hUCMSC-derived exosomes protect against GVHD-induced endoplasmic reticulum stress in CD4+ T cells by targeting the miR-16-5p/ATF6/CHOP axis.

Exosomes generated from mesenchymal stem cells (MSCs) are thought to be a unique therapeutic strategy for several autoimmune deficiency illnesses. The purpose of this study was to elucidate the protective effects of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exo) on CD4+ T cells dysfunction during graft-versus-host disease (GVHD) and to identify the underlying processes involved. Here, we showed that hUCMSC-Exo treatment can effectively attenuate GVHD injury by alleviating redox metabolism disorders and inflammatory cytokine bursts in CD4+ T cells. Furthermore, hUCMSC-Exo ameliorate ER stress and ATF6/CHOP signaling-mediated apoptosis in CD4+ T cells and promote the development of CD4+IL-10+ T cells during GVHD. Moreover, downregulating miR-16-5p in hUCMSC-Exo impaired their ability to prevent CD4+ T cells apoptosis and weakened their ability to promote the differentiation of CD4+IL-10+ T cells. Collectively, the obtained data suggested that hUCMSC-Exo suppress ATF6/CHOP signaling-mediated ER stress and apoptosis in CD4+ T cells, enhance the differentiation of CD4+IL-10+ T cells, and reverse the imbalance of immune homeostasis in the GVHD process by transferring miR-16-5p. Our study provided further evidence that GVHD patients can benefit from hUCMSC-Exo-mediated therapy.

Human placental mesenchymal stromal cells modulate IFN-γ and IL-10 secretion by CD4+T cells via CD73, and alleviate intestinal damage in mice with graft-versus-host disease.

BACKGROUND: Intestinal inflammatory damage is an important factor in the development of graft-versus-host disease (GVHD). IFN-γ and IL-10 play key roles in gastrointestinal inflammation, and human placental mesenchymal stromal cells (hPMSCs) can alleviate inflammatory damage during GVHD. CD73 is highly expressed by hPMSCs. We aimed to study whether hPMSCs could alleviate intestinal damage in GVHD mice by modulating IFN-γ and IL-10 in CD4+T cells by CD73. METHODS: A GVHD mouse model was induced using 8-week-old C57BL/6J and BALB/c mice, which were treated with regular hPMSCs (hPMSCs) or hPMSCs expressing low level of CD73 (shCD73). Then, the levels of IFN-γ and IL-10 in CD4+T cells were determined using flow cytometry. Transmission electron microscopy, western blotting, and morphological staining were employed to observe the intestinal damage. RESULTS: hPMSCs ameliorated pathological damage and inhibited the reduction of the tight junction molecules occludin and ZO-1. They also downregulated IFN-γ and upregulated IL-10 secretion in CD4+T cells via CD73. Moreover, IL-10 mitigated the inhibitory effects of IFN-γ on the expression of occludin in both Caco-2 and NCM460 cells in vitro, but did not affect ZO-1. In addition, hPMSCs upregulated the level of AMPK phosphorylation in CD4+T cells by CD73, which is positively associated with the proportion of CD4+IFN-γ+IL-10+T, and CD4+IFN-γ-IL-10+T cells. CONCLUSIONS: Our findings suggested that hPMSCs may balance the levels of IFN-γ and IL-10 in CD4+T cells by promoting the phosphorylation of AMPK via CD73, which alleviates the loss of occludin and ZO-1 in intestinal epithelial cells and, in turn, reduces inflammatory injury in GVHD mice.

Morphologic variations of the superior intercostal vein: An anatomical study with clinical applications.

This study aimed to validate and compare the anatomical variations of the superior intercostal veins, focusing on their origin, course, anastomoses, and destination. In addition, the results were compared with findings from other relevant studies. Fifty Korean and 16 Chinese adult cadavers were dissected for this study. The superior intercostal veins were dissected and measured. In our study of 66 specimens, the right superior intercostal vein was observed in 92.3% of cases, while the left superior intercostal vein was observed in 50%. The right superior intercostal vein was subdivided into six types based on its composition, which mainly drained the second and third right posterior intercostal veins. Similarly, the left superior intercostal vein was subdivided into eight types, primarily involving the second to fourth left posterior intercostal veins. This detailed anatomical study successfully identified and classified the various morphologic types of the superior intercostal vein and reviewed the clinical significance of this vein. The findings of this study can offer valuable anatomical evidence to physicians, aiding in their understanding and utilization of the superior intercostal vein.

