Milk fat globule membrane(MFGM),which contains abundant glycoproteins and phospholipids,exerts beneficial effects on intestinal health and immunomodulation.The aim of this study was to evaluate the protective effects ...Milk fat globule membrane(MFGM),which contains abundant glycoproteins and phospholipids,exerts beneficial effects on intestinal health and immunomodulation.The aim of this study was to evaluate the protective effects and possible underlying mechanisms of MFGM on cow’s milk allergy(CMA)in aβ-lactoglobulin(BLG)-induced allergic mice model.MFGM was supplemented to allergic mice induced by BLG at a dose of 400 mg/kg body weight.Results demonstrated that MFGM alleviated food allergy symptoms,decreased serum levels of lipopolysaccharide,pro-inflammatory cytokines,immunoglobulin(Ig)E,Ig G1,and Th2 cytokines including interleukin(IL)-4,while increased serum levels of Th1 cytokines including interferon-γand regulatory T cells(Tregs)cytokines including IL-10 and transforming growth factor-β.MFGM modulated gut microbiota and enhanced intestinal barrier of BLG-allergic mice,as evidenced by decreased relative abundance of Desulfobacterota,Rikenellaceae,Lachnospiraceae,and Desulfovibrionaceae,while increased relative abundance of Bacteroidetes,Lactobacillaceae and Muribaculaceae,and enhanced expressions of tight junction proteins including Occludin,Claudin-1 and zonula occludens-1.Furthermore,MFGM increased fecal short-chain fatty acids(SCFAs)levels,which elevated G protein-coupled receptor(GPR)43 and GPR109A expressions.The increased expressions of GPR43 and GPR109A induced CD103+dendritic cells accumulation and promoted Tregs differentiation in mesenteric lymph node to a certain extent.In summary,MFGM alleviated CMA in a BLG-induced allergic mice model through enhancing intestinal barrier and promoting Tregs differentiation,which may be correlated with SCFAs-mediated activation of GPRs.These findings suggest that MFGM may be useful as a promising functional ingredient against CMA.展开更多
Objective:Studies have shown that docosahexaenoic acid(DHA)has a beneficial effect in the treatment of spinal cord injury.A meta-analysis was used to study the effect of DHA on the neurological recovery in the rat spi...Objective:Studies have shown that docosahexaenoic acid(DHA)has a beneficial effect in the treatment of spinal cord injury.A meta-analysis was used to study the effect of DHA on the neurological recovery in the rat spinal cord injury model,and the relationship between the recovery of motor function after spinal cord injury and the time and method of administration and the dose of DHA.Data source:Published studies on the effect of DHA on spinal cord injury animal models from seven databases were searched from their inception to January 2019,including PubMed,MEDLINE,EMBASE,the China National Knowledge Infrastructure,Wanfang,VIP,and SinoMed databases.The search terms included“spinal cord injury”“docosahexaenoic acid”,and“rats”.Data selection:Studies that evaluated the influence of DHA in rat models of spinal cord injury for locomotor functional recovery were included.The intervention group included any form of DHA treatment and the control group included treatment with normal saline,vehicle solution or no treatment.The Systematic Review Centre for Laboratory animal Experimentation’s risk of bias assessment tool was used for the quality assessment of the included studies.Literature inclusion,quality evaluation and data extraction were performed by two researchers.Meta-analysis was then conducted on all studies that met the inclusion criteria.Statistical analysis was performed on the data using RevMan 5.1.2.software.Outcome measures:The primary outcome measure was the score on the Basso,Beattie,and Bresnahan scale.Secondary outcome measures were the sloping plate test,balance beam test,stair test and grid exploration test.Results:A total of 12 related studies were included,3 of which were of higher quality and the remaining 9 were of lower quality.The highest mean Basso,Beattie,and Bresnahan scale score occurred at 42 days after DHA treatment in spinal cord injury rats.At 21 days after treatment,the mean difference in Basso,Beattie,Bresnahan scores between the DHA group and the control group was the most significant(pooled MD=4.14;95%CI=3.58–4.70;P<0.00001).In the subgroup analysis,improvement in the Basso,Beattie,and Bresnahan scale score was more significant in rats administered DHA intravenously(pooled MD=2.74;95%CI=1.41–4.07;P<0.0001)and subcutaneously(pooled