β-Amyloid(1-42)(Aβ_(42))can induce excessive activation of microglia,resulting in exacerbated neuroinflammation and neuronal damage.Milk fat globule-epidermal growth factor-8(MFG-E8)is known to regulate Aβ_(42)-ind...β-Amyloid(1-42)(Aβ_(42))can induce excessive activation of microglia,resulting in exacerbated neuroinflammation and neuronal damage.Milk fat globule-epidermal growth factor-8(MFG-E8)is known to regulate Aβ_(42)-induced neurotoxicity and inflammatory responses via multiple signaling pathways.However,insufficient secretion of endogenous MFG-E8 may lead to autoimmunity in the central nervous system and the accumulation of apoptotic cells.In this study,we systematically investigated the inhibitory effects and potential mechanisms of exogenously administered milk-derived MFG-E8(M-MFG-E8)on Aβ_(42)-induced inflammation in BV-2 microglia using various techniques,including cell morphology analysis,immunofluorescence staining,ELISA,q RT-PCR,and Western blot assays.The results demonstrated that Aβ_(42)significantly increased the expression levels of pro-inflammatory cytokines tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),and interleukin-1β(IL-1β)in BV-2 microglia,whereas treatment with M-MFG-E8 effectively reversed these inflammatory responses.Furthermore,Aβ_(42)stimulation increased the secretion of pro-inflammatory cytokines(TNF-α,IL-1β)and the expression of the M1 marker cluster of differentiation 86(CD86),while suppressing the anti-inflammatory factors(arginase-1(Arg-1),interleukin-10(IL-10))and the M2 marker cluster of differentiation 206(CD206)in microglia.In contrast,M-MFG-E8 treatment promoted the polarization of microglia from the M1 to the M2 phenotype.Notably,M-MFG-E8 also inhibited the Aβ_(42)-induced upregulation of CD68,whereas M-MFG-E8 alone did not elicit this effect.Finally,our findings suggest that exogenous M-MFG-E8 may exert anti-inflammatory actions through the modulation of the NF-κB and PI3K/Akt pathways,providing new insights into neuronal cell repair and the development of functional foods.展开更多
The gastrointestinal tract of livestock and poultry is prone to challenge by feedborne antigens,pathogens,and other stress factors in the farm environment.Excessive physiological inflammation and oxidative stress that...The gastrointestinal tract of livestock and poultry is prone to challenge by feedborne antigens,pathogens,and other stress factors in the farm environment.Excessive physiological inflammation and oxidative stress that arises firstly disrupts the intestinal epithelial barrier followed by other components of the gastrointestinal tract.In the present review,the interrelationship between intestinal barrier inflammation and oxidative stress that contributes to the pathogenesis of inflammatory bowel disease was described.Further,the role of naturally existing immunomodulatory nutrients such as the omega-3 polyunsaturated fatty acids,citrus pectin,and milk-derived exosomes in preventing intestinal barrier inflammation was discussed.Based on the existing evidence,the possible molecular mechanism of these bioactive nutrients in the intestinal barrier was outlined for application in animal diets.展开更多
Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we...Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we systematically investigated the effects of drug loading methods and physicochemical properties(lipophilicity and molecular weight)on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions.Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method,drug lipophilicity,drug molecular weight and exosome/drug proportions.Of note,we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes,which was attributed to the efficient loading capacity and sustained release behavior.Furthermore,milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs(octreotide,exendin-4 and salmon calcitonin).Collectively,our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.展开更多
The imbalance between osteoblasts and osteoclasts is the cause of osteoporosis.Milk-derived extracellular vesicles(mEVs),excellent drug delivery nanocarriers,can promote bone formation and inhibit bone resorption.In t...The imbalance between osteoblasts and osteoclasts is the cause of osteoporosis.Milk-derived extracellular vesicles(mEVs),excellent drug delivery nanocarriers,can promote bone formation and inhibit bone resorption.In this study,we conjugated bone-targeting peptide(AspSerSer,DSS)6 to mEVs by click chemistry and then loaded with SRT2104,a SIRT1(silent mating-type information regulation 2 homolog 1)agonist that was proofed to help reduce bone loss.The engineered(DSS)6-mEV-SRT2104 had the intrinsic anti-osteoporosis function of mEVs and SRT2104 to reverse the imbalance in bone homeostasis by simultaneously regulating osteogenesis and osteoclastogenesis.Furthermore,we labelled mEVs with MnB nanoparticles that can be used for the in vivo magnetic resonance imaging(MRI)visualization.The obtained nanocomposites significantly prevented bone loss in osteoporosis mice and increased bone mineral density,exhibiting superior bone accumulation under MRI.We believe the proposed(DSS)6-mEV-SRT2104/MnB provides a novel paradigm for osteoporosis treatment and monitoring.展开更多
