The Pacific subtropical cells(STCs)are shallow meridional overturning circulations connecting the tropics and subtropics,and are assumed to be an important driver of the tropical Pacific decadal variability.The variab...The Pacific subtropical cells(STCs)are shallow meridional overturning circulations connecting the tropics and subtropics,and are assumed to be an important driver of the tropical Pacific decadal variability.The variability of STCs under global warming is investigated using multimodal outputs from the latest phase of the Coupled Model Inter-comparison Project(CMIP6)and ocean reanalysis products.Firstly,the volume transport diagnostic analysis is employed to evaluate how coupled models and ocean reanalysis products reproduce interior STC transport.The variation of heat transport by the interior STC under the high-emissions warming scenarios is also analyzed.The results show that the multimodal-mean linear trends of the interior STC transport along 9°S and 9°N are-0.02 Sv/a and 0.04 Sv/a under global warming,respectively,which is mainly due to the combined effect of the strengthened upper oceanic stratification and the weakening of wind field.There is a compensation relationship between the interior STC and the western boundary transport in the future climate,and the compensation relationship of 9°S is more significant than that of 9°N.In addition,compared with ocean reanalysis products,the coupled models tend to underestimate the variability of the interior STC transport convergence,and thus may lose some sea surface temperature(SST)driving force,which may be the reason for the low STC-SST correlation simulated by the model.The future scenario simulation shows that the heat transport of interior STC is weakened under global warming,with a general agreement across models.展开更多
BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against...BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.展开更多
Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)iso...Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.展开更多
Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed ...Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.展开更多
Background: Exercise-Induced Bronchospasm (EIB) is an inflammatory condition characterized by severe airway constriction following the mobilization of inflammatory cells and interleukin-6 (IL-6). When severe, EIB can ...Background: Exercise-Induced Bronchospasm (EIB) is an inflammatory condition characterized by severe airway constriction following the mobilization of inflammatory cells and interleukin-6 (IL-6). When severe, EIB can require the use of pressurized salbutamol to treat athletes. This study investigated the nature of the systemic changes in inflammatory cells and post-exercise IL-6 concentrations after salbutamol treatment in EIB-susceptible distance runners. Materials and Methods: This was an experimental study that enrolled 12 long-distance runners. In Session A, the participants completed a treadmill exercise test, and those who had a maximum expiratory volume per second (FEV1) that was decreased by at least 10% compared to their base value were placed in the EIB-susceptible group (EIB+) (n = 6). Those whose FEV1 did not meet this criterion were placed in the nonresponsive (EIB?) group (n = 6). Before the Session B exercise, athletes in the BIE+ group inhaled two puffs of salbutamol (EIB+ Salb), while their EIB? counterparts received no treatment. Spirometry was performed before and after the exercise using a Spirobank G portable spirometer. Blood samples were taken before, immediately after and 2 hours after the stress test. Results: The mean post-exercise FEV1 values were not significantly different (p > 0.05) between the EIB+ Salb group and the EIB? group. The systemic changes in inflammatory cells and IL-6 concentrations in the EIB+ runners after salbutamol treatment were similar to those observed in their EIB? counterparts. Conclusion: Salbutamol pretreatment improved the systemic immune status of EIB-susceptible athletes.展开更多
Organic solar cells(OSCs)are a promising photovoltaic technology for practical applications.However,the design and synthesis of donor materials molecules based on traditional experimental trial-anderror methods are of...Organic solar cells(OSCs)are a promising photovoltaic technology for practical applications.However,the design and synthesis of donor materials molecules based on traditional experimental trial-anderror methods are often complex and expensive in terms of money and time.Machine learning(ML)can effectively learn from data sets and build reliable models to predict the performance of materials with reasonable accuracy.Y6 has become the landmark high-performance OSC acceptor material.We collected