The healing of diabetic wounds poses a significant healthcare burden due to persistent inflammation,M1 macrophage aggregation,and high glucose levels in the microenvironment.Previous studies have demonstrated that imm...The healing of diabetic wounds poses a significant healthcare burden due to persistent inflammation,M1 macrophage aggregation,and high glucose levels in the microenvironment.Previous studies have demonstrated that immunomodulatory hydrogel dressings can facilitate diabetic wound healing.However,current immunomodulatory hydrogels require costly and complex treatments such as cell therapy and cytokines.Herein,a hierarchical hydrogel dressing with continuous biochemical gradient based on glycyrrhizic acid(GA) was constructed to modulate immunomodulatory processes in diabetic wounds.The hydrogels present many desirable features,such as tunable mechanical properties,broad antibacterial ability,outstanding conductive,transparent,and self-adhesive properties.The resultant hydrogel can promote diabetic wound healing by preventing bacterial infection,promoting macrophage polarization,improving the inflammatory microenvironment,and inducing angiogenesis and neurogenesis.Furthermore,electrical stimulation(ES) can further promote the healing of chronic diabetic wounds,providing valuable guidance for relevant clinical practice.展开更多
Intervertebral disc herniation(IVDH)is a common manifestation of intervertebral disc degeneration(IVDD)characterized by inflammation that results in the rupture of the annulus fibrosus(AF)and her-niation of the nucleu...Intervertebral disc herniation(IVDH)is a common manifestation of intervertebral disc degeneration(IVDD)characterized by inflammation that results in the rupture of the annulus fibrosus(AF)and her-niation of the nucleus pulposus(NP).While current clinical research primarily focuses on regulating the degenerative NP,the crucial role of the AF in maintaining the mechanical stability and metabolic balance of the intervertebral disc(IVD)has been overlooked.Resolving immunoregulation and AF repair is im-perative to effectively prevent recurrent herniation.Therefore,this study introduces a bioactive sealant(OD/GM/QCS-sEVs),which combines gelatin methacryloyl(GM)and oxidized dextran(OD)with quater-nized chitosan(QCS)and incorporates small extracellular vesicles(sEVs).The developed sealant possesses injectability,self-healing capabilities,tissue adhesiveness,and mechanical stability,with an average ad-hesive strength of 109.63 kPa.In vitro experiments demonstrate that OD/GM/QCS-sEVs effectively seal AF defects while preserving mechanical properties comparable to those of a normal IVD.Additionally,the sealant releases sEVs through a pH-responsive mechanism,thereby modulating macrophage polarization to the M2 phenotype via the NF-κB signaling pathway.This mechanism facilitates immunoregulation and anti-inflammatory effects,and promotes stem cell differentiation into fibrocartilage.Animal experiments confirm the ability of OD/GM/QCS-sEVs to seal defects,prevent proteoglycan loss,inhibit IVDD develop-ment,and promote AF regeneration.Overall,OD/GM/QCS-sEVs hold promise as an innovative bioactive sealant for recurrent herniation by resolving immunoregulation and AF regeneration.展开更多
Summary： Although mesenchymal stem cells （MSCs） are increasingly used to treat graft-versus-host disease （GVHD）, their immune regulatory mechanism in the process is elusive. The present study aimed to investigate...Summary： Although mesenchymal stem cells （MSCs） are increasingly used to treat graft-versus-host disease （GVHD）, their immune regulatory mechanism in the process is elusive. The present study aimed to investigate the curative effect of third-party umbilical cord blood-derived human MSCs （UCB-hMSCs） on GVHD patients after allogeneic hematopoietic stem cell transplantation （allo-HSCT） and their immune regulatory mechanism. Twenty-four refractory GVHD patients after allo-HSCT were treated with UCB-hMSCs. Immune cells including T lymphocyte subsets, NK ceils, Treg cells and dendritic cells （DCs） and cytokines including interleukin-17 （IL-17） and tumor necrosis factor-alpha （TNF-α） were monitored before and after MSCs transfusion. The results showed that the symptoms of GVHD were alleviated significantly without increased relapse of primary disease and transplant-related complications after MSCs transfusion. The number of CD3^＋, CD3＋CD4^＋ and CD3＋CD8^＋ cells decreased significantly, and that of NK cells remained unchanged, whereas the number of CD4^＋ and CD8^＋ Tregs increased and reached a peak at 4 weeks; the number of mature DCs, and the levels of TNF-α and IL-17 decreased and reached a trough at 2 weeks. It was concluded that MSCs ameliorate GVHD and spare GVL effect via immunoregulations.展开更多
The most recent outbreak of 2019 novel coronavirus,named as COVID-19,caused pneumonia epidemic in Wuhan with 2121 deaths cases as of February 20th 2020.Identification of effective antiviral agents to combat the novel ...The most recent outbreak of 2019 novel coronavirus,named as COVID-19,caused pneumonia epidemic in Wuhan with 2121 deaths cases as of February 20th 2020.Identification of effective antiviral agents to combat the novel coronavirus is urgently needed.Citrus fruit peel or wild citrus are rich in flavonoids,and clinically documented for roles in relief of cough and promotion of digestive health.Therefore,citrus fruits are assumed to possess antivirus activities or enhance the host immunity.A previous study found that hesperetin could act as a high potent inhibitor of SARS-CoV 3CLpro.We determined six flavonoid compounds’content in three citrus species by using LC-MS technique.The content of naringin and naringenin was at higher levels in pummelo.Hesperetin and hesperidin were highly accumulated in mandarin and sweet orange.The subsequent in vitro and in vivo experiments indicated that naringin could inhibit the expression of the proinflammatory cytokines(COX-2,iNOS,IL-1βand IL-6)induced by LPS in Raw macrophage cell line,and may restrain cytokine through inhibiting HMGB1 expression in a mouse model.The results revealed that naringin may have a potential application for preventing cytokine storm.We simulated molecular docking to predict the binding affinity of those flavonoids to bind Angiotensin-converting enzyme 2(ACE 2),which is a receptor of the coronavirus.Consideration of the potential anti-coronavirus and anti-inflammatory activity of flavonoids,the citrus fruit or its derived phytochemicals are promising in the use of prevention and treatment of SARS-CoV-2 infection.展开更多
The spleenic and thymus T lymphocyte proliferaitivc reactions (TLPR) were enhanced, the intcrlcukin 2(IL-2) inductive activity was raised, and the IL-2 receptor (IL-2R) inductive expression was increased significantly...The spleenic and thymus T lymphocyte proliferaitivc reactions (TLPR) were enhanced, the intcrlcukin 2(IL-2) inductive activity was raised, and the IL-2 receptor (IL-2R) inductive expression was increased significantly in chickens after inoculation with trivalcnt Marck’s disease vaccine in comparison with control chickens and those after vaccination with herpcsvirus of turkey (HVT) vaccine. In chickens after inoculation with HVT vaccine, in contrast with control chickens, the splcenic TLPR was strengthened and IL-2R inductive expression was hoisted significantly, the thymus TLPR, splccnic and thymus T lymphocyte IL-2 inductive activity, the thymus T lymphocyte IL-2R inductive expression were not significantly increased.展开更多
