In previous study,we got a purified ginger polysaccharide UGP1 and verified its significant antitumor activities on colon cancer HCT116 cells.In this article,we aimed to illustrate the underlying mechanism of UGP1 exe...In previous study,we got a purified ginger polysaccharide UGP1 and verified its significant antitumor activities on colon cancer HCT116 cells.In this article,we aimed to illustrate the underlying mechanism of UGP1 exerted antitumor activities on colon cancer by using in vitro cell models and in vivo animal models.The results demonstrated that UGP1 could induce S-phase cell cycle arrest,up-regulate the expression of Bax and p53,down-regulate the expression of Bcl-2,and activate the downstream protein caspase-9 and caspase-3,which was related to intrinsic apoptosis pathway on HCT116 cells.Moreover,UGP1 significantly stimulated RAW264.7 cell proliferation and secretion activity.Similarly,UGP1 inhibited tumor proliferation on tumor-bearing mice,increased the expression of p53 and the ratio of Bax/Bcl-2,enhanced the secretion of pro-inflammatory cytokines TNF-α,IL-2,IL-6 and decreased the secretion of pro-tumor cytokines TGF-βand b FGF in serum.In conclusion,it indicated that the UGP 1 could sup press human colon cancer growth by inducing apoptosis via the regulation of p53,caspase-3,and Bax/Bcl-2 ratio-dependent pathway and regulating immune system activity.Thi s investigation provided basic theoretical mechanism of ginger polysaccharideexerted antitumor activities,and contributed to develop a possible functional food or adjuvant agent for prevention or treatment of colon cancer.展开更多
Ischemic stroke(IS)is the most prevalent form of brain disease,characterized by high morbidity,disability,and mortality.However,there is still a lack of ideal prevention and treatment measures in clinical practice.Not...Ischemic stroke(IS)is the most prevalent form of brain disease,characterized by high morbidity,disability,and mortality.However,there is still a lack of ideal prevention and treatment measures in clinical practice.Notably,the trans-plantation therapy of mesenchymal stem cells(MSCs)has been a hot research topic in stroke.Nevertheless,there are risks associated with this cell therapy,including tumor formation,coagulation dysfunction,and vascular occlusion.Also,a growing number of studies suggest that the therapeutic effect after transplantation of MSCs is mainly attributed to MSC-derived exosomes(MSC-Exos).And this cell-free mediated therapy appears to circumvent many risks and difficulties when compared to cell therapy,and it may be the most promising new strategy for treating stroke as stem cell replacement therapy.Studies suggest that suppressing inflammation via modulation of the immune response is an additional treatment option for IS.Intriguingly,MSC-Exos mediates the inflam-matory immune response following IS by modulating the central nervous system,the peripheral immune system,and immunomodulatory molecules,thereby promoting neurofunctional recovery after stroke.Thus,this paper reviews the role,potential mechanisms,and therapeutic potential of MSC-Exos in post-IS inflammation in order to identify new research targets.展开更多
Mesenchymal stem cells(MSCs) possess immunomodulatory properties, which confer enormous potential for clinical application. Considerable evidence revealed their efficacy on various animal models of autoimmune diseases...Mesenchymal stem cells(MSCs) possess immunomodulatory properties, which confer enormous potential for clinical application. Considerable evidence revealed their efficacy on various animal models of autoimmune diseases, such as multiple sclerosis, systemic lupus erythematosus and uveitis. MSCs elicit their immunomodulatory effects by inhibiting lymphocyte activation and proliferation, forbidding the secretion of proinflammatory cytokines, limiting the function of antigen presenting cells, and inducing regulatory T(Treg) and B(Breg) cells. The induction of Treg and Breg cells is of particular interest since Treg and Breg cells have significant roles in maintaining immune tolerance. Several mechanisms have been proposed regarding to the MSCs-mediated induction of Treg and Breg cells. Accordingly, MSCs induce regulatory lymphocytes through secretion of multiple pleiotropic cytokines, cell-to-cell contact with target cells and modulation of antigen-presenting cells. Here, we summarized how MSCs induce Treg and Breg cells to provoke immunosuppression.展开更多
BACKGROUND: Dexmedetomidine has already been used in septic patients as a new sedative agent, few studies have examined its effects on immunomodulation. Therefore, the authors have designed a controlled experimental s...BACKGROUND: Dexmedetomidine has already been used in septic patients as a new sedative agent, few studies have examined its effects on immunomodulation. Therefore, the authors have designed a controlled experimental study to characterize the immunomodulation effects of dexmedetomidine in the cecal ligation and puncture(CLP) model in rats. METHODS: After CLP, 48 Wistar rats were randomly allocated into four groups:(1) CLP group;(2) small-dose treatment group(2.5 g·kg^(-1)·h^(-1));(3) medium-dose treatment group(5.0 g·kg^(-1)·h^(-1)); and(4) large-dose treatment group(10.0 g·kg^(-1)·h^(-1)). HLA-DR and plasma cytokine(IL-4, IL-6, IL-10 and TNF-α) levels were measured, and the mean arterial blood pressure(MAP), heart rate(HR), arterial blood gases, lactate concentrations and mortality were also documented. RESULTS: The HLA-DR level, inflammatory mediator levels, MAP and HR had no obvious changes among Dexmedetomidine treatment groups(DEX groups). Compared with the CLP group, the DEX groups exhibited decreased HLA-DR levels(P_(group)=0.0202) and increased IL-6 production, which was increased at 3 h(P= 0.0113) and was then attenuated at 5 h; additionally, the DEX groups exhibited decreased HR(P<0.001) while maintaining MAP(P_(group)=0.1238), and remarkably improving lactate(P<0.0001). All of these factors led to a significant decrease in the mortality, with observed rates of 91.7%, 66.7%, 25% and 18% for the CLP, DEX2.5, DEX5.0, DEX10.0 groups, respectively.CONCLUSION: Dexmedetomidine treatment in the setting of a CLP sepsis rat model has partially induced immunomodulation that was initiated within 5 h, causing a decreased HR while maintaining MAP, remarkably improving metabolic acidosis and improving mortality dosedependently.展开更多
Mesenchymal stem cells(MSCs)are a heterogeneous population that can be isolated from various tissues,including bone marrow,adipose tissue,umbilical cord blood,and craniofacial tissue.MSCs have attracted increasingly m...Mesenchymal stem cells(MSCs)are a heterogeneous population that can be isolated from various tissues,including bone marrow,adipose tissue,umbilical cord blood,and craniofacial tissue.MSCs have attracted increasingly more attention over the years due to their regenerative capacity and function in immunomodulation.The foundation of tissue regeneration is the potential of cells to differentiate into multiple cell lineages and give rise to multiple tissue types.In addition,the immunoregulatory function of MSCs has provided insights into therapeutic treatments for immune-mediated diseases.DNA methylation and demethylation are important epigenetic mechanisms that have been shown to modulate embryonic stem cell maintenance,proliferation,differentiation and apoptosis by activating or suppressing a number of genes.In most studies,DNA hypermethylation is associated with gene suppression,while hypomethylation or demethylation is associated with gene activation.The dynamic balance of DNA methylation and demethylation is required for normal mammalian development and inhibits the onset of abnormal phenotypes.However,the exact role of DNA methylation and demethylation in MSC-based tissue regeneration and immunomodulation requires further investigation.In this review,we discuss how DNA methylation and demethylation function in multi-lineage cell differentiation and immunomodulation of MSCs based on previously published work.Furthermore,we discuss the implications of the role of DNA methylation and demethylation in MSCs for the treatment of metabolic or immune-related diseases.展开更多