MD=2.99;95%CI=2.29–3.69;P<0.00001)than in the groups administered DHA orally(pooled MD=3.04;95%CI=–1.01 to 7.09;P=0.14).Intravenous injection of DHA at 250 nmol/kg(pooled MD=2.94;95%CI=2.47–3.41;P<0.00001]and 1000 nmol/kg[pooled MD=3.60;95%CI=2.66–4.54;P<0.00001)significantly improved the Basso,Beattie,and Bresnahan scale score in rats and promoted the recovery of motor function.Conclusion:DHA can promote motor functional recovery after spinal cord injury in rats.The administration of DHA by intravenous or subcutaneous injection is more effective than oral administration of DHA.Intravenous injection of DHA at doses of 250 nmol/kg or 1000 nmol/kg is beneficial.Because of the small number and the low quality of the included studies,more high-quality research is needed in future to substantiate the results.展开更多
To investigate the fatty acid-based functional lipidomics of patients on long-term home parenteral nutrition receiving different intravenous lipid emulsions. METHODSA cross-sectional comparative study was carried out ...To investigate the fatty acid-based functional lipidomics of patients on long-term home parenteral nutrition receiving different intravenous lipid emulsions. METHODSA cross-sectional comparative study was carried out on 3 groups of adults on home parenteral nutrition (HPN), receiving an HPN admixture containing an olive-soybean oil-based intravenous lipid emulsion (IVLE) (OO-IVLE; n = 15), a soybean- medium-chain triacylglycerol-olive-fish oil-based IVLE (SMOF-IVLE; n = 8) or HPN without IVLE (No-IVLE; n = 8) and 42 healthy controls (HCs). The inclusion criteria were: duration of HPN ≥ 3 mo, current HPN admixtures ≥ 2 mo and HPN infusions ≥ 2/wk. Blood samples were drawn 4-6 h after the discontinuation of the overnight HPN infusion. The functional lipidomics panel included: the red blood cell (RBC) fatty acid (FA) profile, molecular biomarkers [membrane fluidity: saturated/monounsaturated FA ratio = saturated fatty acid (SFA)/monounsaturated fatty acid (MUFA) index; inflammatory risk: n-6/n-3 polyunsaturated fatty acid (PUFA) ratio = n-6/n-3 index; cardiovascular risk: sum of n-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) = n-3 index; free radical stress: sum of FA trans isomers = %trans index] and FA pathway enzyme activity estimate (delta-9-desaturase = D9D; delta-6-desaturase = D6D; delta-5-desaturase = D5D; elongase = ELO). Statistics were carried out using nonparametric tests. The amount of each FA was calculated as a percentage of the total FA content (relative%). RESULTSIn the OO-IVLE group, the percentage of oleic acid in the RBCs was positively correlated with the weekly load of OO-IVLE (r = 0.540, P = 0.043). In the SMOF-IVLE cohort, the RBC membrane EPA and DHA were positively correlated with the daily amount of SMOF-IVLE (r = 0.751, P = 0.044) and the number of HPN infusions per week (r = 0.753; P = 0.046), respectively. The SMOF-IVLE group showed the highest EPA and DHA and the lowest arachidonic acid percentages (P < 0.001). The RBC membrane linoleic acid content was lower, and oleic and vaccenic acids were higher in all the HPN groups in comparison to the HCs. Vaccenic acid was positively correlated with the weekly HPN load of glucose in both the OO-IVLE (r = 0.716; P = 0.007) and the SMOF-IVLE (r = 0.732; P = 0.053) groups. The estimated activity of D9D was higher in all the HPN groups than in the HCs (P < 0.001). The estimated activity of D5D was lower in the SMOF-IVLE group than in the HCs (P = 0.013). The SFA/MUFA ratio was lower in all the HPN groups than in the HCs (P < 0.001). The n-6/n-3 index was lower and the n-3 index was higher in the SMOF-IVLE group in comparison to the HCs and to the other HPN groups (P < 0.001). The %trans index did not differ among the four groups. CONCLUSIONThe FA profile of IVLEs significantly influenced the cell membrane functional lipidomics. The amount of glucose in the HPN may play a relevant role, mediated by the insulin regulation of the FA pathway enzyme activities.展开更多