Anti-murine IL-1α, IL-6 antibodies were intra-peritoneally injected to the lupus-like NZB/W F1 mice of 4 months with the dosage of 10μg per day for three days and then per month for three months. The mice were kille...Anti-murine IL-1α, IL-6 antibodies were intra-peritoneally injected to the lupus-like NZB/W F1 mice of 4 months with the dosage of 10μg per day for three days and then per month for three months. The mice were killed at the age of 11 months. The results showed that the treatment of the dosage could not absolutely prevent lupus nephritis; it could alleviate proteinuria, obviously reduce the levels of serum IL-lα and inhibit the secretion of IL-1α by celiac macrophage.As to the level of IL-6 and TNF-α no significant change was observed.展开更多
[Objectives]The paper was to observe the effects of red ginseng aqueous extract on immune function of mice.[Methods]The aqueous extract of red ginseng was obtained by water extraction and concentration,and 10 mL of aq...[Objectives]The paper was to observe the effects of red ginseng aqueous extract on immune function of mice.[Methods]The aqueous extract of red ginseng was obtained by water extraction and concentration,and 10 mL of aqueous extract was equivalent to 2.86 g of raw materials.Total 240 mice were randomly divided into blank control group,low dose,medium dose and high dose groups of red ginseng aqueous extract,60 mice each group.Mice in low dose,medium dose and high dose groups were intragastrically administered with 0.24,0.48,1.43 g/kg red ginseng aqueous extract once a day respectively,and those in blank control group were intragastrically administered with equal volume of deionized water at the dose of 0.1 mL/10 g once a day for consecutive 30 d.The immunoregulation effects of red ginseng aqueous extract on mice were explored by organ/body weight ratio measurement,delayed type hypersensitivity(DTH)reaction,Con A-induced spleen T lymphocyte transformation test,antibody-producing cells test,half hemolytic value(HC 50)test,carbon particle clearance test,phagocytosis test of chicken red blood cells by macrophages and NK cell activity test.[Results]Compared with the blank control group,the degree of toe swelling in low dose group and medium dose group of red ginseng aqueous extract[(0.62±0.14)mm,(0.53±0.12)mm vs.(0.36±0.10)mm]significantly increased(P<0.05).The ability of T lymphocytes proliferation(0.173±0.054,0.189±0.063 vs.0.098±0.012)in low dose group and high dose group significantly increased(P<0.05).The number of haemolytic plaque(137.49×10^(3)±24.73×10^(3),148.43×10^(3)±27.53×10^(3) vs.112.96×10^(3)±26.28×10^(3))in medium dose group and high dose group significantly increased(P<0.05).The phagocytosis rate(35.67%±3.82%,49.26%±6.54%,57.92%±7.36%vs.24.34%±4.22%)and phagocytosis index(0.72±0.23,0.82±0.15,0.91±0.26 vs.0.35±0.11)of low dose,medium dose,high dose groups significantly increased(P<0.05).However,there was no statistical difference in spleen/body weight ratio,thymus/body weight ratio,half hemolytic value,carbon particle clearance and NK cell activity.[Conclusions]Red ginseng aqueous extract could enhance the immunity of mice.展开更多
Objective: To evaluate the immunoregulation of KangAi (KA) injection combined with chemo-treatment (chemo) for Non-small cell lung cancer (NSCLC). Methods: We systematically searched the literature of PubMed, EMBASE, ...Objective: To evaluate the immunoregulation of KangAi (KA) injection combined with chemo-treatment (chemo) for Non-small cell lung cancer (NSCLC). Methods: We systematically searched the literature of PubMed, EMBASE, CENTRAL, MEDLINE, CNKI, Wanfang, and VIP databases for all Randomized controlled trials (published from the earliest possible year to January 2019, no language restrictions) comparing KA injection combined with chemo and chemo alone in patients with NSCLC. Our main endpoints were immune function, clinical efficiency, KPS score and adverse events. The Cochrane Risk of Bias tool was applied for quality assessment. Results: 11 studies involving 1060 participants were included. The immune function (MD=3.18, 95% CI: 0.98-4.00, P<0.00001), clinical response rate (RR=1.28, 95%CI: 1.17-1.40, P<0.00001), KPS score (RR=1.86, 95%CI: 1.35-2.57, P=0.0002), and adverse events (RR=0.57, 95%CI: 0.50-0.65, P<0.00001) in the group of KA injection plus Chemo were vastly different from those in Chemo alone. Conclusion: KA injection combined with Chemo in the treatment of NSCLC improved the immune function, clinical efficiency and safety compared to Chemo alone. However, because many of the methodologies included in randomized controlled trials are of poor quality, more rigorous design and large randomized controlled trials are needed to test this benefit.展开更多
Background： We summarized the Polyporusus Bellatus （PPS） efficacy of immunomodulation, liver protection and anti-tumor, then provide scientific basis for further research and clinical application. This diss...Background： We summarized the Polyporusus Bellatus （PPS） efficacy of immunomodulation, liver protection and anti-tumor, then provide scientific basis for further research and clinical application. This dissertation first overview relevant literatures of PPS recent years and describe comprehensively the research progress of the immunoregulation, liver protection and anti-tumor effects and mechanism of PPS. The review shows that the PPS play anti-tumor effects through antioxidation, scavenging free radicals, inhibiting tumor cell proliferation, inducing apoptosis, affecting tumor gene expressions and enhancing immune functions. PPS can exert immunoregulatory, hepatoprotective and anti-tumor effects through multiple pathways and multiple targets, which provides a good application prospect in clinic.展开更多
Chronic osteomyelitis caused by implant infections is a common complication following orthopedic surgery.Preventing bacterial infection and simultaneously improving bone regeneration are the key for osteomyelitis.Curr...Chronic osteomyelitis caused by implant infections is a common complication following orthopedic surgery.Preventing bacterial infection and simultaneously improving bone regeneration are the key for osteomyelitis.Current treatments include systemic antibiotics and multiple surgical interventions,but the strategies available for treatment are limited.In this study,a multifunctional engineered Bacillus subtilis(B.sub)hydrogel with sulfasalazine(SSZ)is developed to treat methicillin-resistant Staphylococcus aureus(MRSA)infection and antiinflammatory and promote bone regeneration.B.sub in alginate hydrogels protects B.sub from being cleared by the host immune system while allowing the release of its bioactive substances,including antibacterial peptides and anti-inflammatory agents such as SSZ.The results show that the engineered probiotic hydrogels exhibit excellent antibacterial efficacy against MRSA(97%)and prevent the development of bacterial resistance.The antibacterial effect is primarily mediated through the secretion of bioactive peptides by B.sub,which not only inhibit MRSA growth but also reduce the likelihood of resistance development.Meanwhile,the probiotic hydrogel has a greater ability to induce M2 polarization of macrophages and promote angiogenesis,resulting in enhanced osteogenic differentiation in bone marrow mesenchymal stem cells(BMSCs)and thus enhancing bone regeneration.This engineered probiotic hydrogel offers a promising strategy by simultaneously combating bacterial infection and enhancing osteogenic differentiation for chronic osteomyelitis.展开更多