Hepatocellular carcinoma(HCC)is the most prevalent primary malignancy in patients suffering from chronic liver diseases and cirrhosis.Recent attention has been paid to the involvement of the gut-liver axis(GLA)in HCC ...Hepatocellular carcinoma(HCC)is the most prevalent primary malignancy in patients suffering from chronic liver diseases and cirrhosis.Recent attention has been paid to the involvement of the gut-liver axis(GLA)in HCC pathogenesis.This axis results from a bidirectional,anatomical and functional relationship between the gastrointestinal system and the liver.Moreover,the complex network of interactions between the intestinal microbiome and the liver plays a crucial role in modulation of the HCC-tumor microenvironment,contributing to the pathogenesis of HCC by exposing the liver to pathogen-associated molecular patterns,such as bacterial lipopolysaccharides,DNA,peptidoglycans and flagellin.Indeed,the alteration of gut microflora may disturb the intestinal barrier,bringing several toll-like receptor ligands to the liver thus activating the inflammatory response.This review explores the new therapeutic opportunities that may arise from novel insights into the mechanisms by which microbiota immunomodulation,represented by probiotics,and prebiotics,affects HCC through the GLA.展开更多
To observe immunomodulation and antitumor effect of melatonin (MLT) in tumor-bearing mice. Methods: By means of flow cytometry and MTT colorimetry, the immunological indexes of H22 hepatomabearing mice were investigat...To observe immunomodulation and antitumor effect of melatonin (MLT) in tumor-bearing mice. Methods: By means of flow cytometry and MTT colorimetry, the immunological indexes of H22 hepatomabearing mice were investigated. Results: MLT administration could increase the CD4+/CD8+ cell ratio in the peripheral blood of the tumor-bearing mice, cooperate with IL-2 to promote the proliferation of lymphocytes and eosinophils, increase NK and LAK activity of splenocytes, and enhance the production of IL-2 from splenocytes.We also found that MLT could inhibit tumor growth and prolong the survival time of the tumor-bearing mice in vivo. Moreover, a synergetic effect of IL-2 and MLT was observed. It seems that MLT hadno effect on H22 hepatoma cell growth in vitro. Conclusion: It is suggested that MLT may be a potential candidate for tumor immunotherapy as one of the biological reaction modulators (BRM).展开更多
Objective To investigate melatonin-related mechanisms of action on immunoregulation in aged and immunodeficient mice. Methods T lymPhocytes subunit CD4 + ,CD8 + and CD4 + /CD8 + ratio were measured by Flow Cytometer i...Objective To investigate melatonin-related mechanisms of action on immunoregulation in aged and immunodeficient mice. Methods T lymPhocytes subunit CD4 + ,CD8 + and CD4 + /CD8 + ratio were measured by Flow Cytometer in normal, aged and Cyclophosphamide injected mice which treated with melatonin, and compared with the results of T lymphocytes subunit in the group without melatonin as control group. Results The percentage of CD4 + , CD8 + T cells in the normal mice which treated with melatonin was significantly higher than that in control group ( P <0.01), CD4 + /CD8 + ratio was higher but had no significant difference. In the cyclophosphamide injected group which melatonin treated, the percentage of CD4 + T cells and CD4 + /CD8 + ratio were higher than those in control, The difference was significant ( P <0.01), while CD8 + was lower ( P <0.01). In aged melatonin treated mice group, the percentage of CD4 + , CD8 + T cells and CD4 + /CD8 + ratio were significantly higher than those in control ( P <0.01). Conclusion Melatonin could adjust the quantity and the ratio of CD4 + , CD8 + T cells in aged and immunodeficient mice. it implied that melatonin could mediate helper and suppression T lymphocytes to reinforce their immunodefence.展开更多
Exogenously delivered mesenchymal stromal cells(MSCs)are therapeutically beneficial owing to their paracrine effect;they secrete various cytokines,nucleic acids,and proteins.Multiple bioengineering techniques can help...Exogenously delivered mesenchymal stromal cells(MSCs)are therapeutically beneficial owing to their paracrine effect;they secrete various cytokines,nucleic acids,and proteins.Multiple bioengineering techniques can help MSC cultures to release secretomes by providing stem cell niche-like conditions(both structurally and functionally).Various scaffolds mimic the natural extracellular matrix(ECM)using both natural and synthetic polymers,providing favorable environments for MSC proliferation and differentiation.Depending on material properties,either topographically or elastically structured scaffolds can be fabricated.Three-dimensional scaffolds have tunable substrate rigidities and structures,aiding MSC cultivation.Decellularized ECM-derived hydrogels are similar to the natural ECM,thus improving the paracrine effects of MSCs.Here,we discuss recent research on the application of scaffolds to maximize the immunomodulatory function of MSCs.展开更多
The initial trauma to the spinal cord is just the starting point for a cascade of endogenous events that will collectively determine the injury extension.These secondary events include,but are not limited to:glutamate...The initial trauma to the spinal cord is just the starting point for a cascade of endogenous events that will collectively determine the injury extension.These secondary events include,but are not limited to:glutamate excitoxicity,induction of apoptotic pathways,ionic imbalances and the development of a strong and dysfunctional inflammatory response.The secondary injury is associated to an aggravation of neuronal damage increasing the extent of neurological deficits(Ek et al.,2010).展开更多
Rabbit anti-thymocyte globulin's manifold mechanisms of action may be attribuited to its polyclonal nature. Its T-cell depleting effect on lymphoid cells is well established: Occurring in the blood and secondary l...Rabbit anti-thymocyte globulin's manifold mechanisms of action may be attribuited to its polyclonal nature. Its T-cell depleting effect on lymphoid cells is well established: Occurring in the blood and secondary lymphoid tissues, depletion proceeds through complement-dependent lysis, opsonization and apoptotic pathways. Clinical studies have shown that rabbit antithymocyte globulin's immunomodulatory effect extends beyond the initial T-cell depletion and up to the period during which lymphocyte populations begin to recover. The drug is able to mediate immunomodulation and graft tolerance by functionally inactivating cell surface receptors involved in antigen recognition, leukocyte trafficking and leukocyte endothelium adhesion. The complex and prolonged immunomodulation induced by this drug contributes to its efficacy in solid organ transplantation, mainly by reducing the incidence of acute graft rejection.展开更多
Recent research has demonstrated that critically ill patients with coronavirus disease 2019(COVID-19)show significant immune system dysregulation.Due to that,some nutrients that influence immunomodulation have been su...Recent research has demonstrated that critically ill patients with coronavirus disease 2019(COVID-19)show significant immune system dysregulation.Due to that,some nutrients that influence immunomodulation have been suggested as a form of treatment against the infection.This review collected the information on the impact of vitamins on the prognosis of COVID-19,with the intention of facilitating treatment and prevention of the disease risk status in patients.The collected information was obtained using the PubMed electronic database by searching for articles that relate COVID-19 and the mechanisms/effects of the nutrients:Proteins,glucose,lipids,vitamin B12,vitamin D,calcium,iron,copper,zinc,and magnesium,including prospective,retrospective,and support articles.The findings reveal an optimal response related mainly to omega-3,eicosapentaenoic acid,docosahexaenoic acid,calcium,and iron that might represent benefits in the treatment of critically ill patients.However,nutrient supplementation should be done with caution due to the limited availability of randomized controlled studies.展开更多
