Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly ele...Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly elevated in the serum and synovial fluid of rheumatoid arthritis patients and we demonstrated that itaconate is primarily produced by inflammatory macrophages rather than osteoclasts or osteoblasts.In TNF-transgenic and Irg1−/−hybrid mice,a more severe bone destruction phenotype was observed.展开更多
Itaconate(ITA),an immunomodulatory metabolite with known anti-inflammatory properties,has underexplored therapeutic or prophylactic potential against coronavirus disease 2019(COVID-19).Using an interanimal transmissio...Itaconate(ITA),an immunomodulatory metabolite with known anti-inflammatory properties,has underexplored therapeutic or prophylactic potential against coronavirus disease 2019(COVID-19).Using an interanimal transmission golden hamster model of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-induced acute lung injury,we first assessed ITA changes in dNS1-RBD-vaccinated hamsters via metabolomic profiling.Then,we evaluated prophylactic intranasal(20 mg/kg at 9,6,and 3 days before SARS-CoV-2 infection)and therapeutic intraperitoneal(100 mg/kg at 6,24,and 48 hours post-infection)ITA administration,assessed by histopathology,transcriptomic,and metabolomic profiling,followed by multi-omics integration,including gene expression clustering,pathway enrichment,and cytokine/chemokine–metabolites correlation analyses.Public bronchoalveolar lavage fluid(BALF)single-cell RNA-sequencing(scRNA-seq)datasets from COVID-19 patients were re-analyzed to explore macrophage heterogeneity.Intranasal dNS1-RBD vaccine upregulated ITA levels,prompting further exploration of its immunomodulatory role.Both prophylactic and therapeutic ITA treatments significantly mitigated weight loss and improved lung pathology.Correlation analyses implied a potential regulatory crosstalk between fatty acid b-oxidation(FAO)and reduced inflammatory response.Reanalysis of BALF scRNA-seq dataset highlighted transcriptional networks involving PPARG,RARA,BHLHE41,TCF7L2,and ESRRA—genes linked to macrophage self-renewal and metabolic homeostasis,which appeared to be preserved in ITA-treated hamsters.These findings underscore ITA’s role in modulating immunometabolic responses,particularly through FAO-driven macrophage reprogramming,to attenuate SARS-CoV-2-induced lung damage.Together,this study provides insights into host-directed therapies targeting metabolic reprogramming to mitigate COVID-19 severity.展开更多
Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate(4-OI) is...Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate(4-OI) is a cell-permeable itaconate derivative and has been recognized as a promising therapeutic target for the treatment of inflammatory diseases. Here, we explored, for the first time,the protective effect of 4-OI on inhibiting periodontal destruction, ameliorating local inflammation, and the underlying mechanism in periodontitis. Here we showed that 4-OI treatment ameliorates inflammation induced by lipopolysaccharide in the periodontal microenvironment. 4-OI can also significantly alleviate inflammation and alveolar bone loss via Nrf2 activation as observed on samples from experimental periodontitis in the C57BL/6 mice. This was further confirmed as silencing Nrf2 blocked the antioxidant effect of 4-OI by downregulating the expression of downstream antioxidant enzymes. Additionally, molecular docking simulation indicated the possible mechanism under Nrf2 activation. Also, in Nrf2-/-mice, 4-OI treatment did not protect against alveolar bone dysfunction due to induced periodontitis, which underlined the importance of the Nrf2 in 4-OI mediated periodontitis treatment.Our results indicated that 4-OI attenuates inflammation and oxidative stress via disassociation of KEAP1-Nrf2 and activation of Nrf2 signaling cascade. Taken together, local administration of 4-OI offers clinical potential to inhibit periodontal destruction,ameliorate local inflammation for more predictable periodontitis.展开更多
The unperturbed dimension and temperature character of poly(dibenzyl itaconate)s (PDBzI) are studied by a revised rotational isomeric state (RIS) method. The improved formulas of the mean-square radius of gyration, de...The unperturbed dimension and temperature character of poly(dibenzyl itaconate)s (PDBzI) are studied by a revised rotational isomeric state (RIS) method. The improved formulas of the mean-square radius of gyration, deduced by the pseudo-stereochemical equilibrium approach, may be used to investigate the configurational-conformational properties of atactic polymers with large side groups [poly(itaconates) for instance]. The calculated results showed that poly(itaconates) have larger dimension of the molecule than other vinyl polymers. Comparison of the dimension between considering and without considering side groups showed that the effect of large side groups on the unperturbed dimension for short-chain polymers is more obvious than that of long-chain polymers and, if the dimension of side groups increases, the effect also increases. The dimension differences of PDBzI between short-chain and long-chain polymers are investigated by the relation of characteristic ratios and temperature coefficients with temperature. Moreover, the dependence between the temperature coefficients and the tacticity of chains shows that the temperature characters of the isotactic, syndiotactic and atactic PDBzI chains have remarkable difference.展开更多
Dodecyl itaconate (DI) was used as the dispersant for preparation of mono-dispersed carbon nanotubes in aqueous solution in this study. It is a unique type of anionic surfactant synthesized by the authors, and its hig...Dodecyl itaconate (DI) was used as the dispersant for preparation of mono-dispersed carbon nanotubes in aqueous solution in this study. It is a unique type of anionic surfactant synthesized by the authors, and its high capability for dispersing CNTs is attributed to the double bond moiety on its head-group. Furthermore, author mixed aqueous mono-dispersed CNTs with pulp to produce the CNT-based paper. Different from the reported papermaking process, a novel adjusting PH process was employed to prepare paper. This method could transfer easily dispersing mono-dispersed CNTs in aqueous onto the surfaces of cellulose fibers, because PH adjustment of CNT-pulp is from the initial neutrality to weak acidity and then raising to alkalinity, The dispersion of tubes in cellulose matrix and characteristics of composite were investigated. Also, electrical resistance for retrieved CNT-based sheets was measured using fore-probe method.展开更多