L.Zhang et al.proposed novel immunotherapeutic strategies to limit the progression of inflammatory bowel diseases by targeting the interplay between the membrane-bound CD39 molecule and cellular metabolism—specifical...L.Zhang et al.proposed novel immunotherapeutic strategies to limit the progression of inflammatory bowel diseases by targeting the interplay between the membrane-bound CD39 molecule and cellular metabolism—specifically,by increasing regulatory T-cell function through the modulation of glucose metabolism and suppressing pathogenic proinflammatory Th17 responses via the modulation of oxidative metabolism.展开更多
As a“cold tumor”,triple-negative breast cancer(TNBC)exhibits limited responsiveness to current immunotherapy.How to enhance the immunogenicity and reverse the immunosuppressive microenvironment of TNBC remain a form...As a“cold tumor”,triple-negative breast cancer(TNBC)exhibits limited responsiveness to current immunotherapy.How to enhance the immunogenicity and reverse the immunosuppressive microenvironment of TNBC remain a formidable challenge.Herein,an“in situ nanovaccine”Au/CuNDs-R848 was designed for imagingguided photothermal therapy(PTT)/chemodynamic therapy(CDT)synergistic therapy to trigger dual immunoregulatory effects on TNBC.On the one hand,Au/CuNDs-R848 served as a promising photothermal agent and nanozyme,achieving PTT and photothermal-enhanced CDT against the primary tumor of TNBC.Meanwhile,the released antigens and damage-associated molecular patterns(DAMPs)promoted the maturation of dendritic cells(DCs)and facilitated the infiltration of T lymphocytes.Thus,Au/CuNDs-R848 played a role as an“in situ nanovaccine”to enhance the immunogenicity of TNBC by inducing immunogenic cell death(ICD).On the other hand,the nanovaccine suppressed the myeloid-derived suppressor cells(MDSCs),thereby reversing the immunosuppressive microenvironment.Through the dual immunoregulation,“cold tumor”was transformed into a“hot tumor”,not only implementing a“turning foes to friends”therapeutic strategy but also enhancing immunotherapy against metastatic TNBC.Furthermore,Au/CuNDs-R848 acted as an excellent nanoprobe,enabling high-resolution near-infrared fluorescence and computed tomography imaging for precise visualization of TNBC.This feature offers potential applications in clinical cancer detection and surgical guidance.Collectively,this work provides an effective strategy for enhancing immune response and offers novel insights into the potential clinical applications for tumor immunotherapy.展开更多
Diabetes mellitus(DM)is a serious health problem in the world,and infections are common complications in diabetic patients,particularly methicillin-resistant Staphylococcus aureus(MRSA)infections,which substantially i...Diabetes mellitus(DM)is a serious health problem in the world,and infections are common complications in diabetic patients,particularly methicillin-resistant Staphylococcus aureus(MRSA)infections,which substantially increases mortality in patients.In clinical practice,the treatment of diabetic complicationrelated infections involves multiple issues such as drug resistance when combining antidiabetic drugs with antibiotics.In this study,a series of derivatives were synthesized with alkyl radicals with different chain lengths substituted at the C8 and C12 positions of berberine,with compounds CY1 and CY3with good antidiabetic and antibacterial activities screened out after identification.Then,oral liposomes(CY1-Lip and CY3-Lip)were prepared,and their particle sizes,stability,and pharmacokinetics were investigated.In acquired mouse models of diabetes,induced with an acute MRSA lung infection,we demonstrate that CY1-Lip and CY3-Lip can effectively reduce levels of fasting blood glucose(FBG),fasting insulin(FINS),and insulin resistance index among diabetic mice with pneumonia,thus exerting their multitargets effects.Furthermore,both preparations significantly reduced lung MRSA loads and improved lung tissue lesions,reduced high infiltration of M1 macrophages in lung,and suppressed the expression levels of pro-infiammatory factors such as necrosis factor-α(TNF-α)and interleukin-6(IL-6).This provides new insights into the clinical treatment of diabetes complicated with pulmonary infections.展开更多
Lupus nephritis(LN)is one of the most common and serious complications of systemic lupus erythematosus,which can lead to end-stage renal disease,and is an important cause of death in patients with systemic lupus eryth...Lupus nephritis(LN)is one of the most common and serious complications of systemic lupus erythematosus,which can lead to end-stage renal disease,and is an important cause of death in patients with systemic lupus erythematosus.Treatment options include glucocorticoids,immunosuppressive agents and the addition of biologics.Recently,the therapeutic role of mesenchymal stem cells(MSCs)in LN has received extensive attention worldwide.MSCs can suppress autoimmunity,alleviate proteinuria and restore renal function by modulating the functions of various immune cells and reducing the secretion of inflammatory cytokines.Several clinical trials have investigated MSC treatment in LN with promising but sometimes inconsistent outcomes.This review summarizes the sources of MSCs and mechanisms in immunoregulation.Furthermore,it examines clinical trials evaluating the efficacy,safety,and limitations of MSC therapy in LN.By highlighting advances and ongoing challenges,this review underscores the potential of MSCs for LN treatment.More large-scale randomized controlled trials are needed to support the effectiveness of this therapy and pave the way for personalized and combinatorial therapeutic approaches.展开更多
Dendritic cells （DCs） are known to be the most powerful professional antigen-presenting cells so far. It could activate primary immune response, and also downregulate immune response. DCs have a unique character of ...Dendritic cells （DCs） are known to be the most powerful professional antigen-presenting cells so far. It could activate primary immune response, and also downregulate immune response. DCs have a unique character of immunoregulation. DC-SIGN, a molecule designated as CD209, is one member of the C-type lectin superfamily. It is not only a pattern recognition receptor but implicated in immunoregulation of DCs. DC-SIGN has become hotspot of recent studies because of its important role in mediating DC adhesion, migration, inflammation, activating primary T cell, triggering immune response and participating in immune escape of pathogens and tumors. These studies on DC-SIGN involved in primary and secondary immune response and relevant mechanism will certainly provide us with a new method in treating and preventing certain diseases.展开更多
Despite great efforts and achievement of nanomaterials in immune-associated diseases,the selection of appropriate nanomaterials and preparation technology remain some challenges and vast room for improvement.Immunothe...Despite great efforts and achievement of nanomaterials in immune-associated diseases,the selection of appropriate nanomaterials and preparation technology remain some challenges and vast room for improvement.Immunotherapy has received tremendous attention throughout the medical process due to its clinical successes with the pathways of immunoactivation or immunosuppression.Recently,fibrous nanomaterials have facilitated advances in tissue repair and cancer treatments owing to the superiority of multi-channel structure,biocompatibility,tunable size and controlled surface modification.The immunoactivation-based nanofibers can potentially deliver functional agents to lesions and further actively promote immunologic intervention.On the contrary,the immunosuppression-based nanofibers prevent the immune system from overreacting through the blockage of critical pathways in vivo.This review summarizes the current application of nanofiber materials in diverse diseases,including cancer therapy,tissue regeneration(cartilage/bone,skin,tendon,nerves),myocardial infarction,psoriasis and organ defects.Some common fabrication technologies of biomedical nanofibers are also introduced.Meanwhile,the existing technical barriers and perspectives are rationally discussed,providing a constructive inspiration for the follow-up basic research and clinical transformation of nanofibers in the vibrant biomedical fields.展开更多