Oral administration facilitates the direct delivery of drugs to lesions within the small intestine and colon,making it an ideal approach for treating patients with inflammatory bowel disease.However,multiple physical ...Oral administration facilitates the direct delivery of drugs to lesions within the small intestine and colon,making it an ideal approach for treating patients with inflammatory bowel disease.However,multiple physical barriers impede the delivery of oral RNA drugs through the gastrointestinal tract.Herein,we developed a novel oral siRNA delivery system that protects nucleic acids in extreme environments by employing exosomes derived from milk to encapsulate tumor necrosis factor-alpha(TNF-α)siRNA completely.The remarkable structural stability of milk-derived exosomes(M-Exos),as opposed to those from HEK293T cells,makes them exceptional siRNA carriers.Results demonstrate that milk exosomes loaded with TNF-αsiRNA(M-Exo/siR)can effectively inhibit the expression of TNF-α-related inflammatory cytokines.Moreover,given that milk exosomes are composed of unique lipids with high bioavailability,orally administered M-Exo/siR effectively reach colonic tissues,leading to decreased TNF-αexpression and successful alleviation of colitis symptoms in a dextran sulfate sodium-induced inflammatory bowel disease murine model.Hence,milk-derived exosomes carrying TNF-αsiRNA can be effectively employed to treat inflammatory bowel disease.Indeed,using exosomes naturally derived from milk may shift the current paradigm of oral gene delivery,including siRNA.展开更多
As endogenous courier vesicles,exosomes play crucial roles in macromolecule transmission and intercellular communication.Therefore,exosomes have drawn increasing attention as biomimetic drug-delivery vehicles over the...As endogenous courier vesicles,exosomes play crucial roles in macromolecule transmission and intercellular communication.Therefore,exosomes have drawn increasing attention as biomimetic drug-delivery vehicles over the past few years.However,few studies have investigated the encapsulation of peptide/protein drugs into exosomes for oral administration.Additionally,the mechanisms underlying their biomimetic properties as oral delivery vehicles remain unknown.Herein,insulin-loaded milk-derived exosomes(EXO@INS)were fabricated and the in vivo hypoglycemic effect was investigated on type I diabetic rats.Surprisingly,EXO@INS(50 and 30 IU/kg)elicited a more superior and more sustained hypoglycemic effect compared with that obtained with subcutaneously injected insulin.Further mechanism studies indicated that the origin of excellent oral-performance of milk-derived exosomes combined active multi-targeting uptake,pH adaptation during gastrointestinal transit,nutrient assimilation related ERK1/2 and p38 MAPK signal pathway activation and intestinal mucus penetration.This study provides the first demonstration that multifunctional milk-derived exosomes offer solutions to many of the challenges arising from oral drug delivery and thus provide new insights into developing naturally-equipped nanovehicles for oral drug administration.展开更多
基金the financial support received from the Science and Technology Planning Project of Sichuan Province(Jiebangguashuai Project)(2023YFN0101)。
文摘β-Amyloid(1-42)(Aβ_(42))can induce excessive activation of microglia,resulting in exacerbated neuroinflammation and neuronal damage.Milk fat globule-epidermal growth factor-8(MFG-E8)is known to regulate Aβ_(42)-induced neurotoxicity and inflammatory responses via multiple signaling pathways.However,insufficient secretion of endogenous MFG-E8 may lead to autoimmunity in the central nervous system and the accumulation of apoptotic cells.In this study,we systematically investigated the inhibitory effects and potential mechanisms of exogenously administered milk-derived MFG-E8(M-MFG-E8)on Aβ_(42)-induced inflammation in BV-2 microglia using various techniques,including cell morphology analysis,immunofluorescence staining,ELISA,q RT-PCR,and Western blot assays.The results demonstrated that Aβ_(42)significantly increased the expression levels of pro-inflammatory cytokines tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),and interleukin-1β(IL-1β)in BV-2 microglia,whereas treatment with M-MFG-E8 effectively reversed these inflammatory responses.Furthermore,Aβ_(42)stimulation increased the secretion of pro-inflammatory cytokines(TNF-α,IL-1β)and the expression of the M1 marker cluster of differentiation 86(CD86),while suppressing the anti-inflammatory factors(arginase-1(Arg-1),interleukin-10(IL-10))and the M2 marker cluster of differentiation 206(CD206)in microglia.In contrast,M-MFG-E8 treatment promoted the polarization of microglia from the M1 to the M2 phenotype.Notably,M-MFG-E8 also inhibited the Aβ_(42)-induced upregulation of CD68,whereas M-MFG-E8 alone did not elicit this effect.Finally,our findings suggest that exogenous M-MFG-E8 may exert anti-inflammatory actions through the modulation of the NF-κB and PI3K/Akt pathways,providing new insights into neuronal cell repair and the development of functional foods.
基金a European Joint Doctorate Degree programme in Molecular Animal Nutrition(MANNA)between University of Milan(Italy)and University of Veterinary Medicine and Pharmacy in Kosice(Slovakia)funding from the European Union’s Horizon 2020 programme under the Marie Slodowska-Curie Grant agreement No 765423.
