Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis

Doxorubicin(DOX)is a commonly administered chemotherapy drug for treating hematological malignancies and solid tumors;however,its clinical application is limited by significant cardiotoxicity.Cynaroside(Cyn)is a flavonoid glycoside distributed in honeysuckle,with confirmed potential biological functions in regulating inflammation,pyroptosis,and oxidative stress.Herein,the effects of Cyn were evaluated in a DOX-induced cardiotoxicity(DIC)mouse model,which was established by intraperitoneal injections of DOX(5 mg/kg)once a week for three weeks.The mice in the treatment group received dexrazoxane,MCC950,and Cyn every two days.Blood biochemistry,histopathology,immunohistochemistry,reverse transcription-quantitative polymerase chain reaction(RT-qPCR),and western blotting were conducted to investigate the cardioprotective effects and potential mechanisms of Cyn treatment.The results demonstrated the significant benefits of Cyn treatment in mitigating DIC;it could effectively alleviate oxidative stress to a certain extent,maintain the equilibrium of cell apoptosis,and enhance the cardiac function of mice.These effects were realized via regulating the transcription levels of pyroptosis-related genes,such as nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),caspase-1,and gasdermin D(GSDMD).Mechanistically,for DOX-induced myocardial injury,Cyn could significantly modulate the expression of pivotal genes,including adenosine monophosphate-activated protein kinase(AMPK),peroxisome proliferator-activated receptorγcoactivator-1α(PGC-1α),sirtuin 3(SIRT3),and nuclear factor erythroid 2-related factor 2(Nrf2).We attribute it to the mediation of AMPK/SIRT3/Nrf2 pathway,which plays a central role in preventing DOX-induced cardiomyocyte injury.In conclusion,the present study confirms the therapeutic potential of Cyn in DIC by regulating the AMPK/SIRT3/Nrf2 pathway.

Human hair follicle-derived mesenchymal stem cells promote tendon repair in a rabbit Achilles tendinopathy model

Background:Hair follicles are easily accessible and contain stem cells with different developmental origins,including mesenchymal stem cells(MSCs),that consequently reveal the potential of human hair follicle(hHF)-derived MSCs in repair and regeneration.However,the role of hHF-MSCs in Achilles tendinopathy(AT)remains unclear.The present study investigated the effects of hHF-MSCs on Achilles tendon repair in rabbits.Methods:First,we extracted and characterized hHF-MSCs.Then,a rabbit tendinopathy model was constructed to analyze the ability of hHF-MSCs to promote repair in vivo.Anatomical observation and pathological and biomechanical analyses were performed to determine the effect of hHF-MSCs on AT,and quantitative real-time polymerase chain reaction,enzyme-linked immunosorbent assay,and immunohistochemical staining were performed to explore the molecular mechanisms through which hHF-MSCs affects AT.Furthermore,statistical analyses were performed using independent sample t test,one-way analysis of variance(ANOVA),and one-way repeated measures multivariate ANOVA as appropriate.Results:Flow cytometry,a trilineage-induced differentiation test,confirmed that hHF-derived stem cells were derived from MSCs.The effect of hHF-MSCs on AT revealed that the Achilles tendon was anatomically healthy,as well as the maximum load carried by the Achilles tendon and hydroxyproline proteomic levels were increased.Moreover,collagen I and III were upregulated in rabbit AT treated with hHF-MSCs(compared with AT group;P<0.05).Analysis of the molecular mechanisms revealed that hHF-MSCs promoted collagen fiber regeneration,possibly through Tenascin-C(TNC)upregulation and matrix metalloproteinase(MMP)-9 downregulation.Conclusions:hHF-MSCs can be a treatment modality to promote AT repair in rabbits by upregulating collagen I and III.Further analysis revealed that treatment of AT using hHF-MSCs promoted the regeneration of collagen fiber,possibly because of upregulation of TNC and downregulation of MMP-9,thus suggesting that hHF-MSCs are more promising for AT.

3D printing of Mg-substituted wollastonite reinforcing diopside porous bioceramics with enhanced mechanical and biological performances

Mechanical strength and its long-term stability of bioceramic scaffolds is still a problem to treat the osteonecrosis of the femoral head.Considering the long-term stability of diopside(DIO)ceramic but poor mechanical strength,we developed the DIO-based porous bioceramic composites via dilute magnesium substituted wollastonite reinforcing and three-dimensional(3D)printing.The experimental results showed that the secondary phase(i.e.10%magnesium substituting calcium silicate;CSM10)could readily improve the sintering property of the bioceramic composites(DIO/CSM10-x,x=0-30)with increasing the CSM10 content from 0%to 30%,and the presence of the CSM10 also improved the biomimetic apatite mineralization ability in the pore struts of the scaffolds.Furthermore,the flexible strength(12.5 -30 MPa)and compressive strength(14-37 MPa)of the 3D printed porous bioceramics remarkably increased with increasing CSM10 content,and the compressive strength of DIO/CSM10-30 showed a limited decay(from 37 MPa to 29 MPa)in the Tris buffer solution for a long time stage(8 weeks).These findings suggest that the new CSM10-reinforced diopside porous constructs possess excellent mechanical properties and can potentially be used to the clinic,especially for the treatment of osteonecrosis of the femoral head work as a bioceramic rod.

BSA stabilized photothermal-fenton reactor with cisplatin for chemo/chemodynamic cascade oncotherapy

Cisplatin(CDDP)-based chemotherapy is substantially limited in the clinic due to its high postoperative recurrence rate.Synergy therapy has been proven as a potent approach to minimize recurrence and achieve enhanced treatment effects.Herein,chemotherapy drug CDDP is assembled with the photothermal-Fenton agent of bovine serum albumin(BSA)stabilized gallic acid-functionalized iron nanoparticles(GA-Fe NPs)to achieve chemo/chemodynamic synergistic cascade oncotherapy.The Pt-GA-Fe NPs can be utilized to generate H_(2)O_(2) via the activation of nicotinamide adenine dinucleotide phosphate(NADPH)oxidases(NOXs)in the tumor microenvironment(TME),which would then greatly boost H2O2-depending chemodynamic therapy(CDT).The generated cytotoxic reactive oxygen species(hydroxyl radicals,·OH)and the depletion of glutathione(GSH)would further promote CDDP-induced DNA damage.Moreover,benefiting from the absorption in the near-infrared(NIR)region,Pt-GA-Fe NPs exhibit excellent photothermal conversion efficiency(η=45.5%)and allow photoacoustic imaging(PAI)guided photothermal therapy(PTT).In vitro and in vivo experiments show that synergy therapy can effectively kill cancer cells and successfully cure cancer without systemic toxicity.The work highlights a new type of therapeutic agent based on CDDP with the ability of H_(2)O_(2) self-generation,thermal responsiveness,and enhanced CDT effects for applications in cancer therapy.