We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming.Fenofibrate was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles(F...We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming.Fenofibrate was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles(F/ANs),and the surfaces of F/ANs were modified with an anti-CD3e f(ab′)2 fragment,yielding aCD3/F/ANs.An in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells compared with plain F/ANs.aCD3/F/AN-treated T cells exhibited clear mitochondrial cristae,a higher membrane potential,and a greater mitochondrial oxygen consumption rate under glucose-deficient conditions compared with T cells treated with other nanoparticle preparations.Peroxisome proliferatoractivated receptor-αand downstream fatty acid metabolismrelated genes are expressed to a greater extent in aCD3/F/AN-treated T cells.Activation of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor microenvironment.Real-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma cells.In vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor tissues.The treatment of tumor-bearing mice with aCD3/F/ANs enhances production of various cytokines in tumor tissues and prevented tumor growth.Our findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.展开更多
Background:Human heart changes its energetic substrates from lactate and glucose to fatty acids during the neonatal period.Noticing the lack of fatty acids in media for the culture of cardiomyocytes derived from human...Background:Human heart changes its energetic substrates from lactate and glucose to fatty acids during the neonatal period.Noticing the lack of fatty acids in media for the culture of cardiomyocytes derived from human pluripotent stem cells(hiPS-CM),researchers have supplemented mixtures of fatty acids to hiPS-CM and reported the enhancement in the maturation of hiPS-CM.In our previous studies,we separately supplemented two polyunsaturated fatty acids(PUFAs),docosahexaenoic acid(DHA)or arachidonic acid(AA),to rat fetal cardiomyocytes and found that the supplementations upregulated the expressions of mRNAs for cardiomyocyte differentiation,fatty acid metabolism,and cellular adhesion.The enhancement in cellular contractility was attributed to the improvement in intercellular connection rather than a direct enhancement of the contractile force.Methods:This study reports the successive results of the effects of DHA or AA supplementation on hiPS-CM.In addition to the contractile force and mRNA measurements used in the previous study,we further investigated the effect of different cellular aggregations on the contractile force output by means of finite element analysis,measured glucose and fatty acids metabolites,and assessed cTNT and MLC2v expressions through immunofluorecsence evaluation.Results:It showed that the sole supplementation of albumin-conjugated DHA or AA can be taken up by hiPS-CM without other uptake-enhancing factors,and the supplementations may activate the CD36_ERRγmetabolic pathway.DHA or AA supplementation increased the cellular contractile ratio on collagen gels and AA supplementation stimulated hiPS-CM aggregation to form cellular clusters.The enhancement effect on the hiPS-CM contractile force was modest since the increase in contractile force was not significant.AA supplementation was more effective than DHA supplementation because it significantly upregulated mRNA expressions of P300 and CD36.However,finite element analysis showed that the formation of clusters on a collagen gel attenuated the contractile force exerted by the gel on its surroundings.Conclusion:DHA and AA,as having been supplemented in infant formulas,have no direct and significant enhancement effect on the performance of the hiPS-CM when they were supplemented individually,although they were able to enter the cellular metabolic system.The AA supplementation showed some auxiliary effect on the maturation of hiPS-CM,which is worthy of further investigation under the consideration of membrane composition alteration and remodeling of membrane molecules.展开更多
Transcription factor engineering has unique advantages in improving the performance of microbial cell factories due to the global regulation of gene transcription.Omics analyses and reverse engineering enable learning...Transcription factor engineering has unique advantages in improving the performance of microbial cell factories due to the global regulation of gene transcription.Omics analyses and reverse engineering enable learning and subsequent incorporation of novel design strategies for further engineering.Here,we identify the role of the global regulator IhfA for overproduction of free fatty acids(FFAs)using CRISPRi-facilitated reverse engineering and cellular physiological characterization.From the differentially expressed genes in the ihfALstrain,a total of 14 beneficial targets that enhance FFAs production by above 20% are identified,which involve membrane function,oxidative stress,and others.For membrane-related genes,the engineered strains obtain lower cell surface hydrophobicity and increased average length of membrane lipid tails.For oxidative stress-related genes,the engineered strains present decreased reactive oxygen species(ROS)levels.These gene modulations enhance cellular robustness and save cellular resources,contributing to FFAs production.This study provides novel targets and strategies for engineering microbial cell factories with improved FFAs bioproduction.展开更多