Background and aims:Methane has shown protective effects against ischemia and reperfusion injury(IRI)in the liver,but the mechanism underlying these beneficial effects is unclear.To investigate the hypothesis that ita...Background and aims:Methane has shown protective effects against ischemia and reperfusion injury(IRI)in the liver,but the mechanism underlying these beneficial effects is unclear.To investigate the hypothesis that itaconate facilitates in methane-induced Nrf2 pathway activation to mitigate liver IRI.Methods:An oxygen and glucose derivation(OGD)model using RAW 264.7 cells and a liver IRI model in mice were established.Methane's beneficial effects were assessed through hematoxylin and eosin(HE)staining,Suzuki's score,serum alanine transferase level,superoxide dismutase(SOD)level,malondialdehyde(MDA)level,and cell viability.The relative expression levels of Nrf2,its downstream molecules and some inflammatory factors were detected via western blotting.Itaconate levels were analyzed using liquid chromatography.RAW 264.7 cells were transfected with short hairpin RNA targeting mouse aconitate decarboxylase 1(Acod1)mRNA for itaconate downregulation.Results:Methane significantly alleviated liver IRI,as shown by the significant reduction in Suzuki's scores and alanine transferase(ALT)levels in vivo.Methane treatment significantly increased MTT and SOD levels and decreased MDA levels in the OGD injury model in vitro.Methane also increased the total and nuclear Nrf2 expression levels,activated downstream molecules including heme oxygenase-1(HO-1),NQO1 and affected the production of inflammatory cytokines such as IL-10,IL-1β,and IL-12.Itaconate levels were significantly elevated after methane treatment compared with the OGD injury group.The protective effects of methane were abolished after itaconate downregulation through Acod1 knockdown.Conclusions:Methane alleviates liver IRI through itaconate/Nrf2 pathway activation,with itaconate being critical for methane's beneficial effects.展开更多
Purpose:To investigate the pathological changes of the synovium in mice with post-traumatic osteoarthritis(PTOA)treated with 4-octyl itaconate(4-OI)and evaluate the therapeutic effects of 4-OI.Methods:In the phenotypi...Purpose:To investigate the pathological changes of the synovium in mice with post-traumatic osteoarthritis(PTOA)treated with 4-octyl itaconate(4-OI)and evaluate the therapeutic effects of 4-OI.Methods:In the phenotypic validation experiment,the mice were randomly divided into 3 groups:wildtype(WT)group,sham group,and destabilization of the medial meniscus(DMM)group.Through MRI,micro-CT,and histological analysis,it was determined that the DMM surgery induced a mouse PTOA model with significant signs of synovitis.At 12 weeks post-DMM surgery,synovial tissues from the DMM group and WT group mice were collected for ribonucleic acid sequencing analysis.In the 4-OI treatment experiment,mice were randomly divided into the sham group,DMM group,DMM+4-OI(50 mg/kg)group,and DMM+4-OI(100 mg/kg)group.Von Frey tests and open field tests were conducted at intervals during the 12 weeks following the DMM surgery.After 12 weeks of surgery,the efficacy of 4-OI treatment on PTOA in mice was evaluated using MRI,micro-CT,histological analysis,and quantitative real-time polymerase chain reaction.Finally,we utilized network pharmacology analysis to predict the mechanism of 4-OI in treating PTOA synovitis and conducted preliminary validation.Statistical analysis was performed using one-way ANOVA and the Kruskal-Wallis test.Difference was considered statistically significant at p<0.05.Results:The DMM surgery effectively induced a PTOA mouse model,which displayed significant symptoms of synovitis.These symptoms included a notable increase in both the number of calcified tissues and osteophytes(p<0.001),an enlargement of the calcified meniscus and synovial tissue volume(p<0.001),and thickening of the synovial lining layer attributable to M1 macrophage accumulation(p=0.035).Additionally,we observed elevated histological scores for synovitis(p<0.001).Treatment with 4-OI inhibited the thickening of M1 macrophages in the synovial lining layer of PTOA mice(p<0.001)and reduced fibrosis in the synovial stroma(p=0.004).Furthermore,it reduced the histological scores of knee synovitis in PTOA mice(p=0.006)and improved the inflammatory microenvironment associated with synovitis.Consequently,this treatment alleviated pain in PTOA mice(p<0.001)and reduced spontaneous activity(p=0.003).Bioinformatics and network pharmacology analyses indicated that 4-OI may exert its therapeutic effects by inhibiting the differentiation of synovial Th17 cells.Specifically,compared to the lipopolysaccharide stimulation group,4-OI reduced the levels of positive regulatory factors of Th17 cell differentiation(IL-1:p<0.001,IL-6:p<0.001),key effector molecules(IL-17A:p<0.001,IL-17F:p=0.004),and downstream effector molecules in the IL-17 signaling pathway(CCL2:p<0.001,MMP13:p<0.001).Conclusion:4-OI is effective in inhibiting synovitis in PTOA,thereby alleviating the associated painful symptoms.展开更多
Cytokine storm syndrome(CSS)is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies,infections,and autoimmune conditions.However,the potential interpla...Cytokine storm syndrome(CSS)is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies,infections,and autoimmune conditions.However,the potential interplay between innate immune cells is not fully understood.Here,using poly I:C and lipopolysaccharide(LPS)-induced cytokine storm models,a protective role of neutrophils through the modulation of macrophage activation was identified in a CSS model.Intravital imaging revealed neutrophil-derived extracellular vesicles(NDEVs)in the liver and spleen,which were captured by macrophages.NDEVs suppressed proinflammatory cytokine production by macrophages when cocultured in vitro or infused into CSS models.Metabolic profiling of macrophages treated with NDEV revealed elevated levels of the anti-inflammatory metabolite,itaconate,which is produced from cis-aconitate in the Krebs cycle by cis-aconitate decarboxylase(Acod1,encoded by Irg1).Irg1 in macrophages,but not in neutrophils,was critical for the NDEV-mediated anti-inflammatory effects.Mechanistically,NDEVs delivered miR-27a-3p,which suppressed the expression of Suclg1,the gene encoding the enzyme that metabolizes itaconate,thereby resulting in the accumulation of itaconate in macrophages.These findings demonstrated that neutrophil-to-macrophage communication mediated by extracellular vesicles is critical for promoting the anti-inflammatory reprogramming of macrophages in CSS and may have potential implications for the treatment of this fatal condition.展开更多