Hericium erinaceus is a nutritious edible and medicinal fungi,rich in a variety of functional active ingredients,with various physiological functions such as antioxidation,anticancer,and enhancing immunity.It is also ...Hericium erinaceus is a nutritious edible and medicinal fungi,rich in a variety of functional active ingredients,with various physiological functions such as antioxidation,anticancer,and enhancing immunity.It is also effective in protecting the digestive system and preventing neurodegenerative diseases.In this review paper,we summarize the sources,structures and efficacies of the main active components in H.erinaceus fruiting body,mycelium,and culture media,and update the latest research progress on their biological activities and the related molecular mechanisms.Based on this information,we provide detailed challenges in current research,industrialization and information on the active ingredients of H.erinaceus.Perspectives for future studies and new applications of H.erinaceus are proposed.展开更多
Oxalate is an organic dicarboxylic acid that is a common component of plant foods.The kidneys are essential organs for oxalate excretion,but excessive oxalates may induce kidney stones.Jupiter microtubule associated h...Oxalate is an organic dicarboxylic acid that is a common component of plant foods.The kidneys are essential organs for oxalate excretion,but excessive oxalates may induce kidney stones.Jupiter microtubule associated homolog 2(JPT2)is a critical molecule in Ca^(2+)mobilization,and its intrinsic mechanism in oxalate exposure and kidney stones remains unclear.This study aimed to reveal the mechanism of JPT2 in oxalate exposure and kidney stones.Genetic approaches were used to control JPT2 expression in cells and mice,and the JPT2 mechanism of action was analyzed using transcriptomics and untargeted metabolomics.The results showed that oxalate exposure triggered the upregulation of JPT2,which is involved in nicotinic acid adenine dinucleotide phosphate(NAADP)-mediated Ca^(2+)mobilization.Transcriptomic analysis revealed that cell adhesion and macrophage inflammatory polarization were inhibited by JPT2 knockdown,and these were dominated by phosphatidylinositol 3-kinase(PI3K)/AKT signaling,respectively.Untargeted metabolomics indicated that JPT2 knockdown inhibited the production of succinic acid semialdehyde(SSA)in macrophages.Furthermore,JPT2 deficiency in mice inhibited kidney stones mineralization.In conclusion,this study demonstrates that oxalate exposure facilitates kidney stones by promoting crystal-cell adhesion,and modulating macrophage metabolism and inflammatory polarization via JPT2/PI3K/AKT signaling.展开更多
Inflammatory bowel disease(IBD)is a complex relapsing inflammatory disease in the gut and is driven by complicated host-gut microbiome interactions.Gut commensals have shown different functions in IBD prevention and t...Inflammatory bowel disease(IBD)is a complex relapsing inflammatory disease in the gut and is driven by complicated host-gut microbiome interactions.Gut commensals have shown different functions in IBD prevention and treatment.To gain a mechanistic understanding of how different commensals affect intestinal inflammation,we compared the protective effects of 6 probiotics(belonging to the genera Akkermansia,Bifidobacterium,Clostridium,and Enterococcus)on dextran sulfate sodium(DSS)-induced colitis in mice with or without gut microbiota.Anti-inflammatory properties(ratio of interleukin(IL)-10 and IL-12)of these strains were also evaluated in an in vitro mesenteric lymph nodes(MLN)co-culture system.Results showed that 4 probiotics(belonging to the species Bifidobacterium breve,Bifidobacterium bifidum,and Enterococcus faecalis)can alleviate colitis in normal mice.The probiotic strains differed in regulating the intestinal microbiota,cytokines(IL-10,IL-1βand interferon(IFN)-γ),and tight junction function(Zonulin-1 and Occludin).By constrast,Akkermansia muciniphila AH39 and Clostridium butyricum FHuNHHMY49T1 were not protective.Interestingly,B.breve JSNJJNM2 with high anti-inflammatory potential in the MLN model could relieve colitis symptoms in antibiotic cocktail(Abx)-treated mice.Meanwhile,E.faecalis FJSWX25M1induced low levels of cytokines in vitro and showed no beneficial effects.Therefore,we provided insight into the clinical application of probiotics in IBD treatment.展开更多
Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer. In particular, the density of T CD8<sup>+</sup> and CD45<sup>+</sup> lymphocyte infiltration w...Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer. In particular, the density of T CD8<sup>+</sup> and CD45<sup>+</sup> lymphocyte infiltration was recently shown to have a better prognostic value than the classic tumor node metastasis classification factor. Other immune subsets, as macrophages, natural killer cells or unconventionnal lymphocytes, seem to play an important role. Induction of regulatory T cells (Tregs) or immunosuppressive molecules such as PD-1 or CTLA-4 and downregulation of antigen-presenting molecules are major escape mechanisms to antitumor immune response. The development of these mechanisms is a major obstacle to the establishment of an effective immune response, but also to the use of immunotherapy. Although immunotherapy is not yet routinely used in colorectal cancer, we now know that most treatments used (chemotherapy and biotherapy) have immunomodulatory effects, such as induction of immunogenic cell death by chemotherapy, inhibition of immunosuppression by antiangiogenic agents, and antibody-dependent cytotoxicity induced by cetuximab. Finally, many immunotherapy strategies are being developed and tested in phase I to III clinical trials. The most promising strategies are boosting the immune system with cytokines, inhibition of immunoregulatory checkpoints, vaccination with vectorized antigens, and adoptive cell therapy. Comprehension of antitumor immune response and combination of the different approaches of immunotherapy may allow the use of effective immunotherapy for treatment of colorectal cancer in the near future.展开更多
基金supported by Natural Science Foundation of Jilin Province(No.SKL202302002)。
文摘The healing of diabetic wounds poses a significant healthcare burden due to persistent inflammation,M1 macrophage aggregation,and high glucose levels in the microenvironment.Previous studies have demonstrated that immunomodulatory hydrogel dressings can facilitate diabetic wound healing.However,current immunomodulatory hydrogels require costly and complex treatments such as cell therapy and cytokines.Herein,a hierarchical hydrogel dressing with continuous biochemical gradient based on glycyrrhizic acid(GA) was constructed to modulate immunomodulatory processes in diabetic wounds.The hydrogels present many desirable features,such as tunable mechanical properties,broad antibacterial ability,outstanding conductive,transparent,and self-adhesive properties.The resultant hydrogel can promote diabetic wound healing by preventing bacterial infection,promoting macrophage polarization,improving the inflammatory microenvironment,and inducing angiogenesis and neurogenesis.Furthermore,electrical stimulation(ES) can further promote the healing of chronic diabetic wounds,providing valuable guidance for relevant clinical practice.