Coronavirus disease 2019(COVID-19)and helminths infections can be in a synergistic epidemic in developing and suburban areas of industrialized countries.The coinfected hosts will derive a parasite-specific Th2 innate ...Coronavirus disease 2019(COVID-19)and helminths infections can be in a synergistic epidemic in developing and suburban areas of industrialized countries.The coinfected hosts will derive a parasite-specific Th2 innate and adaptive immune response with CD4+T cells,eosinophils,interleukin-4,interleukin-5,and interleukin-10.In the early stages of severe acute respiratory syndrome coronavirus type 2(SARS-CoV-2)infection,virus-specific Th1 cytotoxic CD8+T cell,interleukin-6,interferon-γ,and interleukin-27 by lung are keys in controlling viral replication in the lung epithelial cells and limiting the pathology to other organs,like the intestine.CD4+and CD8+T cells are associated with protective immunity against and during COVID-19.However,viral evasion mechanisms occur.Interference of the interferon-γsecretion,like in helminths immunomodulation,can contribute to COVID-19 severity.Immunomodulation can result in mild,moderate,or severe COVID-19 depending on which helminth is coinfecting by regulating or avoiding host cytokine and pro-inflammatory response,decreasing viral load,and affecting vaccine-induced antibody response.We discuss the implications of immunomodulation on COVID-19 caused by helminth co-infection and for public health in the context of COVID-19 vaccine use in helminth endemic zones.展开更多
AIM: To investigate the effect of omega-3 fatty acid parenteral supplementation postoperatively on clinical outcomes and immunomodulation in colorectal cancer patients. METHODS: Forty-two patients undergoing radical c...AIM: To investigate the effect of omega-3 fatty acid parenteral supplementation postoperatively on clinical outcomes and immunomodulation in colorectal cancer patients. METHODS: Forty-two patients undergoing radical colorectal cancer resection with an indication for total parenteral nutrition postoperatively were enrolled in this prospective, double-blind, randomized, controlled study. Patients received total parenteral nutrition supplemented with either soybean oil (LCT; Intralipid, Fresenius-Kabi, SO group, n = 21) or a combination of omega-3 fish oil and soybean oil (LCT:fish oil = 5:1, fish oil; Omegaven, Fresenius-Kabi, FO group, n = 21), up to a total of 1.2 g lipid/kg per day for 7 d postoperatively. A same volume calorie and nitrogen was administrated. Routine blood test, biochemistry, systemic levels of IL-6 and TNF-α, percentage of CD3+, CD4+, and CD8+ lymphocytes were evaluated preoperatively and on postoperative d 1 and 8. Patient outcome was evaluated considering mortality during the hospital stay, length of postoperative hospital stay, and occurrence of infectious complications. RESULTS: Both lipid regimens were well tolerated. No differences between the two groups were noticed in demographics, baseline blood test, biochemistry, serum levels of IL-6 and TNF-α, percentage of CD4+, CD8+ lymphocytes, and ratios of CD4+/CD8+. Compared with those on postoperative d 1, serum IL-6 levels onpostoperative d 8 were significantly depressed in the FO group than in the reference group (-44.43 ± 30.53 vs -8.39 ± 69.08, P = 0.039). Simultaneously, the ratios of CD4+/CD8+ were significantly increased in the FO group (0.92 ± 0.62 vs 0.25 ± 1.22, P = 0.035). In addition, depression of serum TNF-α levels (-0.82 ± 2.71 vs 0.27 ± 1.67, P = 0.125) and elevation of CD3+ and CD4+ lymphocyte percentage (12.85 ± 11.61 vs 3.84 ± 19.62, P = 0.081, 17.80 ± 10.86 vs 9.66 ± 17.55, P = 0.084, respectively) were higher in the FO group than in the reference group. Patients in the FO group trended to need a shorter postoperative hospital stay (17.45 ± 4.80 d vs 19.62 ± 5.59 d, P = 0.19). No statistically significant difference was found when stratified to mortality and occurrence of infectious complications. CONCLUSION: Postoperative supplementation of omega-3 fatty acids may have a favorable effect on the outcomes in colorectal cancer patients undergoing radical resection by lowering the magnitude of inflammatory responses and modulating the immune response.展开更多
The immunomodulation of several charged synthetic polymers containing phosphorus in the backbone was studied in vitro through examining their inhibition or promotion effect on the proliferation of both T and B lymphoc...The immunomodulation of several charged synthetic polymers containing phosphorus in the backbone was studied in vitro through examining their inhibition or promotion effect on the proliferation of both T and B lymphocytes. It is found that polymers based on long chain alkyl ester of tyrosine exhibit immunomodulative activity. Negatively charged polymers show stimulative activiactivity on LPS-induced B lymphocytes proliferation. Positively charged polymers exhibit inhibitory activity on both Con A-induced T lymphocytes and LPS-induced B lymphocytes proliferation.展开更多
A major challenge facing photodynamic therapy(PDT) is that the activity of the immuneinduced infiltrating CD8^(+)T cells is subject to the regulatory T lymphocytes(Tregs), leaving the tumor at risk of recurrence and m...A major challenge facing photodynamic therapy(PDT) is that the activity of the immuneinduced infiltrating CD8^(+)T cells is subject to the regulatory T lymphocytes(Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment(TME), a supramolecular photodynamic nanoparticle(DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin(DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration(Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs.The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.展开更多
BACKGROUND Accumulating evidence has shown that adipose tissue-derived mesenchymal stem cells(ADSCs)are an effective therapeutic approach for managing coronavirus disease 2019(COVID-19);however,further elucidation is ...BACKGROUND Accumulating evidence has shown that adipose tissue-derived mesenchymal stem cells(ADSCs)are an effective therapeutic approach for managing coronavirus disease 2019(COVID-19);however,further elucidation is required to determine their underlying immunomodulatory effect on the mRNA expression of T helper cell-related transcription factors(TFs)and cytokine release in peripheral blood mononuclear cells(PBMCs).AIM To investigate the impact of ADSCs on the mRNA expression of TFs and cytokine release in PBMCs from colorectal cancer(CRC)patients with severe COVID-19(CRC^(+)patients).METHODS PBMCs from CRC^(+)patients(PBMCs-C+)and age-matched CRC patients(PBMCs-C)were stimulated and cultured in the presence/absence of ADSCs.The mRNA levels of T-box TF TBX21(T-bet),GATA binding protein 3(GATA-3),RAR-related orphan receptor C(RORC),and forkhead box P3(FoxP3)in the PBMCs were determined by reverse transcriptase-polymerase chain reaction.Culture supernatants were evaluated for levels of interferon gamma(IFN-γ),interleukin 4(IL-4),IL-17A,and transforming growth factor beta 1(TGF-β1)using an enzyme-linked immunosorbent assay.RESULTS Compared with PBMCs-C,PBMCs-C+exhibited higher mRNA levels of T-bet and RORC,and increased levels of IFN-γ and IL-17A.Additionally,a significant decrease in FoxP3 mRNA and TGF-β1,as well as an increase in Tbet/GATA-3,RORC/FoxP3,IFN-γ/IL-4,and IL-17A/TGF-β1 ratios were observed in PBMCs-C+.Furthermore,ADSCs significantly induced a functional regulatory T cell(Treg)subset,as evidenced by an increase in FoxP3 mRNA and TGF-β1 release levels.This was accompanied by a significant decrease in the mRNA levels of T-bet and RORC,release of IFN-γ and IL-17A,and T-bet/GATA-3,RORC/FoxP3,IFN-γ/IL-4,and IL-17A/TGF-β1 ratios,compared with the PBMCs-C+alone.CONCLUSION The present in vitro studies showed that ADSCs contributed to the immunosuppressive effects on PBMCs-C+,favoring Treg responses.Thus,ADSC-based cell therapy could be a beneficial approach for patients with severe COVID-19 who fail to respond to conventional therapies.展开更多