Functional materials synthesized from bio-based building blocks are fascinating and challenging in the fields of chemistry and materials science.Herein,we present a versatile strategy for synthesizing bio-based stimul...Functional materials synthesized from bio-based building blocks are fascinating and challenging in the fields of chemistry and materials science.Herein,we present a versatile strategy for synthesizing bio-based stimulus-responsive polymers derived from itaconic acid(IA).Bearing an azobenzene-containing side chain,the IA-based epoxy polymer exhibited both photoresponsiveness and acid/base-stimulus responsiveness.With controllable manipulation of the stress field of the wrinkling IA-polymer film via the stress relaxation effect resulting from the reversible cis-trans isomerization of the azobenzene moieties or solvent-induced swelling of the film,various tailor-made patterned wrinkling surfaces were conveniently fabricated.More importantly,the azobenzene protonation/deprotonation yields a reversible visual color transformation between pale yellow and purple in the film,which allows these IA-based polymer-coated surfaces to be utilized as rewritable information storage media.Various elegant pattern information can be acid-printed and base-erased(within 10 s)for multiple cycles and legible for over one day under laboratory conditions.Notably,the aforementioned dual-stimulus responsiveness of the IA-based polymer film enables its surface to be applied in information encryption.This study not only paves a new avenue for the convenient fabrication of stimulus-responsive surfaces but also sheds light on the development of functional polymers through green engineering.展开更多
The most widely used bisphenol A-type epoxy resin(DGEBA)in electrical engineering demonstrates excellent mechanical and electrical properties.However,the insoluble and infusible characteristics of cured DGEBA make it ...The most widely used bisphenol A-type epoxy resin(DGEBA)in electrical engineering demonstrates excellent mechanical and electrical properties.However,the insoluble and infusible characteristics of cured DGEBA make it difficult to efficiently degrade and recycle decommissioned electrical equipment.In this study,a degradable itaconic acid-based epoxy resin incorporating dynamic covalent bonds was prepared through the integration of ester bonds and disulfide bonds,with itaconic acid as the precursor.The covalent bonding effects on the mechanical,thermal,electrical,and degradation characteristics were systematically evaluated.The experimental results revealed that the introduction of dynamic ester bonds enhanced the mechanical properties and thermal stability of the resin system,achieving a flexural strength of 141.57 MPa and an initial decomposition temperature T_(5%)of up to 344.9℃.The resin system containing dynamic disulfide bonds exhibited a dielectric breakdown strength of 41.11 k V/mm.Simultaneously,the incorporation of disulfide bonds endowed the epoxy resin with remarkable degradability,enabling complete dissolution within 1.5 h at 90℃ in a mixed solution of dithiothreitol(DTT)and N-methylpyrrolidone(NMP).This research provides a valuable reference for the application of itaconic acid-based vitrimer with dynamic covalent bonds in electrical materials,contributing to the development and utilization of environmentally friendly electrical equipment.展开更多
The synthesis of methacrylic acid from biomass-derived itaconic acid is a green route,for it can get rid of the dependence on fossil resource.In order to solve the problems on this route such as use of a preciousmetal...The synthesis of methacrylic acid from biomass-derived itaconic acid is a green route,for it can get rid of the dependence on fossil resource.In order to solve the problems on this route such as use of a preciousmetal catalyst and a corrosive homogeneous alkali,we prepared a series of hydroxyapatite catalysts by an ionic liquid-assisted hydrothermal method and evaluated their catalytic performance.The results showed that the ionic liquid[Bmim]BF_(4) can affect the crystal growth of hydroxyapatite,provide fluoride ion for fluorination of hydroxyapatite,and adjust the surface acidity and basicity,morphology,textural properties,crystallinity,and composition of hydroxyapatite.The[Bmim]BF4 dosage and hydrothermal temperature can affect the fluoride ion concentration in the hydrothermal system,thus changing the degree of fluoridation of hydroxyapatite.High fluoride-ion concentration can lead to the formation of CaF_(2) and thus significantly decrease the catalytic performance of hydroxyapatite.The hydrothermal time mainly affects the growth of hydroxyapatite crystals on the c axis,leading to different catalytic performance.The suitable conditions for the preparation of this fluoridized hydroxyapatite are as follows:a mass ratio of[Bmim]BF4 to calcium salt=0.2:1,a hydrothermal time of 12 h,and a hydrothermal temperature of 130℃.A maximal methacrylic acid yield of 54.7%was obtained using the fluoridized hydroxyapatite under relatively mild reaction conditions(250℃ and 2 MPa of N_(2))in the absence of a precious-metal catalyst and a corrosive homogeneous alkali.展开更多
Acute liver failure(ALF)is a mortal and critical hepatic disease,in which oxidative stress,inflammation storm and hepatocyte death are crucial in the pathogenesis.Hence,in contrast to the control of a single link,a co...Acute liver failure(ALF)is a mortal and critical hepatic disease,in which oxidative stress,inflammation storm and hepatocyte death are crucial in the pathogenesis.Hence,in contrast to the control of a single link,a combination therapy targeting multiple pathogenic links of the disease will be a favorable means to control the progression of the disease.In this study,we constructed dimethyl itaconate-loaded liposomes modified with dodecyl gallate as a cocktail activator to investigate its functional role in acetaminophen(APAP)-induced ALF.Our results demonstrated that the cocktail activator acted on hepatocytes and triggered cocktail efficacy,thereby simultaneously attenuating APAP-induced hepatocyte damage and remodeling the damage microenvironment.The cocktail activator could effectively scavenge reactive oxygen species,inhibit excessive inflammatory responses and reduce cell death in impaired hepatocytes for detoxification.More importantly,the cocktail activator could remodel the damage microenvironment,thus further promoting hepatocyte expansion and specifically switching macrophages from the M1 to M2 phenotype for a favorable liver regeneration of ALF.Furthermore,in APAP-induced ALF mouse model,the cocktail activator improved liver function,alleviated histopathological damage and increased survival rate.In summary,these findings indicate that the cocktail activator may provide a promising therapeutic approach for ALF treatment as a nanomedicine.展开更多