4-PBA inhibits hypoxia-induced lipolysis in rat adipose tissue and lipid accumulation in the liver through regulating ER stress.

High-altitude hypoxia may disturb the metabolic modulation and function of both adipose tissue and liver. The endoplasmic reticulum (ER) is a crucial organelle in lipid metabolism and ER stress is closely correlated with lipid metabolism dysfunction. The aim of this study is to elucidate whether the inhibition of ER stress could alleviate hypoxia-induced white adipose tissue (WAT) lipolysis and liver lipid accumulation-mediated hepatic injury. A rat model of high-altitude hypoxia (5500 m) was established using hypobaric chamber. The response of ER stress and lipolysis-related pathways were analyzed in WAT under hypoxia exposure with or without 4-phenylbutyric acid (PBA) treatment. Liver lipid accumulation, liver injury, and apoptosis were evaluated. Hypoxia evoked significant ER stress in WAT, evidenced by increased GRP78, CHOP, and phosphorylation of IRE1α, PERK. Moreover, Lipolysis in perirenal WAT significantly increased under hypoxia, accompanied with increased phosphorylation of hormone-sensitive lipase (HSL) and perilipin. Treatment with 4-PBA, inhibitor of ER stress, effectively attenuated hypoxia-induced lipolysis via cAMP-PKA-HSL/perilipin pathway. In addition, 4-PBA treatment significantly inhibited the increase in fatty acid transporters (CD36, FABP1, FABP4) and ameliorated liver FFA accumulation. 4-PBA treatment significantly attenuated liver injury and apoptosis, which is likely resulting from decreased liver lipid accumulation. Our results highlight the importance of ER stress in hypoxia-induced WAT lipolysis and liver lipid accumulation.

Protective effect of hydroxysafflor yellow A on renal ischemia­-reperfusion injury by targeting the Akt­Nrf2 axis in mice.

Ischemic/reperfusion (I/R) injury is the primary cause of acute kidney injury (AKI). Hydroxysafflor yellow A (HSYA), a natural compound isolated from Carthamus tinctorius L., has been found to possess anti-inflammatory and antioxidant properties. However, the protective effects and potential mechanism of HSYA on I/R-induced AKI remains unclear. In the present study, the in vitro hypoxia/reoxygenation (H/R) and in vivo renal I/R models were employed to investigate the renal protective effects and molecular mechanisms of HSYA on I/R-induced AKI. The present results indicated that HSYA pretreatment significantly ameliorated renal damage and dysfunction in the I/R injury mice via enhancing the antioxidant capacity and suppressing the oxidative stress injury, inflammatory response, and apoptosis. Mechanistic studies showed that HSYA could upregulate Akt/GSK-3ß/Fyn-Nrf2 axis-mediated antioxidant gene expression both in vitro and in vivo. Moreover, HSYA-mediated improvement in antioxidant, anti-inflammatory, and anti-apoptotic effects in H/R-treated HK-2 cells was abrogated by Akt inhibitor LY294002 supplementation. In summary, the present results demonstrated that HSYA attenuated kidney oxidative stress, inflammation response, and apoptosis induced by I/R, at least in part, via activating the Akt/GSK-3ß/Fyn-Nrf2 axis pathway. These findings provided evidence that HSYA may be applied as a potential therapeutic agent in the treatment of I/R induced AKI.

hPMSCs-Derived Exosomal miRNA-21 Protects Against Aging-Related Oxidative Damage of CD4+ T Cells by Targeting the PTEN/PI3K-Nrf2 Axis.

