Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune check...Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.展开更多
Aging is a complex biological process characterized by nine hallmarks,including genomic instability,mitochondrial dysfunction,and chronic inflammation,which collectively drive the progression of age-related chronic no...Aging is a complex biological process characterized by nine hallmarks,including genomic instability,mitochondrial dysfunction,and chronic inflammation,which collectively drive the progression of age-related chronic non-communicable diseases.Phytonutrients,a class of bioactive secondary metabolites abundant in plants,have emerged as a promising research focus for intervening in the aging process due to their multifaceted biological activities.This review systematically elaborates on the molecular mechanisms,key signaling pathways,specifically SIRT1,Nrf2/ARE,and AMPK/mTOR,and the synergistic anti-aging effects of four typical phytonutrient categories:polyphenols(e.g.,resveratrol,quercetin),carotenoids(e.g.,lycopene,astaxanthin),sulfur compounds(e.g.,α-lipoic acid,ergothioneine),and phytoestrogens(e.g.,soybean isoflavones).The evidence indicates that these compounds combat aging through a multidimensional network involving direct antioxidant actions,free radical scavenging,metal chelation,promotion of autophagy,and modulation of inflammatory and epigenetic pathways.Crucially,the review highlights that synergistic interactions between different phytonutrients can significantly enhance their efficacy beyond the effect of any single compound.The aim is to consolidate the anti-aging evidence of phytonutrients and address the current translational challenges,such as bioavailability and a lack of robust human trials,thereby providing a comprehensive theoretical framework for developing effective,diet-centered strategies to promote healthy aging and reduce the global burden of non-communicable diseases.展开更多
With the growth of global protein demand and the development of plant-based foods,pea protein,as a low-allergenic,nutritionally balanced and environmentally friendly plant protein,has shown great potential in replacin...With the growth of global protein demand and the development of plant-based foods,pea protein,as a low-allergenic,nutritionally balanced and environmentally friendly plant protein,has shown great potential in replacing animal protein.Pea protein is mainly composed of globulin and albumin,with a protein content of 20%to 30%,and has a balanced amino acid composition,as well as being rich in minerals and dietary fiber.It also possesses good foaming,gelling,emulsifying and antioxidant functional properties.However,pea protein also has inherent defects that limit its application in the food industry.This article systematically reviews the extraction techniques,functional properties,modification methods and application fields of pea protein,and focuses on evaluating the effects of different extraction and modification strategies on protein yield and functional properties.Research shows that ultrasonic-assisted alkaline extraction can reduce solvent usage by 55%,shorten extraction time by 50%,and increase extraction rate by 12.51%;under optimized conditions,ultrafiltration membrane technology can achieve a protein purity of 91%.In terms of modification,ultrasonic treatment increases foaming capacity by 37.4%,and phenolic cross-linking increases gel strength from 3.0 kPa to 48 kPa.This article provides data support and theoretical reference for the efficient extraction and functional optimization of pea protein,and has promoting significance for its wide application in plant-based foods.展开更多