Methacrylic acid,an important organic chemical,is commercially manufactured starting from fossil feedstock.The decarboxylation of itaconic acid derived for biomass is a green route to the synthesis of methacrylic acid...Methacrylic acid,an important organic chemical,is commercially manufactured starting from fossil feedstock.The decarboxylation of itaconic acid derived for biomass is a green route to the synthesis of methacrylic acid.In view of the problems existing in the researches on this route such as use of noble metal catalyst,harsh reaction conditions and low desired-product yield,we prepared a series of hydroxyapatite catalysts with different Ca/P molar ratios and evaluated their catalytic performance.The results showed that the hydroxyapatite catalyst with a Ca/P molar ratio of 1.58 had the best catalytic activity.The highest yield of MAA up to 61.2%was achieved with basically complete conversion of itaconic acid under the suitable reaction conditions of 1 equivalent of NaOH,2 MPa of N_(2),250℃,and 2 h.On this basis,a reaction network for the decarboxylation of itaconic acid to methacrylic acid catalyzed by hydroxyapatite was established.With the aid of catalyst characterization using X-ray powder diffraction,NH3/CO2 temperature-programmed desorption,N_(2)physisorption,inductively coupled plasma optical emission spectrometry,and scanning electron microscopy,we found that the distribution of surface acid sites and basic sites,crystal growth orientation,texture properties and morphology of hydroxyapatite varied with the Ca/P molar ratio.Furthermore,the change of the crystal growth orientation and its influence on the surface acidity and alkalinity were clarified.展开更多
Hydrocarbon-derived polymers have been utilized in various packaging applications, such as pouches, films, foamed containers, rigid containers, and multiple components for medical, food, and other uses. However, mount...Hydrocarbon-derived polymers have been utilized in various packaging applications, such as pouches, films, foamed containers, rigid containers, and multiple components for medical, food, and other uses. However, mounting environmental considerations increased knowledge of the harmful consequences of greenhouse gas emissions, landfills, and disposal difficulties. Rising oil prices are forcing researchers and businesses to produce environmentally friendly packaging. These new sustainability requirements are particularly suited to biomass-based products, instead of petroleum sources;sourced from biomass entities. More functional and performance-oriented packaging is necessary despite the widespread usage of bio-based materials like paper. As a result, the transition to eco-friendly packaging will necessitate the improvement of existing bio-derived packaging and the development of new bio-derived materials like biopolymer paper coatings. The goal of this brief study was to give a synopsis of the present status of bio-derived packaging and an insight into ongoing and prospective developments in sustainable next-generation paper coatings for the packaging industry.展开更多
Poly(aspartic acid-itaconic acid) copolymer was synthesized from aspartic acid(Asp) and itaconic acid(Ita) under microwave irradiation. The effects of microwave power, microwave irradiation time, molar ratio of itacon...Poly(aspartic acid-itaconic acid) copolymer was synthesized from aspartic acid(Asp) and itaconic acid(Ita) under microwave irradiation. The effects of microwave power, microwave irradiation time, molar ratio of itaconic acid and aspartic acid, catalyst type, catalyst and organic solvent content on copolymer yield, and the performance for inhibition of CaCO_3 fouling were investigated. It was found that the product yield achieved a highest record of 95% when the amount of catalyst Na H_2PO_4 was 0.012 mol, the amount of organic solvent propylene carbonate was 16 m L, the molar ratio of Asp/Ita was 3:1, the microwave output power was 1200 W and the irradiation time was 5.5 min. And the product performance for inhibition of calcium carbonate also reached a highest value of 94.38%. Structural characterization of the product showed that the product was the aspartic acid-itaconic acid copolymer.展开更多
The terpolymer of itaconic acid, acrylamide and 2-acrylamido-2-methyl-1-propane sulfonic acid was synthesized through the free-radical polymerization. The IR spectra confirmed that there was no olefinic band, while th...The terpolymer of itaconic acid, acrylamide and 2-acrylamido-2-methyl-1-propane sulfonic acid was synthesized through the free-radical polymerization. The IR spectra confirmed that there was no olefinic band, while the TGA results revealed that the terpolymer was of high thermal stability.展开更多
Cotton fabric samples are padded with maleic acid (MA) and itaconic acid (IA) finishing bath in the presence of potassium persulfate (K 2S 2O 8), and then dried at different temperatures for different time intervals. ...Cotton fabric samples are padded with maleic acid (MA) and itaconic acid (IA) finishing bath in the presence of potassium persulfate (K 2S 2O 8), and then dried at different temperatures for different time intervals. The portion of unreacted monomers on cotton fabric samples is determined by means of measuring the double bond content. The kinetic data (rate constants, Arrhenius activation energy, frequency factor) of the in-situ polymerization have been calculated.展开更多
The reaction mechanism of IA/MA copolymer system andcotton cellulose is conjectured and verified, the two keysteps, such as the formation of cyclic anhydride interme-diates and the building of ester crosslinklng, and ...The reaction mechanism of IA/MA copolymer system andcotton cellulose is conjectured and verified, the two keysteps, such as the formation of cyclic anhydride interme-diates and the building of ester crosslinklng, and the ef-fect of sodium hypophosphite are especially emphasized,by FT - IR spectroscopy and acid- base titration anal-yses. The experiments reveal that carboxylic acids main.ly change to cyclic anhydride in the pre - drying step andSodium Hypophosphite (SHP) has effect on it, but mostester - crosslinkages are built in the curing step and SHPhas effects on both anhydride formation and ester -crosslinking formation.展开更多
With N-vinyl-2-pyrrolidone (NVP) and itaconic acid(IA), poly(N-vinyl-2-pyrrolidone/itaconic acid)[P(NVP/IA)] hydrogel was synthesized by free radical solution polymerization. The structure of this (P(NVP/IA)) was char...With N-vinyl-2-pyrrolidone (NVP) and itaconic acid(IA), poly(N-vinyl-2-pyrrolidone/itaconic acid)[P(NVP/IA)] hydrogel was synthesized by free radical solution polymerization. The structure of this (P(NVP/IA)) was characterized by IR. Effects of concentration of itaconic acid, amount of cross-link agent, N,N′-methylene-bis-acrylamide, reaction temperature, and time on properties of swelling ratio(SR) of the hydrogel were investigated.The results show that the best swelling property of the hydrogel is obtained at 50 ℃ and 1.5 h. pH sensitivity increases as the concentration of itaconic acid in the hydrogel system increases. Swelling ratio of the hydrogel decreases as the amount of cross-link agent increases.展开更多
基金supported by the National Natural Science Foundation of China(NSFC)(No.82130073,No.82372430,No.31871431,No.31821002,No.32101011,No.22177073)Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System+3 种基金Shanghai Science and Technology Committee(No.23ZR1437600,No.24410710600,No.24141901302)Shenzhen Medical Research Fund(No.B2302005)The Open Project Funding of Shanghai Key Laboratory of Orthopedics(No.KFKT202201)Biomaterials and Regenerative Medicine Institute Cooperative,Research Project,Shanghai Jiao Tong University School of Medicine(No.2022LHA01).