Mesenchymal stem cells (MSCs)-derived exosomes were considered a novel therapeutic approach in many aging-related diseases. This study aimed to clarify the protective effects of human placenta MSCs-derived exosomes (hPMSC-Exo) in aging-related CD4+ T cell senescence and identified the underlying mechanisms using a D-gal induced mouse aging model. Senescent T cells were detected SA-ß-gal stain. The degree of DNA damage was evaluated by detecting the level of 8-OH-dG. The superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activities were measured. The expression of aging-related proteins and senescence-associated secretory phenotype (SASP) were detected by Western blot and RT-PCR. We found that hPMSC-Exo treatment markedly decreased oxidative stress damage (ROS and 8-OH-dG), SA-ß-gal positive cell number, aging-related protein expression (p53 and γ-H2AX), and SASP expression (IL-6 and OPN) in senescent CD4+ T cells. Additionally, hPMSC-Exo containing miR-21 effectively downregulated the expression of PTEN, increased p-PI3K and p-AKT expression, and Nrf2 nuclear translocation and the expression of downstream target genes (NQO1 and HO-1) in senescent CD4+ T cells. Furthermore, in vitro studies uncovered that hPMSC-Exo attenuated CD4+ T cell senescence by improving the PTEN/PI3K-Nrf2 axis by using the PTEN inhibitor bpV (HOpic). We also validated that PTEN was a target of miR-21 by using a luciferase reporter assay. Collectively, the obtained results suggested that hPMSC-Exo attenuates CD4+ T cells senescence via carrying miRNA-21 and activating PTEN/PI3K-Nrf2 axis mediated exogenous antioxidant defenses.

Protective effect of Salidroside on hypoxia-related liver oxidative stress and inflammation via Nrf2 and JAK2/STAT3 signaling pathways.

High-altitude hypoxia-induced oxidative stress and inflammation played an essential role in the incidence and development of liver injury. Salidroside (Sal), a phenylpropanoid glycoside extracted from the plant Rhodiola rosea, has recently demonstrated antioxidant, anti-inflammatory, and antihypoxia properties. Herein, we hypothesized that salidroside may alleviate hypoxia-induced liver injury via antioxidant and antiinflammatory-related pathways. A high-altitude hypoxia animal model was established using hypobaric chamber. Male SD rats were randomly divided into the control group, hypoxia group, control +Sal group, and hypoxia +Sal group. Salidroside treatment significantly inhibited hypoxia-induced increases of serum and hepatic pro-inflammatory cytokines release, hepatic ROS production and MDA contents; attenuated hypoxia-induced decrease of hepatic SOD, CAT, and GSH-Px activities. Furthermore, salidroside treatment also potentiated the activation of Nrf2-mediated anti-oxidant pathway, as indicated by upregulation of n-Nrf2 and its downstream HO-1 and NQO-1. In vitro study found that blocking the Nrf2 pathway using specific inhibitor ML385 significantly reversed the protective effect of salidroside on hypoxia-induced liver oxidative stress. In addition, salidroside treatment significantly inhibited hepatic pro-inflammatory cytokines release via JAK2/STAT3-mediated pathway. Taken together, our findings suggested that salidroside protected against hypoxia-induced hepatic oxidative stress and inflammation via Nrf2 and JAK2/STAT3 signaling pathways.

hPMSCs inhibit the expression of PD-1 in CD4+IL-10+ T cells and mitigate liver damage in a GVHD mouse model by regulating the crosstalk between Nrf2 and NF-κB signaling pathway.

BACKGROUND: The activation of T cells and imbalanced redox metabolism enhances the development of graft-versus-host disease (GVHD). Human placenta-derived mesenchymal stromal cells (hPMSCs) can improve GVHD through regulating T cell responses. However, whether hPMSCs balance the redox metabolism of CD4+IL-10+ T cells and liver tissue and alleviate GVHD remains unclear. This study aimed to investigate the effect of hPMSC-mediated treatment of GVHD associated with CD4+IL-10+ T cell generation via control of redox metabolism and PD-1 expression and whether the Nrf2 and NF-κB signaling pathways were both involved in the process. METHODS: A GVHD mouse model was induced using 6-8-week-old C57BL/6 and Balb/c mice, which were treated with hPMSCs. In order to observe whether hPMSCs affect the generation of CD4+IL-10+ T cells via control of redox metabolism and PD-1 expression, a CD4+IL-10+ T cell culture system was induced using human naive CD4+ T cells. The percentage of CD4+IL-10+ T cells and their PD-1 expression levels were determined in vivo and in vitro using flow cytometry, and Nrf2, HO-1, NQO1, GCLC, GCLM, and NF-κB levels were determined by western blotting, qRT-PCR, and immunofluorescence, respectively. Hematoxylin-eosin, Masson's trichrome, and periodic acid-Schiff staining methods were employed to analyze the changes in hepatic tissue. RESULTS: A decreased activity of superoxide dismutase (SOD) and a proportion of CD4+IL-10+ T cells with increased PD-1 expression were observed in GVHD patients and the mouse model. Treatment with hPMSCs increased SOD activity and GCL and GSH levels in the GVHD mouse model. The percentage of CD4+IL-10+ T cells with decreased PD-1 expression, as well as Nrf2, HO-1, NQO1, GCLC, and GCLM levels, both in the GVHD mouse model and in the process of CD4+IL-10+ T cell generation, were also increased, but NF-κB phosphorylation and nuclear translocation were inhibited after treatment with hPMSCs, which was accompanied by improvement of hepatic histopathological changes. CONCLUSIONS: The findings suggested that hPMSC-mediated redox metabolism balance and decreased PD-1 expression in CD4+IL-10+ T cells were achieved by controlling the crosstalk between Nrf2 and NF-κB, which further provided evidence for the application of hPMSC-mediated treatment of GVHD.