Spinal cord injury(SCI)causes motor,sensory,and autonomic dysfunctions.The gut microbiome has an important role in SCI,while short-chain fatty acids(SCFAs)are one of the main bioactive mediators of microbiota.In the p...Spinal cord injury(SCI)causes motor,sensory,and autonomic dysfunctions.The gut microbiome has an important role in SCI,while short-chain fatty acids(SCFAs)are one of the main bioactive mediators of microbiota.In the present study,we explored the effects of oral administration of exogenous SCFAs on the recovery of locomotor function and tissue repair in SCI.Allen’s method was utilized to establish an SCI model in Sprague-Dawley(SD)rats.The animals received water containing a mixture of 150 mmol/L SCFAs after SCI.After 21 d of treatment,the Basso,Beattie,and Bresnahan(BBB)score increased,the regularity index improved,and the base of support(BOS)value declined.Spinal cord tissue inflammatory infiltration was alleviated,the spinal cord necrosis cavity was reduced,and the numbers of motor neurons and Nissl bodies were elevated.Enzyme-linked immunosorbent assay(ELISA),real-time quantitative polymerase chain reaction(qPCR),and immunohistochemistry assay revealed that the expression of interleukin(IL)-10 increased and that of IL-17 decreased in the spinal cord.SCFAs promoted gut homeostasis,induced intestinal T cells to shift toward an anti-inflammatory phenotype,and promoted regulatory T(Treg)cells to secrete IL-10,affecting Treg cells and IL-17^(+)γδT cells in the spinal cord.Furthermore,we observed that Treg cells migrated from the gut to the spinal cord region after SCI.The above findings confirm that SCFAs can regulate Treg cells in the gut and affect the balance of Treg and IL-17^(+)γδT cells in the spinal cord,which inhibits the inflammatory response and promotes the motor function in SCI rats.Our findings suggest that there is a relationship among gut,spinal cord,and immune cells,and the“gut-spinal cord-immune”axis may be one of the mechanisms regulating neural repair after SCI.展开更多
基金supported by the National Key Research and Development Program of China(Grant No.2019YFC1605000)National Natural Science Foundation of China(Grant No.31871806)the Beijing Livestock Industry Innovation Team(BAIC05-2023)。
文摘Milk fat globule membrane(MFGM),which contains abundant glycoproteins and phospholipids,exerts beneficial effects on intestinal health and immunomodulation.The aim of this study was to evaluate the protective effects and possible underlying mechanisms of MFGM on cow’s milk allergy(CMA)in aβ-lactoglobulin(BLG)-induced allergic mice model.MFGM was supplemented to allergic mice induced by BLG at a dose of 400 mg/kg body weight.Results demonstrated that MFGM alleviated food allergy symptoms,decreased serum levels of lipopolysaccharide,pro-inflammatory cytokines,immunoglobulin(Ig)E,Ig G1,and Th2 cytokines including interleukin(IL)-4,while increased serum levels of Th1 cytokines including interferon-γand regulatory T cells(Tregs)cytokines including IL-10 and transforming growth factor-β.MFGM modulated gut microbiota and enhanced intestinal barrier of BLG-allergic mice,as evidenced by decreased relative abundance of Desulfobacterota,Rikenellaceae,Lachnospiraceae,and Desulfovibrionaceae,while increased relative abundance of Bacteroidetes,Lactobacillaceae and Muribaculaceae,and enhanced expressions of tight junction proteins including Occludin,Claudin-1 and zonula occludens-1.Furthermore,MFGM increased fecal short-chain fatty acids(SCFAs)levels,which elevated G protein-coupled receptor(GPR)43 and GPR109A expressions.The increased expressions of GPR43 and GPR109A induced CD103+dendritic cells accumulation and promoted Tregs differentiation in mesenteric lymph node to a certain extent.In summary,MFGM alleviated CMA in a BLG-induced allergic mice model through enhancing intestinal barrier and promoting Tregs differentiation,which may be correlated with SCFAs-mediated activation of GPRs.These findings suggest that MFGM may be useful as a promising functional ingredient against CMA.
