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
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
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
Summary： The activation of hepatic stellate cells （HSCs） and their transformation to myofibroblasts are the key steps in the pathological progress of liver fibrosis. The transforming growth factor-J3 （TGFβ）/Smad...Summary： The activation of hepatic stellate cells （HSCs） and their transformation to myofibroblasts are the key steps in the pathological progress of liver fibrosis. The transforming growth factor-J3 （TGFβ）/Smad pathway is involved in the proliferation and collagen synthesis of HSCs. This study aimed to examine the effect of the protease inhibitor MG132 on the signaling pathway of TGFβ/Smad in HSC-T6 cells and seek a novel therapeutic approach for liver fibrosis. The HSC-T6 cells were treated with MG132 at different concentrations （0-10 maol/L）. Cell proliferation was detected by MTT method. The mRNA and protein expression levels of TGFI31, Smad3 and Smad7 were determined in HSC-T6 cells by real-time PCR and Western blotting, respectively, after treatment with MG132 at different con- centrations （1, 2, 3 μtmol/L） or RPMI1640 alone （serving as control）. The results showed that MG132 could inhibit the proliferation of HSC-T6 cells in a dose-dependent manner, and the IC50 of MG132 was 6.84 μmol/L. After treatment with MG132 at 1, 2 or 3 nol/L for 24 h, the mRNA expression levels of TGF-β1 and Smad3 were significantly decreased （P〈0.05）, but the Smad7 mRNA expression had no significant change （P〉0.05）. There was also a significant decrease in the protein expression level of TGF-β1 and Smad3 （P〈0.05）. However, the expression of Smad7 protein was substantially increased when compared with the control group （P〈0.05）. It was concluded that the inhibition of TGFi/Smad pathway in HSC-T6 cells by MG132 can reduce the production of profibrosis factors （TGFI31, Smad3） and promote the expression of anti-fibrosis factor （Smad7）, suggesting that MG132 may become a po- tential therapeutic alternative for liver fibrosis.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
Skin-derived precursor Schwann cells have been reported to play a protective role in the central nervous system. The neuroprotective effects of skin-derived precursor Schwann cells may be attributable to the release o...Skin-derived precursor Schwann cells have been reported to play a protective role in the central nervous system. The neuroprotective effects of skin-derived precursor Schwann cells may be attributable to the release of growth factors that nourish host cells. In this study, we first established a cellular model of Parkinson’s disease using 6-hydroxydopamine. When SH-SY5 Y cells were pretreated with conditioned medium from skin-derived precursor Schwann cells, their activity was greatly increased. The addition of insulin-like growth factor-2 neutralizing antibody markedly attenuated the neuroprotective effects of skin-derived precursor Schwann cells. We also found that insulin-like growth factor-2 levels in the peripheral blood were greatly increased in patients with Parkinson’s disease and in a mouse model of Parkinson’s disease. Next, we pretreated cell models of Parkinson’s disease with insulin-like growth factor-2 and administered insulin-like growth factor-2 intranasally to a mouse model of Parkinson’s disease induced by 6-hydroxydopamine and found that the level of tyrosine hydroxylase, a marker of dopamine neurons, was markedly restored, α-synuclein aggregation decreased, and insulin-like growth factor-2 receptor downregulation was alleviated. Finally, in vitro experiments showed that insulin-like growth factor-2 activated the phosphatidylinositol 3 kinase(PI3 K)/AKT pathway. These findings suggest that the neuroprotective effects of skin-derived precursor Schwann cells on the central nervous system were achieved through insulinlike growth factor-2, and that insulin-like growth factor-2 may play a neuroprotective role through the insulin-like growth factor-2 receptor/PI3 K/AKT pathway. Therefore, insulin-like growth factor-2 may be an useful target for Parkinson’s disease treatment.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.
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.
基金supported by a grant from the Natural Science Foundation of Hubei Province(No.2010CHB00401)
文摘Summary： The activation of hepatic stellate cells （HSCs） and their transformation to myofibroblasts are the key steps in the pathological progress of liver fibrosis. The transforming growth factor-J3 （TGFβ）/Smad pathway is involved in the proliferation and collagen synthesis of HSCs. This study aimed to examine the effect of the protease inhibitor MG132 on the signaling pathway of TGFβ/Smad in HSC-T6 cells and seek a novel therapeutic approach for liver fibrosis. The HSC-T6 cells were treated with MG132 at different concentrations （0-10 maol/L）. Cell proliferation was detected by MTT method. The mRNA and protein expression levels of TGFI31, Smad3 and Smad7 were determined in HSC-T6 cells by real-time PCR and Western blotting, respectively, after treatment with MG132 at different con- centrations （1, 2, 3 μtmol/L） or RPMI1640 alone （serving as control）. The results showed that MG132 could inhibit the proliferation of HSC-T6 cells in a dose-dependent manner, and the IC50 of MG132 was 6.84 μmol/L. After treatment with MG132 at 1, 2 or 3 nol/L for 24 h, the mRNA expression levels of TGF-β1 and Smad3 were significantly decreased （P〈0.05）, but the Smad7 mRNA expression had no significant change （P〉0.05）. There was also a significant decrease in the protein expression level of TGF-β1 and Smad3 （P〈0.05）. However, the expression of Smad7 protein was substantially increased when compared with the control group （P〈0.05）. It was concluded that the inhibition of TGFi/Smad pathway in HSC-T6 cells by MG132 can reduce the production of profibrosis factors （TGFI31, Smad3） and promote the expression of anti-fibrosis factor （Smad7）, suggesting that MG132 may become a po- tential therapeutic alternative for liver fibrosis.
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 National Natural Science Foundation of China,Nos. 81873742 (to KFK), 81901195 (to JBS)Nantong Technology Project,Nos. JC2020052 (to XSG),JCZ19087 (to XSG)。
文摘Skin-derived precursor Schwann cells have been reported to play a protective role in the central nervous system. The neuroprotective effects of skin-derived precursor Schwann cells may be attributable to the release of growth factors that nourish host cells. In this study, we first established a cellular model of Parkinson’s disease using 6-hydroxydopamine. When SH-SY5 Y cells were pretreated with conditioned medium from skin-derived precursor Schwann cells, their activity was greatly increased. The addition of insulin-like growth factor-2 neutralizing antibody markedly attenuated the neuroprotective effects of skin-derived precursor Schwann cells. We also found that insulin-like growth factor-2 levels in the peripheral blood were greatly increased in patients with Parkinson’s disease and in a mouse model of Parkinson’s disease. Next, we pretreated cell models of Parkinson’s disease with insulin-like growth factor-2 and administered insulin-like growth factor-2 intranasally to a mouse model of Parkinson’s disease induced by 6-hydroxydopamine and found that the level of tyrosine hydroxylase, a marker of dopamine neurons, was markedly restored, α-synuclein aggregation decreased, and insulin-like growth factor-2 receptor downregulation was alleviated. Finally, in vitro experiments showed that insulin-like growth factor-2 activated the phosphatidylinositol 3 kinase(PI3 K)/AKT pathway. These findings suggest that the neuroprotective effects of skin-derived precursor Schwann cells on the central nervous system were achieved through insulinlike growth factor-2, and that insulin-like growth factor-2 may play a neuroprotective role through the insulin-like growth factor-2 receptor/PI3 K/AKT pathway. Therefore, insulin-like growth factor-2 may be an useful target for Parkinson’s disease treatment.