基金supported by the National Natural Science Foundation of China(Grant Nos.51873069,52272276,52073103,52203164)the Zhongshan Innovation Project of high-end Scientific Research Institutions(Grant No.2020AG020)+2 种基金the Key-Area Research and Development Program of Guangdong Province(No.2020B090924004)Beijing Municipal Health Commission(Grant Nos.BMHC-2018-4,BMHC-2019-9,PXM2020026275000002)the Postdoctoral Research Foundation of China(No.2022M711183).
文摘Intervertebral disc herniation(IVDH)is a common manifestation of intervertebral disc degeneration(IVDD)characterized by inflammation that results in the rupture of the annulus fibrosus(AF)and her-niation of the nucleus pulposus(NP).While current clinical research primarily focuses on regulating the degenerative NP,the crucial role of the AF in maintaining the mechanical stability and metabolic balance of the intervertebral disc(IVD)has been overlooked.Resolving immunoregulation and AF repair is im-perative to effectively prevent recurrent herniation.Therefore,this study introduces a bioactive sealant(OD/GM/QCS-sEVs),which combines gelatin methacryloyl(GM)and oxidized dextran(OD)with quater-nized chitosan(QCS)and incorporates small extracellular vesicles(sEVs).The developed sealant possesses injectability,self-healing capabilities,tissue adhesiveness,and mechanical stability,with an average ad-hesive strength of 109.63 kPa.In vitro experiments demonstrate that OD/GM/QCS-sEVs effectively seal AF defects while preserving mechanical properties comparable to those of a normal IVD.Additionally,the sealant releases sEVs through a pH-responsive mechanism,thereby modulating macrophage polarization to the M2 phenotype via the NF-κB signaling pathway.This mechanism facilitates immunoregulation and anti-inflammatory effects,and promotes stem cell differentiation into fibrocartilage.Animal experiments confirm the ability of OD/GM/QCS-sEVs to seal defects,prevent proteoglycan loss,inhibit IVDD develop-ment,and promote AF regeneration.Overall,OD/GM/QCS-sEVs hold promise as an innovative bioactive sealant for recurrent herniation by resolving immunoregulation and AF regeneration.
基金supported by grants from the National Natural Science Foundation of China(No.81172826)Collaborative Innovation Center of Hematology,China
文摘Summary： Although mesenchymal stem cells （MSCs） are increasingly used to treat graft-versus-host disease （GVHD）, their immune regulatory mechanism in the process is elusive. The present study aimed to investigate the curative effect of third-party umbilical cord blood-derived human MSCs （UCB-hMSCs） on GVHD patients after allogeneic hematopoietic stem cell transplantation （allo-HSCT） and their immune regulatory mechanism. Twenty-four refractory GVHD patients after allo-HSCT were treated with UCB-hMSCs. Immune cells including T lymphocyte subsets, NK ceils, Treg cells and dendritic cells （DCs） and cytokines including interleukin-17 （IL-17） and tumor necrosis factor-alpha （TNF-α） were monitored before and after MSCs transfusion. The results showed that the symptoms of GVHD were alleviated significantly without increased relapse of primary disease and transplant-related complications after MSCs transfusion. The number of CD3^＋, CD3＋CD4^＋ and CD3＋CD8^＋ cells decreased significantly, and that of NK cells remained unchanged, whereas the number of CD4^＋ and CD8^＋ Tregs increased and reached a peak at 4 weeks; the number of mature DCs, and the levels of TNF-α and IL-17 decreased and reached a trough at 2 weeks. It was concluded that MSCs ameliorate GVHD and spare GVL effect via immunoregulations.
基金supported by the National Key Research and Development Program (2018YFD1000200)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202005)the Ability Establishment of Sustainable Use for Valuable Chinese Medicine Resources (2060302).
文摘The most recent outbreak of 2019 novel coronavirus,named as COVID-19,caused pneumonia epidemic in Wuhan with 2121 deaths cases as of February 20th 2020.Identification of effective antiviral agents to combat the novel coronavirus is urgently needed.Citrus fruit peel or wild citrus are rich in flavonoids,and clinically documented for roles in relief of cough and promotion of digestive health.Therefore,citrus fruits are assumed to possess antivirus activities or enhance the host immunity.A previous study found that hesperetin could act as a high potent inhibitor of SARS-CoV 3CLpro.We determined six flavonoid compounds’content in three citrus species by using LC-MS technique.The content of naringin and naringenin was at higher levels in pummelo.Hesperetin and hesperidin were highly accumulated in mandarin and sweet orange.The subsequent in vitro and in vivo experiments indicated that naringin could inhibit the expression of the proinflammatory cytokines(COX-2,iNOS,IL-1βand IL-6)induced by LPS in Raw macrophage cell line,and may restrain cytokine through inhibiting HMGB1 expression in a mouse model.The results revealed that naringin may have a potential application for preventing cytokine storm.We simulated molecular docking to predict the binding affinity of those flavonoids to bind Angiotensin-converting enzyme 2(ACE 2),which is a receptor of the coronavirus.Consideration of the potential anti-coronavirus and anti-inflammatory activity of flavonoids,the citrus fruit or its derived phytochemicals are promising in the use of prevention and treatment of SARS-CoV-2 infection.
基金The project is supported financially by National Natural Science Foundation of China
文摘The spleenic and thymus T lymphocyte proliferaitivc reactions (TLPR) were enhanced, the intcrlcukin 2(IL-2) inductive activity was raised, and the IL-2 receptor (IL-2R) inductive expression was increased significantly in chickens after inoculation with trivalcnt Marck’s disease vaccine in comparison with control chickens and those after vaccination with herpcsvirus of turkey (HVT) vaccine. In chickens after inoculation with HVT vaccine, in contrast with control chickens, the splcenic TLPR was strengthened and IL-2R inductive expression was hoisted significantly, the thymus TLPR, splccnic and thymus T lymphocyte IL-2 inductive activity, the thymus T lymphocyte IL-2R inductive expression were not significantly increased.