基金supported by the National Natural Science Foundation of China,No.81704096,81603635,81873317(to MY,JY,XJC)Shanghai Science and Technology Commission-Key Project of Traditional Chinese Medicine,No.16401970100(to YJW)+4 种基金the Shanghai Traditional Chinese Medicine Medical Center of Chronic Disease of China,No.2017ZZ01010(to YJW)the National Thirteenth Five-Year Science and Technology Major Special Project for New Drug Innovation and Development of China,No.2017ZX09304001(to YJW)the Program for Innovative Research Team of Ministry of Science and Technology of China,No.2015RA4002(to YJW)the “Innovation Team” Development Projects of China,No.IRT1270(to YJW)the Three Years Action to Accelerate the Development of Traditional Chinese Medicine Plan of China,No.ZY(2018-2020)-CCCX-3003(to YJW)
文摘Objective:Studies have shown that docosahexaenoic acid(DHA)has a beneficial effect in the treatment of spinal cord injury.A meta-analysis was used to study the effect of DHA on the neurological recovery in the rat spinal cord injury model,and the relationship between the recovery of motor function after spinal cord injury and the time and method of administration and the dose of DHA.Data source:Published studies on the effect of DHA on spinal cord injury animal models from seven databases were searched from their inception to January 2019,including PubMed,MEDLINE,EMBASE,the China National Knowledge Infrastructure,Wanfang,VIP,and SinoMed databases.The search terms included“spinal cord injury”“docosahexaenoic acid”,and“rats”.Data selection:Studies that evaluated the influence of DHA in rat models of spinal cord injury for locomotor functional recovery were included.The intervention group included any form of DHA treatment and the control group included treatment with normal saline,vehicle solution or no treatment.The Systematic Review Centre for Laboratory animal Experimentation’s risk of bias assessment tool was used for the quality assessment of the included studies.Literature inclusion,quality evaluation and data extraction were performed by two researchers.Meta-analysis was then conducted on all studies that met the inclusion criteria.Statistical analysis was performed on the data using RevMan 5.1.2.software.Outcome measures:The primary outcome measure was the score on the Basso,Beattie,and Bresnahan scale.Secondary outcome measures were the sloping plate test,balance beam test,stair test and grid exploration test.Results:A total of 12 related studies were included,3 of which were of higher quality and the remaining 9 were of lower quality.The highest mean Basso,Beattie,and Bresnahan scale score occurred at 42 days after DHA treatment in spinal cord injury rats.At 21 days after treatment,the mean difference in Basso,Beattie,Bresnahan scores between the DHA group and the control group was the most significant(pooled MD=4.14;95%CI=3.58–4.70;P<0.00001).In the subgroup analysis,improvement in the Basso,Beattie,and Bresnahan scale score was more significant in rats administered DHA intravenously(pooled MD=2.74;95%CI=1.41–4.07;P<0.0001)and subcutaneously(pooled MD=2.99;95%CI=2.29–3.69;P<0.00001)than in the groups administered DHA orally(pooled MD=3.04;95%CI=–1.01 to 7.09;P=0.14).Intravenous injection of DHA at 250 nmol/kg(pooled MD=2.94;95%CI=2.47–3.41;P<0.00001]and 1000 nmol/kg[pooled MD=3.60;95%CI=2.66–4.54;P<0.00001)significantly improved the Basso,Beattie,and Bresnahan scale score in rats and promoted the recovery of motor function.Conclusion:DHA can promote motor functional recovery after spinal cord injury in rats.The administration of DHA by intravenous or subcutaneous injection is more effective than oral administration of DHA.Intravenous injection of DHA at doses of 250 nmol/kg or 1000 nmol/kg is beneficial.Because of the small number and the low quality of the included studies,more high-quality research is needed in future to substantiate the results.