文摘Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly elevated in the serum and synovial fluid of rheumatoid arthritis patients and we demonstrated that itaconate is primarily produced by inflammatory macrophages rather than osteoclasts or osteoblasts.In TNF-transgenic and Irg1−/−hybrid mice,a more severe bone destruction phenotype was observed.
基金funded by the National Natural Science Foun-dation of China(grant numbers 82322027 to T.Z.,82341043 to T.Z.,and 92369108 to J.Z.)the National Key Research and Development Program of China(grant number 2023YFC2307602 to J.Z.)+1 种基金the Natural Science Foundation of Beijing Municipal(grant number L234007 to T.Z.)the Fundamental Research Funds for the Central Universities(grant number 20720220003 to N.X.).
文摘Itaconate(ITA),an immunomodulatory metabolite with known anti-inflammatory properties,has underexplored therapeutic or prophylactic potential against coronavirus disease 2019(COVID-19).Using an interanimal transmission golden hamster model of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-induced acute lung injury,we first assessed ITA changes in dNS1-RBD-vaccinated hamsters via metabolomic profiling.Then,we evaluated prophylactic intranasal(20 mg/kg at 9,6,and 3 days before SARS-CoV-2 infection)and therapeutic intraperitoneal(100 mg/kg at 6,24,and 48 hours post-infection)ITA administration,assessed by histopathology,transcriptomic,and metabolomic profiling,followed by multi-omics integration,including gene expression clustering,pathway enrichment,and cytokine/chemokine–metabolites correlation analyses.Public bronchoalveolar lavage fluid(BALF)single-cell RNA-sequencing(scRNA-seq)datasets from COVID-19 patients were re-analyzed to explore macrophage heterogeneity.Intranasal dNS1-RBD vaccine upregulated ITA levels,prompting further exploration of its immunomodulatory role.Both prophylactic and therapeutic ITA treatments significantly mitigated weight loss and improved lung pathology.Correlation analyses implied a potential regulatory crosstalk between fatty acid b-oxidation(FAO)and reduced inflammatory response.Reanalysis of BALF scRNA-seq dataset highlighted transcriptional networks involving PPARG,RARA,BHLHE41,TCF7L2,and ESRRA—genes linked to macrophage self-renewal and metabolic homeostasis,which appeared to be preserved in ITA-treated hamsters.These findings underscore ITA’s role in modulating immunometabolic responses,particularly through FAO-driven macrophage reprogramming,to attenuate SARS-CoV-2-induced lung damage.Together,this study provides insights into host-directed therapies targeting metabolic reprogramming to mitigate COVID-19 severity.
基金supported by the National Natural Science Foundation of China (31971282 and 32071362)2019 Chongqing Graduate Tutor Team Construction Project (dstd201903)Scientific and Technological Research Program of Chongqing Municipal Education Commission (KJQN201900415)。
文摘Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate(4-OI) is a cell-permeable itaconate derivative and has been recognized as a promising therapeutic target for the treatment of inflammatory diseases. Here, we explored, for the first time,the protective effect of 4-OI on inhibiting periodontal destruction, ameliorating local inflammation, and the underlying mechanism in periodontitis. Here we showed that 4-OI treatment ameliorates inflammation induced by lipopolysaccharide in the periodontal microenvironment. 4-OI can also significantly alleviate inflammation and alveolar bone loss via Nrf2 activation as observed on samples from experimental periodontitis in the C57BL/6 mice. This was further confirmed as silencing Nrf2 blocked the antioxidant effect of 4-OI by downregulating the expression of downstream antioxidant enzymes. Additionally, molecular docking simulation indicated the possible mechanism under Nrf2 activation. Also, in Nrf2-/-mice, 4-OI treatment did not protect against alveolar bone dysfunction due to induced periodontitis, which underlined the importance of the Nrf2 in 4-OI mediated periodontitis treatment.Our results indicated that 4-OI attenuates inflammation and oxidative stress via disassociation of KEAP1-Nrf2 and activation of Nrf2 signaling cascade. Taken together, local administration of 4-OI offers clinical potential to inhibit periodontal destruction,ameliorate local inflammation for more predictable periodontitis.
基金Project supported by the National Basic Research Program (973) of China (No. 10574109)the Zhejiang Provincial Science and Technology Department (No. 2005C24008)the Natural Science Foundation of Zhejiang Province (No. Y604064), China
文摘The unperturbed dimension and temperature character of poly(dibenzyl itaconate)s (PDBzI) are studied by a revised rotational isomeric state (RIS) method. The improved formulas of the mean-square radius of gyration, deduced by the pseudo-stereochemical equilibrium approach, may be used to investigate the configurational-conformational properties of atactic polymers with large side groups [poly(itaconates) for instance]. The calculated results showed that poly(itaconates) have larger dimension of the molecule than other vinyl polymers. Comparison of the dimension between considering and without considering side groups showed that the effect of large side groups on the unperturbed dimension for short-chain polymers is more obvious than that of long-chain polymers and, if the dimension of side groups increases, the effect also increases. The dimension differences of PDBzI between short-chain and long-chain polymers are investigated by the relation of characteristic ratios and temperature coefficients with temperature. Moreover, the dependence between the temperature coefficients and the tacticity of chains shows that the temperature characters of the isotactic, syndiotactic and atactic PDBzI chains have remarkable difference.