Cellular nanovesicles which are referred to as cell-derived,nanosized lipid bilayer structures,have emerged as a promising platform for regulating immune responses.Owing to their outstanding advantages such as high bi...Cellular nanovesicles which are referred to as cell-derived,nanosized lipid bilayer structures,have emerged as a promising platform for regulating immune responses.Owing to their outstanding advantages such as high biocompatibility,prominent structural stability,and high loading capacity,cellular nanovesicles are suitable for delivering various immunomodulatory molecules,such as small molecules,nucleic acids,peptides,and proteins.Immunomodulation induced by cellular nanovesicles has been exploited to modulate immune cell behaviors,which is considered as a novel cell-free immunotherapeutic strategy for the prevention and treatment of diverse diseases.Here we review emerging concepts and new advances in leveraging cellular nanovesicles to activate or suppress immune responses,with the aim to explicate their applications for immunomodulation.We overview the general considerations and principles for the design of engineered cellular nanovesicles with tailored immunomodulatory activities.We also discuss new advances in engineering cellular nanovesicles as immunotherapies for treating major diseases.展开更多
Tissue injury leads to gradients of chemoattractants,which drive multiple processes for tissue repair,including the inflam-matory response as well as endogenous cell recruitment.However,a limited time window for the g...Tissue injury leads to gradients of chemoattractants,which drive multiple processes for tissue repair,including the inflam-matory response as well as endogenous cell recruitment.However,a limited time window for the gradients of chemoattract-ants as well as their poor stability at the injury site may not translate into healthy tissue repair.Consequently,intelligent multifunctional scaffolds with the capability to stabilize injury-induced cytokines and chemokines hold great promise for tissue repair.Vascular endothelial growth factor(VEGF)plays a significant role in wound healing by promoting angiogen-esis.The overarching objective of this research was to develop intelligent multifunctional scaffolds with the capability to endogenously recruit VEGF and promote wound healing via angiogenic and immunomodulatory dual functions.Prominin-1-derived peptide(PR1P)was encapsulated into electrospun poly(L-lactide-coglycolide)/gelatin(P/G)-based bandages.The sustained release of PR1P recruited VEGF in situ,thereby stabilizing the protein concentration peak in vivo and affording a reparative microenvironment with an adequate angiogenic ability at the wound site.Meanwhile,PR1P-recruited VEGF-induced macrophage reprogramming towards M2-like phenotypes further conferred immunomodulatory functions to the bandages.These dual functions of proangiogenesis and immunomodulation formed a cascade amplification,which regulated matrix metalloproteinases(MMP-9)as well as inflammatory factors(nuclear factor(NF)-κb,tumor necrosis factor(TNF)-α)in the wound microenvironment via the VEGF/macrophages/microenvironment axis.Consequently,the bandages realized multifunctional regeneration in splinted excisional wounds in rats,with or without diabetes,affording a higher skin append-age neogenesis,sensory function,and collagen remodeling.Conclusively,our approach encompassing in situ recruitment of VEGF at the injury site with the capability to promote immunomodulation-mediated tissue repair affords a promising avenue for scarless wound regeneration,which may also have implications for other tissue engineering disciplines.展开更多
Injectable bone biomaterials like bone cement should be designed and fabricated with certain biological criteria,which include:1)recruitment and polarization of the macrophages from M1(pro-inflammatory)to M2(anti-infl...Injectable bone biomaterials like bone cement should be designed and fabricated with certain biological criteria,which include:1)recruitment and polarization of the macrophages from M1(pro-inflammatory)to M2(anti-inflammatory)phenotype,2)enhance vascularization,and 3)activate osteogenic differentiation of bone marrow-derived stem cells to promote bone healing.So far,no injectable biomaterials could spontaneously regulate the entire bone healing process that involves inflammation,angiogenesis,and osteogenesis.Therefore,in this study,we designed bone cement comprised of strontium and copper-incorporated borosilicate glass(Sr/Cu-BSG)in the liquid phase of chitosan to modulate bone healing.In vitro studies showed that the controlled release of Sr and Cu ions up-regulated anti-inflammatory genes(IL-1Ra and TGF-β1)while down-regulating pro-inflammatory genes(IL-1βand IL-6)in macrophages at 3 days.Sr and Cu ions also increased the expressions of angiogenic genes(VEGF and bFGF)in HUVECs at 5 days and osteogenic genes(Runx-2,OCN,and OPN)in hBMSCs at 7,14,and 21 days.5Sr3Cu-BSG bone cement exhibited the best anti-inflammatory,angiogenic,and osteogenic properties among the bone cement groups with different Sr and Cu ratios.Short-term and long-term implantation of Sr/Cu-BSGs in femoral condylar bone defects of rats and rabbits confirmed the in vitro results,where the degradation rate of Sr/Cu-BSG matched the bone healing rate.Similar to in vitro,the 5Sr3Cu-BSG group also showed the highest bone formation in vivo.Excellent physical and chemical properties,along with its bone repairing ability,make the Sr/Cu-BSG bone cement a good candidate biomaterial for treating bone defects.展开更多
基金supported by the National Key Research and Development Project“Modern food processing and food storage and transportation technology and equipment”(2017YFD0400203)。
文摘In previous study,we got a purified ginger polysaccharide UGP1 and verified its significant antitumor activities on colon cancer HCT116 cells.In this article,we aimed to illustrate the underlying mechanism of UGP1 exerted antitumor activities on colon cancer by using in vitro cell models and in vivo animal models.The results demonstrated that UGP1 could induce S-phase cell cycle arrest,up-regulate the expression of Bax and p53,down-regulate the expression of Bcl-2,and activate the downstream protein caspase-9 and caspase-3,which was related to intrinsic apoptosis pathway on HCT116 cells.Moreover,UGP1 significantly stimulated RAW264.7 cell proliferation and secretion activity.Similarly,UGP1 inhibited tumor proliferation on tumor-bearing mice,increased the expression of p53 and the ratio of Bax/Bcl-2,enhanced the secretion of pro-inflammatory cytokines TNF-α,IL-2,IL-6 and decreased the secretion of pro-tumor cytokines TGF-βand b FGF in serum.In conclusion,it indicated that the UGP 1 could sup press human colon cancer growth by inducing apoptosis via the regulation of p53,caspase-3,and Bax/Bcl-2 ratio-dependent pathway and regulating immune system activity.Thi s investigation provided basic theoretical mechanism of ginger polysaccharideexerted antitumor activities,and contributed to develop a possible functional food or adjuvant agent for prevention or treatment of colon cancer.