hPMSCs protects against D-galactose-induced oxidative damage of CD4+ T cells through activating Akt-mediated Nrf2 antioxidant signaling.

BACKGROUND: Mesenchymal stem cells (MSCs) were considered a regenerative therapeutic approach in both acute and chronic diseases. However, whether MSCs regulate the antioxidant metabolism of CD4+ T cells and weaken immunosenescence remains unclear. Here, we reported the protective effects of hPMSCs in aging-related CD4+ T cell senescence and identified the underlying mechanisms using a D-gal-induced mouse aging model. METHODS: In vivo study, 40 male C57BL/6 mice (8 weeks) were randomly divided into four groups: control group, D-gal group, hPMSC group, and PBS group. In in vitro experiment, human naive CD4+ T (CD4CD45RA) cells were prepared using a naive CD4+ T cell isolation kit II and pretreated with the Akt inhibitor LY294002 and Nrf2 inhibitor ML385. Then, isolated naive CD4+ T cell were co-cultured with hPMSCs for 72 h in the absence or presence of anti-CD3/CD28 Dynabeads and IL-2 as a mitogenic stimulus. Intracellular ROS changes were detected by flow cytometry. The activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase were measured by colorimetric analysis. The senescent T cells were detected SA-ß-gal stain. The expression of aging-related proteins was detected by Western blotting, RT-PCR, and confocal microscopy. RESULTS: We found that hPMSC treatment markedly decreased the ROS level, SA-ß-gal-positive cells number, senescence-associated secretory phenotype (IL-6 and OPN) expression, and aging-related protein (P16 and P21) expression in senescent CD4+ T cells. Furthermore, hPMSC treatment effectively upregulated Nrf2 nuclear translocation and the expression of downstream target genes (HO-1, CAT, GCLC, and NQO1) in senescent CD4+ T cells. Moreover, in vitro studies revealed that hPMSCs attenuated CD4+ T cell senescence by upregulating the Akt/GSK-3ß/Fyn pathway to activate Nrf2 functions. Conversely, the antioxidant effects of hPMSCs were blocked by the Akt inhibitor LY294002 and Nrf2 inhibitor ML385 in senescent CD4+ T cells. CONCLUSIONS: Our results indicate that hPMSCs attenuate D-gal-induced CD4+ T cell senescence by activating Nrf2-mediated antioxidant defenses and that upregulation of Nrf2 by hPMSCs is regulated via the Akt/GSK-3ß/Fyn pathway.

Downregulated Recycling Process but Not De Novo Synthesis of Glutathione Limits Antioxidant Capacity of Erythrocytes in Hypoxia.

Red blood cells (RBCs) are susceptible to sustained free radical damage during circulation, while the changes of antioxidant capacity and regulatory mechanism of RBCs under different oxygen gradients remain unclear. Here, we investigated the changes of oxidative damage and antioxidant capacity of RBCs in different oxygen gradients and identified the underlying mechanisms using an in vitro model of the hypoxanthine/xanthine oxidase (HX/XO) system. In the present study, we reported that the hypoxic RBCs showed much higher oxidative stress injury and lower antioxidant capacity compared with normoxic RBCs. In addition, we found that the disturbance of the recycling process, but not de novo synthesis of glutathione (GSH), accounted for the significantly decreased antioxidant capacity of hypoxic RBCs compared to normoxic RBCs. We further elucidated the underlying molecular mechanism by which oxidative phosphorylation of Band 3 blocked the hexose monophosphate pathway (HMP) and decreased NADPH production aggravating the dysfunction of GSH synthesis in hypoxic RBCs under oxidative conditions.

