IMMUNITY AND TUMOR Immune system has closely relation to the growth and development of tumor. One of its immune functions is to constantly recognize and kill malignant cells which develop from normal cells. The occura...IMMUNITY AND TUMOR Immune system has closely relation to the growth and development of tumor. One of its immune functions is to constantly recognize and kill malignant cells which develop from normal cells. The occurance of tumor indicates to some extent the failure of this "immune serveillance" function. Many studies have shown that the tumor cells of body have some tumor interrelative antigen that dose not exist in normal tissues. Tests in vitro展开更多
The effect of the Chinese herbal compound (CHC) on solid sarcoma 180 (S180) in Swiss mice was studied either alone or in combination with 5-fluorouracil (5FU), cyclophosphamide (CYT) or mitomycin C (MMC). The prelimin...The effect of the Chinese herbal compound (CHC) on solid sarcoma 180 (S180) in Swiss mice was studied either alone or in combination with 5-fluorouracil (5FU), cyclophosphamide (CYT) or mitomycin C (MMC). The preliminary results indicated that combination treatment seemed to possess better antitumor activity than chemotherapy alone. The treatment with CHC alone however had neither an obvious antitumor effect in tumor bearing mice nor toxicity in normal mice. These results show that CHC may stimulate organs of the immune system such as the spleen to be im-munomodulators and enhance the antitumor activity of some chemotherapeutic agents.展开更多
In the study, the antitumor effect was observed by employing HAC-tumor-bearing mice treated with direct moxibustion on point Guanyuan(CV 4) (Group M), subcutaneous administration of liposome encapsulated immunomodulat...In the study, the antitumor effect was observed by employing HAC-tumor-bearing mice treated with direct moxibustion on point Guanyuan(CV 4) (Group M), subcutaneous administration of liposome encapsulated immunomodulators called IMC(Group IMC), and combination of these two methods(Group M + IMC). Parameters reflecting biological characteristics of tumor cells, including 5 kinds of lectins, mitotic cycle, expression of C-erbB-2 oncogene and counts of AgNORs were further investigated. The results showed that treatment with combination of moxibustion and IMC could significantly lower three lectins (ConA, LCA, RCA) among these five lectins (BSL, ConA, LCA,RCA, WGA), significantly reduce the expression of C-erbB-2 oncogene, the counts of AgNORs ane the percentage of phase S in HAC tumor cells (compared with Group IMC). Moxibustion or IMC alone did render a certain degree of influence on the above-mentioned parameters, although most of changes were not statistically significant. The above-mentioned results indicated that the antitumor efficacy achieved by treatment with combination of moxibustion and IMC was mainly through its influence on biological characteristics of the tumor cells, namely, its reducing effect on DNA synthesis or on the proliferating rate of tumor cells and its influence on other biological characteristics of tumor展开更多
Autoimmune hepatitis (AIH) is a chronic, progressive inflammatory liver disease characterized by autoimmune-mediated hepatic injury. Currently, glucocorticoid drugs, primarily prednisone, with or without azathioprine,...Autoimmune hepatitis (AIH) is a chronic, progressive inflammatory liver disease characterized by autoimmune-mediated hepatic injury. Currently, glucocorticoid drugs, primarily prednisone, with or without azathioprine, are commonly recommended as first-line therapeutic agents in treatment guidelines by many scientific associations. However, the primary objective of treatment is to achieve a complete biochemical response, which is defined as the normalization of both transaminases and immunoglobulin G levels within six to twelve months. Ideally, this should also be accompanied by histological remission. Nevertheless, corticosteroid therapy is associated with significant adverse effects, potentially resulting in treatment discontinuation. In this context, it has become evident that standard treatment is inadequate for a proportion of patients, leading to the emergence of other treatment options and lines. Novel immunomodulatory agents, a class of drugs that regulate the body’s immune functions, have been confirmed to possess properties that modulate immune balance and induce immune tolerance. In recent years, these agents have played an increasingly significant role in the clinical management of AIH. This article provided an in-depth review of recent advancements in the development of novel immunomodulators, including immune cell nucleic acid inhibitors, calmodulin phosphate inhibitors, mammalian target of rapamycin inhibitors, tumor necrosis factor-α inhibitors, interleukin-2, anti-CD20 monoclonal antibodies, and B cell-activating factor inhibitors, for the treatment of AIH.展开更多
In their recent publication in Nature,Miller et al.studied recurrent transcriptional programs across various brain tumors.The authors identified four immunomodulatory expression programs in myeloid cells driven by fac...In their recent publication in Nature,Miller et al.studied recurrent transcriptional programs across various brain tumors.The authors identified four immunomodulatory expression programs in myeloid cells driven by factors within the tumor microenvironment(TME)including hypoxia,IL-1β,TGFβ,and dexamethasone treatment1.Notably,the authors link clinical use of dexamethasone with an immunosuppressive myeloid program,potentially highlighting dexamethason’s compounding effect on glioblastomaassociated immunosuppression.展开更多
Immunotherapy has led to a paradigm shift in the treatment of cancer.Current cancer immunotherapies are mostly antibody-based,thus possessing advantages in regard to pharmacodynamics(e.g.,specificity and efficacy).How...Immunotherapy has led to a paradigm shift in the treatment of cancer.Current cancer immunotherapies are mostly antibody-based,thus possessing advantages in regard to pharmacodynamics(e.g.,specificity and efficacy).However,they have limitations in terms of pharmacokinetics including long half-lives,poor tissue/tumor penetration,and little/no oral bioavailability.In addition,therapeutic antibodies are immunogenic,thus may cause unwanted adverse effects.Therefore,researchers have shifted their efforts towards the development of small molecule-based cancer immunotherapy,as small molecules may overcome the above disadvantages associated with antibodies.Further,small molecule-based immunomodulators and therapeutic antibodies are complementary modalities for cancer treatment,and may be combined to elicit synergistic effects.Recent years have witnessed the rapid development of small molecule-based cancer immunotherapy.In this review,we describe the current progress in small molecule-based immunomodulators(inhibitors/agonists/degraders)for cancer therapy,including those targeting PD-1/PD-L1,chemokine receptors,stimulator of interferon genes(STING),Toll-like receptor(TLR),etc.The tumorigenesis mechanism of various targets and their respective modulators that have entered clinical trials are also summarized.展开更多
Immunomodulators,particularly the thiopurines and to a lesser extent methotrexate,were standard of care for inflammatory bowel diseases,including Crohn’s disease and ulcerative colitis,for>40 years.While there has...Immunomodulators,particularly the thiopurines and to a lesser extent methotrexate,were standard of care for inflammatory bowel diseases,including Crohn’s disease and ulcerative colitis,for>40 years.While there has been a renaissance in available therapies with the advent of biologics and small molecules,an impetus remains for the ongoing use of thiopurines and methotrexate.This is particularly true for the maintenance of remission and when used in combination therapy with infliximab to suppress anti-biologic antibodies.This article summarizes the data behind immunomodulator use in Crohn’s disease,focusing on the beneficial role these drugs still have while acknowledging their clinical limitations.展开更多