文摘Anti-murine IL-1α, IL-6 antibodies were intra-peritoneally injected to the lupus-like NZB/W F1 mice of 4 months with the dosage of 10μg per day for three days and then per month for three months. The mice were killed at the age of 11 months. The results showed that the treatment of the dosage could not absolutely prevent lupus nephritis; it could alleviate proteinuria, obviously reduce the levels of serum IL-lα and inhibit the secretion of IL-1α by celiac macrophage.As to the level of IL-6 and TNF-α no significant change was observed.
基金Supported by Program for Science and Technology Development in Nanyang City(KGGG2018107).
文摘[Objectives]The paper was to observe the effects of red ginseng aqueous extract on immune function of mice.[Methods]The aqueous extract of red ginseng was obtained by water extraction and concentration,and 10 mL of aqueous extract was equivalent to 2.86 g of raw materials.Total 240 mice were randomly divided into blank control group,low dose,medium dose and high dose groups of red ginseng aqueous extract,60 mice each group.Mice in low dose,medium dose and high dose groups were intragastrically administered with 0.24,0.48,1.43 g/kg red ginseng aqueous extract once a day respectively,and those in blank control group were intragastrically administered with equal volume of deionized water at the dose of 0.1 mL/10 g once a day for consecutive 30 d.The immunoregulation effects of red ginseng aqueous extract on mice were explored by organ/body weight ratio measurement,delayed type hypersensitivity(DTH)reaction,Con A-induced spleen T lymphocyte transformation test,antibody-producing cells test,half hemolytic value(HC 50)test,carbon particle clearance test,phagocytosis test of chicken red blood cells by macrophages and NK cell activity test.[Results]Compared with the blank control group,the degree of toe swelling in low dose group and medium dose group of red ginseng aqueous extract[(0.62±0.14)mm,(0.53±0.12)mm vs.(0.36±0.10)mm]significantly increased(P<0.05).The ability of T lymphocytes proliferation(0.173±0.054,0.189±0.063 vs.0.098±0.012)in low dose group and high dose group significantly increased(P<0.05).The number of haemolytic plaque(137.49×10^(3)±24.73×10^(3),148.43×10^(3)±27.53×10^(3) vs.112.96×10^(3)±26.28×10^(3))in medium dose group and high dose group significantly increased(P<0.05).The phagocytosis rate(35.67%±3.82%,49.26%±6.54%,57.92%±7.36%vs.24.34%±4.22%)and phagocytosis index(0.72±0.23,0.82±0.15,0.91±0.26 vs.0.35±0.11)of low dose,medium dose,high dose groups significantly increased(P<0.05).However,there was no statistical difference in spleen/body weight ratio,thymus/body weight ratio,half hemolytic value,carbon particle clearance and NK cell activity.[Conclusions]Red ginseng aqueous extract could enhance the immunity of mice.
基金the Natural Science Foundation of China (grant numbers 81574066,81873362,81704156)the Fundamental Research Funds for the Central Universities, China (grant numbers 21615427,21616318)+1 种基金the Natural Science Foundation of Guangdong Province, China (grant numbers 2016A030310093, 2017A030310024)Administration of Traditional Chinese Medicine of Guangdong Province, China (grant number 20161067).
文摘Objective: To evaluate the immunoregulation of KangAi (KA) injection combined with chemo-treatment (chemo) for Non-small cell lung cancer (NSCLC). Methods: We systematically searched the literature of PubMed, EMBASE, CENTRAL, MEDLINE, CNKI, Wanfang, and VIP databases for all Randomized controlled trials (published from the earliest possible year to January 2019, no language restrictions) comparing KA injection combined with chemo and chemo alone in patients with NSCLC. Our main endpoints were immune function, clinical efficiency, KPS score and adverse events. The Cochrane Risk of Bias tool was applied for quality assessment. Results: 11 studies involving 1060 participants were included. The immune function (MD=3.18, 95% CI: 0.98-4.00, P<0.00001), clinical response rate (RR=1.28, 95%CI: 1.17-1.40, P<0.00001), KPS score (RR=1.86, 95%CI: 1.35-2.57, P=0.0002), and adverse events (RR=0.57, 95%CI: 0.50-0.65, P<0.00001) in the group of KA injection plus Chemo were vastly different from those in Chemo alone. Conclusion: KA injection combined with Chemo in the treatment of NSCLC improved the immune function, clinical efficiency and safety compared to Chemo alone. However, because many of the methodologies included in randomized controlled trials are of poor quality, more rigorous design and large randomized controlled trials are needed to test this benefit.
基金The study was funded by the National Natural Science Foundation of Hebei （No.H2018201179）. Hebei University of Science and Technology （No. QN2016077）. Health and Family Planning Commission of Hebei （No. 20160388）.
文摘Background： We summarized the Polyporusus Bellatus （PPS） efficacy of immunomodulation, liver protection and anti-tumor, then provide scientific basis for further research and clinical application. This dissertation first overview relevant literatures of PPS recent years and describe comprehensively the research progress of the immunoregulation, liver protection and anti-tumor effects and mechanism of PPS. The review shows that the PPS play anti-tumor effects through antioxidation, scavenging free radicals, inhibiting tumor cell proliferation, inducing apoptosis, affecting tumor gene expressions and enhancing immune functions. PPS can exert immunoregulatory, hepatoprotective and anti-tumor effects through multiple pathways and multiple targets, which provides a good application prospect in clinic.
文摘Chronic osteomyelitis caused by implant infections is a common complication following orthopedic surgery.Preventing bacterial infection and simultaneously improving bone regeneration are the key for osteomyelitis.Current treatments include systemic antibiotics and multiple surgical interventions,but the strategies available for treatment are limited.In this study,a multifunctional engineered Bacillus subtilis(B.sub)hydrogel with sulfasalazine(SSZ)is developed to treat methicillin-resistant Staphylococcus aureus(MRSA)infection and antiinflammatory and promote bone regeneration.B.sub in alginate hydrogels protects B.sub from being cleared by the host immune system while allowing the release of its bioactive substances,including antibacterial peptides and anti-inflammatory agents such as SSZ.The results show that the engineered probiotic hydrogels exhibit excellent antibacterial efficacy against MRSA(97%)and prevent the development of bacterial resistance.The antibacterial effect is primarily mediated through the secretion of bioactive peptides by B.sub,which not only inhibit MRSA growth but also reduce the likelihood of resistance development.Meanwhile,the probiotic hydrogel has a greater ability to induce M2 polarization of macrophages and promote angiogenesis,resulting in enhanced osteogenic differentiation in bone marrow mesenchymal stem cells(BMSCs)and thus enhancing bone regeneration.This engineered probiotic hydrogel offers a promising strategy by simultaneously combating bacterial infection and enhancing osteogenic differentiation for chronic osteomyelitis.