the power conversion efficiency(PCE)of small molecular donors and polymer donors based on the Y6 acceptor and calculated their molecule structure descriptors.Then we used six types of algorithms to develop models and compare the predictive performance with the coefficient of determination(R^(2))and Pearson correlation coefficient(r)as the metrics.Among them,decision tree-based algorithms showed excellent predictive capability,especially the Gradient Boosting Regression Tree(GBRT)models based on small molecular donors and polymer donors exhibited that the values of R2are 0.84 and 0.69 for the testing set,respectively.Our work provides a strategy to predict PCEs rapidly,and discovers the influence of the descriptors,thereby being expected to screen high-performance donor material molecules.展开更多
Objective: To explore the role of miR-448 in regulating MAGEA6/AMPK signaling pathway in the biological study of hepatocellular carcinoma (HCC) tumor stem cells. Methods: Using the database, the hepatocellular carcino...Objective: To explore the role of miR-448 in regulating MAGEA6/AMPK signaling pathway in the biological study of hepatocellular carcinoma (HCC) tumor stem cells. Methods: Using the database, the hepatocellular carcinoma related expression chips were obtained and the regulatory mirnas of candidate genes were predicted, and the predicted results were analyzed. The effects of miR-448 and MAGEA6 on the pellet formation rate and clone formation rate of hepatocellular carcinoma stem cells were detected by immunofluorescence identification of stem cell markers and light microscope counting method. The effects of miR-448 and MAGEA6 on migration and invasion of hepatocellular carcinoma stem cells were detected by scratch and Transwell assay. Dual luciferase reporter assay to verify whether miR-448 targets MAGEA6. The expression and influence of miR-448 on MAGEA6 and AMPK pathway were detected by qRT-PCR and Western blot. Results: It was found that miR-448 may directly regulate the expression of MAGEA6. Overexpression of miR-448 inhibited the characteristics, proliferation, migration, and invasion of hepatocellular carcinoma stem cells in vitro, as well as the ability of xenograft tumor formation in vivo. However, inhibition of miR-448 showed opposite results. In addition, miR-448 directly targets MAGEA6 and regulates AMPK signaling. Silencing MAGEA6 and adding AMPK activator further verified that miR-448 activated AMPK signaling pathway by targeting MAGEA6, thus affecting characteristics, proliferation, migration and invasion of hepatoma stem cells. Conclusions: Our results reveal that miR-448 activates AMPK signaling pathway by targeting MAGEA6, thereby affecting characteristics, proliferation, migration and invasion of hepatoma stem cells. It is suggested that overexpression of miR-448 may be a new therapeutic strategy for hepatocellular carcinoma.展开更多
Microglia-mediated inflammatory responses have been shown to play a crucial role in Parkinson’s disease. In addition, exosomes derived from mesenchymal stem cells have shown anti-inflammatory effects in the treatment...Microglia-mediated inflammatory responses have been shown to play a crucial role in Parkinson’s disease. In addition, exosomes derived from mesenchymal stem cells have shown anti-inflammatory effects in the treatment of a variety of diseases. However, whether they can protect neurons in Parkinson’s disease by inhibiting microglia-mediated inflammatory responses is not yet known. In this study, exosomes were isolated from human umbilical cord mesenchymal stem cells and injected into a 6-hydroxydopamine-induced rat model of Parkinson’s disease. We found that the exosomes injected through the tail vein and lateral ventricle were absorbed by dopaminergic neurons and microglia on the affected side of the brain, where they repaired nigral-striatal dopamine system damage and inhibited microglial activation. Furthermore, in an in vitro cell model, pretreating lipopolysaccharide-stimulated BV2 cells with exosomes reduced interleukin-1β and interleukin-18 secretion, prevented the adoption of pyroptosis-associated morphology by BV2 cells, and increased the survival rate of SH-SY5Y cells. Potential targets for treatment with human umbilical cord mesenchymal stem cells and exosomes were further identified by high-throughput microRNA sequencing and protein spectrum sequencing. Our findings suggest that human umbilical cord mesenchymal stem cells and exosomes are a potential treatment for Parkinson’s disease, and that their neuroprotective effects may be mediated by inhibition of excessive microglial proliferation.展开更多