Typhonium flagelliforme(TF)is a Southeast Asian medicinal plant traditionally used for cancer,respiratory disorders,gastrointestinal complaints,wound healing,inflammation,and general health.Contemporary studies valida...Typhonium flagelliforme(TF)is a Southeast Asian medicinal plant traditionally used for cancer,respiratory disorders,gastrointestinal complaints,wound healing,inflammation,and general health.Contemporary studies validate these uses,showing potent anticancer,immunomodulatory,anti-inflammatory,gastroprotective,antibacterial,antioxidant,and wound-healing activities.Ethanol,dichloromethane,methanol,and ethyl acetate extracts exhibit strong cytotoxicity against breast(MCF-7,T47D),lung(NCI-H23),colon(WiDr),and leukemia(CEM-ss,WEHI-3)cells via apoptosis,telomerase inhibition,HER2/neu and BCL-2 suppression,and antiangiogenesis.Notably,2-octenoic acid and 2-hexenoic acid show exceptional activity(IC₅₀=2.66 and 3.10μg/mL)against MCF-7 cells.TF also restores lymphocyte proliferation,enhances macrophage activity,increases both CD4+and CD8+T-cell levels,and modulates cytokines(TNF-α,IL-1α,IL-10).Gastroprotective,anti-ulcer,antibacterial,antioxidant,and wound-healing effects further support traditional claims.Key phytochemicals include flavonoids(isovitexin,kaempferol,vitexin),phenolics(vanillin,4-hydroxybenzaldehyde),phytosterols(β-sitosterol,campesterol,stigmasterol,daucosterol),chlorophyll derivatives(pheophorbides),and long-chain fatty acids(linoleic,linolenic,oleic,stearic).These findings highlight TF as a source of multifunctional bioactive compounds,warranting further pharmacokinetic,safety,and clinical evaluation for evidence-based therapeutic development.展开更多
Mesenchymal stem cells(MSCs) are widely utilized in disease treatment and regenerative medicine due to their potent immunomodulatory properties and capacity for tissue repair.However, limitations—including insufficie...Mesenchymal stem cells(MSCs) are widely utilized in disease treatment and regenerative medicine due to their potent immunomodulatory properties and capacity for tissue repair.However, limitations—including insufficient migratory capacity, suboptimal survival, proliferation, differentiation potential, and variable immunomodulatory responses—significantly hinder their clinical translation and therapeutic impact. Natural products have been shown to enhance MSC homing, stress resilience, immune regulation, and lineage-specific differentiation through multi-target mechanisms, thereby emerging as promising, safe, and practical strategies to improve the in vivo performance of MSC-based therapies. This review examines the key translational challenges associated with MSCs, elucidates the mechanistic basis by which natural products regulate the in vivo fate of MSCs, and explores the potential of integrating natural product adjuvants with MSC therapy for enhanced clinical outcomes.展开更多
The global burden of bacterial infections,exacerbated by antimicrobial resistance(AMR),necessitates innovative strategies.Bacterial protein vaccines offer promise by eliciting targeted immunity while circumventing AMR...The global burden of bacterial infections,exacerbated by antimicrobial resistance(AMR),necessitates innovative strategies.Bacterial protein vaccines offer promise by eliciting targeted immunity while circumventing AMR.However,their clinical translation is hindered by their inherently low immunogenicity,often requiring potent adjuvants and advanced delivery systems.Biomembrane nanostructures(e.g.,liposomes,exosomes,and cell membrane-derived nanostructures),characterized by superior biocompatibility,intrinsic targeting ability,and immune-modulating properties,could serve as versatile platforms that potentiate vaccine efficacy by increasing antigen stability,enabling codelivery of immunostimulants,and facilitating targeted delivery to lymphoid tissues/antigen-presenting cells.This intrinsic immunomodulation promotes robust humoral and cellular immune responses to combat bacteria.This review critically reviews(1)key biomembrane nanostructure classes for bacterial protein antigens,(2)design strategies leveraging biomembrane nanostructures to enhance humoral and cellular immune responses,(3)preclinical efficacy against diverse pathogens,and(4)translational challenges and prospects.Biomembrane nanostructure-driven approaches represent a paradigm shift in the development of next-generation bacterial protein vaccines against resistant infections.展开更多
Objective::To provide new insight into how chronic rhinosinusitis (CRS) is conceptualized and treated with a focus on immunomodulator therapy.Data sources::Pubmed, Medline, and Embase.Methods::A current review of the ...Objective::To provide new insight into how chronic rhinosinusitis (CRS) is conceptualized and treated with a focus on immunomodulator therapy.Data sources::Pubmed, Medline, and Embase.Methods::A current review of the evidence is provided for immunomodulators investigated for treatment of CRS with nasal polyps (CRSwNP).Results::Biologic therapies targeting IgE, IL-4, IL-5, and IL-13 for the treatment of CRSwNP have shown promise and are currently in phase 3 trials. Anti-immunoglobin E (IgE) therapy with omalizumab was assessed in 6 studies, anti-interleukin (IL)-5 therapy in 3 studies (2 mepolizumab, 1 reslizumab) and anti IL-4/IL-13 (dupilumab) therapy in one study. Studied outcomes varied, but the majority of trials identified clinical benefit of therapy over placebo. Other potential targets include thymic stromal lymphopoetin (TSLP), IL-25, IL-33, and sialic acidbinding immunoglobulin-type lectin (Siglec)-8. Small molecule drugs that target the dysregulation of the immune system in CRS are also being investigated for their immunomodulatory effects on inflammation.Conclusion::Immunomodulator therapies for CRS currently in development will likely provide another therapeutic option for patients who have severe disease unresponsive to corticosteroids and surgery. Targeted monoclonal antibody therapies have shown encouraging results and phase 3 trials are underway. IL-4/IL-13 inhibition has shown the most promise to date. Further larger, well-designed trials are needed to improve understanding of these molecules and to offer endotype-driven therapies in the management of CRS. None of these therapeutics have shown long-term immunomodulation when discontinued and therefore further investigation into the pathomechanism of disease continues to be needed.展开更多
Chronic hepatitis B virus(HBV)infection affects approximately 254 million individuals globally,contributing to significant morbidity and mortality due to HBV-related liver failure and cirrhosis,which result in million...Chronic hepatitis B virus(HBV)infection affects approximately 254 million individuals globally,contributing to significant morbidity and mortality due to HBV-related liver failure and cirrhosis,which result in millions of fatalities each year.Although approved antiviral nucleos(t)ide analogues can effectively suppress HBV replication,their ability to reduce hepatitis B surface antigen(HBsAg)levels in plasma remains limited.The clinical application of the immunomodulator interferon-alpha is restricted by concerns regarding its safety and the severity of associated adverse reactions,rendering long-term administration challenging.Therefore,current drug development efforts for chronic hepatitis B aim to achieve a functional cure,which is defined as HBsAg serological clearance and sustained suppression of HBV DNA.This review discusses recent advancements in novel direct-acting therapeutic strategies for the treatment of chronic hepatitis B by focusing on the progresses in HBV entry inhibitors,monoclonal antibodies,RNA interferences,and other agents that directly target the virus.Furthermore,we discuss the development of immunomodulatory therapies,including TLR-7/8 agonists,immune checkpoint inhibitors,and therapeutic vaccines.In the end,we conclude by highlighting the importance of the rational combination-strategy design to improve the functional cure rate of HBV.展开更多