基金Supported by National Natural Science Foundation of China,No.82074533.
文摘Ischemic stroke(IS)is the most prevalent form of brain disease,characterized by high morbidity,disability,and mortality.However,there is still a lack of ideal prevention and treatment measures in clinical practice.Notably,the trans-plantation therapy of mesenchymal stem cells(MSCs)has been a hot research topic in stroke.Nevertheless,there are risks associated with this cell therapy,including tumor formation,coagulation dysfunction,and vascular occlusion.Also,a growing number of studies suggest that the therapeutic effect after transplantation of MSCs is mainly attributed to MSC-derived exosomes(MSC-Exos).And this cell-free mediated therapy appears to circumvent many risks and difficulties when compared to cell therapy,and it may be the most promising new strategy for treating stroke as stem cell replacement therapy.Studies suggest that suppressing inflammation via modulation of the immune response is an additional treatment option for IS.Intriguingly,MSC-Exos mediates the inflam-matory immune response following IS by modulating the central nervous system,the peripheral immune system,and immunomodulatory molecules,thereby promoting neurofunctional recovery after stroke.Thus,this paper reviews the role,potential mechanisms,and therapeutic potential of MSC-Exos in post-IS inflammation in order to identify new research targets.
基金Supported by Matching Fund from Stanley Ho Alumni Challenge for Translational Research in Neuroinflammation,No.20830036
文摘Mesenchymal stem cells(MSCs) possess immunomodulatory properties, which confer enormous potential for clinical application. Considerable evidence revealed their efficacy on various animal models of autoimmune diseases, such as multiple sclerosis, systemic lupus erythematosus and uveitis. MSCs elicit their immunomodulatory effects by inhibiting lymphocyte activation and proliferation, forbidding the secretion of proinflammatory cytokines, limiting the function of antigen presenting cells, and inducing regulatory T(Treg) and B(Breg) cells. The induction of Treg and Breg cells is of particular interest since Treg and Breg cells have significant roles in maintaining immune tolerance. Several mechanisms have been proposed regarding to the MSCs-mediated induction of Treg and Breg cells. Accordingly, MSCs induce regulatory lymphocytes through secretion of multiple pleiotropic cytokines, cell-to-cell contact with target cells and modulation of antigen-presenting cells. Here, we summarized how MSCs induce Treg and Breg cells to provoke immunosuppression.
基金supported by grants from NSFC(National Natural Science Foundation of China,grant number81160232)CMA(Chinese Medical Association Intensive Scientific Research Fund project,grant number 13091520537)the First Affiliated Hospital of Xinjiang Medical University Natural Science Fund project(grant number 2013ZRQN11)
文摘BACKGROUND: Dexmedetomidine has already been used in septic patients as a new sedative agent, few studies have examined its effects on immunomodulation. Therefore, the authors have designed a controlled experimental study to characterize the immunomodulation effects of dexmedetomidine in the cecal ligation and puncture(CLP) model in rats. METHODS: After CLP, 48 Wistar rats were randomly allocated into four groups:(1) CLP group;(2) small-dose treatment group(2.5 g·kg^(-1)·h^(-1));(3) medium-dose treatment group(5.0 g·kg^(-1)·h^(-1)); and(4) large-dose treatment group(10.0 g·kg^(-1)·h^(-1)). HLA-DR and plasma cytokine(IL-4, IL-6, IL-10 and TNF-α) levels were measured, and the mean arterial blood pressure(MAP), heart rate(HR), arterial blood gases, lactate concentrations and mortality were also documented. RESULTS: The HLA-DR level, inflammatory mediator levels, MAP and HR had no obvious changes among Dexmedetomidine treatment groups(DEX groups). Compared with the CLP group, the DEX groups exhibited decreased HLA-DR levels(P_(group)=0.0202) and increased IL-6 production, which was increased at 3 h(P= 0.0113) and was then attenuated at 5 h; additionally, the DEX groups exhibited decreased HR(P<0.001) while maintaining MAP(P_(group)=0.1238), and remarkably improving lactate(P<0.0001). All of these factors led to a significant decrease in the mortality, with observed rates of 91.7%, 66.7%, 25% and 18% for the CLP, DEX2.5, DEX5.0, DEX10.0 groups, respectively.CONCLUSION: Dexmedetomidine treatment in the setting of a CLP sepsis rat model has partially induced immunomodulation that was initiated within 5 h, causing a decreased HR while maintaining MAP, remarkably improving metabolic acidosis and improving mortality dosedependently.