The periodontal ligament-derived mesenchymal stem cell is regarded as a source of adult stem cells due to its multipotency.However, the proof of chondrogenic potential of the cells is scarce.Therefore,we investigated ...The periodontal ligament-derived mesenchymal stem cell is regarded as a source of adult stem cells due to its multipotency.However, the proof of chondrogenic potential of the cells is scarce.Therefore,we investigated the chondrogenic differentiation capacity of periodontal ligament derived mesenchymal stem cells induced by transforming growth factor(TGF)-p3 and bone morphogenetic protein(BMP)-6.After isolation of periodontal ligament stem cells(PDLSCs) from human periodontal ligament,the cells were cultured in Dulbecco’s modified Eagle’s medium(DMEM) with 20%fetal bovine serum(FBS).A mechanical force initiated chondrogenic differentiation of the cells.For chondrogenic differentiation,10μg·LTGF-β3 or 100μg·LBMP-6 and the combination treating group for synergistic effect of the growth factors.We analyzed the PDLSCs by fluorescence-activated cell sorting and chondrogenesis were evaluated by glycosaminoglycans assay,histology,immunohistochemistry and genetic analysis.PDLSCs showed mesenchymal stem cell properties proved by FACS analysis.Glycosaminoglycans contents were increased 217%by TGF-β3 and 220%by BMP-6. The synergetic effect of TGF-β3 and BMP-6 were shown up to 281%compared to control.The combination treatment increased Sox9, aggrecan and collagen II expression compared with not only controls,but also TGF-P3 or BMP-6 single treatment dramatically.The histological analysis also indicated the chondrogenic differentiation of PDLSCs in our conditions.The results of the present study demonstrate the potential of the dental stem cell as a valuable cell source for chondrogenesis,which may be applicable for regeneration of cartilage and bone fracture in the field of cell therapy.展开更多
In the present study, PC12 cells induced by 6-hydroxydopamine as a model of Parkinson's Disease, were used to investigate the protective effects of bone marrow-derived mesenchymal stem cells bone marrow-derived mesen...In the present study, PC12 cells induced by 6-hydroxydopamine as a model of Parkinson's Disease, were used to investigate the protective effects of bone marrow-derived mesenchymal stem cells bone marrow-derived mesenchymal stem cells against 6-hydroxydopamine-induced neurotoxicity and to verify whether the mechanism of action relates to abnormal a-synuclein accumulation in cells Results showed that co-culture with bone marrow-derived mesenchymal stem cells enhanced PC12 cell viability and dopamine secretion in a cell dose-dependent manner. MitoLight staining was used to confirm that PC12 cells co-cultured with bone marrow-derived mesenchymal stem cells demonstrate reduced levels of cell apoptosis. Immunocytochemistry and western blot analysis found the quantity of α-synuclein accumulation was significantly reduced in PC12 cell and bone marrow-derived mesenchymal stem cell co-cultures. These results indicate that bone marrow-derived mesenchymal stem cells can attenuate 6-hydroxydopamine-induced cytotoxicity by reducing abnormal α-synuclein accumulation in PC12 cells.展开更多
Objective To investigate ultrastructural effects of cadmium(Cd) and zinc(Zn) on rat Leydig cells (LCs) and the possible mechanisms of Cd induced injury. Methods The Wistar rats were injected with low dose c...Objective To investigate ultrastructural effects of cadmium(Cd) and zinc(Zn) on rat Leydig cells (LCs) and the possible mechanisms of Cd induced injury. Methods The Wistar rats were injected with low dose cadmium chloride (CdCl 2, 2 mg/kg body weight).The specimens obtained from 1 h to 60 d after dosing were studied by using transmission electron microscope (TEM) combined with a quantitative analysis of glucose 6 phosphatase(G 6 Pase) cytochemistry. Meanwhile, the protective effects of Zn on Cd induced injury were observed. Results The ultrastructural changes of LCs were detected at 4 h after Cd treatment and became more serious after 24 h. The main alterations were dilatation of smooth endoplasmic reticulum (SER), increasing of lipid droplets and myelin figures as well as appearing of vacuoles in the endothelial cell of lymphatic and blood capillaries. At 3,7 and 15 d, the degeneration above mentioned was most prominent, numerous necrotic LCs and flocculent densities in mitochondria were observed. After 30 d, the injuries of LCs appeared to be alleviated. But most of LCs still not recovered to normal after 60 d. However, the G 6 Pase reaction products was found to be reduced at 1 h after Cd treatment, and such decrease was most pronounced within 3~15 d. After 30 d, there was an obviously recovery of the G 6 Pase reaction product. The injuries of LCs of Zn protected groups were gentle and the G 6 Pase reaction products were more than that of Cd treated groups at the same time. Conclusions The early injuries of LCs were related to the direct action of Cd; the effects of Cd on the G 6 Pase activities occured earlier than the morphological alterations; the damage of lymphatic and blood capillaries as well as interstitial fibrosis might accelerate the degeneration and Zn could protect obviously LCs from damage by Cd.展开更多