BACKGROUND Mesenchymal stem cells,found in various tissues,possess significant healing and immunomodulatory properties,influencing macrophage polarization,which is essential for wound repair.However,chronic wounds pre...BACKGROUND Mesenchymal stem cells,found in various tissues,possess significant healing and immunomodulatory properties,influencing macrophage polarization,which is essential for wound repair.However,chronic wounds present significant therapeutic challenges,requiring novel strategies to improve healing outcomes.AIM To investigate the potential of fetal dermal mesenchymal stem cells(FDMSCs)in enhancing wound healing through modulation of macrophage polarization,specifically by promoting the M2 phenotype to address inflammatory responses in chronic wounds.METHODS FDMSCs were isolated from BalB/C mice and co-cultured with RAW264.7 macrophages to assess their effects on macrophage polarization.Flow cytometry,quantitative reverse transcriptase polymerase chain reaction,and histological analyses were employed to evaluate shifts in macrophage phenotype and wound healing in a mouse model.Statistical analysis was performed using GraphPad Prism.RESULTS FDMSCs induced macrophage polarization from the M1 to M2 phenotype,as demonstrated by a reduction in proinflammatory markers(inducible nitric oxide synthase,interleukin-6)and an increase in anti-inflammatory markers[mannose receptor(CD206),arginase-1]in co-cultured RAW264.7 macrophages.These shifts were confirmed by flow cytometry.In an acute skin wound model,FDMSC-treated mice exhibited faster wound healing,enhanced collagen deposition,and improved vascular regeneration compared to controls.Significantly higher expression of arginase-1 further indicated an enriched M2 macrophage environment.CONCLUSION FDMSCs effectively modulate macrophage polarization from M1 to M2,reduce inflammation,and enhance tissue repair,demonstrating their potential as an immunomodulatory strategy in wound healing.These findings highlight the promising therapeutic application of FDMSCs in managing chronic wounds.展开更多
Background Broiler chickens are most vulnerable immediately after hatching due to their immature immune systems,making them susceptible to infectious diseases.The yolk plays an important role in early immune defence b...Background Broiler chickens are most vulnerable immediately after hatching due to their immature immune systems,making them susceptible to infectious diseases.The yolk plays an important role in early immune defence by showing relevant antioxidant and passive immunity capabilities during broiler embryonic development.The immunomodulatory effects of phytogenic compound carvacrol have been widely reported.After in ovo delivery in the amniotic fluid during embryonic development carvacrol is known to migrate to the yolk sac.However,it is unknown whether carvacrol in the yolk could enhance defence responsiveness in the yolk sac.Therefore,the aim of this study was to improve early immune function in chicken embryos,and it was hypothesized that in ovo delivery of carvacrol would result in immunomodulatory effects in the yolk sac,potentially improving post-hatch resilience.Methods On embryonic day(E)17.5,either a saline(control)or carvacrol solution was injected into the amniotic fluid.Yolk sac tissue samples were collected at E19.5,and transcriptomic analyses using RNA sequencing were performed,following functional enrichment analyses comparing the control(saline)and carvacrol-injected groups.Results The results showed that 268 genes were upregulated and 174 downregulated in the carvacrol group compared to the control(P<0.05;logFC<-0.5 or log FC>0.5).Functional analyses of these differentially expressed genes,using KEGG,REACTOME,and Gene Ontology databases,showed enrichment of several immune-related pathways.This included the pathways‘Antimicrobial peptides’(P=0.001)and‘Chemoattractant activity’(P=0.004),amongst others.Moreover,the‘NOD-like receptor signaling’pathway was enriched(P=0.002).Antimicrobial peptides are part of the innate immune defence and are amongst the molecules produced after the nucleotide oligomeriza-tion domain(NOD)-like receptor pathway activation.While these responses may be associated with an inflammatory reaction to an exogenous threat,they could also indicate that in ovo delivery of carvacrol could prepare the newly hatched chick against bacterial pathogens by potentially promoting antimicrobial peptide production through acti-vation of NOD-like receptor signaling in the yolk sac.Conclusion In conclusion,these findings suggest that in ovo delivery of carvacrol has the potential to enhance anti-pathogenic and pro-inflammatory responses in the yolk sac via upregulation of antimicrobial peptides,and NOD-like receptor pathways.展开更多
Cancer vaccines are a notable area of immunotherapy due to their capacity to elicit specific antitumor immune responses and to create immune memory.However,they encounter challenges in clinical practice due to several...Cancer vaccines are a notable area of immunotherapy due to their capacity to elicit specific antitumor immune responses and to create immune memory.However,they encounter challenges in clinical practice due to several bottlenecks,including tumor heterogeneity,low immunogenicity,immunosuppressive tumor environment,and delivery obstacles,which collectively impact their clinical effectiveness.In this study,we developed nanocomposites containing positively charged melittin(MEL)and negatively charged photosensitizer indocyanine green(ICG),embedded in dissolving microneedles(MEL/ICG-HA@DMNs).This approach allows precise drug delivery by creating microchannels that bypass the stratum corneum barrier,targeting superficial lesions directly.Our results demonstrated that the complexation of MEL and ICG significantly reduced the hemolytic activity of MEL while maintaining its ability to disrupt cell membranes.After loading MEL/ICG-HA into the microneedle,MEL/ICG-HA@DMNs not only effectively concentrated the drug at the tumor site,inducing localized hyperthermia and successfully ablating the tumor,but also formed an in situ whole-cell vaccine containing a rich source of tumor-associated antigens.Moreover,the system promoted dendritic cell maturation and increased the M1/M2 macrophage ratio,enhancing the immune response.By overcoming the limitations of traditional cancer vaccines,this system ensures precise drug delivery and robust immune activation.This innovative approach holds the potential to revolutionize cancer treatment,offering a new paradigm in precision oncology.展开更多