基金supported by the CRUK Hepatocellular Carcinoma Expediter Network(HUNTER)Accelerator Award 2018(Project 620 Id.122794)(VB)Associazione Italiana per la Ricerca sul Cancro(AIRC)IGV19939(VB)+2 种基金Fondazione Italiana Sclerosi Multipla(FISM)onlus(cod.2015/RVsingle/04 and 2019/RVsingle/053)(VB)AIRC-IG 2023(ID 29244)(SS),Ministero della Salute(PNRR-MAD-2022-12375947)(SS)the European Union-Next Generation EU in the context of the National Recovery and Resilience Plan,Investment Partenariato Esteso PE8“Conseguenze e sfide dell’invecchiamento”,Project Age-It(Aging Well in an Aging Society)(SS).
文摘L.Zhang et al.proposed novel immunotherapeutic strategies to limit the progression of inflammatory bowel diseases by targeting the interplay between the membrane-bound CD39 molecule and cellular metabolism—specifically,by increasing regulatory T-cell function through the modulation of glucose metabolism and suppressing pathogenic proinflammatory Th17 responses via the modulation of oxidative metabolism.
基金supported by the National Key Research and Development Program of China(2022YFC2504200)the National Natural Science Foundation of China(Nos.82270959 and 81970903)+5 种基金the Natural Science Foundation of Jilin Province(No.SKL202302002)the Key Research and Development Project of Jilin Provincial Science and Technology Department(Nos.20210204142YY)the Jilin University Norman Bethune Program(No.2023B28)the Fundamental Research Funds for the Central Universities,the Natural Science Foundation of Liaoning Province(No.2022-BS-123)the Science and Technology Project of Shenyang(No.21-173-9-34)“Medical+X”Interdisciplinary Innovation Team“Announcement and Leadership”Construction Project(2022JBGS08).
文摘As a“cold tumor”,triple-negative breast cancer(TNBC)exhibits limited responsiveness to current immunotherapy.How to enhance the immunogenicity and reverse the immunosuppressive microenvironment of TNBC remain a formidable challenge.Herein,an“in situ nanovaccine”Au/CuNDs-R848 was designed for imagingguided photothermal therapy(PTT)/chemodynamic therapy(CDT)synergistic therapy to trigger dual immunoregulatory effects on TNBC.On the one hand,Au/CuNDs-R848 served as a promising photothermal agent and nanozyme,achieving PTT and photothermal-enhanced CDT against the primary tumor of TNBC.Meanwhile,the released antigens and damage-associated molecular patterns(DAMPs)promoted the maturation of dendritic cells(DCs)and facilitated the infiltration of T lymphocytes.Thus,Au/CuNDs-R848 played a role as an“in situ nanovaccine”to enhance the immunogenicity of TNBC by inducing immunogenic cell death(ICD).On the other hand,the nanovaccine suppressed the myeloid-derived suppressor cells(MDSCs),thereby reversing the immunosuppressive microenvironment.Through the dual immunoregulation,“cold tumor”was transformed into a“hot tumor”,not only implementing a“turning foes to friends”therapeutic strategy but also enhancing immunotherapy against metastatic TNBC.Furthermore,Au/CuNDs-R848 acted as an excellent nanoprobe,enabling high-resolution near-infrared fluorescence and computed tomography imaging for precise visualization of TNBC.This feature offers potential applications in clinical cancer detection and surgical guidance.Collectively,this work provides an effective strategy for enhancing immune response and offers novel insights into the potential clinical applications for tumor immunotherapy.
基金financial support provided by Young Scientists Fund of the National Natural Science Foundation of China(No.32201086)Postdoctoral Science Foundation of Chongqing Natural Science Foundation(No.cstc2021jcyj-bsh X0125)the project for Chongqing University Innovation Research Group,Chongqing Education Committee(No.CXQT20006)。
文摘Diabetes mellitus(DM)is a serious health problem in the world,and infections are common complications in diabetic patients,particularly methicillin-resistant Staphylococcus aureus(MRSA)infections,which substantially increases mortality in patients.In clinical practice,the treatment of diabetic complicationrelated infections involves multiple issues such as drug resistance when combining antidiabetic drugs with antibiotics.In this study,a series of derivatives were synthesized with alkyl radicals with different chain lengths substituted at the C8 and C12 positions of berberine,with compounds CY1 and CY3with good antidiabetic and antibacterial activities screened out after identification.Then,oral liposomes(CY1-Lip and CY3-Lip)were prepared,and their particle sizes,stability,and pharmacokinetics were investigated.In acquired mouse models of diabetes,induced with an acute MRSA lung infection,we demonstrate that CY1-Lip and CY3-Lip can effectively reduce levels of fasting blood glucose(FBG),fasting insulin(FINS),and insulin resistance index among diabetic mice with pneumonia,thus exerting their multitargets effects.Furthermore,both preparations significantly reduced lung MRSA loads and improved lung tissue lesions,reduced high infiltration of M1 macrophages in lung,and suppressed the expression levels of pro-infiammatory factors such as necrosis factor-α(TNF-α)and interleukin-6(IL-6).This provides new insights into the clinical treatment of diabetes complicated with pulmonary infections.
基金Supported by Natural Science Foundation of Zhejiang Province,No.LY23H050005Zhejiang Medical Technology Project,No.2020KY439,No.2022RC009,No.2024KY645,and No.2024KY697.
文摘Lupus nephritis(LN)is one of the most common and serious complications of systemic lupus erythematosus,which can lead to end-stage renal disease,and is an important cause of death in patients with systemic lupus erythematosus.Treatment options include glucocorticoids,immunosuppressive agents and the addition of biologics.Recently,the therapeutic role of mesenchymal stem cells(MSCs)in LN has received extensive attention worldwide.MSCs can suppress autoimmunity,alleviate proteinuria and restore renal function by modulating the functions of various immune cells and reducing the secretion of inflammatory cytokines.Several clinical trials have investigated MSC treatment in LN with promising but sometimes inconsistent outcomes.This review summarizes the sources of MSCs and mechanisms in immunoregulation.Furthermore,it examines clinical trials evaluating the efficacy,safety,and limitations of MSC therapy in LN.By highlighting advances and ongoing challenges,this review underscores the potential of MSCs for LN treatment.More large-scale randomized controlled trials are needed to support the effectiveness of this therapy and pave the way for personalized and combinatorial therapeutic approaches.
基金supported by National Natural Science Foundation of China(No.39970340,No.30570865)Natural Science Foundation of Shanghai(No.02ZB14041,No.034119916).
文摘Dendritic cells （DCs） are known to be the most powerful professional antigen-presenting cells so far. It could activate primary immune response, and also downregulate immune response. DCs have a unique character of immunoregulation. DC-SIGN, a molecule designated as CD209, is one member of the C-type lectin superfamily. It is not only a pattern recognition receptor but implicated in immunoregulation of DCs. DC-SIGN has become hotspot of recent studies because of its important role in mediating DC adhesion, migration, inflammation, activating primary T cell, triggering immune response and participating in immune escape of pathogens and tumors. These studies on DC-SIGN involved in primary and secondary immune response and relevant mechanism will certainly provide us with a new method in treating and preventing certain diseases.