文摘Dodecyl itaconate (DI) was used as the dispersant for preparation of mono-dispersed carbon nanotubes in aqueous solution in this study. It is a unique type of anionic surfactant synthesized by the authors, and its high capability for dispersing CNTs is attributed to the double bond moiety on its head-group. Furthermore, author mixed aqueous mono-dispersed CNTs with pulp to produce the CNT-based paper. Different from the reported papermaking process, a novel adjusting PH process was employed to prepare paper. This method could transfer easily dispersing mono-dispersed CNTs in aqueous onto the surfaces of cellulose fibers, because PH adjustment of CNT-pulp is from the initial neutrality to weak acidity and then raising to alkalinity, The dispersion of tubes in cellulose matrix and characteristics of composite were investigated. Also, electrical resistance for retrieved CNT-based sheets was measured using fore-probe method.
基金funded by National Natural Science Foundation of China(82000587,82202382)the Beijing Municipal Natural Science Foundation(7242135)。
文摘Background and aims:Methane has shown protective effects against ischemia and reperfusion injury(IRI)in the liver,but the mechanism underlying these beneficial effects is unclear.To investigate the hypothesis that itaconate facilitates in methane-induced Nrf2 pathway activation to mitigate liver IRI.Methods:An oxygen and glucose derivation(OGD)model using RAW 264.7 cells and a liver IRI model in mice were established.Methane's beneficial effects were assessed through hematoxylin and eosin(HE)staining,Suzuki's score,serum alanine transferase level,superoxide dismutase(SOD)level,malondialdehyde(MDA)level,and cell viability.The relative expression levels of Nrf2,its downstream molecules and some inflammatory factors were detected via western blotting.Itaconate levels were analyzed using liquid chromatography.RAW 264.7 cells were transfected with short hairpin RNA targeting mouse aconitate decarboxylase 1(Acod1)mRNA for itaconate downregulation.Results:Methane significantly alleviated liver IRI,as shown by the significant reduction in Suzuki's scores and alanine transferase(ALT)levels in vivo.Methane treatment significantly increased MTT and SOD levels and decreased MDA levels in the OGD injury model in vitro.Methane also increased the total and nuclear Nrf2 expression levels,activated downstream molecules including heme oxygenase-1(HO-1),NQO1 and affected the production of inflammatory cytokines such as IL-10,IL-1β,and IL-12.Itaconate levels were significantly elevated after methane treatment compared with the OGD injury group.The protective effects of methane were abolished after itaconate downregulation through Acod1 knockdown.Conclusions:Methane alleviates liver IRI through itaconate/Nrf2 pathway activation,with itaconate being critical for methane's beneficial effects.
基金supported by the Foundation of Chongqing Talents(grant no.CQYC2021059825).
文摘Purpose:To investigate the pathological changes of the synovium in mice with post-traumatic osteoarthritis(PTOA)treated with 4-octyl itaconate(4-OI)and evaluate the therapeutic effects of 4-OI.Methods:In the phenotypic validation experiment,the mice were randomly divided into 3 groups:wildtype(WT)group,sham group,and destabilization of the medial meniscus(DMM)group.Through MRI,micro-CT,and histological analysis,it was determined that the DMM surgery induced a mouse PTOA model with significant signs of synovitis.At 12 weeks post-DMM surgery,synovial tissues from the DMM group and WT group mice were collected for ribonucleic acid sequencing analysis.In the 4-OI treatment experiment,mice were randomly divided into the sham group,DMM group,DMM+4-OI(50 mg/kg)group,and DMM+4-OI(100 mg/kg)group.Von Frey tests and open field tests were conducted at intervals during the 12 weeks following the DMM surgery.After 12 weeks of surgery,the efficacy of 4-OI treatment on PTOA in mice was evaluated using MRI,micro-CT,histological analysis,and quantitative real-time polymerase chain reaction.Finally,we utilized network pharmacology analysis to predict the mechanism of 4-OI in treating PTOA synovitis and conducted preliminary validation.Statistical analysis was performed using one-way ANOVA and the Kruskal-Wallis test.Difference was considered statistically significant at p<0.05.Results:The DMM surgery effectively induced a PTOA mouse model,which displayed significant symptoms of synovitis.These symptoms included a notable increase in both the number of calcified tissues and osteophytes(p<0.001),an enlargement of the calcified meniscus and synovial tissue volume(p<0.001),and thickening of the synovial lining layer attributable to M1 macrophage accumulation(p=0.035).Additionally,we observed elevated histological scores for synovitis(p<0.001).Treatment with 4-OI inhibited the thickening of M1 macrophages in the synovial lining layer of PTOA mice(p<0.001)and reduced fibrosis in the synovial stroma(p=0.004).Furthermore,it reduced the histological scores of knee synovitis in PTOA mice(p=0.006)and improved the inflammatory microenvironment associated with synovitis.Consequently,this treatment alleviated pain in PTOA mice(p<0.001)and reduced spontaneous activity(p=0.003).Bioinformatics and network pharmacology analyses indicated that 4-OI may exert its therapeutic effects by inhibiting the differentiation of synovial Th17 cells.Specifically,compared to the lipopolysaccharide stimulation group,4-OI reduced the levels of positive regulatory factors of Th17 cell differentiation(IL-1:p<0.001,IL-6:p<0.001),key effector molecules(IL-17A:p<0.001,IL-17F:p=0.004),and downstream effector molecules in the IL-17 signaling pathway(CCL2:p<0.001,MMP13:p<0.001).Conclusion:4-OI is effective in inhibiting synovitis in PTOA,thereby alleviating the associated painful symptoms.
基金supported by grants from The Ministry of Science and Technology of China(2020YFC2002800 to Jing Wang)the National Natural Science Foundation of China(82371760 to Jing Wang and 82272181 to Yan Luo).