Oligosaccharide attenuates aging-related liver dysfunction by activating Nrf2 antioxidant signaling.

Chitosan oligosaccharide (COS) is the depolymerized product of chitosan possessing various biological activities and protective effects against inflammation and oxidative injury. The aim of the present study was to investigate the antioxidant effects of COS supplements on aging-related liver dysfunction. We found that COS treatment significantly attenuated elevated liver function biomarkers and oxidative stress biomarkers and decreased antioxidative enzyme activities in liver tissues in D-galactose (D-gal)-treated mice. Furthermore, COS treatment significantly upregulated the expression of Nrf2 and its downstream target genes HO-1, NQO1, and CAT. Moreover, in vitro experiments showed that COS treatment played a vital role in protecting H2O2-exposed L02 cells against oxidative stress by activating Nrf2 antioxidant signaling. These data indicate that COS could protect against D-gal-induced hepatic aging by activating Nrf2 antioxidant signaling, which may provide novel applications for the prevention and treatment of aging-related hepatic dysfunction.

Salidroside alleviated hypoxia-induced liver injury by inhibiting endoplasmic reticulum stress-mediated apoptosis via IRE1α/JNK pathway.

Endoplasmic reticulum (ER) stress and subsequent apoptosis played vital role in liver injury and dysfunction. The aim of this study was to investigate the protective effect and mechanism of salidroside on hypoxia induced liver injury both in vivo and in vitro. Male SD rats were exposed to hypobaric chamber to simulate high altitude hypoxia model. High altitude hypoxia led to significant liver injury and apoptosis, increased the expression levels of p-JNK, BAX and ER stress markers. Salidroside treatment significantly inhibited hypoxia induced ER stress by decreasing the protein expression of glucose-regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP) and phosphorylated inositol-requiring enzyme 1α (p-IRE1α). In addition, salidroside treatment also restrained the ER stress-mediated apoptotic pathway, as indicated by decreased pro-apoptotic proteins p-JNK, TRAF2, BAX, and cleaved caspase 9 and caspase 12, as well as upregulation of Bcl-2. Furthermore, in vitro study found that blocking IRE1α pathway using specific inhibitor STF-083010 subsequently reversed the protective effect of salidroside on liver apoptosis. Taken together, our findings revealed that salidroside exerts protective effects against hypoxia induced liver injury through inhibiting ER stress mediated apoptosis via IRE1α/JNK pathway.

IL-1ß enhances human placenta-derived mesenchymal stromal cells ability to mediate Th1/Th2 and Th1/CD4+IL-10+ T cell balance and regulates its adhesion, proliferation and migration via PD-L1.

Human placenta-derived mesenchymal stromal cells (hPMSCs) are promising candidates for the treatment of graft-versus-host disease (GVHD), which is associated with high IL-1ß levels. In this study, the effects of IL-1ß and hPMSCs on each other were investigated by analyzing the proportion of Th1, Th2 and CD4+IL-10+ T cells and PD-L1 expression, as well as the adhesion, migration, and proliferation of hPMSCs. The results showed that hPMSCs decreased IL-1ß levels and downregulated Th1/Th2 and Th1/CD4+IL-10+ T cells ratios in the GVHD model. The in vitro results revealed that IL-1ß strengthened the hPMSCs capacity to reduce the Th1/Th2 and Th1/CD4+IL-10+ T cell ratios, inhibited the adhesion and proliferation of hPMSCs and increased PD-L1 expression on hPMSCs via the JAK and NF-κB pathways. Overall, these findings suggested that hPMSCs alleviate GVHD by decreasing IL-1ß level and maintaining the balance among different T cell subsets. IL-1ß enhanced the ability of hPMSCs to balance different T cell subsets and inhibited hPMSCs adhesion and proliferation by regulating PD-L1 expression via the JAK and NF-κB pathways.

Elevated SH3BP5 Correlates with Poor Outcome and Contributes to the Growth of Acute Myeloid Leukemia Cells.