Objective:To study the expression of TRPC6 among prostate cancer cells,establish high expression cell lines of TRPC6,and to provide potential cell mode for prostate cancer oncogenesis and development.Methods:Occurrenc...Objective:To study the expression of TRPC6 among prostate cancer cells,establish high expression cell lines of TRPC6,and to provide potential cell mode for prostate cancer oncogenesis and development.Methods:Occurrence and development of prostate cancer cells,PC3,PC—3m DU145,22 rvl,LNCaP and normal prostate epithelial cells in the PrEC TRPC6 expression level were detected by QPCR method.Calcium phosphate transfection method was used to package retrovirus pLEGFP-Nl-TRPC6 and pLEGFP-Nl-vector and infect the prostate cancer cells,a stable high expression of TRPC6 prostate cancer cells.Sable cell lines of TRPC6,matrix metalloproteinase(MMP)2,MMP9 expression was detected by QPCR and Western blot.Change of cell invasion ability was detected by Transwell.Results:The expression level of prostate cancer cells TRPC6 were higher than control group PrEC cells.Among TPRC6 the expression of cell line PC 3 transfer potential wre the lowest,and high transfer cell tone PC-3M express was the highest.Real-time fluorescent quantitative PCR and western blot results showed that after filter,the seventh generation of cell TRPC6 protein and mRNA expression levels were higher than the control group obviously.Transwell experimental results showed that the overexpression of TRPC6could promote the invasion ability of PC.3 prostate cancer cells.Conclusions:TRPC6 expressed in prostate cancer cells is in disorder,and its action may be associated with the invasion and metastasis of prostate cancer cells;successful establishment of stable high expression of TRPC6prostate cancer cells primarily confirm the invasion-trigger ability of TRPC6 on prostate cancer,and lay down the foundation for exploring the TRPC6's role in the occurrence and development of prostate cancer展开更多
基金the National Natural Science Foundation of China(NSFC)(No.41976027)。
文摘The Pacific subtropical cells(STCs)are shallow meridional overturning circulations connecting the tropics and subtropics,and are assumed to be an important driver of the tropical Pacific decadal variability.The variability of STCs under global warming is investigated using multimodal outputs from the latest phase of the Coupled Model Inter-comparison Project(CMIP6)and ocean reanalysis products.Firstly,the volume transport diagnostic analysis is employed to evaluate how coupled models and ocean reanalysis products reproduce interior STC transport.The variation of heat transport by the interior STC under the high-emissions warming scenarios is also analyzed.The results show that the multimodal-mean linear trends of the interior STC transport along 9°S and 9°N are-0.02 Sv/a and 0.04 Sv/a under global warming,respectively,which is mainly due to the combined effect of the strengthened upper oceanic stratification and the weakening of wind field.There is a compensation relationship between the interior STC and the western boundary transport in the future climate,and the compensation relationship of 9°S is more significant than that of 9°N.In addition,compared with ocean reanalysis products,the coupled models tend to underestimate the variability of the interior STC transport convergence,and thus may lose some sea surface temperature(SST)driving force,which may be the reason for the low STC-SST correlation simulated by the model.The future scenario simulation shows that the heat transport of interior STC is weakened under global warming,with a general agreement across models.
文摘BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.
基金supported by the NIH grants,R01 NS111801(to ZGZ)American Heart Association 16SDG29860003(to YZ)。
文摘Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.
基金supported by the Postdoctoral Research Funds of Hebei Medical University(30705010016-3759)Natural Science Foundation of China(32272328)+4 种基金Natural Science Foundation of Hebei Province(B2022321001)National Key Research Project of Hebei Province(20375502D)Postdoctoral Research Project of Hebei Province(B2022003031)Science and Technology Research Program of Hebei Provincial Colleges(QN2023229)Hebei Provincial Key Laboratory of Nutrition and Health(2023YDYY-KF05)。
文摘Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.