基金Supported by Beijing Natural Science Foundation,No.7182182the Young Elite Scientist Sponsorship Program by Cast,No.YESS20170089+1 种基金the National Natural Science Foundation of China,No.81600865 and No.81970940the National Science and Technology Major Project of the Ministry of Science and Technology of China,No.2018ZX10302207。
文摘Mesenchymal stem cells(MSCs)are a heterogeneous population that can be isolated from various tissues,including bone marrow,adipose tissue,umbilical cord blood,and craniofacial tissue.MSCs have attracted increasingly more attention over the years due to their regenerative capacity and function in immunomodulation.The foundation of tissue regeneration is the potential of cells to differentiate into multiple cell lineages and give rise to multiple tissue types.In addition,the immunoregulatory function of MSCs has provided insights into therapeutic treatments for immune-mediated diseases.DNA methylation and demethylation are important epigenetic mechanisms that have been shown to modulate embryonic stem cell maintenance,proliferation,differentiation and apoptosis by activating or suppressing a number of genes.In most studies,DNA hypermethylation is associated with gene suppression,while hypomethylation or demethylation is associated with gene activation.The dynamic balance of DNA methylation and demethylation is required for normal mammalian development and inhibits the onset of abnormal phenotypes.However,the exact role of DNA methylation and demethylation in MSC-based tissue regeneration and immunomodulation requires further investigation.In this review,we discuss how DNA methylation and demethylation function in multi-lineage cell differentiation and immunomodulation of MSCs based on previously published work.Furthermore,we discuss the implications of the role of DNA methylation and demethylation in MSCs for the treatment of metabolic or immune-related diseases.
文摘Hepatocellular carcinoma(HCC)is the most prevalent primary malignancy in patients suffering from chronic liver diseases and cirrhosis.Recent attention has been paid to the involvement of the gut-liver axis(GLA)in HCC pathogenesis.This axis results from a bidirectional,anatomical and functional relationship between the gastrointestinal system and the liver.Moreover,the complex network of interactions between the intestinal microbiome and the liver plays a crucial role in modulation of the HCC-tumor microenvironment,contributing to the pathogenesis of HCC by exposing the liver to pathogen-associated molecular patterns,such as bacterial lipopolysaccharides,DNA,peptidoglycans and flagellin.Indeed,the alteration of gut microflora may disturb the intestinal barrier,bringing several toll-like receptor ligands to the liver thus activating the inflammatory response.This review explores the new therapeutic opportunities that may arise from novel insights into the mechanisms by which microbiota immunomodulation,represented by probiotics,and prebiotics,affects HCC through the GLA.
文摘To observe immunomodulation and antitumor effect of melatonin (MLT) in tumor-bearing mice. Methods: By means of flow cytometry and MTT colorimetry, the immunological indexes of H22 hepatomabearing mice were investigated. Results: MLT administration could increase the CD4+/CD8+ cell ratio in the peripheral blood of the tumor-bearing mice, cooperate with IL-2 to promote the proliferation of lymphocytes and eosinophils, increase NK and LAK activity of splenocytes, and enhance the production of IL-2 from splenocytes.We also found that MLT could inhibit tumor growth and prolong the survival time of the tumor-bearing mice in vivo. Moreover, a synergetic effect of IL-2 and MLT was observed. It seems that MLT hadno effect on H22 hepatoma cell growth in vitro. Conclusion: It is suggested that MLT may be a potential candidate for tumor immunotherapy as one of the biological reaction modulators (BRM).
文摘Objective To investigate melatonin-related mechanisms of action on immunoregulation in aged and immunodeficient mice. Methods T lymPhocytes subunit CD4 + ,CD8 + and CD4 + /CD8 + ratio were measured by Flow Cytometer in normal, aged and Cyclophosphamide injected mice which treated with melatonin, and compared with the results of T lymphocytes subunit in the group without melatonin as control group. Results The percentage of CD4 + , CD8 + T cells in the normal mice which treated with melatonin was significantly higher than that in control group ( P <0.01), CD4 + /CD8 + ratio was higher but had no significant difference. In the cyclophosphamide injected group which melatonin treated, the percentage of CD4 + T cells and CD4 + /CD8 + ratio were higher than those in control, The difference was significant ( P <0.01), while CD8 + was lower ( P <0.01). In aged melatonin treated mice group, the percentage of CD4 + , CD8 + T cells and CD4 + /CD8 + ratio were significantly higher than those in control ( P <0.01). Conclusion Melatonin could adjust the quantity and the ratio of CD4 + , CD8 + T cells in aged and immunodeficient mice. it implied that melatonin could mediate helper and suppression T lymphocytes to reinforce their immunodefence.
基金This research is supported by a National Research Foundation of Korea(NRF)grant funded by the Korean government(Grant No.2020R1A2C2011617)by a Chung-Ang University Research Scholarship Grants in 2019.
文摘Exogenously delivered mesenchymal stromal cells(MSCs)are therapeutically beneficial owing to their paracrine effect;they secrete various cytokines,nucleic acids,and proteins.Multiple bioengineering techniques can help MSC cultures to release secretomes by providing stem cell niche-like conditions(both structurally and functionally).Various scaffolds mimic the natural extracellular matrix(ECM)using both natural and synthetic polymers,providing favorable environments for MSC proliferation and differentiation.Depending on material properties,either topographically or elastically structured scaffolds can be fabricated.Three-dimensional scaffolds have tunable substrate rigidities and structures,aiding MSC cultivation.Decellularized ECM-derived hydrogels are similar to the natural ECM,thus improving the paracrine effects of MSCs.Here,we discuss recent research on the application of scaffolds to maximize the immunomodulatory function of MSCs.
基金supported by Prémios Santa Casa Neurociências-Prize Meloe Castro for Spinal Cord Injury ResearchPortuguese Foundation for Science and Technology(Financiado noambito do Projecto 3599-Promover a Producao Científica e Desenvolvimento Tecnológico e a Constituicao de Redes Temáticas(3599-PPCDT)+2 种基金project:PTDC/DTP-FTO/5109/2014Post-Doctoral fellowship-SFRH/BPD/97701/2013-to N.A.SilvaIF Development Grant to A.J.Salgado
文摘The initial trauma to the spinal cord is just the starting point for a cascade of endogenous events that will collectively determine the injury extension.These secondary events include,but are not limited to:glutamate excitoxicity,induction of apoptotic pathways,ionic imbalances and the development of a strong and dysfunctional inflammatory response.The secondary injury is associated to an aggravation of neuronal damage increasing the extent of neurological deficits(Ek et al.,2010).
文摘Rabbit anti-thymocyte globulin's manifold mechanisms of action may be attribuited to its polyclonal nature. Its T-cell depleting effect on lymphoid cells is well established: Occurring in the blood and secondary lymphoid tissues, depletion proceeds through complement-dependent lysis, opsonization and apoptotic pathways. Clinical studies have shown that rabbit antithymocyte globulin's immunomodulatory effect extends beyond the initial T-cell depletion and up to the period during which lymphocyte populations begin to recover. The drug is able to mediate immunomodulation and graft tolerance by functionally inactivating cell surface receptors involved in antigen recognition, leukocyte trafficking and leukocyte endothelium adhesion. The complex and prolonged immunomodulation induced by this drug contributes to its efficacy in solid organ transplantation, mainly by reducing the incidence of acute graft rejection.