Diabetes,a metabolic disease stemming from impaired or defective insulin secretion,ranks among the most severe chronic illnesses globally.While several approved drugs exist for its treatment,they often come with multi...Diabetes,a metabolic disease stemming from impaired or defective insulin secretion,ranks among the most severe chronic illnesses globally.While several approved drugs exist for its treatment,they often come with multiple side effects.Therefore,there is a pressing need for safe and effective anti-diabetic medications.Traditional Chinese medicine has recognized Lycium barbarum(LB;goji berry)plant,commonly known as“wolfberry fruit”in China,for over 2,000 years.Natural compounds derived from LB show promise in reducing diabetes levels.Although research on the impact of LB on diabetes is still limited,our review aims to explore the potential of LB in reducing the risk of diabetes and examine the underlying mechanisms involved.LB can modulate diabetes through various pathways,such as inhibitingα-amylase andα-glucosidase activities,promotingβ-cell proliferation,stimulating insulin secretion,inhibiting glucagon secretion,improving insulin resistance and glucose tolerance,and enhancing antioxidant and anti-inflammatory activities.Additionally,LB improves gut flora and immunomodulation,further aiding diabetes management.These findings highlight the potential clinical utility of LB in managing diabetes and its complications within the framework of evidence-based modern medicine.展开更多
Severe tissue defects present formidable challenges to human health,persisting as major contributors to mortality rates.The complex pathological microenvironment,particularly the disrupted immune landscape within thes...Severe tissue defects present formidable challenges to human health,persisting as major contributors to mortality rates.The complex pathological microenvironment,particularly the disrupted immune landscape within these defects,poses substantial hurdles to existing tissue regeneration strategies.However,the emergence of nanobiotechnology has opened a new direction in immunomodulatory nanomedicine,providing encouraging prospects for tissue regeneration and restoration.This review aims to gather recent advances in immunomodulatory nanomedicine to foster tissue regeneration.We begin by elucidating the distinctive features of the local immune microenvironment within defective tissues and its crucial role in tissue regeneration.Subsequently,we explore the design and functional properties of immunomodulatory nanosystems.Finally,we address the challenges and prospects of clinical translation in nanomedicine development,aiming to propose a potent approach to enhance tissue regeneration through synergistic immune modulation and nanomedicine integration.展开更多
Humans and other vertebrates are safeguarded from invading pathogenic microbes by the immune system.Black seed,scientifically known as Nigella sativa,has garnered attention for its potential immunomodulatory effects i...Humans and other vertebrates are safeguarded from invading pathogenic microbes by the immune system.Black seed,scientifically known as Nigella sativa,has garnered attention for its potential immunomodulatory effects in both clinical and preclinical studies.This comprehensive review aims to consolidate and analyze the existing body of evidence surrounding the immunological impact of black seeds.In this review,we analyze the immunomodulatory potentials of black seeds(N.sativa).For the purpose of finding pertinent publications,the literatures was searched in web-based databases,including Web of Science,Medline/PMC/PubMed,Embase,EBSCO,Google Scholar,Science Direct,and reference lists.Several clinical,in vivo,and in vitro studies have demonstrated that supplementation with black seeds(N.sativa)has potential immunomodulatory activity.Black seeds(N.sativa)may influence immune responses through a variety of mechanisms.By synthesizing and critically assessing the current state of knowledge on the immunomodulatory effects of black seeds,this review aims to provide valuable insights into the potential therapeutic uses and future research directions for harnessing the immunological benefits of this natural remedy.展开更多
The remodeling of macrophages mediated by biomaterials is an important step in osseointegration.The biointerfacial characteristics shaped by implants and the bioenergetic state derived from macrophages are considered ...The remodeling of macrophages mediated by biomaterials is an important step in osseointegration.The biointerfacial characteristics shaped by implants and the bioenergetic state derived from macrophages are considered the key to macrophage reprogramming.In this study,the integrated Ti/Zn composites with optimized morphology and bioactive phase were prepared by friction stir processing,which could meet the multi-biofunctional requirements in the application of narrow-diameter implants.The severe plastic deformation and the hindrance of Zn particles to grain growth promote grain refinement,resulting in enhanced mechanical properties.The cell interfacial adhesion mediated by the grain boundary collaborated the energy metabolism reprogramming induced by the released Zn ion,promoting jointly anti-inflammatory cascade in macrophages and favorable osteogenesis in bone marrow mesenchymal stem cells(BMSCs).This study provides a new simultaneous approach of morphology and composition modification for titanium implants,and reveals the important role of grain size and bioactive element in the reversion of macrophage fate as well.展开更多
The treatment of prolonged inflammation and cartilage damage due to osteoarthritis(OA)is a major clinical challenge.We developed a comprehensive cartilage repair therapy using a dual drug-loaded nanocomposite hydrogel...The treatment of prolonged inflammation and cartilage damage due to osteoarthritis(OA)is a major clinical challenge.We developed a comprehensive cartilage repair therapy using a dual drug-loaded nanocomposite hydrogel that leveraged the spatiotemporal immunomodulatory effects of a naturally degradable protein-based nanocomposite hydrogel.The hydrogel acted as a scaffold that created a favorable microenvironment for cartilage regeneration.The hydrogel recruited macrophages and human mesenchymal stem cells(hMSCs),which supported the growth and adhesion of osteoblasts,and degraded to provide nutrition.Silk protein nanoparticles were chemically cross-linked with kartogenin,and humanlike collagen was physically cross-linked with dexamethasone through hydrogen bonding.In the early stages of cartilage repair,a large quantity of dexamethasone was released.The dexamethasone acted as an anti-inflammatory agent and a spatiotemporal modulator of the polarization of M1 macrophages into M2 macrophages.In the middle and late stages of cartilage repair,kartogenin underwent sustained release from the hydrogel,inducing the differentiation of hMSCs into chondrocytes and maintaining chondrocyte stability.Therefore,kartogenin and dexamethasone acted synergistically to induce cartilage repair.In conclusion,we developed an integrated therapeutic system by constructing a cartilage regeneration microenvironment and inducing synergistic drug-based cartilage regeneration.The therapeutic system demonstrated satisfactory efficacy for repairing cartilage damage in rabbits.展开更多
文摘IMMUNITY AND TUMOR Immune system has closely relation to the growth and development of tumor. One of its immune functions is to constantly recognize and kill malignant cells which develop from normal cells. The occurance of tumor indicates to some extent the failure of this "immune serveillance" function. Many studies have shown that the tumor cells of body have some tumor interrelative antigen that dose not exist in normal tissues. Tests in vitro
文摘The effect of the Chinese herbal compound (CHC) on solid sarcoma 180 (S180) in Swiss mice was studied either alone or in combination with 5-fluorouracil (5FU), cyclophosphamide (CYT) or mitomycin C (MMC). The preliminary results indicated that combination treatment seemed to possess better antitumor activity than chemotherapy alone. The treatment with CHC alone however had neither an obvious antitumor effect in tumor bearing mice nor toxicity in normal mice. These results show that CHC may stimulate organs of the immune system such as the spleen to be im-munomodulators and enhance the antitumor activity of some chemotherapeutic agents.