基金This work was financially supported by the National Natural Science Foundation of China(32071350,31771048)Fundamental Research Funds for the Central Universities(2232018A3-07,2232019A3-06)International Cooperation Fund of the Science and Technology Commission of Shanghai Municipality(19440741600).
文摘Despite great efforts and achievement of nanomaterials in immune-associated diseases,the selection of appropriate nanomaterials and preparation technology remain some challenges and vast room for improvement.Immunotherapy has received tremendous attention throughout the medical process due to its clinical successes with the pathways of immunoactivation or immunosuppression.Recently,fibrous nanomaterials have facilitated advances in tissue repair and cancer treatments owing to the superiority of multi-channel structure,biocompatibility,tunable size and controlled surface modification.The immunoactivation-based nanofibers can potentially deliver functional agents to lesions and further actively promote immunologic intervention.On the contrary,the immunosuppression-based nanofibers prevent the immune system from overreacting through the blockage of critical pathways in vivo.This review summarizes the current application of nanofiber materials in diverse diseases,including cancer therapy,tissue regeneration(cartilage/bone,skin,tendon,nerves),myocardial infarction,psoriasis and organ defects.Some common fabrication technologies of biomedical nanofibers are also introduced.Meanwhile,the existing technical barriers and perspectives are rationally discussed,providing a constructive inspiration for the follow-up basic research and clinical transformation of nanofibers in the vibrant biomedical fields.
基金supported by the fund from Natural Science Foundation of Zhejiang Province,China(LY17C200017)。
文摘Hericium erinaceus is a nutritious edible and medicinal fungi,rich in a variety of functional active ingredients,with various physiological functions such as antioxidation,anticancer,and enhancing immunity.It is also effective in protecting the digestive system and preventing neurodegenerative diseases.In this review paper,we summarize the sources,structures and efficacies of the main active components in H.erinaceus fruiting body,mycelium,and culture media,and update the latest research progress on their biological activities and the related molecular mechanisms.Based on this information,we provide detailed challenges in current research,industrialization and information on the active ingredients of H.erinaceus.Perspectives for future studies and new applications of H.erinaceus are proposed.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82070723,82270797)Nature Science Foundation of Hubei Province,China(Grant No.:2022CFC020).
文摘Oxalate is an organic dicarboxylic acid that is a common component of plant foods.The kidneys are essential organs for oxalate excretion,but excessive oxalates may induce kidney stones.Jupiter microtubule associated homolog 2(JPT2)is a critical molecule in Ca^(2+)mobilization,and its intrinsic mechanism in oxalate exposure and kidney stones remains unclear.This study aimed to reveal the mechanism of JPT2 in oxalate exposure and kidney stones.Genetic approaches were used to control JPT2 expression in cells and mice,and the JPT2 mechanism of action was analyzed using transcriptomics and untargeted metabolomics.The results showed that oxalate exposure triggered the upregulation of JPT2,which is involved in nicotinic acid adenine dinucleotide phosphate(NAADP)-mediated Ca^(2+)mobilization.Transcriptomic analysis revealed that cell adhesion and macrophage inflammatory polarization were inhibited by JPT2 knockdown,and these were dominated by phosphatidylinositol 3-kinase(PI3K)/AKT signaling,respectively.Untargeted metabolomics indicated that JPT2 knockdown inhibited the production of succinic acid semialdehyde(SSA)in macrophages.Furthermore,JPT2 deficiency in mice inhibited kidney stones mineralization.In conclusion,this study demonstrates that oxalate exposure facilitates kidney stones by promoting crystal-cell adhesion,and modulating macrophage metabolism and inflammatory polarization via JPT2/PI3K/AKT signaling.
基金supported by the Natural Science Foundation of Jiangsu Province (BK20200084)The National Natural Science Foundation of China (U1903205 and 31972971)Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province。
文摘Inflammatory bowel disease(IBD)is a complex relapsing inflammatory disease in the gut and is driven by complicated host-gut microbiome interactions.Gut commensals have shown different functions in IBD prevention and treatment.To gain a mechanistic understanding of how different commensals affect intestinal inflammation,we compared the protective effects of 6 probiotics(belonging to the genera Akkermansia,Bifidobacterium,Clostridium,and Enterococcus)on dextran sulfate sodium(DSS)-induced colitis in mice with or without gut microbiota.Anti-inflammatory properties(ratio of interleukin(IL)-10 and IL-12)of these strains were also evaluated in an in vitro mesenteric lymph nodes(MLN)co-culture system.Results showed that 4 probiotics(belonging to the species Bifidobacterium breve,Bifidobacterium bifidum,and Enterococcus faecalis)can alleviate colitis in normal mice.The probiotic strains differed in regulating the intestinal microbiota,cytokines(IL-10,IL-1βand interferon(IFN)-γ),and tight junction function(Zonulin-1 and Occludin).By constrast,Akkermansia muciniphila AH39 and Clostridium butyricum FHuNHHMY49T1 were not protective.Interestingly,B.breve JSNJJNM2 with high anti-inflammatory potential in the MLN model could relieve colitis symptoms in antibiotic cocktail(Abx)-treated mice.Meanwhile,E.faecalis FJSWX25M1induced low levels of cytokines in vitro and showed no beneficial effects.Therefore,we provided insight into the clinical application of probiotics in IBD treatment.
文摘Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer. In particular, the density of T CD8<sup>+</sup> and CD45<sup>+</sup> lymphocyte infiltration was recently shown to have a better prognostic value than the classic tumor node metastasis classification factor. Other immune subsets, as macrophages, natural killer cells or unconventionnal lymphocytes, seem to play an important role. Induction of regulatory T cells (Tregs) or immunosuppressive molecules such as PD-1 or CTLA-4 and downregulation of antigen-presenting molecules are major escape mechanisms to antitumor immune response. The development of these mechanisms is a major obstacle to the establishment of an effective immune response, but also to the use of immunotherapy. Although immunotherapy is not yet routinely used in colorectal cancer, we now know that most treatments used (chemotherapy and biotherapy) have immunomodulatory effects, such as induction of immunogenic cell death by chemotherapy, inhibition of immunosuppression by antiangiogenic agents, and antibody-dependent cytotoxicity induced by cetuximab. Finally, many immunotherapy strategies are being developed and tested in phase I to III clinical trials. The most promising strategies are boosting the immune system with cytokines, inhibition of immunoregulatory checkpoints, vaccination with vectorized antigens, and adoptive cell therapy. Comprehension of antitumor immune response and combination of the different approaches of immunotherapy may allow the use of effective immunotherapy for treatment of colorectal cancer in the near future.