文摘Recent research has demonstrated that critically ill patients with coronavirus disease 2019(COVID-19)show significant immune system dysregulation.Due to that,some nutrients that influence immunomodulation have been suggested as a form of treatment against the infection.This review collected the information on the impact of vitamins on the prognosis of COVID-19,with the intention of facilitating treatment and prevention of the disease risk status in patients.The collected information was obtained using the PubMed electronic database by searching for articles that relate COVID-19 and the mechanisms/effects of the nutrients:Proteins,glucose,lipids,vitamin B12,vitamin D,calcium,iron,copper,zinc,and magnesium,including prospective,retrospective,and support articles.The findings reveal an optimal response related mainly to omega-3,eicosapentaenoic acid,docosahexaenoic acid,calcium,and iron that might represent benefits in the treatment of critically ill patients.However,nutrient supplementation should be done with caution due to the limited availability of randomized controlled studies.
文摘Coronavirus disease 2019(COVID-19)and helminths infections can be in a synergistic epidemic in developing and suburban areas of industrialized countries.The coinfected hosts will derive a parasite-specific Th2 innate and adaptive immune response with CD4+T cells,eosinophils,interleukin-4,interleukin-5,and interleukin-10.In the early stages of severe acute respiratory syndrome coronavirus type 2(SARS-CoV-2)infection,virus-specific Th1 cytotoxic CD8+T cell,interleukin-6,interferon-γ,and interleukin-27 by lung are keys in controlling viral replication in the lung epithelial cells and limiting the pathology to other organs,like the intestine.CD4+and CD8+T cells are associated with protective immunity against and during COVID-19.However,viral evasion mechanisms occur.Interference of the interferon-γsecretion,like in helminths immunomodulation,can contribute to COVID-19 severity.Immunomodulation can result in mild,moderate,or severe COVID-19 depending on which helminth is coinfecting by regulating or avoiding host cytokine and pro-inflammatory response,decreasing viral load,and affecting vaccine-induced antibody response.We discuss the implications of immunomodulation on COVID-19 caused by helminth co-infection and for public health in the context of COVID-19 vaccine use in helminth endemic zones.
文摘AIM: To investigate the effect of omega-3 fatty acid parenteral supplementation postoperatively on clinical outcomes and immunomodulation in colorectal cancer patients. METHODS: Forty-two patients undergoing radical colorectal cancer resection with an indication for total parenteral nutrition postoperatively were enrolled in this prospective, double-blind, randomized, controlled study. Patients received total parenteral nutrition supplemented with either soybean oil (LCT; Intralipid, Fresenius-Kabi, SO group, n = 21) or a combination of omega-3 fish oil and soybean oil (LCT:fish oil = 5:1, fish oil; Omegaven, Fresenius-Kabi, FO group, n = 21), up to a total of 1.2 g lipid/kg per day for 7 d postoperatively. A same volume calorie and nitrogen was administrated. Routine blood test, biochemistry, systemic levels of IL-6 and TNF-α, percentage of CD3+, CD4+, and CD8+ lymphocytes were evaluated preoperatively and on postoperative d 1 and 8. Patient outcome was evaluated considering mortality during the hospital stay, length of postoperative hospital stay, and occurrence of infectious complications. RESULTS: Both lipid regimens were well tolerated. No differences between the two groups were noticed in demographics, baseline blood test, biochemistry, serum levels of IL-6 and TNF-α, percentage of CD4+, CD8+ lymphocytes, and ratios of CD4+/CD8+. Compared with those on postoperative d 1, serum IL-6 levels onpostoperative d 8 were significantly depressed in the FO group than in the reference group (-44.43 ± 30.53 vs -8.39 ± 69.08, P = 0.039). Simultaneously, the ratios of CD4+/CD8+ were significantly increased in the FO group (0.92 ± 0.62 vs 0.25 ± 1.22, P = 0.035). In addition, depression of serum TNF-α levels (-0.82 ± 2.71 vs 0.27 ± 1.67, P = 0.125) and elevation of CD3+ and CD4+ lymphocyte percentage (12.85 ± 11.61 vs 3.84 ± 19.62, P = 0.081, 17.80 ± 10.86 vs 9.66 ± 17.55, P = 0.084, respectively) were higher in the FO group than in the reference group. Patients in the FO group trended to need a shorter postoperative hospital stay (17.45 ± 4.80 d vs 19.62 ± 5.59 d, P = 0.19). No statistically significant difference was found when stratified to mortality and occurrence of infectious complications. CONCLUSION: Postoperative supplementation of omega-3 fatty acids may have a favorable effect on the outcomes in colorectal cancer patients undergoing radical resection by lowering the magnitude of inflammatory responses and modulating the immune response.
文摘The immunomodulation of several charged synthetic polymers containing phosphorus in the backbone was studied in vitro through examining their inhibition or promotion effect on the proliferation of both T and B lymphocytes. It is found that polymers based on long chain alkyl ester of tyrosine exhibit immunomodulative activity. Negatively charged polymers show stimulative activiactivity on LPS-induced B lymphocytes proliferation. Positively charged polymers exhibit inhibitory activity on both Con A-induced T lymphocytes and LPS-induced B lymphocytes proliferation.
基金supported by the National Natural Science Foundation of China(82173762,China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2022JDJQ0050,China)the Fundamental of Research Funds for the Central Universities.
文摘A major challenge facing photodynamic therapy(PDT) is that the activity of the immuneinduced infiltrating CD8^(+)T cells is subject to the regulatory T lymphocytes(Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment(TME), a supramolecular photodynamic nanoparticle(DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin(DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration(Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs.The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.
基金Supported by National Natural Science Foundation of China,No.81470982.
