexes of formulae [Dy2(L1)2(NO3)2(MeOH)2]·2MeOH (1) and Dy2(L2)2(NO3)2(MeOH)2 (2), (H2L1 = 4-chloro-2-(((2-hydroxy-3-methoxybenzyl)imino)methyl)phenol, H2L2 = 2-(((2-hydroxybenzylidene)amino)methyl)-6-methoxyphenol) have been synthesized under solvothermal conditions. The two ligands differ in the substituents at the phenol moieties of the ligands. The purposeful exclusion of the functional group -Cl at the phenol backbone significantly changed the geometries of the metal centers, as evidenced by the X-ray crystallographic analysis. In complex 1, two DyIII ions are in D2d local symmetry, while the DyIII ions of 2 are in D4d local symmetry. Consequently, these two complexes demonstrate distinct magnetic properties. Complexes 1 and 2 both exhibit SMM behavior with energy barriers of 51.97 K for 1 and 87.16 K for 2 under a zero direct-current field. Complete-active-space self-consistent field (CASSCF) calculations were performed on the two Dy2 complexes to rationalize the remarkable observed discrepancy in their magnetic behavior. Theoretical calculations reveal that the angle θ between the magnetic axis and the vector connecting two dysprosium(iii) ions is the vital factor for the energy barriers of SMMs. The smaller θ angle of 2 renders it as an SMM with a higher energy barrier. This work demonstrates that tuning the functional groups on the bridging ligands is an effective strategy in modulating the energy barriers of SMMs.

Optimization of Extraction of Hypoglycemic Ingredients from Grape Seeds and Evaluation of α-Glucosidase and α-Amylase Inhibitory Effects In Vitro.

Grape seeds full with oil and also rich in hypoglycemic ingredients. This study is to improve the comprehensive utilization of grape seeds and the quality of grape seeds oil. Extract water soluble active substances before extracting oil from grape seeds, which show the grape seeds in water soluble extracts containing TP, TC, PC contents, respectively, are 171.1 ± 1.1, 658.8 ± 0.2, 482.3 ± 0.2 (mg GSAE/g). Also we found GSAE samples containing catechin and epicatechin were 44.12 ± 0.21 mg/mL, 111.23 ± 1.29 mg/g, GSAE against α-glucosidase IC50 was 25.25 ± 0.53 g/mL and GSAE against α-amylase IC50 was 66.68 ± 1.1 g/mL, both were competitive way, the effects of Inhibitory were obviously better than that of acarbose. In addition, our process guarantee the fat ingredients remained in the grape seeds and not reduce functional components of oil, our study suggests that GSAE can be used to develop functional foods for prevention and treatment of diabetes and its complications. PRACTICAL APPLICATION: Grape seeds, by-products of brewing wines, are rich in polyphenol and other ingredients. The optimized extraction, composition of constituents and hypoglycemic activity were investigated in this study. The results showed that grape seeds were rich in anthocyanins and polyphenols and other active substances, inhibited α-glucosidase and α-amylase activity, which provide background and practical knowledge for the deep-processed products of grape seeds with high added value.

A series of Ln4 III clusters: Dy4 single molecule magnet and Tb4 multi-responsive luminescent sensor for Fe3+, CrO4 2-/Cr2O7 2- and 4-nitroaniline.

Five tetranuclear lanthanide clusters of compositions [Ln4L4(NO3)2(Piv)2]·2CH3OH (Ln = Gd (1), Tb (2), Dy (3), Ho (4), Er (5); H2L = 2-(((2-hydroxy-3-methoxybenzyl)imino)methyl)-6-methoxyphenol; Piv = pivalic acid) were synthesized under solvothermal conditions. The structures of 1-5 were characterized by single-crystal X-ray crystallography. Complexes 1-5 possess a zig-zag topology with [Ln4O6] cores being formed by the fusion of oxygen atom-bridged two [Ln2O2] moieties. Direct-current magnetic susceptibility studied in the 2-300 K range revealed weak antiferromagnetic interactions in 1, 2, 4, 5 and ferromagnetic interactions in 3. Complex 3 exhibits single molecule magnet (SMM) behavior. The luminescence studies indicated that complex 2 can serve as highly sensitive and selective luminescent materials for Fe3+, CrO4 2-, Cr2O7 2- and 4-nitroaniline (4-NA), demonstrating that complex 2 should be a potential candidate for multi-responsive luminescent sensor.