文摘To investigate the fatty acid-based functional lipidomics of patients on long-term home parenteral nutrition receiving different intravenous lipid emulsions. METHODSA cross-sectional comparative study was carried out on 3 groups of adults on home parenteral nutrition (HPN), receiving an HPN admixture containing an olive-soybean oil-based intravenous lipid emulsion (IVLE) (OO-IVLE; n = 15), a soybean- medium-chain triacylglycerol-olive-fish oil-based IVLE (SMOF-IVLE; n = 8) or HPN without IVLE (No-IVLE; n = 8) and 42 healthy controls (HCs). The inclusion criteria were: duration of HPN ≥ 3 mo, current HPN admixtures ≥ 2 mo and HPN infusions ≥ 2/wk. Blood samples were drawn 4-6 h after the discontinuation of the overnight HPN infusion. The functional lipidomics panel included: the red blood cell (RBC) fatty acid (FA) profile, molecular biomarkers [membrane fluidity: saturated/monounsaturated FA ratio = saturated fatty acid (SFA)/monounsaturated fatty acid (MUFA) index; inflammatory risk: n-6/n-3 polyunsaturated fatty acid (PUFA) ratio = n-6/n-3 index; cardiovascular risk: sum of n-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) = n-3 index; free radical stress: sum of FA trans isomers = %trans index] and FA pathway enzyme activity estimate (delta-9-desaturase = D9D; delta-6-desaturase = D6D; delta-5-desaturase = D5D; elongase = ELO). Statistics were carried out using nonparametric tests. The amount of each FA was calculated as a percentage of the total FA content (relative%). RESULTSIn the OO-IVLE group, the percentage of oleic acid in the RBCs was positively correlated with the weekly load of OO-IVLE (r = 0.540, P = 0.043). In the SMOF-IVLE cohort, the RBC membrane EPA and DHA were positively correlated with the daily amount of SMOF-IVLE (r = 0.751, P = 0.044) and the number of HPN infusions per week (r = 0.753; P = 0.046), respectively. The SMOF-IVLE group showed the highest EPA and DHA and the lowest arachidonic acid percentages (P < 0.001). The RBC membrane linoleic acid content was lower, and oleic and vaccenic acids were higher in all the HPN groups in comparison to the HCs. Vaccenic acid was positively correlated with the weekly HPN load of glucose in both the OO-IVLE (r = 0.716; P = 0.007) and the SMOF-IVLE (r = 0.732; P = 0.053) groups. The estimated activity of D9D was higher in all the HPN groups than in the HCs (P < 0.001). The estimated activity of D5D was lower in the SMOF-IVLE group than in the HCs (P = 0.013). The SFA/MUFA ratio was lower in all the HPN groups than in the HCs (P < 0.001). The n-6/n-3 index was lower and the n-3 index was higher in the SMOF-IVLE group in comparison to the HCs and to the other HPN groups (P < 0.001). The %trans index did not differ among the four groups. CONCLUSIONThe FA profile of IVLEs significantly influenced the cell membrane functional lipidomics. The amount of glucose in the HPN may play a relevant role, mediated by the insulin regulation of the FA pathway enzyme activities.
基金supported by grants from the Ministry of Science and ICT,Republic of Korea(NRF-2018R1A2A1A05019203,NRF-2018R1A5A2024425)the Korean Health Technology R&D Project(No.HI15C2842,HI18C2177,HI19C0664),Ministry of Health&Welfare,Republic of Korea.
文摘We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming.Fenofibrate was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles(F/ANs),and the surfaces of F/ANs were modified with an anti-CD3e f(ab′)2 fragment,yielding aCD3/F/ANs.An in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells compared with plain F/ANs.aCD3/F/AN-treated T cells exhibited clear mitochondrial cristae,a higher membrane potential,and a greater mitochondrial oxygen consumption rate under glucose-deficient conditions compared with T cells treated with other nanoparticle preparations.Peroxisome proliferatoractivated receptor-αand downstream fatty acid metabolismrelated genes are expressed to a greater extent in aCD3/F/AN-treated T cells.Activation of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor microenvironment.Real-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma cells.In vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor tissues.The treatment of tumor-bearing mice with aCD3/F/ANs enhances production of various cytokines in tumor tissues and prevented tumor growth.Our findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.
基金supported financially in part by Grants-in-Aid for Scientific Research(C)(21K12661)from the Japan Society for the Promotion of Science and Grant 12-003-111 from Takahashi Industrial and Economic Research Foundation.