Background:Excessive use of inorganic trace minerals(ITMs)in swine production leads to high fecal mineral excretion and environmental risks,while most studies on organic trace minerals(OTMs)focus on single elements,wi...Background:Excessive use of inorganic trace minerals(ITMs)in swine production leads to high fecal mineral excretion and environmental risks,while most studies on organic trace minerals(OTMs)focus on single elements,with limited data on the synergistic effects and molecular mechanisms of combined OTMs(Fe,Cu,Mn,Zn)in growing-finishing pigs.Methods:This study aimed to investigate the effects of graded levels of micromineral proteinates(combined OTMs)on growth performance,mineral metabolism,and mRNA expression of mineral regulatory proteins.A total of 360 crossbred Duroc×Landrace×Large White pigs(initial body weight 47.1±4.8 kg)were randomly assigned to 6 dietary treatments:basal diet without microminerals(CON),basal diet with ITMs at commercially recommended levels(IT),and basal diets with 15%(OT 15%),25%(OT 25%),35%(OT 35%)commercially recommended levels(CRL)of combined micromineral proteinates.After a 70-day feeding trial,samples were analyzed using ICP-OES,ELISA,and RT-qPCR.Results:Results showed that reduced levels(15-35%CRL)of micromineral proteinates did not significantly affect average daily gain,average daily feed intake,or feed conversion ratio(gain-to-feed ratio)compared to IT(P>0.05),but significantly increased plasma Cu(1.73-1.83μg/mL)and Zn(1.72-1.97μg/mL)concentrations(P<0.05)and elevated activities of Cu/Zn-superoxide dismutase(32.9-35.9 U/L)and manganese superoxide dismutase(20.5-24.1 U/L)compared to CON(P<0.05),with no significant differences from IT(P>0.05).Fecal excretion of Fe,Cu,Mn,and Zn was significantly reduced by 35-50%in OT 15%-OT 35%groups compared to IT(P<0.05).OT 25%group exhibited the highest apparent absorptivity of Fe(38.5%),Cu(27.8%),and Zn(42.4%)(P<0.05),which was associated with significantly regulated mRNA expression of mineral regulatory proteins:upregulated DMT1,FPN1,ZIP4,and MT1A in the duodenum,and modulated HAMP,ATP7B,ZIP14,and ZnT1 in the liver(P<0.05).Conclusion:In conclusion,dietary supplementation with 25%CRL or less of combined micromineral proteinates can fully meet the nutritional needs of growing-finishing pigs,improve mineral absorptivity,and reduce fecal mineral excretion by regulating intestinal and hepatic mineral transport and homeostatic proteins,providing a sustainable alternative to high-dose ITMs.展开更多
Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations...Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations,and functional implications of RIPK family members across various cancers.Methods:We collected multi-omics data from The Cancer Genome Atlas and other public databases,including gene expression,copy number variation(CNV),mutation,methylation,tumor mutation burden(TMB),and microsatellite instability(MSI).Differential expression and survival analyses were performed using DESeq2 and Cox proportional hazards models.CNV and mutation data were analyzed with GISTIC2 and Mutect2,and methylation data with the ChAMP package.Correlations with TMB and MSI were assessed using Pearson coefficients,and gene set enrichment analysis was conducted with the MSigDB Hallmark gene sets.Results:RIPK family members show significant differential expression in various cancers,with RIPK1 and RIPK4 frequently altered.Survival analysis reveals heterogeneous impacts on overall survival.CNV and mutation analyses identify high alteration frequencies for RIPK2 and RIPK7,affecting gene expression.RIPK1 and RIPK7 are hypermethylated in several cancers,inversely correlating with RIPK3 expression.RIPK1,RIPK2,RIPK5,RIPK6,and RIPK7 correlate positively with TMB,while RIPK3 shows negative correlations in some cancers.MSI analysis indicates associations with DNA mismatch repair.G ene set enrichment analysis highlights immune-related pathway enrichment for RIPK1,RIPK2,RIPK3,and RIPK6,and cell proliferation and DNA repair pathways for RIPK4 and RIPK5.RIPK family members showed heterogeneous alterations across cancers:for example,RIPK7 was mutated in up to~15%of u terine c orpus e ndometrial c arcinoma and l ung s quamous c ell c arcinoma cases,and RIPK1 and RIPK7 exhibited frequent promoter hypermethylation in multiple tumor types.Several genes displayed context-dependent associations with overall survival and with TMB/MSI.Conclusion:This pan-cancer analysis of the RIPK family reveals their diverse roles and potential as biomarkers and therapeutic targets.The findings emphasize the importance of RIPK genes in tumorigenesis and suggest context-dependent functions across cancer types.Further studies are needed to explore their mechanisms in cancer development and clinical applications.展开更多