Two Series of Homodinuclear Lanthanide Complexes: Greatly Enhancing Energy Barriers through Tuning Terminal Solvent Ligands in Dy2 Single-Molecule Magnets.

The utilization of 2-ethoxy-6-{[(2-hydroxy-3-methoxybenzyl)imino]methyl}phenol (H2 L) as a chelating ligand, in combination with the employment of alcohols (EtOH and MeOH) as auxiliary ligands, in 4 f-metal chemistry afforded two series of dinuclear lanthanide complexes of compositions [Ln2 L2 (NO3 )2 (EtOH)2 ] (Ln=Sm (1), Eu (2), Gd (3), Tb (4), Dy (5), Ho (6), Er (7)) and [Ln2 L2 (NO3 )2 (MeOH)2 ] (Ln=Sm (8), Eu (9), Gd (10), Tb (11), Dy (12), Ho (13), Er (14)). The structures of 1-14 were determined by single-crystal X-ray crystallography. Complexes 1-7 are isomorphous. The two lanthanide(III) ions in 1-7 are doubly bridged by two deprotonated aminophenoxide oxygen atoms of two µ2 :η0 :η1 :η2 :η1 :η1 :η0 -L2- ligands. One nitrogen atom, two oxygen atoms of the NO3- anion, two methoxide oxygen atoms of two ligand sets, and one oxygen atom of the terminally coordinated EtOH molecule complete the distorted dodecahedron geometry of each lanthanide(III) ion. Compounds 8-14 are isomorphous and their structures are similar to those of 1-7. The slight difference between 1-7 and 8-14 stems from purposefully replacing the EtOH ligands in 1-7 with MeOH in 8-14. Direct-current magnetic susceptibility studies in the 2-300 K range reveal weak antiferromagnetic interactions for 3, 4, 7, 10, 11, and 14, and ferromagnetic interactions at low temperature for 5, 6, 12, and 13. Complexes 5 and 12 exhibit single-molecule magnet (SMM) behavior with energy barriers of 131.3 K for 5 and 198.8 K for 12. The energy barrier is significantly enhanced by dexterously regulating the terminal ligands. To rationalize the observed difference in the magnetic behavior, complete-active-space self-consistent field (CASSCF) calculations were performed on two Dy2 complexes. Subtle variation in the angle between the magnetic axes and the vector connecting two dysprosium(III) ions results in a weaker influence on the tunneling gap of individual dysprosium(III) ions by the dipolar field in 12. This work proposes an efficient strategy for synthesizing Dy2 SMMs with high energy barriers.

Adipose-Derived Mesenchymal Stem Cells Ameliorate Lipid Metabolic Disturbance in Mice.

UNLABELLED: : Adipose-derived mesenchymal stem cells (AD-MSCs) have been shown to ameliorate hyperglycemia in diabetic animals and individuals. However, little is known about whether AD-MSCs affect lipid metabolism. Here we have demonstrated for the first time that AD-MSC infusion can significantly suppress the increase in body weight and remarkably improve dyslipidemia in db/db obese mice and diet-induced obesity mice. Induction of white fat tissue "browning" and activation of adenosine monophosphate-activated protein kinase and its downstream hormone-sensitive lipase in adipose tissue contribute to the antiobesity and lipid-lowering effects. Thus, AD-MSC infusion holds great therapeutic potential for dyslipidemia and associated cardiovascular diseases. SIGNIFICANCE: Mesenchymal stem cells (MSCs) are considered one of the most promising types of stem cells for translational application because of their rich tissue sources, multilineage differentiation capacity, and easy amplification in vitro and unique immunobiological properties. This study demonstrated that adipose-derived MSCs (AD-MSCs) infusion can significantly suppress the increase in body weight and remarkably improve dyslipidemia in obese mice. Induction of white fat tissue "browning" and activation of adenosine monophosphate-activated protein kinase and its downstream hormone-sensitive lipase in adipose tissue were demonstrated to contribute to the antiobesity and lipid-lowering effects. Thus, AD-MSC infusion holds great therapeutic potential for dyslipidemia.