文摘Background:Human heart changes its energetic substrates from lactate and glucose to fatty acids during the neonatal period.Noticing the lack of fatty acids in media for the culture of cardiomyocytes derived from human pluripotent stem cells(hiPS-CM),researchers have supplemented mixtures of fatty acids to hiPS-CM and reported the enhancement in the maturation of hiPS-CM.In our previous studies,we separately supplemented two polyunsaturated fatty acids(PUFAs),docosahexaenoic acid(DHA)or arachidonic acid(AA),to rat fetal cardiomyocytes and found that the supplementations upregulated the expressions of mRNAs for cardiomyocyte differentiation,fatty acid metabolism,and cellular adhesion.The enhancement in cellular contractility was attributed to the improvement in intercellular connection rather than a direct enhancement of the contractile force.Methods:This study reports the successive results of the effects of DHA or AA supplementation on hiPS-CM.In addition to the contractile force and mRNA measurements used in the previous study,we further investigated the effect of different cellular aggregations on the contractile force output by means of finite element analysis,measured glucose and fatty acids metabolites,and assessed cTNT and MLC2v expressions through immunofluorecsence evaluation.Results:It showed that the sole supplementation of albumin-conjugated DHA or AA can be taken up by hiPS-CM without other uptake-enhancing factors,and the supplementations may activate the CD36_ERRγmetabolic pathway.DHA or AA supplementation increased the cellular contractile ratio on collagen gels and AA supplementation stimulated hiPS-CM aggregation to form cellular clusters.The enhancement effect on the hiPS-CM contractile force was modest since the increase in contractile force was not significant.AA supplementation was more effective than DHA supplementation because it significantly upregulated mRNA expressions of P300 and CD36.However,finite element analysis showed that the formation of clusters on a collagen gel attenuated the contractile force exerted by the gel on its surroundings.Conclusion:DHA and AA,as having been supplemented in infant formulas,have no direct and significant enhancement effect on the performance of the hiPS-CM when they were supplemented individually,although they were able to enter the cellular metabolic system.The AA supplementation showed some auxiliary effect on the maturation of hiPS-CM,which is worthy of further investigation under the consideration of membrane composition alteration and remodeling of membrane molecules.
基金supported by the National Key Research and Development Program of China(2021YFC2104400)the National Natural Science Foundation of China(NSFC 22078240)the China Postdoctoral Science Foundation(2022M722359).
文摘Transcription factor engineering has unique advantages in improving the performance of microbial cell factories due to the global regulation of gene transcription.Omics analyses and reverse engineering enable learning and subsequent incorporation of novel design strategies for further engineering.Here,we identify the role of the global regulator IhfA for overproduction of free fatty acids(FFAs)using CRISPRi-facilitated reverse engineering and cellular physiological characterization.From the differentially expressed genes in the ihfALstrain,a total of 14 beneficial targets that enhance FFAs production by above 20% are identified,which involve membrane function,oxidative stress,and others.For membrane-related genes,the engineered strains obtain lower cell surface hydrophobicity and increased average length of membrane lipid tails.For oxidative stress-related genes,the engineered strains present decreased reactive oxygen species(ROS)levels.These gene modulations enhance cellular robustness and save cellular resources,contributing to FFAs production.This study provides novel targets and strategies for engineering microbial cell factories with improved FFAs bioproduction.
基金National Natural Science Foundation of China(No.82060399)Guangxi Medical High-level Key Talents Training“139”Program Training Project(No.[2020]15),China.
文摘Spinal cord injury(SCI)causes motor,sensory,and autonomic dysfunctions.The gut microbiome has an important role in SCI,while short-chain fatty acids(SCFAs)are one of the main bioactive mediators of microbiota.In the present study,we explored the effects of oral administration of exogenous SCFAs on the recovery of locomotor function and tissue repair in SCI.Allen’s method was utilized to establish an SCI model in Sprague-Dawley(SD)rats.The animals received water containing a mixture of 150 mmol/L SCFAs after SCI.After 21 d of treatment,the Basso,Beattie,and Bresnahan(BBB)score increased,the regularity index improved,and the base of support(BOS)value declined.Spinal cord tissue inflammatory infiltration was alleviated,the spinal cord necrosis cavity was reduced,and the numbers of motor neurons and Nissl bodies were elevated.Enzyme-linked immunosorbent assay(ELISA),real-time quantitative polymerase chain reaction(qPCR),and immunohistochemistry assay revealed that the expression of interleukin(IL)-10 increased and that of IL-17 decreased in the spinal cord.SCFAs promoted gut homeostasis,induced intestinal T cells to shift toward an anti-inflammatory phenotype,and promoted regulatory T(Treg)cells to secrete IL-10,affecting Treg cells and IL-17^(+)γδT cells in the spinal cord.Furthermore,we observed that Treg cells migrated from the gut to the spinal cord region after SCI.The above findings confirm that SCFAs can regulate Treg cells in the gut and affect the balance of Treg and IL-17^(+)γδT cells in the spinal cord,which inhibits the inflammatory response and promotes the motor function in SCI rats.Our findings suggest that there is a relationship among gut,spinal cord,and immune cells,and the“gut-spinal cord-immune”axis may be one of the mechanisms regulating neural repair after SCI.