Background:Tandem gene repeats naturally occur as important genomic features and determine many traits in living organisms,like human diseases and microbial productivities of target bioproducts.Methods:Here,we develop...Background:Tandem gene repeats naturally occur as important genomic features and determine many traits in living organisms,like human diseases and microbial productivities of target bioproducts.Methods:Here,we developed a bacterial type-II toxin-antitoxin-mediated method to manipulate genomic integration of tandem gene repeats in Saccharomyces cerevisiae and further visualised the evolutionary trajectories of gene repeats.We designed a tri-vector system to introduce toxin-antitoxin-driven gene amplification modules.Results:This system delivered multi-copy gene integration in the form of tandem gene repeats spontaneously and independently from toxin-antitoxin-mediated selection.Inducing the toxin(RelE)expressing via a copper(II)-inducible CUP1 promoter successfully drove the in-situ gene amplification of the antitoxin(RelB)module,resulting in~40 copies of a green fluorescence reporter gene per copy of genome.Copy-number changes,copy-number increase and copy-number decrease,and stable maintenance were visualised using the green fluorescence protein and blue chromoprotein AeBlue as reporters.Copy-number increases happened spontaneously and independent on a selection pressure.Increased copy number was quickly enriched through toxin-antitoxin-mediated selection.Conclusion:In summary,the bacterial toxin-antitoxin systems provide a flexible mechanism to manipulate gene copy number in eukaryotic cells and can be exploited for synthetic biology and metabolic engineering applications.展开更多
人偏肺病毒(human metapneumovirus,hMPV)作为一种感染性病毒病原体,可导致严重的呼吸道感染,被世界卫生组织列为重要病原体之一。尽管疫苗在疾病预防与传播控制中发挥了重要作用,但由于hMPV的结构蛋白具有相对较高的突变率,野生型病毒...人偏肺病毒(human metapneumovirus,hMPV)作为一种感染性病毒病原体,可导致严重的呼吸道感染,被世界卫生组织列为重要病原体之一。尽管疫苗在疾病预防与传播控制中发挥了重要作用,但由于hMPV的结构蛋白具有相对较高的突变率,野生型病毒通常易于发生免疫逃逸。因此,设计能针对多种病毒变异株并为人体提供广泛保护的广谱hMPV疫苗具有重要意义。本研究基于共识序列方法,设计了一种广谱T细胞表位疫苗,该疫苗由478个氨基酸残基组成,涵盖来自病毒融合蛋白、附着糖蛋白、基质蛋白及小疏水性蛋白的10个细胞毒性T细胞(cytotoxic T lymphocyte,CTL)表位和11个辅助性T细胞(helper T lymphocyte,HTL)表位。进一步的分析表明,该多表位疫苗无致敏性,且具有高人群覆盖率、强抗原性和免疫原性,以及适宜的物理化学特性和较高的溶解性。同时,疫苗的结构与天然病毒高度相似。结构生物学分析表明,构建的疫苗在结构紧凑性和结合稳定性方面表现出较强的性能。计算机模拟的免疫学分析表明,该疫苗能激发人体的免疫应答。综上所述,本研究设计的广谱hMPV疫苗可作为一种用于预防hMPV感染的优秀候选疫苗;研究采用的预测流程可用于高效筛选其他病原体的免疫表位。展开更多
文摘Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.
基金supported by the Shanghai Sailing Program(No.21YF1418500)the Shanghai Chenguang Program(No.21CGA70)+1 种基金the three-year action plan for strengthening the construction of the public health system in Shanghai(No.GWVI-11.2-YQ12)Additionally,we would like to thank the Shanghai Oriental Talents Program-Youth Project(Education Platform)for its support of this study.
文摘Aging is a complex biological process characterized by nine hallmarks,including genomic instability,mitochondrial dysfunction,and chronic inflammation,which collectively drive the progression of age-related chronic non-communicable diseases.Phytonutrients,a class of bioactive secondary metabolites abundant in plants,have emerged as a promising research focus for intervening in the aging process due to their multifaceted biological activities.This review systematically elaborates on the molecular mechanisms,key signaling pathways,specifically SIRT1,Nrf2/ARE,and AMPK/mTOR,and the synergistic anti-aging effects of four typical phytonutrient categories:polyphenols(e.g.,resveratrol,quercetin),carotenoids(e.g.,lycopene,astaxanthin),sulfur compounds(e.g.,α-lipoic acid,ergothioneine),and phytoestrogens(e.g.,soybean isoflavones).The evidence indicates that these compounds combat aging through a multidimensional network involving direct antioxidant actions,free radical scavenging,metal chelation,promotion of autophagy,and modulation of inflammatory and epigenetic pathways.Crucially,the review highlights that synergistic interactions between different phytonutrients can significantly enhance their efficacy beyond the effect of any single compound.The aim is to consolidate the anti-aging evidence of phytonutrients and address the current translational challenges,such as bioavailability and a lack of robust human trials,thereby providing a comprehensive theoretical framework for developing effective,diet-centered strategies to promote healthy aging and reduce the global burden of non-communicable diseases.