文摘Cytokine storm syndrome(CSS)is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies,infections,and autoimmune conditions.However,the potential interplay between innate immune cells is not fully understood.Here,using poly I:C and lipopolysaccharide(LPS)-induced cytokine storm models,a protective role of neutrophils through the modulation of macrophage activation was identified in a CSS model.Intravital imaging revealed neutrophil-derived extracellular vesicles(NDEVs)in the liver and spleen,which were captured by macrophages.NDEVs suppressed proinflammatory cytokine production by macrophages when cocultured in vitro or infused into CSS models.Metabolic profiling of macrophages treated with NDEV revealed elevated levels of the anti-inflammatory metabolite,itaconate,which is produced from cis-aconitate in the Krebs cycle by cis-aconitate decarboxylase(Acod1,encoded by Irg1).Irg1 in macrophages,but not in neutrophils,was critical for the NDEV-mediated anti-inflammatory effects.Mechanistically,NDEVs delivered miR-27a-3p,which suppressed the expression of Suclg1,the gene encoding the enzyme that metabolizes itaconate,thereby resulting in the accumulation of itaconate in macrophages.These findings demonstrated that neutrophil-to-macrophage communication mediated by extracellular vesicles is critical for promoting the anti-inflammatory reprogramming of macrophages in CSS and may have potential implications for the treatment of this fatal condition.
基金supported by the Natural Science Foundation of Shandong Province(No.ZR2022MB034)。
文摘Functional materials synthesized from bio-based building blocks are fascinating and challenging in the fields of chemistry and materials science.Herein,we present a versatile strategy for synthesizing bio-based stimulus-responsive polymers derived from itaconic acid(IA).Bearing an azobenzene-containing side chain,the IA-based epoxy polymer exhibited both photoresponsiveness and acid/base-stimulus responsiveness.With controllable manipulation of the stress field of the wrinkling IA-polymer film via the stress relaxation effect resulting from the reversible cis-trans isomerization of the azobenzene moieties or solvent-induced swelling of the film,various tailor-made patterned wrinkling surfaces were conveniently fabricated.More importantly,the azobenzene protonation/deprotonation yields a reversible visual color transformation between pale yellow and purple in the film,which allows these IA-based polymer-coated surfaces to be utilized as rewritable information storage media.Various elegant pattern information can be acid-printed and base-erased(within 10 s)for multiple cycles and legible for over one day under laboratory conditions.Notably,the aforementioned dual-stimulus responsiveness of the IA-based polymer film enables its surface to be applied in information encryption.This study not only paves a new avenue for the convenient fabrication of stimulus-responsive surfaces but also sheds light on the development of functional polymers through green engineering.
基金financially supported by the National Natural Science Foundation of China(No.52377025)。
文摘The most widely used bisphenol A-type epoxy resin(DGEBA)in electrical engineering demonstrates excellent mechanical and electrical properties.However,the insoluble and infusible characteristics of cured DGEBA make it difficult to efficiently degrade and recycle decommissioned electrical equipment.In this study,a degradable itaconic acid-based epoxy resin incorporating dynamic covalent bonds was prepared through the integration of ester bonds and disulfide bonds,with itaconic acid as the precursor.The covalent bonding effects on the mechanical,thermal,electrical,and degradation characteristics were systematically evaluated.The experimental results revealed that the introduction of dynamic ester bonds enhanced the mechanical properties and thermal stability of the resin system,achieving a flexural strength of 141.57 MPa and an initial decomposition temperature T_(5%)of up to 344.9℃.The resin system containing dynamic disulfide bonds exhibited a dielectric breakdown strength of 41.11 k V/mm.Simultaneously,the incorporation of disulfide bonds endowed the epoxy resin with remarkable degradability,enabling complete dissolution within 1.5 h at 90℃ in a mixed solution of dithiothreitol(DTT)and N-methylpyrrolidone(NMP).This research provides a valuable reference for the application of itaconic acid-based vitrimer with dynamic covalent bonds in electrical materials,contributing to the development and utilization of environmentally friendly electrical equipment.
基金supported by National Natural Science Foundation of China(21978066)Basic Research Program of Hebei Province for Natural Science Foundation and Key Basic Research Project(18964308D)the Key Program of Natural Science Foundation of Hebei Province(B2020202048).
文摘The synthesis of methacrylic acid from biomass-derived itaconic acid is a green route,for it can get rid of the dependence on fossil resource.In order to solve the problems on this route such as use of a preciousmetal catalyst and a corrosive homogeneous alkali,we prepared a series of hydroxyapatite catalysts by an ionic liquid-assisted hydrothermal method and evaluated their catalytic performance.The results showed that the ionic liquid[Bmim]BF_(4) can affect the crystal growth of hydroxyapatite,provide fluoride ion for fluorination of hydroxyapatite,and adjust the surface acidity and basicity,morphology,textural properties,crystallinity,and composition of hydroxyapatite.The[Bmim]BF4 dosage and hydrothermal temperature can affect the fluoride ion concentration in the hydrothermal system,thus changing the degree of fluoridation of hydroxyapatite.High fluoride-ion concentration can lead to the formation of CaF_(2) and thus significantly decrease the catalytic performance of hydroxyapatite.The hydrothermal time mainly affects the growth of hydroxyapatite crystals on the c axis,leading to different catalytic performance.The suitable conditions for the preparation of this fluoridized hydroxyapatite are as follows:a mass ratio of[Bmim]BF4 to calcium salt=0.2:1,a hydrothermal time of 12 h,and a hydrothermal temperature of 130℃.A maximal methacrylic acid yield of 54.7%was obtained using the fluoridized hydroxyapatite under relatively mild reaction conditions(250℃ and 2 MPa of N_(2))in the absence of a precious-metal catalyst and a corrosive homogeneous alkali.
基金supported by National Natural Science Foundation of China(Project No.81872805,82073771,82104085)Guangdong Basic and Applied Basic Research Foundation(Project No.2020A1515110147,2021A1515011418,2021A1515012025)。
文摘Acute liver failure(ALF)is a mortal and critical hepatic disease,in which oxidative stress,inflammation storm and hepatocyte death are crucial in the pathogenesis.Hence,in contrast to the control of a single link,a combination therapy targeting multiple pathogenic links of the disease will be a favorable means to control the progression of the disease.In this study,we constructed dimethyl itaconate-loaded liposomes modified with dodecyl gallate as a cocktail activator to investigate its functional role in acetaminophen(APAP)-induced ALF.Our results demonstrated that the cocktail activator acted on hepatocytes and triggered cocktail efficacy,thereby simultaneously attenuating APAP-induced hepatocyte damage and remodeling the damage microenvironment.The cocktail activator could effectively scavenge reactive oxygen species,inhibit excessive inflammatory responses and reduce cell death in impaired hepatocytes for detoxification.More importantly,the cocktail activator could remodel the damage microenvironment,thus further promoting hepatocyte expansion and specifically switching macrophages from the M1 to M2 phenotype for a favorable liver regeneration of ALF.Furthermore,in APAP-induced ALF mouse model,the cocktail activator improved liver function,alleviated histopathological damage and increased survival rate.In summary,these findings indicate that the cocktail activator may provide a promising therapeutic approach for ALF treatment as a nanomedicine.