文摘Background: Exercise-Induced Bronchospasm (EIB) is an inflammatory condition characterized by severe airway constriction following the mobilization of inflammatory cells and interleukin-6 (IL-6). When severe, EIB can require the use of pressurized salbutamol to treat athletes. This study investigated the nature of the systemic changes in inflammatory cells and post-exercise IL-6 concentrations after salbutamol treatment in EIB-susceptible distance runners. Materials and Methods: This was an experimental study that enrolled 12 long-distance runners. In Session A, the participants completed a treadmill exercise test, and those who had a maximum expiratory volume per second (FEV1) that was decreased by at least 10% compared to their base value were placed in the EIB-susceptible group (EIB+) (n = 6). Those whose FEV1 did not meet this criterion were placed in the nonresponsive (EIB?) group (n = 6). Before the Session B exercise, athletes in the BIE+ group inhaled two puffs of salbutamol (EIB+ Salb), while their EIB? counterparts received no treatment. Spirometry was performed before and after the exercise using a Spirobank G portable spirometer. Blood samples were taken before, immediately after and 2 hours after the stress test. Results: The mean post-exercise FEV1 values were not significantly different (p > 0.05) between the EIB+ Salb group and the EIB? group. The systemic changes in inflammatory cells and IL-6 concentrations in the EIB+ runners after salbutamol treatment were similar to those observed in their EIB? counterparts. Conclusion: Salbutamol pretreatment improved the systemic immune status of EIB-susceptible athletes.
基金financially supported by the National Natural Science Foundation of China(21776067)the Hunan Provincial Distinguished Young Scholars Foundation of China(2020JJ2014)+1 种基金the Hunan Provincial Natural Science Foundation of China(2022JJ30239)the Key Project of Hunan Provincial Education Department,China,No.22A0328。
文摘Organic solar cells(OSCs)are a promising photovoltaic technology for practical applications.However,the design and synthesis of donor materials molecules based on traditional experimental trial-anderror methods are often complex and expensive in terms of money and time.Machine learning(ML)can effectively learn from data sets and build reliable models to predict the performance of materials with reasonable accuracy.Y6 has become the landmark high-performance OSC acceptor material.We collected the power conversion efficiency(PCE)of small molecular donors and polymer donors based on the Y6 acceptor and calculated their molecule structure descriptors.Then we used six types of algorithms to develop models and compare the predictive performance with the coefficient of determination(R^(2))and Pearson correlation coefficient(r)as the metrics.Among them,decision tree-based algorithms showed excellent predictive capability,especially the Gradient Boosting Regression Tree(GBRT)models based on small molecular donors and polymer donors exhibited that the values of R2are 0.84 and 0.69 for the testing set,respectively.Our work provides a strategy to predict PCEs rapidly,and discovers the influence of the descriptors,thereby being expected to screen high-performance donor material molecules.
文摘Objective: To explore the role of miR-448 in regulating MAGEA6/AMPK signaling pathway in the biological study of hepatocellular carcinoma (HCC) tumor stem cells. Methods: Using the database, the hepatocellular carcinoma related expression chips were obtained and the regulatory mirnas of candidate genes were predicted, and the predicted results were analyzed. The effects of miR-448 and MAGEA6 on the pellet formation rate and clone formation rate of hepatocellular carcinoma stem cells were detected by immunofluorescence identification of stem cell markers and light microscope counting method. The effects of miR-448 and MAGEA6 on migration and invasion of hepatocellular carcinoma stem cells were detected by scratch and Transwell assay. Dual luciferase reporter assay to verify whether miR-448 targets MAGEA6. The expression and influence of miR-448 on MAGEA6 and AMPK pathway were detected by qRT-PCR and Western blot. Results: It was found that miR-448 may directly regulate the expression of MAGEA6. Overexpression of miR-448 inhibited the characteristics, proliferation, migration, and invasion of hepatocellular carcinoma stem cells in vitro, as well as the ability of xenograft tumor formation in vivo. However, inhibition of miR-448 showed opposite results. In addition, miR-448 directly targets MAGEA6 and regulates AMPK signaling. Silencing MAGEA6 and adding AMPK activator further verified that miR-448 activated AMPK signaling pathway by targeting MAGEA6, thus affecting characteristics, proliferation, migration and invasion of hepatoma stem cells. Conclusions: Our results reveal that miR-448 activates AMPK signaling pathway by targeting MAGEA6, thereby affecting characteristics, proliferation, migration and invasion of hepatoma stem cells. It is suggested that overexpression of miR-448 may be a new therapeutic strategy for hepatocellular carcinoma.