Current strategies are not especially successful in the treatment of acute myeloid leukemia (AML). The identification and characterization of oncogenes crucial to the survival and growth of leukemia cells will provide potential targets for the exploitation of novel therapies. Herein, we report that the elevated expression of SH3 domain-binding protein 5 (SH3BP5) significantly correlates with poor outcomes of AML patients. To test whether SH3BP5 contributes to the growth and survival of AML cells, we use the shRNA-encoding lentivirus system to achieve the knockdown of SH3BP5 expression in human AML cell lines U937, THP-1, Kasumi-1, and MV4-11. Functionally, the knockdown of SH3BP5 expression markedly inhibits the cell viability and induced apoptosis of these leukemia cells. Mechanistically, western blot analysis indicates that the knockdown of SH3BP5 expression decreases the phosphorylation of JNK and BAD. Moreover, the JNK agonist anisomycin rescues the growth inhibition phenotype of SH3BP5 deficiency in THP-1 cells. Moreover, the expression of SH3BP5 positively correlates with CD25 and CD123 levels. Finally, our study highlights the crucial role of SH3BP5 in promoting the survival of AML cells, and its suppression may be a potential therapeutic strategy for treating human AML.

Octreotide remits endoplasmic reticulum stress to reduce autophagy of intestinal epithelial cell line Caco-2 via upregulation of miR-101.

Octreotide (OCT) shows clinical efficacies in the treatment of liver cirrhosis complicated with gastrointestinal hemorrhage. Experiments were designed to investigate its function mechanism associated with endoplasmic reticulum stress (ERS)-induced autophagy and microRNA (miR). Protein associated with ERS and autophagy was detected by western blot. miR-101 was examined by qRT-PCR. Besides, miR-101 or G protein-coupled receptor 78 (GPR78)-silenced Caco-2 cells were established by transfection. Furthermore, western blot was used to determine TGF-beta activated kinase 1 (TAK1), AMPK, mTOR, p70S6K as well as their phosphorylated forms. Lipopolysaccharide (LPS) enforced the expression of GPR78. Besides, LPS triggered the production of Beclin-1 and LC3-II while mitigated the accumulation of p62. Then all these above results were reversed by OCT pretreatment. Moreover, miR-101 expression was downregulated by LPS while upregulated by OCT. Further, miR-101 knockdown strengthened ERS and promoted autophagy. GPR78 silence retarded autophagy process. In the end, OCT mitigated phosphorylation of TAK1, AMPK while enhanced the phosphorylated expression of mTOR and p70S6K in LPS-treated Caco-2 cells. The anti-autophagy property of OCT was mediated by miR-101-induced suppression of GPR78 in LPS-treated Caco-2 cells.

Repair of Peripheral Nerve Sensory Impairments via the Transplantation of Bone Marrow Neural Tissue-Committed Stem Cell-Derived Sensory Neurons.

The present study aimed to investigate the efficacy of transplantation of bone marrow neural tissue-committed stem cell-derived sensory neuron-like cells for the repair of peripheral nerve sensory impairments in rats. Bone marrow was isolated and cultured to obtain the neural tissue-committed stem cells (NTCSCs), and the differentiation of these cells into sensory neuron-like cells was induced. Bone marrow mesenchymal stem cells (BMSCs), bone marrow NTCSCs, and bone marrow NTCSC-derived sensory neurons (NTCSC-SNs) were transplanted by microinjection into the L4 and L5 dorsal root ganglions (DRGs) in an animal model of sensory defect. On the 2nd, 4th, 8th, and 12th week after the transplantation, the effects of the three types of stem cells on the repair of the sensory functional defect were analyzed via behavioral observation, sensory function evaluation, electrophysiological examination of the sciatic nerve, and morphological observation of the DRGs. The results revealed that the transplanted BMSCs, NTCSCs, and NTCSC-SNs were all able to repair the sensory nerves. In addition, the effect of the NTCSC-SNs was significantly better than that of the other two types of stem cells. The general posture and gait of the animals in the sensory defect model exhibited evident improvement over time. Plantar temperature sensitivity and pain sensitivity gradually recovered, and the sensation latency was reduced, with faster sensory nerve conduction velocity. Transplantation of NTCSC-SNs can improve the repair of peripheral nerve sensory defects in rats.

IL-27 Promotes Human Placenta-Derived Mesenchymal Stromal Cell Ability To Induce the Generation of CD4+IL-10+IFN-γ+ T Cells via the JAK/STAT Pathway in the Treatment of Experimental Graft-versus-Host Disease.