文摘BACKGROUND Accumulating evidence has shown that adipose tissue-derived mesenchymal stem cells(ADSCs)are an effective therapeutic approach for managing coronavirus disease 2019(COVID-19);however,further elucidation is required to determine their underlying immunomodulatory effect on the mRNA expression of T helper cell-related transcription factors(TFs)and cytokine release in peripheral blood mononuclear cells(PBMCs).AIM To investigate the impact of ADSCs on the mRNA expression of TFs and cytokine release in PBMCs from colorectal cancer(CRC)patients with severe COVID-19(CRC^(+)patients).METHODS PBMCs from CRC^(+)patients(PBMCs-C+)and age-matched CRC patients(PBMCs-C)were stimulated and cultured in the presence/absence of ADSCs.The mRNA levels of T-box TF TBX21(T-bet),GATA binding protein 3(GATA-3),RAR-related orphan receptor C(RORC),and forkhead box P3(FoxP3)in the PBMCs were determined by reverse transcriptase-polymerase chain reaction.Culture supernatants were evaluated for levels of interferon gamma(IFN-γ),interleukin 4(IL-4),IL-17A,and transforming growth factor beta 1(TGF-β1)using an enzyme-linked immunosorbent assay.RESULTS Compared with PBMCs-C,PBMCs-C+exhibited higher mRNA levels of T-bet and RORC,and increased levels of IFN-γ and IL-17A.Additionally,a significant decrease in FoxP3 mRNA and TGF-β1,as well as an increase in Tbet/GATA-3,RORC/FoxP3,IFN-γ/IL-4,and IL-17A/TGF-β1 ratios were observed in PBMCs-C+.Furthermore,ADSCs significantly induced a functional regulatory T cell(Treg)subset,as evidenced by an increase in FoxP3 mRNA and TGF-β1 release levels.This was accompanied by a significant decrease in the mRNA levels of T-bet and RORC,release of IFN-γ and IL-17A,and T-bet/GATA-3,RORC/FoxP3,IFN-γ/IL-4,and IL-17A/TGF-β1 ratios,compared with the PBMCs-C+alone.CONCLUSION The present in vitro studies showed that ADSCs contributed to the immunosuppressive effects on PBMCs-C+,favoring Treg responses.Thus,ADSC-based cell therapy could be a beneficial approach for patients with severe COVID-19 who fail to respond to conventional therapies.
基金support from the College of Pharmacy at University of Illinois Chicago。
文摘Cellular nanovesicles which are referred to as cell-derived,nanosized lipid bilayer structures,have emerged as a promising platform for regulating immune responses.Owing to their outstanding advantages such as high biocompatibility,prominent structural stability,and high loading capacity,cellular nanovesicles are suitable for delivering various immunomodulatory molecules,such as small molecules,nucleic acids,peptides,and proteins.Immunomodulation induced by cellular nanovesicles has been exploited to modulate immune cell behaviors,which is considered as a novel cell-free immunotherapeutic strategy for the prevention and treatment of diverse diseases.Here we review emerging concepts and new advances in leveraging cellular nanovesicles to activate or suppress immune responses,with the aim to explicate their applications for immunomodulation.We overview the general considerations and principles for the design of engineered cellular nanovesicles with tailored immunomodulatory activities.We also discuss new advances in engineering cellular nanovesicles as immunotherapies for treating major diseases.
基金Funding National Natural Science Foundation of China,81770091,Chang Chen,NSFC32050410286Shafiq Muhammad,Science and Technology Innovation Plan Of Shanghai Science and Technology Commission,No.20DZ2253700+2 种基金Chang Chen,Japan Society for the Promotion of Science,JP21F21353Shafiq Muhammad,Sino German Science Foundation Research Exchange Center,M-0263Xiumei Mo,Science and Technology Commission of Shanghai Municipality,20S31900900,Xiumei Mo,20DZ2254900,Xiumei Mo.
文摘Tissue injury leads to gradients of chemoattractants,which drive multiple processes for tissue repair,including the inflam-matory response as well as endogenous cell recruitment.However,a limited time window for the gradients of chemoattract-ants as well as their poor stability at the injury site may not translate into healthy tissue repair.Consequently,intelligent multifunctional scaffolds with the capability to stabilize injury-induced cytokines and chemokines hold great promise for tissue repair.Vascular endothelial growth factor(VEGF)plays a significant role in wound healing by promoting angiogen-esis.The overarching objective of this research was to develop intelligent multifunctional scaffolds with the capability to endogenously recruit VEGF and promote wound healing via angiogenic and immunomodulatory dual functions.Prominin-1-derived peptide(PR1P)was encapsulated into electrospun poly(L-lactide-coglycolide)/gelatin(P/G)-based bandages.The sustained release of PR1P recruited VEGF in situ,thereby stabilizing the protein concentration peak in vivo and affording a reparative microenvironment with an adequate angiogenic ability at the wound site.Meanwhile,PR1P-recruited VEGF-induced macrophage reprogramming towards M2-like phenotypes further conferred immunomodulatory functions to the bandages.These dual functions of proangiogenesis and immunomodulation formed a cascade amplification,which regulated matrix metalloproteinases(MMP-9)as well as inflammatory factors(nuclear factor(NF)-κb,tumor necrosis factor(TNF)-α)in the wound microenvironment via the VEGF/macrophages/microenvironment axis.Consequently,the bandages realized multifunctional regeneration in splinted excisional wounds in rats,with or without diabetes,affording a higher skin append-age neogenesis,sensory function,and collagen remodeling.Conclusively,our approach encompassing in situ recruitment of VEGF at the injury site with the capability to promote immunomodulation-mediated tissue repair affords a promising avenue for scarless wound regeneration,which may also have implications for other tissue engineering disciplines.
基金This work was supported by the National Key R&D Program of China(Grant No.2021YFC2400500 and 2018YFC1106300)the National Natural Science Foundation of China(Grant No.52072398,31870956,32161160327,U2001221,31771041,81860385)+2 种基金the Frontier Science Key Research Programs of CAS(Grant No.QYZDB-SSW-JSC030)the Shenzhen Significant Strategy Layout Project(Grant No.JCYJ20200109114620793)Natural Science Foundation of Guangxi Province(Grant No.2020GXNSFBA297154 and 2022GXNSFAA035472).
文摘Injectable bone biomaterials like bone cement should be designed and fabricated with certain biological criteria,which include:1)recruitment and polarization of the macrophages from M1(pro-inflammatory)to M2(anti-inflammatory)phenotype,2)enhance vascularization,and 3)activate osteogenic differentiation of bone marrow-derived stem cells to promote bone healing.So far,no injectable biomaterials could spontaneously regulate the entire bone healing process that involves inflammation,angiogenesis,and osteogenesis.Therefore,in this study,we designed bone cement comprised of strontium and copper-incorporated borosilicate glass(Sr/Cu-BSG)in the liquid phase of chitosan to modulate bone healing.In vitro studies showed that the controlled release of Sr and Cu ions up-regulated anti-inflammatory genes(IL-1Ra and TGF-β1)while down-regulating pro-inflammatory genes(IL-1βand IL-6)in macrophages at 3 days.Sr and Cu ions also increased the expressions of angiogenic genes(VEGF and bFGF)in HUVECs at 5 days and osteogenic genes(Runx-2,OCN,and OPN)in hBMSCs at 7,14,and 21 days.5Sr3Cu-BSG bone cement exhibited the best anti-inflammatory,angiogenic,and osteogenic properties among the bone cement groups with different Sr and Cu ratios.Short-term and long-term implantation of Sr/Cu-BSGs in femoral condylar bone defects of rats and rabbits confirmed the in vitro results,where the degradation rate of Sr/Cu-BSG matched the bone healing rate.Similar to in vitro,the 5Sr3Cu-BSG group also showed the highest bone formation in vivo.Excellent physical and chemical properties,along with its bone repairing ability,make the Sr/Cu-BSG bone cement a good candidate biomaterial for treating bone defects.