文摘In the study, the antitumor effect was observed by employing HAC-tumor-bearing mice treated with direct moxibustion on point Guanyuan(CV 4) (Group M), subcutaneous administration of liposome encapsulated immunomodulators called IMC(Group IMC), and combination of these two methods(Group M + IMC). Parameters reflecting biological characteristics of tumor cells, including 5 kinds of lectins, mitotic cycle, expression of C-erbB-2 oncogene and counts of AgNORs were further investigated. The results showed that treatment with combination of moxibustion and IMC could significantly lower three lectins (ConA, LCA, RCA) among these five lectins (BSL, ConA, LCA,RCA, WGA), significantly reduce the expression of C-erbB-2 oncogene, the counts of AgNORs ane the percentage of phase S in HAC tumor cells (compared with Group IMC). Moxibustion or IMC alone did render a certain degree of influence on the above-mentioned parameters, although most of changes were not statistically significant. The above-mentioned results indicated that the antitumor efficacy achieved by treatment with combination of moxibustion and IMC was mainly through its influence on biological characteristics of the tumor cells, namely, its reducing effect on DNA synthesis or on the proliferating rate of tumor cells and its influence on other biological characteristics of tumor
基金supported by the Yunnan Revitalization Talent Support ProgramPriority Union Foundation of Yunnan Provincial Science and Technology Department and Kunming Medical University(202401AY070001-245)The“535”High-level Talent Disciplinary Leader Project of the First Affiliated Hospital of Kunming Medical University(2023535D14).
文摘Autoimmune hepatitis (AIH) is a chronic, progressive inflammatory liver disease characterized by autoimmune-mediated hepatic injury. Currently, glucocorticoid drugs, primarily prednisone, with or without azathioprine, are commonly recommended as first-line therapeutic agents in treatment guidelines by many scientific associations. However, the primary objective of treatment is to achieve a complete biochemical response, which is defined as the normalization of both transaminases and immunoglobulin G levels within six to twelve months. Ideally, this should also be accompanied by histological remission. Nevertheless, corticosteroid therapy is associated with significant adverse effects, potentially resulting in treatment discontinuation. In this context, it has become evident that standard treatment is inadequate for a proportion of patients, leading to the emergence of other treatment options and lines. Novel immunomodulatory agents, a class of drugs that regulate the body’s immune functions, have been confirmed to possess properties that modulate immune balance and induce immune tolerance. In recent years, these agents have played an increasingly significant role in the clinical management of AIH. This article provided an in-depth review of recent advancements in the development of novel immunomodulators, including immune cell nucleic acid inhibitors, calmodulin phosphate inhibitors, mammalian target of rapamycin inhibitors, tumor necrosis factor-α inhibitors, interleukin-2, anti-CD20 monoclonal antibodies, and B cell-activating factor inhibitors, for the treatment of AIH.
基金support by the Open Access Publication Fund of the University of Freiburg enabled and organized by Projekt DEALsupported by the IMMediate Advanced Clinician Scientist-Program,Department of Medicine II,Medical Center,University of Freiburg and Faculty of Medicine,University of Freiburg,funded by the Bundesministerium für Bildung und Forschung(Federal Ministry of Education and Research),01EO2103supported by the Fritz Thyssen Foundation.Y.L.and J.F.were supported with scholarships by The First Affiliated Hospital of Wannan Medical College,Yijishan Hospital of Wannan Medical College of Wuhu,Wuhu,241000,Anhui,China.
文摘In their recent publication in Nature,Miller et al.studied recurrent transcriptional programs across various brain tumors.The authors identified four immunomodulatory expression programs in myeloid cells driven by factors within the tumor microenvironment(TME)including hypoxia,IL-1β,TGFβ,and dexamethasone treatment1.Notably,the authors link clinical use of dexamethasone with an immunosuppressive myeloid program,potentially highlighting dexamethason’s compounding effect on glioblastomaassociated immunosuppression.
基金This work was supported by the National Natural Science Foundation of China(No.82173668)Scientific Research Project of High-Level Talents(No.C1034335,China)in Southern Medical University of ChinaThousand Youth Talents Program(No.C1080094,China)from the Organization Department of the CPC Central Committee,China.
文摘Immunotherapy has led to a paradigm shift in the treatment of cancer.Current cancer immunotherapies are mostly antibody-based,thus possessing advantages in regard to pharmacodynamics(e.g.,specificity and efficacy).However,they have limitations in terms of pharmacokinetics including long half-lives,poor tissue/tumor penetration,and little/no oral bioavailability.In addition,therapeutic antibodies are immunogenic,thus may cause unwanted adverse effects.Therefore,researchers have shifted their efforts towards the development of small molecule-based cancer immunotherapy,as small molecules may overcome the above disadvantages associated with antibodies.Further,small molecule-based immunomodulators and therapeutic antibodies are complementary modalities for cancer treatment,and may be combined to elicit synergistic effects.Recent years have witnessed the rapid development of small molecule-based cancer immunotherapy.In this review,we describe the current progress in small molecule-based immunomodulators(inhibitors/agonists/degraders)for cancer therapy,including those targeting PD-1/PD-L1,chemokine receptors,stimulator of interferon genes(STING),Toll-like receptor(TLR),etc.The tumorigenesis mechanism of various targets and their respective modulators that have entered clinical trials are also summarized.
