Bone morphogenetic protein 9 (BMP9) has remarkable potential to induce the differentiation of mesenchymal stem cells (MSCs) towards the osteoblastic lineage. Additionally,research suggests that certain growth factors ...Bone morphogenetic protein 9 (BMP9) has remarkable potential to induce the differentiation of mesenchymal stem cells (MSCs) towards the osteoblastic lineage. Additionally,research suggests that certain growth factors have the ability to potentiate BMP9-inducedosteogenic differentiation of MSCs. Sonic Hedgehog (Shh) plays an indispensable role in theregulation of skeletal development. The objective of this research was to assess the potentialinfluence of Shh on BMP9-induced osteogenic differentiation of MSCs. Our findings indicatedthat Shh effectively enhanced BMP9-induced early and late osteogenic differentiation of MSCs,and increased BMP9-induced expression/transcriptional activity of osteogenesis-related transcription factors. Besides, it was observed that Shh promoted BMP9-induced ectopic bone formation of MSCs in vivo. Moreover, BMP9 was able to facilitate the repair of bone defects inrats, while Shh further accelerated this reparative process. Mechanistically, Shh enhancedthe activation of the Smad1/5/8 signaling pathway which was induced by BMP9. Furthermore,GANT-61, an inhibitor of Gli1 and Gli2, attenuated the enhancing effect of Shh on BMP9-induced osteogenic differentiation of MSCs. Collectively, the co-administration of BMP9 andShh may present a promising therapeutic approach for the treatment of fracture nonunion, delayed fracture healing, and bone defects.展开更多
Subcellular mitochondria serve as sensors for energy metabolism and redox balance, and the dynamic regulation of functional and dysfunctional mitochondria plays a crucial role in determining cells' fate. Selective...Subcellular mitochondria serve as sensors for energy metabolism and redox balance, and the dynamic regulation of functional and dysfunctional mitochondria plays a crucial role in determining cells' fate. Selective removal of dysfunctional mitochondria at the subcellular level can provide chondrocytes with energy to prevent degeneration, thereby treating osteoarthritis. Herein, to achieve an ideal subcellular therapy, cartilage affinity peptide (WYRGRL)-decorated liposomes loaded with mitophagy activator (urolithin A) were integrated into hyaluronic acid methacrylate hydrogel microspheres through microfluidic technology, named HM@WY-Lip/UA, that could efficiently target chondrocytes and selectively remove subcellular dysfunctional mitochondria. As a result, this system demonstrated an advantage in mitochondria function restoration, reactive oxygen species scavenging, cell survival rescue, and chondrocyte homeostasis maintenance through increasing mitophagy. In a rat post-traumatic osteoarthritis model, the intra-articular injection of HM@WY-Lip/UA ameliorated cartilage matrix degradation, osteophyte formation, and subchondral bone sclerosis at 8 weeks. Overall, this study indicated that HM@WY-Lip/UA provided a protective effect on cartilage degeneration in an efficacious and clinically relevant manner, and a mitochondrial-oriented strategy has great potential in the subcellular therapy of osteoarthritis.展开更多
Bladder cancer (BC) is one of the most common malignant tumors in the urinary system.Due to the poor prognosis and high mortality rate of the disease,it is urgent to develop new drugs with high efficacy and low toxici...Bladder cancer (BC) is one of the most common malignant tumors in the urinary system.Due to the poor prognosis and high mortality rate of the disease,it is urgent to develop new drugs with high efficacy and low toxicity to treat BC.Echinatin (Ecn) is a bioactive natural flavonoid oflicorice that has attracted special attention for its promising anti-tumor potential.Herein,we explored the inhibitory effects of Echinatin on BC cells and probed the possible molecular mechanism.We found that Ecnin vitro inhibited the proliferation,migration,and invasion,arrested the cell cycle at the G2/M phase,and promoted apoptosis in BC cells.Besides,Ecn had no notable cytotoxicity towards human normal cells.We subsequently confirmed that Ecn restrained xenograft tumor growth and metastasis of BC cells in vivo .Mechanistically,Ecn activated the p38 signaling pathway but inactivated the Wnt/β-catenin signaling pathway,while over-expression of β-catenin and the p38 inhibitor both attenuated the inhibitory effects of Ecn on BC cells.Remarkably,Ecn combined with cisplatin (DDP) or gemcitabine (Gem) had synergistic inhibitory effects on BC cells.In summary,our results validate that Ecn inhibits the tumor growth of human BC cells via p38 and Wnt/β-catenin signaling pathways.More meaningfully,our results suggest a potential strategy to enhance DDP- or Gem-induced inhibitory effects on BC cells by combining with Ecn.展开更多