基金supported by the National Natural Science Foundation of China(Grant No.21978066)Basic Research Program of Hebei Province for Natural Science Foundation and Key Basic Research Project(Grant No.18964308D)the Key Program of Natural Science Foundation of Hebei Province(Grant No.B2020202048).
文摘Methacrylic acid,an important organic chemical,is commercially manufactured starting from fossil feedstock.The decarboxylation of itaconic acid derived for biomass is a green route to the synthesis of methacrylic acid.In view of the problems existing in the researches on this route such as use of noble metal catalyst,harsh reaction conditions and low desired-product yield,we prepared a series of hydroxyapatite catalysts with different Ca/P molar ratios and evaluated their catalytic performance.The results showed that the hydroxyapatite catalyst with a Ca/P molar ratio of 1.58 had the best catalytic activity.The highest yield of MAA up to 61.2%was achieved with basically complete conversion of itaconic acid under the suitable reaction conditions of 1 equivalent of NaOH,2 MPa of N_(2),250℃,and 2 h.On this basis,a reaction network for the decarboxylation of itaconic acid to methacrylic acid catalyzed by hydroxyapatite was established.With the aid of catalyst characterization using X-ray powder diffraction,NH3/CO2 temperature-programmed desorption,N_(2)physisorption,inductively coupled plasma optical emission spectrometry,and scanning electron microscopy,we found that the distribution of surface acid sites and basic sites,crystal growth orientation,texture properties and morphology of hydroxyapatite varied with the Ca/P molar ratio.Furthermore,the change of the crystal growth orientation and its influence on the surface acidity and alkalinity were clarified.
文摘Hydrocarbon-derived polymers have been utilized in various packaging applications, such as pouches, films, foamed containers, rigid containers, and multiple components for medical, food, and other uses. However, mounting environmental considerations increased knowledge of the harmful consequences of greenhouse gas emissions, landfills, and disposal difficulties. Rising oil prices are forcing researchers and businesses to produce environmentally friendly packaging. These new sustainability requirements are particularly suited to biomass-based products, instead of petroleum sources;sourced from biomass entities. More functional and performance-oriented packaging is necessary despite the widespread usage of bio-based materials like paper. As a result, the transition to eco-friendly packaging will necessitate the improvement of existing bio-derived packaging and the development of new bio-derived materials like biopolymer paper coatings. The goal of this brief study was to give a synopsis of the present status of bio-derived packaging and an insight into ongoing and prospective developments in sustainable next-generation paper coatings for the packaging industry.
基金supported financially from the National Natural Science Foundation of China (Grant No. 51308211)the State Key Laboratory of Urban Water Resource and Environment (HIT) (Grant No. ES200903)the Fundamental Research Funds for the Central Universities (Grant No. 2015MS63)
文摘Poly(aspartic acid-itaconic acid) copolymer was synthesized from aspartic acid(Asp) and itaconic acid(Ita) under microwave irradiation. The effects of microwave power, microwave irradiation time, molar ratio of itaconic acid and aspartic acid, catalyst type, catalyst and organic solvent content on copolymer yield, and the performance for inhibition of CaCO_3 fouling were investigated. It was found that the product yield achieved a highest record of 95% when the amount of catalyst Na H_2PO_4 was 0.012 mol, the amount of organic solvent propylene carbonate was 16 m L, the molar ratio of Asp/Ita was 3:1, the microwave output power was 1200 W and the irradiation time was 5.5 min. And the product performance for inhibition of calcium carbonate also reached a highest value of 94.38%. Structural characterization of the product showed that the product was the aspartic acid-itaconic acid copolymer.
文摘The terpolymer of itaconic acid, acrylamide and 2-acrylamido-2-methyl-1-propane sulfonic acid was synthesized through the free-radical polymerization. The IR spectra confirmed that there was no olefinic band, while the TGA results revealed that the terpolymer was of high thermal stability.
基金Shanghaimunicipalscienceandtechnologydevelopmentfund (No .0 113110 15 )andShanghaimunicipalkeydisciplineproject
文摘Cotton fabric samples are padded with maleic acid (MA) and itaconic acid (IA) finishing bath in the presence of potassium persulfate (K 2S 2O 8), and then dried at different temperatures for different time intervals. The portion of unreacted monomers on cotton fabric samples is determined by means of measuring the double bond content. The kinetic data (rate constants, Arrhenius activation energy, frequency factor) of the in-situ polymerization have been calculated.
文摘The reaction mechanism of IA/MA copolymer system andcotton cellulose is conjectured and verified, the two keysteps, such as the formation of cyclic anhydride interme-diates and the building of ester crosslinklng, and the ef-fect of sodium hypophosphite are especially emphasized,by FT - IR spectroscopy and acid- base titration anal-yses. The experiments reveal that carboxylic acids main.ly change to cyclic anhydride in the pre - drying step andSodium Hypophosphite (SHP) has effect on it, but mostester - crosslinkages are built in the curing step and SHPhas effects on both anhydride formation and ester -crosslinking formation.
文摘With N-vinyl-2-pyrrolidone (NVP) and itaconic acid(IA), poly(N-vinyl-2-pyrrolidone/itaconic acid)[P(NVP/IA)] hydrogel was synthesized by free radical solution polymerization. The structure of this (P(NVP/IA)) was characterized by IR. Effects of concentration of itaconic acid, amount of cross-link agent, N,N′-methylene-bis-acrylamide, reaction temperature, and time on properties of swelling ratio(SR) of the hydrogel were investigated.The results show that the best swelling property of the hydrogel is obtained at 50 ℃ and 1.5 h. pH sensitivity increases as the concentration of itaconic acid in the hydrogel system increases. Swelling ratio of the hydrogel decreases as the amount of cross-link agent increases.