文摘Immunomodulators,particularly the thiopurines and to a lesser extent methotrexate,were standard of care for inflammatory bowel diseases,including Crohn’s disease and ulcerative colitis,for>40 years.While there has been a renaissance in available therapies with the advent of biologics and small molecules,an impetus remains for the ongoing use of thiopurines and methotrexate.This is particularly true for the maintenance of remission and when used in combination therapy with infliximab to suppress anti-biologic antibodies.This article summarizes the data behind immunomodulator use in Crohn’s disease,focusing on the beneficial role these drugs still have while acknowledging their clinical limitations.
基金the Ministry of Higher Education(MOHE),Malaysia,for funding this research through grant no.IF070-2020the Science and Technology Research Partnership for Sustainable Development(SATREPS)program,administered by the Japan Agency for Medical Research and Development(AMED)and the Japan International Cooperation Agency(JICA).
文摘Typhonium flagelliforme(TF)is a Southeast Asian medicinal plant traditionally used for cancer,respiratory disorders,gastrointestinal complaints,wound healing,inflammation,and general health.Contemporary studies validate these uses,showing potent anticancer,immunomodulatory,anti-inflammatory,gastroprotective,antibacterial,antioxidant,and wound-healing activities.Ethanol,dichloromethane,methanol,and ethyl acetate extracts exhibit strong cytotoxicity against breast(MCF-7,T47D),lung(NCI-H23),colon(WiDr),and leukemia(CEM-ss,WEHI-3)cells via apoptosis,telomerase inhibition,HER2/neu and BCL-2 suppression,and antiangiogenesis.Notably,2-octenoic acid and 2-hexenoic acid show exceptional activity(IC₅₀=2.66 and 3.10μg/mL)against MCF-7 cells.TF also restores lymphocyte proliferation,enhances macrophage activity,increases both CD4+and CD8+T-cell levels,and modulates cytokines(TNF-α,IL-1α,IL-10).Gastroprotective,anti-ulcer,antibacterial,antioxidant,and wound-healing effects further support traditional claims.Key phytochemicals include flavonoids(isovitexin,kaempferol,vitexin),phenolics(vanillin,4-hydroxybenzaldehyde),phytosterols(β-sitosterol,campesterol,stigmasterol,daucosterol),chlorophyll derivatives(pheophorbides),and long-chain fatty acids(linoleic,linolenic,oleic,stearic).These findings highlight TF as a source of multifunctional bioactive compounds,warranting further pharmacokinetic,safety,and clinical evaluation for evidence-based therapeutic development.
基金supported by the Leading Technology Foundation Research Project of Jiangsu Province (No. BK20232035)the Key Project of Basic Research Program of Jiangsu Province(No. BK20243061)+1 种基金the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University (No.SKLNMZZ202302)the Haihe Laboratory of Cell Ecosystem Innovation Fund (No. 22HHXBSS00005)。
文摘Mesenchymal stem cells(MSCs) are widely utilized in disease treatment and regenerative medicine due to their potent immunomodulatory properties and capacity for tissue repair.However, limitations—including insufficient migratory capacity, suboptimal survival, proliferation, differentiation potential, and variable immunomodulatory responses—significantly hinder their clinical translation and therapeutic impact. Natural products have been shown to enhance MSC homing, stress resilience, immune regulation, and lineage-specific differentiation through multi-target mechanisms, thereby emerging as promising, safe, and practical strategies to improve the in vivo performance of MSC-based therapies. This review examines the key translational challenges associated with MSCs, elucidates the mechanistic basis by which natural products regulate the in vivo fate of MSCs, and explores the potential of integrating natural product adjuvants with MSC therapy for enhanced clinical outcomes.
基金the National Natural Science Foundation of China(82573571)the Shanghai 2025 Basic Research Plan Natural Science Foundation(25ZR1401393)the First Batch of Open Topics of the Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices(2025QN13)。
文摘The global burden of bacterial infections,exacerbated by antimicrobial resistance(AMR),necessitates innovative strategies.Bacterial protein vaccines offer promise by eliciting targeted immunity while circumventing AMR.However,their clinical translation is hindered by their inherently low immunogenicity,often requiring potent adjuvants and advanced delivery systems.Biomembrane nanostructures(e.g.,liposomes,exosomes,and cell membrane-derived nanostructures),characterized by superior biocompatibility,intrinsic targeting ability,and immune-modulating properties,could serve as versatile platforms that potentiate vaccine efficacy by increasing antigen stability,enabling codelivery of immunostimulants,and facilitating targeted delivery to lymphoid tissues/antigen-presenting cells.This intrinsic immunomodulation promotes robust humoral and cellular immune responses to combat bacteria.This review critically reviews(1)key biomembrane nanostructure classes for bacterial protein antigens,(2)design strategies leveraging biomembrane nanostructures to enhance humoral and cellular immune responses,(3)preclinical efficacy against diverse pathogens,and(4)translational challenges and prospects.Biomembrane nanostructure-driven approaches represent a paradigm shift in the development of next-generation bacterial protein vaccines against resistant infections.
文摘Objective::To provide new insight into how chronic rhinosinusitis (CRS) is conceptualized and treated with a focus on immunomodulator therapy.Data sources::Pubmed, Medline, and Embase.Methods::A current review of the evidence is provided for immunomodulators investigated for treatment of CRS with nasal polyps (CRSwNP).Results::Biologic therapies targeting IgE, IL-4, IL-5, and IL-13 for the treatment of CRSwNP have shown promise and are currently in phase 3 trials. Anti-immunoglobin E (IgE) therapy with omalizumab was assessed in 6 studies, anti-interleukin (IL)-5 therapy in 3 studies (2 mepolizumab, 1 reslizumab) and anti IL-4/IL-13 (dupilumab) therapy in one study. Studied outcomes varied, but the majority of trials identified clinical benefit of therapy over placebo. Other potential targets include thymic stromal lymphopoetin (TSLP), IL-25, IL-33, and sialic acidbinding immunoglobulin-type lectin (Siglec)-8. Small molecule drugs that target the dysregulation of the immune system in CRS are also being investigated for their immunomodulatory effects on inflammation.Conclusion::Immunomodulator therapies for CRS currently in development will likely provide another therapeutic option for patients who have severe disease unresponsive to corticosteroids and surgery. Targeted monoclonal antibody therapies have shown encouraging results and phase 3 trials are underway. IL-4/IL-13 inhibition has shown the most promise to date. Further larger, well-designed trials are needed to improve understanding of these molecules and to offer endotype-driven therapies in the management of CRS. None of these therapeutics have shown long-term immunomodulation when discontinued and therefore further investigation into the pathomechanism of disease continues to be needed.