文摘With the growth of global protein demand and the development of plant-based foods,pea protein,as a low-allergenic,nutritionally balanced and environmentally friendly plant protein,has shown great potential in replacing animal protein.Pea protein is mainly composed of globulin and albumin,with a protein content of 20%to 30%,and has a balanced amino acid composition,as well as being rich in minerals and dietary fiber.It also possesses good foaming,gelling,emulsifying and antioxidant functional properties.However,pea protein also has inherent defects that limit its application in the food industry.This article systematically reviews the extraction techniques,functional properties,modification methods and application fields of pea protein,and focuses on evaluating the effects of different extraction and modification strategies on protein yield and functional properties.Research shows that ultrasonic-assisted alkaline extraction can reduce solvent usage by 55%,shorten extraction time by 50%,and increase extraction rate by 12.51%;under optimized conditions,ultrafiltration membrane technology can achieve a protein purity of 91%.In terms of modification,ultrasonic treatment increases foaming capacity by 37.4%,and phenolic cross-linking increases gel strength from 3.0 kPa to 48 kPa.This article provides data support and theoretical reference for the efficient extraction and functional optimization of pea protein,and has promoting significance for its wide application in plant-based foods.
基金financially supported by the Hainan Province Science and Technology Special Fund(Grant no:ZDYF2024XDNY187).
文摘Background:Excessive use of inorganic trace minerals(ITMs)in swine production leads to high fecal mineral excretion and environmental risks,while most studies on organic trace minerals(OTMs)focus on single elements,with limited data on the synergistic effects and molecular mechanisms of combined OTMs(Fe,Cu,Mn,Zn)in growing-finishing pigs.Methods:This study aimed to investigate the effects of graded levels of micromineral proteinates(combined OTMs)on growth performance,mineral metabolism,and mRNA expression of mineral regulatory proteins.A total of 360 crossbred Duroc×Landrace×Large White pigs(initial body weight 47.1±4.8 kg)were randomly assigned to 6 dietary treatments:basal diet without microminerals(CON),basal diet with ITMs at commercially recommended levels(IT),and basal diets with 15%(OT 15%),25%(OT 25%),35%(OT 35%)commercially recommended levels(CRL)of combined micromineral proteinates.After a 70-day feeding trial,samples were analyzed using ICP-OES,ELISA,and RT-qPCR.Results:Results showed that reduced levels(15-35%CRL)of micromineral proteinates did not significantly affect average daily gain,average daily feed intake,or feed conversion ratio(gain-to-feed ratio)compared to IT(P>0.05),but significantly increased plasma Cu(1.73-1.83μg/mL)and Zn(1.72-1.97μg/mL)concentrations(P<0.05)and elevated activities of Cu/Zn-superoxide dismutase(32.9-35.9 U/L)and manganese superoxide dismutase(20.5-24.1 U/L)compared to CON(P<0.05),with no significant differences from IT(P>0.05).Fecal excretion of Fe,Cu,Mn,and Zn was significantly reduced by 35-50%in OT 15%-OT 35%groups compared to IT(P<0.05).OT 25%group exhibited the highest apparent absorptivity of Fe(38.5%),Cu(27.8%),and Zn(42.4%)(P<0.05),which was associated with significantly regulated mRNA expression of mineral regulatory proteins:upregulated DMT1,FPN1,ZIP4,and MT1A in the duodenum,and modulated HAMP,ATP7B,ZIP14,and ZnT1 in the liver(P<0.05).Conclusion:In conclusion,dietary supplementation with 25%CRL or less of combined micromineral proteinates can fully meet the nutritional needs of growing-finishing pigs,improve mineral absorptivity,and reduce fecal mineral excretion by regulating intestinal and hepatic mineral transport and homeostatic proteins,providing a sustainable alternative to high-dose ITMs.
基金supported by grants from the Tianjin Health Technology Project(Grant no.2022QN106).