基金supported by the Natural Science Foundation of Hebei Province,Nos.18967728D (to XQC),H2021423063 (to HXC)Youth Top Talent Project of Colleges and Universities in Hebei Province,No.BJ2021033 (to HXC)。
文摘Microglia-mediated inflammatory responses have been shown to play a crucial role in Parkinson’s disease. In addition, exosomes derived from mesenchymal stem cells have shown anti-inflammatory effects in the treatment of a variety of diseases. However, whether they can protect neurons in Parkinson’s disease by inhibiting microglia-mediated inflammatory responses is not yet known. In this study, exosomes were isolated from human umbilical cord mesenchymal stem cells and injected into a 6-hydroxydopamine-induced rat model of Parkinson’s disease. We found that the exosomes injected through the tail vein and lateral ventricle were absorbed by dopaminergic neurons and microglia on the affected side of the brain, where they repaired nigral-striatal dopamine system damage and inhibited microglial activation. Furthermore, in an in vitro cell model, pretreating lipopolysaccharide-stimulated BV2 cells with exosomes reduced interleukin-1β and interleukin-18 secretion, prevented the adoption of pyroptosis-associated morphology by BV2 cells, and increased the survival rate of SH-SY5Y cells. Potential targets for treatment with human umbilical cord mesenchymal stem cells and exosomes were further identified by high-throughput microRNA sequencing and protein spectrum sequencing. Our findings suggest that human umbilical cord mesenchymal stem cells and exosomes are a potential treatment for Parkinson’s disease, and that their neuroprotective effects may be mediated by inhibition of excessive microglial proliferation.
基金supported by the Bio & Medical Technology Development Program of the National Research Foundation(NRF) funded by the Korean government(MEST)(No.860-20110087)
文摘The periodontal ligament-derived mesenchymal stem cell is regarded as a source of adult stem cells due to its multipotency.However, the proof of chondrogenic potential of the cells is scarce.Therefore,we investigated the chondrogenic differentiation capacity of periodontal ligament derived mesenchymal stem cells induced by transforming growth factor(TGF)-p3 and bone morphogenetic protein(BMP)-6.After isolation of periodontal ligament stem cells(PDLSCs) from human periodontal ligament,the cells were cultured in Dulbecco’s modified Eagle’s medium(DMEM) with 20%fetal bovine serum(FBS).A mechanical force initiated chondrogenic differentiation of the cells.For chondrogenic differentiation,10μg·LTGF-β3 or 100μg·LBMP-6 and the combination treating group for synergistic effect of the growth factors.We analyzed the PDLSCs by fluorescence-activated cell sorting and chondrogenesis were evaluated by glycosaminoglycans assay,histology,immunohistochemistry and genetic analysis.PDLSCs showed mesenchymal stem cell properties proved by FACS analysis.Glycosaminoglycans contents were increased 217%by TGF-β3 and 220%by BMP-6. The synergetic effect of TGF-β3 and BMP-6 were shown up to 281%compared to control.The combination treatment increased Sox9, aggrecan and collagen II expression compared with not only controls,but also TGF-P3 or BMP-6 single treatment dramatically.The histological analysis also indicated the chondrogenic differentiation of PDLSCs in our conditions.The results of the present study demonstrate the potential of the dental stem cell as a valuable cell source for chondrogenesis,which may be applicable for regeneration of cartilage and bone fracture in the field of cell therapy.