文摘The gastrointestinal tract of livestock and poultry is prone to challenge by feedborne antigens,pathogens,and other stress factors in the farm environment.Excessive physiological inflammation and oxidative stress that arises firstly disrupts the intestinal epithelial barrier followed by other components of the gastrointestinal tract.In the present review,the interrelationship between intestinal barrier inflammation and oxidative stress that contributes to the pathogenesis of inflammatory bowel disease was described.Further,the role of naturally existing immunomodulatory nutrients such as the omega-3 polyunsaturated fatty acids,citrus pectin,and milk-derived exosomes in preventing intestinal barrier inflammation was discussed.Based on the existing evidence,the possible molecular mechanism of these bioactive nutrients in the intestinal barrier was outlined for application in animal diets.
基金The authors gratefully acknowledge financial support from National Natural Science Foundation of China(81872818)National Key R&D Program of China(2021YFE0115200).
文摘Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we systematically investigated the effects of drug loading methods and physicochemical properties(lipophilicity and molecular weight)on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions.Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method,drug lipophilicity,drug molecular weight and exosome/drug proportions.Of note,we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes,which was attributed to the efficient loading capacity and sustained release behavior.Furthermore,milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs(octreotide,exendin-4 and salmon calcitonin).Collectively,our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.
基金supported by National Natural Science Foundation of China(52103198,52311530079)Basic and Applied Basic Research Foundation of Guangdong Province(2023A1515010067)Natural Science Foundation of Shenzhen Municipality(RCBS20210609104333005,JCYJ20220530145001003).
文摘The imbalance between osteoblasts and osteoclasts is the cause of osteoporosis.Milk-derived extracellular vesicles(mEVs),excellent drug delivery nanocarriers,can promote bone formation and inhibit bone resorption.In this study,we conjugated bone-targeting peptide(AspSerSer,DSS)6 to mEVs by click chemistry and then loaded with SRT2104,a SIRT1(silent mating-type information regulation 2 homolog 1)agonist that was proofed to help reduce bone loss.The engineered(DSS)6-mEV-SRT2104 had the intrinsic anti-osteoporosis function of mEVs and SRT2104 to reverse the imbalance in bone homeostasis by simultaneously regulating osteogenesis and osteoclastogenesis.Furthermore,we labelled mEVs with MnB nanoparticles that can be used for the in vivo magnetic resonance imaging(MRI)visualization.The obtained nanocomposites significantly prevented bone loss in osteoporosis mice and increased bone mineral density,exhibiting superior bone accumulation under MRI.We believe the proposed(DSS)6-mEV-SRT2104/MnB provides a novel paradigm for osteoporosis treatment and monitoring.
基金supported by the Bio&Medical Technology Development Program(NRF-2022M3E5F2018170)the Intramural Research Program of the Korea Institute of Science and Technology(KIST).
文摘Oral administration facilitates the direct delivery of drugs to lesions within the small intestine and colon,making it an ideal approach for treating patients with inflammatory bowel disease.However,multiple physical barriers impede the delivery of oral RNA drugs through the gastrointestinal tract.Herein,we developed a novel oral siRNA delivery system that protects nucleic acids in extreme environments by employing exosomes derived from milk to encapsulate tumor necrosis factor-alpha(TNF-α)siRNA completely.The remarkable structural stability of milk-derived exosomes(M-Exos),as opposed to those from HEK293T cells,makes them exceptional siRNA carriers.Results demonstrate that milk exosomes loaded with TNF-αsiRNA(M-Exo/siR)can effectively inhibit the expression of TNF-α-related inflammatory cytokines.Moreover,given that milk exosomes are composed of unique lipids with high bioavailability,orally administered M-Exo/siR effectively reach colonic tissues,leading to decreased TNF-αexpression and successful alleviation of colitis symptoms in a dextran sulfate sodium-induced inflammatory bowel disease murine model.Hence,milk-derived exosomes carrying TNF-αsiRNA can be effectively employed to treat inflammatory bowel disease.Indeed,using exosomes naturally derived from milk may shift the current paradigm of oral gene delivery,including siRNA.
基金We gratefully acknowledge financial support from the National Science Foundation for Distinguished Young Scholars(81625023,China)the National Natural Science Foundation of China(81872818)the Major Research Plan of National Natural Science Foundation of China(81690261).
文摘As endogenous courier vesicles,exosomes play crucial roles in macromolecule transmission and intercellular communication.Therefore,exosomes have drawn increasing attention as biomimetic drug-delivery vehicles over the past few years.However,few studies have investigated the encapsulation of peptide/protein drugs into exosomes for oral administration.Additionally,the mechanisms underlying their biomimetic properties as oral delivery vehicles remain unknown.Herein,insulin-loaded milk-derived exosomes(EXO@INS)were fabricated and the in vivo hypoglycemic effect was investigated on type I diabetic rats.Surprisingly,EXO@INS(50 and 30 IU/kg)elicited a more superior and more sustained hypoglycemic effect compared with that obtained with subcutaneously injected insulin.Further mechanism studies indicated that the origin of excellent oral-performance of milk-derived exosomes combined active multi-targeting uptake,pH adaptation during gastrointestinal transit,nutrient assimilation related ERK1/2 and p38 MAPK signal pathway activation and intestinal mucus penetration.This study provides the first demonstration that multifunctional milk-derived exosomes offer solutions to many of the challenges arising from oral drug delivery and thus provide new insights into developing naturally-equipped nanovehicles for oral drug administration.