Human mesenchymal stromal cells (MSCs) harbor immunomodulatory properties to induce the generation of suppressive T cells. MSCs have been successfully used in treating graft-versus-host disease (GVHD) accompanied by abundant inflammatory cytokines such as IL-27. This study investigated the effects of IL-27 on the human placenta-derived MSCs (hPMSCs) to induce generation of CD4+IL-10+IFN-γ+ T cells in vitro and in the humanized xenogenic GVHD NOD/SCID model. The results showed that the percentages of CD4+IL-10+IFN-γ+ T cells were significantly increased in activated human PBMC from both healthy donors and GVHD patients with hPMSCs and in the liver and spleen of hPMSC-treated GVHD mice, and the level of CD4+IL-10+IFN-γ+ T cells in the liver was greater than that in the spleen in hPMSC-treated GVHD mice. The serum level of IL-27 decreased and the symptoms abated in hPMSC-treated GVHD. Further, in vitro results showed that IL-27 promoted the regulatory effects of hPMSCs by enhancing the generation of CD4+IL-10+IFN-γ+ T cells from activated PBMC. Activation occurred through increases in the expression of programmed death ligand 2 (PDL2) in hPMSCs via the JAK/STAT signaling pathway. These findings indicated that hPMSCs could alleviate GVHD mice symptoms by upregulating the production of CD4+IL-10+IFN-γ+ T cells in the spleen and liver and downregulating serum levels of IL-27. In turn, the ability of hPMSCs to induce the generation of CD4+IL-10+IFN-γ+ T cells could be promoted by IL-27 through increases in PDL2 expression in hPMSCs. The results of this study will be of benefit for the application of hPMSCs in clinical trials.

Hydroxysafflor yellow A suppresses angiogenesis of hepatocellular carcinoma through inhibition of p38 MAPK phosphorylation.

The antitumor effect of hydroxysafflor yellow A (HSYA), an active ingredient of the herb Carthamus tinctorius L. (Asteraceae) (safflower), was investigated in the current work. Researches of HSYA on vasculogenesis inhibition, along with the related molecular mechanisms, including the expression of MMP-2, MMP-9, and p38MAPK (COX-2, ATF-2, p-p38MAPK, and p38MAPK) signaling pathway in H22 tumor-bearing mice or HepG2 cells were performed. The animal experiments proved the level of MMP-2 and MMP-9 in H22-transplanted tumor tissue in mice markedly decreased by HSYA, and results both in vivo and in vitro confirmed that COX-2 expression was reduced significantly via p38MAPK|ATF-2 signaling pathway. According to the outcomes, HSYA suppressed p38MAPK phosphorylation in a concentration-dependent manner, while exerting no effect on the total p38MAPK protein expression. It was also showed that suppression of p38 activation by SB203580 decreased the HepG2 cell viability, proliferation, and migration, wherein HSYA exhibited a similar effect. Furthermore, Western blot analysis on caspase-3 and cleaved-caspase-3 revealed that HSYA could induce apoptosis of HepG2 cells. These findings provided experimental evidences that HSYA might be a promising anticancer agent for HCC.

Inhibition of Glutathione Synthesis via Decreased Glucose Metabolism in Stored RBCs.

BACKGROUND/AIMS: Although red blood cells (RBCs) transfusions can be lifesaving, they are not without risk. RBCs storage is associated with the abnormal metabolism of glutathione (GSH), which may increase the risk of the oxidative damage of RBCs after transfusion. The responsible mechanisms remain unknown. METHODS: We determined the L-cysteine efflux and influx by evaluating the changes of free -SH concentrations in stored RBCs. The glutamate cysteine ligase (GCL) activities and protein content in stored RBCs was determined by fluorescence assay and western blotting. In addition, the glucose metabolism enzyme activity of RBCs was measured by spectrophotometric assay under in vitro incubation conditions. RESULTS: We found that both L-cysteine transport and GCL activity significantly declined, thereby inducing the dysfunction of GSH synthesis during blood storage, which could be attenuated by ATP supplement and DTT treatment. In addition, the glycometabolic enzyme (G6PDH, HK, PK and LDH) activity significantly decreased after 6 weeks storage. Oxidant stress-induced dysfunction in glucose metabolism was the driving force for decreased GSH synthesis during storage. CONCLUSION: These experimental findings reflect an underlying molecular mechanism that oxidant stress induced glucose metabolism dysfunction contribute to decreased GSH synthesis in stored RBCs.