文摘Chronic hepatitis B virus(HBV)infection affects approximately 254 million individuals globally,contributing to significant morbidity and mortality due to HBV-related liver failure and cirrhosis,which result in millions of fatalities each year.Although approved antiviral nucleos(t)ide analogues can effectively suppress HBV replication,their ability to reduce hepatitis B surface antigen(HBsAg)levels in plasma remains limited.The clinical application of the immunomodulator interferon-alpha is restricted by concerns regarding its safety and the severity of associated adverse reactions,rendering long-term administration challenging.Therefore,current drug development efforts for chronic hepatitis B aim to achieve a functional cure,which is defined as HBsAg serological clearance and sustained suppression of HBV DNA.This review discusses recent advancements in novel direct-acting therapeutic strategies for the treatment of chronic hepatitis B by focusing on the progresses in HBV entry inhibitors,monoclonal antibodies,RNA interferences,and other agents that directly target the virus.Furthermore,we discuss the development of immunomodulatory therapies,including TLR-7/8 agonists,immune checkpoint inhibitors,and therapeutic vaccines.In the end,we conclude by highlighting the importance of the rational combination-strategy design to improve the functional cure rate of HBV.
基金National Natural Science Foundation of China,No.81873934and Jinan Science and Technology Planning Project,No.202225065.
文摘BACKGROUND Mesenchymal stem cells,found in various tissues,possess significant healing and immunomodulatory properties,influencing macrophage polarization,which is essential for wound repair.However,chronic wounds present significant therapeutic challenges,requiring novel strategies to improve healing outcomes.AIM To investigate the potential of fetal dermal mesenchymal stem cells(FDMSCs)in enhancing wound healing through modulation of macrophage polarization,specifically by promoting the M2 phenotype to address inflammatory responses in chronic wounds.METHODS FDMSCs were isolated from BalB/C mice and co-cultured with RAW264.7 macrophages to assess their effects on macrophage polarization.Flow cytometry,quantitative reverse transcriptase polymerase chain reaction,and histological analyses were employed to evaluate shifts in macrophage phenotype and wound healing in a mouse model.Statistical analysis was performed using GraphPad Prism.RESULTS FDMSCs induced macrophage polarization from the M1 to M2 phenotype,as demonstrated by a reduction in proinflammatory markers(inducible nitric oxide synthase,interleukin-6)and an increase in anti-inflammatory markers[mannose receptor(CD206),arginase-1]in co-cultured RAW264.7 macrophages.These shifts were confirmed by flow cytometry.In an acute skin wound model,FDMSC-treated mice exhibited faster wound healing,enhanced collagen deposition,and improved vascular regeneration compared to controls.Significantly higher expression of arginase-1 further indicated an enriched M2 macrophage environment.CONCLUSION FDMSCs effectively modulate macrophage polarization from M1 to M2,reduce inflammation,and enhance tissue repair,demonstrating their potential as an immunomodulatory strategy in wound healing.These findings highlight the promising therapeutic application of FDMSCs in managing chronic wounds.
基金support by AgriFutures Australia’s Chicken Meat Program[grant number PRJ-011584]is gratefully acknowledged.
文摘Background Broiler chickens are most vulnerable immediately after hatching due to their immature immune systems,making them susceptible to infectious diseases.The yolk plays an important role in early immune defence by showing relevant antioxidant and passive immunity capabilities during broiler embryonic development.The immunomodulatory effects of phytogenic compound carvacrol have been widely reported.After in ovo delivery in the amniotic fluid during embryonic development carvacrol is known to migrate to the yolk sac.However,it is unknown whether carvacrol in the yolk could enhance defence responsiveness in the yolk sac.Therefore,the aim of this study was to improve early immune function in chicken embryos,and it was hypothesized that in ovo delivery of carvacrol would result in immunomodulatory effects in the yolk sac,potentially improving post-hatch resilience.Methods On embryonic day(E)17.5,either a saline(control)or carvacrol solution was injected into the amniotic fluid.Yolk sac tissue samples were collected at E19.5,and transcriptomic analyses using RNA sequencing were performed,following functional enrichment analyses comparing the control(saline)and carvacrol-injected groups.Results The results showed that 268 genes were upregulated and 174 downregulated in the carvacrol group compared to the control(P<0.05;logFC<-0.5 or log FC>0.5).Functional analyses of these differentially expressed genes,using KEGG,REACTOME,and Gene Ontology databases,showed enrichment of several immune-related pathways.This included the pathways‘Antimicrobial peptides’(P=0.001)and‘Chemoattractant activity’(P=0.004),amongst others.Moreover,the‘NOD-like receptor signaling’pathway was enriched(P=0.002).Antimicrobial peptides are part of the innate immune defence and are amongst the molecules produced after the nucleotide oligomeriza-tion domain(NOD)-like receptor pathway activation.While these responses may be associated with an inflammatory reaction to an exogenous threat,they could also indicate that in ovo delivery of carvacrol could prepare the newly hatched chick against bacterial pathogens by potentially promoting antimicrobial peptide production through acti-vation of NOD-like receptor signaling in the yolk sac.Conclusion In conclusion,these findings suggest that in ovo delivery of carvacrol has the potential to enhance anti-pathogenic and pro-inflammatory responses in the yolk sac via upregulation of antimicrobial peptides,and NOD-like receptor pathways.
基金supported by the National Natural Science Foundation of China(Nos.82173747,82373803)the Special Fund Project for Science and Technology Innovation Strategy of Guangdong Province(No.2021TQ060944)。
文摘Cancer vaccines are a notable area of immunotherapy due to their capacity to elicit specific antitumor immune responses and to create immune memory.However,they encounter challenges in clinical practice due to several bottlenecks,including tumor heterogeneity,low immunogenicity,immunosuppressive tumor environment,and delivery obstacles,which collectively impact their clinical effectiveness.In this study,we developed nanocomposites containing positively charged melittin(MEL)and negatively charged photosensitizer indocyanine green(ICG),embedded in dissolving microneedles(MEL/ICG-HA@DMNs).This approach allows precise drug delivery by creating microchannels that bypass the stratum corneum barrier,targeting superficial lesions directly.Our results demonstrated that the complexation of MEL and ICG significantly reduced the hemolytic activity of MEL while maintaining its ability to disrupt cell membranes.After loading MEL/ICG-HA into the microneedle,MEL/ICG-HA@DMNs not only effectively concentrated the drug at the tumor site,inducing localized hyperthermia and successfully ablating the tumor,but also formed an in situ whole-cell vaccine containing a rich source of tumor-associated antigens.Moreover,the system promoted dendritic cell maturation and increased the M1/M2 macrophage ratio,enhancing the immune response.By overcoming the limitations of traditional cancer vaccines,this system ensures precise drug delivery and robust immune activation.This innovative approach holds the potential to revolutionize cancer treatment,offering a new paradigm in precision oncology.