基金supported by the Science and Technology Development Foundation of Beijing Science and Technology Commission, No. Z101107052210004
文摘In the present study, PC12 cells induced by 6-hydroxydopamine as a model of Parkinson's Disease, were used to investigate the protective effects of bone marrow-derived mesenchymal stem cells bone marrow-derived mesenchymal stem cells against 6-hydroxydopamine-induced neurotoxicity and to verify whether the mechanism of action relates to abnormal a-synuclein accumulation in cells Results showed that co-culture with bone marrow-derived mesenchymal stem cells enhanced PC12 cell viability and dopamine secretion in a cell dose-dependent manner. MitoLight staining was used to confirm that PC12 cells co-cultured with bone marrow-derived mesenchymal stem cells demonstrate reduced levels of cell apoptosis. Immunocytochemistry and western blot analysis found the quantity of α-synuclein accumulation was significantly reduced in PC12 cell and bone marrow-derived mesenchymal stem cell co-cultures. These results indicate that bone marrow-derived mesenchymal stem cells can attenuate 6-hydroxydopamine-induced cytotoxicity by reducing abnormal α-synuclein accumulation in PC12 cells.
文摘Objective To investigate ultrastructural effects of cadmium(Cd) and zinc(Zn) on rat Leydig cells (LCs) and the possible mechanisms of Cd induced injury. Methods The Wistar rats were injected with low dose cadmium chloride (CdCl 2, 2 mg/kg body weight).The specimens obtained from 1 h to 60 d after dosing were studied by using transmission electron microscope (TEM) combined with a quantitative analysis of glucose 6 phosphatase(G 6 Pase) cytochemistry. Meanwhile, the protective effects of Zn on Cd induced injury were observed. Results The ultrastructural changes of LCs were detected at 4 h after Cd treatment and became more serious after 24 h. The main alterations were dilatation of smooth endoplasmic reticulum (SER), increasing of lipid droplets and myelin figures as well as appearing of vacuoles in the endothelial cell of lymphatic and blood capillaries. At 3,7 and 15 d, the degeneration above mentioned was most prominent, numerous necrotic LCs and flocculent densities in mitochondria were observed. After 30 d, the injuries of LCs appeared to be alleviated. But most of LCs still not recovered to normal after 60 d. However, the G 6 Pase reaction products was found to be reduced at 1 h after Cd treatment, and such decrease was most pronounced within 3~15 d. After 30 d, there was an obviously recovery of the G 6 Pase reaction product. The injuries of LCs of Zn protected groups were gentle and the G 6 Pase reaction products were more than that of Cd treated groups at the same time. Conclusions The early injuries of LCs were related to the direct action of Cd; the effects of Cd on the G 6 Pase activities occured earlier than the morphological alterations; the damage of lymphatic and blood capillaries as well as interstitial fibrosis might accelerate the degeneration and Zn could protect obviously LCs from damage by Cd.
基金supported by Sichuan Province Department of Health(Grant Project:130188)
文摘Objective:To study the expression of TRPC6 among prostate cancer cells,establish high expression cell lines of TRPC6,and to provide potential cell mode for prostate cancer oncogenesis and development.Methods:Occurrence and development of prostate cancer cells,PC3,PC—3m DU145,22 rvl,LNCaP and normal prostate epithelial cells in the PrEC TRPC6 expression level were detected by QPCR method.Calcium phosphate transfection method was used to package retrovirus pLEGFP-Nl-TRPC6 and pLEGFP-Nl-vector and infect the prostate cancer cells,a stable high expression of TRPC6 prostate cancer cells.Sable cell lines of TRPC6,matrix metalloproteinase(MMP)2,MMP9 expression was detected by QPCR and Western blot.Change of cell invasion ability was detected by Transwell.Results:The expression level of prostate cancer cells TRPC6 were higher than control group PrEC cells.Among TPRC6 the expression of cell line PC 3 transfer potential wre the lowest,and high transfer cell tone PC-3M express was the highest.Real-time fluorescent quantitative PCR and western blot results showed that after filter,the seventh generation of cell TRPC6 protein and mRNA expression levels were higher than the control group obviously.Transwell experimental results showed that the overexpression of TRPC6could promote the invasion ability of PC.3 prostate cancer cells.Conclusions:TRPC6 expressed in prostate cancer cells is in disorder,and its action may be associated with the invasion and metastasis of prostate cancer cells;successful establishment of stable high expression of TRPC6prostate cancer cells primarily confirm the invasion-trigger ability of TRPC6 on prostate cancer,and lay down the foundation for exploring the TRPC6's role in the occurrence and development of prostate cancer