Neuroprotective effects of human umbilical cord-derived mesenchymal stromal cells combined with nimodipine against radiation-induced brain injury through inhibition of apoptosis.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) possess the ability to repair brain injuries. Additionally, nimodipine is a neuroprotective agent that increases cerebral blood flow and may help with the homing of MSCs to the injury site. Here we investigate the effectiveness of a combined human umbilical cord-derived MSCs and nimodipine therapy in radiation-induced brain injury (RIBI). METHODS: Female mice received whole brain irradiation (WBI) and were treated with saline, nimodipine, hUC-MSCs, or hUC-MSCs combined with nimodipine. Body weight was measured weekly. An open field test for locomotor activity and a step-down avoidance test for learning and memory function were conducted at week 4 and week 12 post-WBI. The histological damage was evaluated by hematoxylin and eosin staining and glial fibrillary acidic protein immunohistochemistry. Quantitative polymerase chain reaction and Western blotting were used to detect apoptosis-related mediators (p53, Bax and Bcl-2). RESULTS: In mice receiving the hUC-MSCs or the combined treatment, their body weight recovered, their locomotor and cognitive ability improved, and the percentage of necrotic neurons and astrocytes was reduced. The combined therapy was significantly (P < 0.05) more effective than hUC-MSCs alone; these mice showed decreased expression of pro-apoptotic indicators (p53, Bax) and increased expression of an anti-apoptotic indicator (Bcl-2), which may protect brain cells. CONCLUSIONS: We demonstrated that hUC-MSCs therapy helps recover body weight loss and behavior dysfunction in a mice model of RIBI. Moreover, the effectiveness of the combined hUC-MSCs and nimodipine therapy is due to apoptosis inhibition and enhancing homing of MSCs to the injured brain.

Short-term memory of danger signals or environmental stimuli in mesenchymal stem cells: implications for therapeutic potential.

Mesenchymal stem/stromal cells (MSCs) possess some characteristics of immune cells, including a pro-inflammatory phenotype, an immunosuppressive phenotype, antibacterial properties and the expression of Toll-like receptor proteins. Here we show that, similar to immune cells, MSCs retain information from danger signals or environmental stimuli for a period of time. When treated with the pro-inflammatory factors lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), MSCs display increased expression of IL-6, IL-8 and MCP-1. Following re-plating and several rounds of cell division in the absence of stimulating factors, the expression of IL-6, IL-8 and MCP-1 remained higher than in untreated cells for over 7 days. A spike in cytokine secretion occurred when cells were exposed to a second round of stimulation. We primed MSCs with LPS and LPS-primed MSCs had better therapeutic efficacy at promoting skin flap survival in a diabetic rat model than did unprimed MSCs. Finally, we found that several microRNAs, including miR146a, miR150 and miR155, along with the modification of DNA by 5-hydroxymethylcytosine (5hmC), mediate the MSC response to LPS and TNF-α stimulation. Collectively, our data suggest that MSCs have a short-term memory of environmental signals, which may impact their therapeutic potential.

TLR4 plays a crucial role in MSC-induced inhibition of NK cell function.

Mesenchymal stem cells (MSC) are a kind of stromal cell within the tumor microenvironment. In our research, MSC derived from acute myeloid leukemia patients' bone marrow (AML-MSC) and lung cancer tissues (LC-MSC) as well as normal bone marrow-derived MSC (BM-MSC) cultured in conditioned medium of HeLa cells were found to have higher expressions of Toll-like receptor (TLR4) mRNA compared with BM-MSC. The sorted TLR4-positive MSC (TLR4+ MSC) differed in cytokine (interleukin-6, interleukin-8, and monocyte chemoattractant protein-1) secretion from those of unsorted MSC. MSC was reported to inhibit natural killer (NK) cell proliferation and function. In this research, we confirmed that TLR4+ MSC aggravate this suppression. Furthermore, when TLR4 in the sorted cells were stimulated by LPS or following blocked by antibody, the suppression on NK cell proliferation and cytotoxicity were more intensive or recovered respectively. Compared to unsorted MSC, NKG2D receptor expression on NK cells were also inhibited by TLR4+ MSC. These findings suggest that activation of TLR4 pathway is important for TLR4+ MSC and MSC to obstruct anti-tumor immunity by inhibiting NK cell function, which may provide a potential stroma-targeted tumor therapy.