文摘Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations,and functional implications of RIPK family members across various cancers.Methods:We collected multi-omics data from The Cancer Genome Atlas and other public databases,including gene expression,copy number variation(CNV),mutation,methylation,tumor mutation burden(TMB),and microsatellite instability(MSI).Differential expression and survival analyses were performed using DESeq2 and Cox proportional hazards models.CNV and mutation data were analyzed with GISTIC2 and Mutect2,and methylation data with the ChAMP package.Correlations with TMB and MSI were assessed using Pearson coefficients,and gene set enrichment analysis was conducted with the MSigDB Hallmark gene sets.Results:RIPK family members show significant differential expression in various cancers,with RIPK1 and RIPK4 frequently altered.Survival analysis reveals heterogeneous impacts on overall survival.CNV and mutation analyses identify high alteration frequencies for RIPK2 and RIPK7,affecting gene expression.RIPK1 and RIPK7 are hypermethylated in several cancers,inversely correlating with RIPK3 expression.RIPK1,RIPK2,RIPK5,RIPK6,and RIPK7 correlate positively with TMB,while RIPK3 shows negative correlations in some cancers.MSI analysis indicates associations with DNA mismatch repair.G ene set enrichment analysis highlights immune-related pathway enrichment for RIPK1,RIPK2,RIPK3,and RIPK6,and cell proliferation and DNA repair pathways for RIPK4 and RIPK5.RIPK family members showed heterogeneous alterations across cancers:for example,RIPK7 was mutated in up to~15%of u terine c orpus e ndometrial c arcinoma and l ung s quamous c ell c arcinoma cases,and RIPK1 and RIPK7 exhibited frequent promoter hypermethylation in multiple tumor types.Several genes displayed context-dependent associations with overall survival and with TMB/MSI.Conclusion:This pan-cancer analysis of the RIPK family reveals their diverse roles and potential as biomarkers and therapeutic targets.The findings emphasize the importance of RIPK genes in tumorigenesis and suggest context-dependent functions across cancer types.Further studies are needed to explore their mechanisms in cancer development and clinical applications.
基金supported partially by the Australian Government through the Australian Research Council Centres of Excellence funding scheme(project CE200100029)。
文摘Background:Tandem gene repeats naturally occur as important genomic features and determine many traits in living organisms,like human diseases and microbial productivities of target bioproducts.Methods:Here,we developed a bacterial type-II toxin-antitoxin-mediated method to manipulate genomic integration of tandem gene repeats in Saccharomyces cerevisiae and further visualised the evolutionary trajectories of gene repeats.We designed a tri-vector system to introduce toxin-antitoxin-driven gene amplification modules.Results:This system delivered multi-copy gene integration in the form of tandem gene repeats spontaneously and independently from toxin-antitoxin-mediated selection.Inducing the toxin(RelE)expressing via a copper(II)-inducible CUP1 promoter successfully drove the in-situ gene amplification of the antitoxin(RelB)module,resulting in~40 copies of a green fluorescence reporter gene per copy of genome.Copy-number changes,copy-number increase and copy-number decrease,and stable maintenance were visualised using the green fluorescence protein and blue chromoprotein AeBlue as reporters.Copy-number increases happened spontaneously and independent on a selection pressure.Increased copy number was quickly enriched through toxin-antitoxin-mediated selection.Conclusion:In summary,the bacterial toxin-antitoxin systems provide a flexible mechanism to manipulate gene copy number in eukaryotic cells and can be exploited for synthetic biology and metabolic engineering applications.
文摘人偏肺病毒(human metapneumovirus,hMPV)作为一种感染性病毒病原体,可导致严重的呼吸道感染,被世界卫生组织列为重要病原体之一。尽管疫苗在疾病预防与传播控制中发挥了重要作用,但由于hMPV的结构蛋白具有相对较高的突变率,野生型病毒通常易于发生免疫逃逸。因此,设计能针对多种病毒变异株并为人体提供广泛保护的广谱hMPV疫苗具有重要意义。本研究基于共识序列方法,设计了一种广谱T细胞表位疫苗,该疫苗由478个氨基酸残基组成,涵盖来自病毒融合蛋白、附着糖蛋白、基质蛋白及小疏水性蛋白的10个细胞毒性T细胞(cytotoxic T lymphocyte,CTL)表位和11个辅助性T细胞(helper T lymphocyte,HTL)表位。进一步的分析表明,该多表位疫苗无致敏性,且具有高人群覆盖率、强抗原性和免疫原性,以及适宜的物理化学特性和较高的溶解性。同时,疫苗的结构与天然病毒高度相似。结构生物学分析表明,构建的疫苗在结构紧凑性和结合稳定性方面表现出较强的性能。计算机模拟的免疫学分析表明,该疫苗能激发人体的免疫应答。综上所述,本研究设计的广谱hMPV疫苗可作为一种用于预防hMPV感染的优秀候选疫苗;研究采用的预测流程可用于高效筛选其他病原体的免疫表位。