基金supported by the Kunlun Mountain Scholar Project of Qinghai Province,China(Project No.:2021-13).
文摘Diabetes,a metabolic disease stemming from impaired or defective insulin secretion,ranks among the most severe chronic illnesses globally.While several approved drugs exist for its treatment,they often come with multiple side effects.Therefore,there is a pressing need for safe and effective anti-diabetic medications.Traditional Chinese medicine has recognized Lycium barbarum(LB;goji berry)plant,commonly known as“wolfberry fruit”in China,for over 2,000 years.Natural compounds derived from LB show promise in reducing diabetes levels.Although research on the impact of LB on diabetes is still limited,our review aims to explore the potential of LB in reducing the risk of diabetes and examine the underlying mechanisms involved.LB can modulate diabetes through various pathways,such as inhibitingα-amylase andα-glucosidase activities,promotingβ-cell proliferation,stimulating insulin secretion,inhibiting glucagon secretion,improving insulin resistance and glucose tolerance,and enhancing antioxidant and anti-inflammatory activities.Additionally,LB improves gut flora and immunomodulation,further aiding diabetes management.These findings highlight the potential clinical utility of LB in managing diabetes and its complications within the framework of evidence-based modern medicine.
基金supported by the National Science Foundation of China(82202714).
文摘Severe tissue defects present formidable challenges to human health,persisting as major contributors to mortality rates.The complex pathological microenvironment,particularly the disrupted immune landscape within these defects,poses substantial hurdles to existing tissue regeneration strategies.However,the emergence of nanobiotechnology has opened a new direction in immunomodulatory nanomedicine,providing encouraging prospects for tissue regeneration and restoration.This review aims to gather recent advances in immunomodulatory nanomedicine to foster tissue regeneration.We begin by elucidating the distinctive features of the local immune microenvironment within defective tissues and its crucial role in tissue regeneration.Subsequently,we explore the design and functional properties of immunomodulatory nanosystems.Finally,we address the challenges and prospects of clinical translation in nanomedicine development,aiming to propose a potent approach to enhance tissue regeneration through synergistic immune modulation and nanomedicine integration.
文摘Humans and other vertebrates are safeguarded from invading pathogenic microbes by the immune system.Black seed,scientifically known as Nigella sativa,has garnered attention for its potential immunomodulatory effects in both clinical and preclinical studies.This comprehensive review aims to consolidate and analyze the existing body of evidence surrounding the immunological impact of black seeds.In this review,we analyze the immunomodulatory potentials of black seeds(N.sativa).For the purpose of finding pertinent publications,the literatures was searched in web-based databases,including Web of Science,Medline/PMC/PubMed,Embase,EBSCO,Google Scholar,Science Direct,and reference lists.Several clinical,in vivo,and in vitro studies have demonstrated that supplementation with black seeds(N.sativa)has potential immunomodulatory activity.Black seeds(N.sativa)may influence immune responses through a variety of mechanisms.By synthesizing and critically assessing the current state of knowledge on the immunomodulatory effects of black seeds,this review aims to provide valuable insights into the potential therapeutic uses and future research directions for harnessing the immunological benefits of this natural remedy.
基金the National Natural Science Foundation of China(Nos.31971246&52274387)the Fundamental Research Funds for the Central Universities(No.YG2023QNA21)the Shanghai Science and Technology Commission(No.20S31900100)for their financial and project support.
文摘The remodeling of macrophages mediated by biomaterials is an important step in osseointegration.The biointerfacial characteristics shaped by implants and the bioenergetic state derived from macrophages are considered the key to macrophage reprogramming.In this study,the integrated Ti/Zn composites with optimized morphology and bioactive phase were prepared by friction stir processing,which could meet the multi-biofunctional requirements in the application of narrow-diameter implants.The severe plastic deformation and the hindrance of Zn particles to grain growth promote grain refinement,resulting in enhanced mechanical properties.The cell interfacial adhesion mediated by the grain boundary collaborated the energy metabolism reprogramming induced by the released Zn ion,promoting jointly anti-inflammatory cascade in macrophages and favorable osteogenesis in bone marrow mesenchymal stem cells(BMSCs).This study provides a new simultaneous approach of morphology and composition modification for titanium implants,and reveals the important role of grain size and bioactive element in the reversion of macrophage fate as well.
基金supported by the National Key Research and Development Program of China(2019YFA0905200).
文摘The treatment of prolonged inflammation and cartilage damage due to osteoarthritis(OA)is a major clinical challenge.We developed a comprehensive cartilage repair therapy using a dual drug-loaded nanocomposite hydrogel that leveraged the spatiotemporal immunomodulatory effects of a naturally degradable protein-based nanocomposite hydrogel.The hydrogel acted as a scaffold that created a favorable microenvironment for cartilage regeneration.The hydrogel recruited macrophages and human mesenchymal stem cells(hMSCs),which supported the growth and adhesion of osteoblasts,and degraded to provide nutrition.Silk protein nanoparticles were chemically cross-linked with kartogenin,and humanlike collagen was physically cross-linked with dexamethasone through hydrogen bonding.In the early stages of cartilage repair,a large quantity of dexamethasone was released.The dexamethasone acted as an anti-inflammatory agent and a spatiotemporal modulator of the polarization of M1 macrophages into M2 macrophages.In the middle and late stages of cartilage repair,kartogenin underwent sustained release from the hydrogel,inducing the differentiation of hMSCs into chondrocytes and maintaining chondrocyte stability.Therefore,kartogenin and dexamethasone acted synergistically to induce cartilage repair.In conclusion,we developed an integrated therapeutic system by constructing a cartilage regeneration microenvironment and inducing synergistic drug-based cartilage regeneration.The therapeutic system demonstrated satisfactory efficacy for repairing cartilage damage in rabbits.