Lipid-based boundary layers formed on liposome-containing hydrogels can facilitate lubrication.However,these boundary layers can be damaged by shear,resulting in decreased lubrication.Here,a shear-responsive boundary-...Lipid-based boundary layers formed on liposome-containing hydrogels can facilitate lubrication.However,these boundary layers can be damaged by shear,resulting in decreased lubrication.Here,a shear-responsive boundary-lubricated drug-loaded hydrogel is created by incorporating celecoxib(CLX)-loaded liposomes within dynamic covalent bond-based hyaluronic acid(HA)hydrogels(CLX@Lipo@HA-gel).The dynamic cross-linked network enables the hydrogel to get restructured in response to shear,and the HA matrix allows the accumulation of internal liposome microreservoirs on the sliding surfaces,which results in the formation of boundary layers to provide stable lubrication.Moreover,hydration shells formed surrounding the hydrogel can retard the degradation process,thus helping in sustaining lubrication.Furthermore,in vitro and in vivo experiments found that CLX@Lipo@HA-gels can maintain anabolic-catabolic balance,alleviate cartilage wear,and attenuate osteoarthritis progression by delivering CLX and shear-responsive boundary lubrication.Overall,CLX@Lipo@HA-gels can serve as shear-responsive boundary lubricants and drug-delivery vehicles to alleviate friction-related diseases like osteoarthritis.展开更多
Although there are many therapeutic strategies such as surgery and chemotherapy,the prognosis of osteosarcoma(OS)is still far from being satisfactory.It is urgent to develop more effective,tolerable and safe drugs for...Although there are many therapeutic strategies such as surgery and chemotherapy,the prognosis of osteosarcoma(OS)is still far from being satisfactory.It is urgent to develop more effective,tolerable and safe drugs for the treatment of OS.In the present study,we investigated the anti-OS activity of Alantolactone(ALT),a natural eucalyptone sesquiterpene lactone mainly exists in Inula helenium,and probed the possible mechanism involved.We demonstrated that ALT significantly inhibited cell proliferation of various human OS cell lines while had relative lower cytotoxicity against normal cells.Then,we validated that ALT reduced migration,decreased invasion possibly through reversing epithelial mesenchymal transition(EMT)process and suppressing Matrix metalloproteinases(MMPs).Moreover,we confirmed that ALT promoted apoptosis and arrested cell cycle at G2/M phase of human OS cells in vitro.In addition,we confirmed that ALT restrained tumor growth and metastasis of OS 143 cells in a xenograft model in vivo.Mechanistically,ALT inhibited the activity of Wnt/β-catenin and p38,ERK1/2 and JNK Mitogen Activated Protein Kinases(MAPKs)signal pathway.Notably,the combination of ALT and Wnt/β-catenin inhibitor,as well as the combination of ALT and MAPKs inhibitors resulted in a synergistically effect on inhibiting the proliferation,migration and invasion of OS cells.Collectively,our results validate the ALT may inhibit proliferation,metastasis and promotes apoptosis of human OS cells possibly through suppressing Wnt/β-Catenin and MAPKs signaling pathways.展开更多
基金supported by the Chongqing Young and Middle-aged Medical High-end Talent Project(China)(No.2019GDRC001)Chongqing Talent Innovation and Entrepreneurship Leader Project(China)(No.cstc2022ycjhbgzxm0103)+1 种基金the funding from Deyang Science and Technology Foundation(Sichuan,China)(No.2021SZZ060)the Program for Youth Innovation in Future Medicine of Chongqing Medical University(No.W0086).
文摘Bone morphogenetic protein 9 (BMP9) has remarkable potential to induce the differentiation of mesenchymal stem cells (MSCs) towards the osteoblastic lineage. Additionally,research suggests that certain growth factors have the ability to potentiate BMP9-inducedosteogenic differentiation of MSCs. Sonic Hedgehog (Shh) plays an indispensable role in theregulation of skeletal development. The objective of this research was to assess the potentialinfluence of Shh on BMP9-induced osteogenic differentiation of MSCs. Our findings indicatedthat Shh effectively enhanced BMP9-induced early and late osteogenic differentiation of MSCs,and increased BMP9-induced expression/transcriptional activity of osteogenesis-related transcription factors. Besides, it was observed that Shh promoted BMP9-induced ectopic bone formation of MSCs in vivo. Moreover, BMP9 was able to facilitate the repair of bone defects inrats, while Shh further accelerated this reparative process. Mechanistically, Shh enhancedthe activation of the Smad1/5/8 signaling pathway which was induced by BMP9. Furthermore,GANT-61, an inhibitor of Gli1 and Gli2, attenuated the enhancing effect of Shh on BMP9-induced osteogenic differentiation of MSCs. Collectively, the co-administration of BMP9 andShh may present a promising therapeutic approach for the treatment of fracture nonunion, delayed fracture healing, and bone defects.
基金the National Natural Science Foundation of China(82072443 and 82372425)the China Postdoctoral Science Foundation(Grant No.2022M710557)+1 种基金the Natural Science Foundation of Chongqing,China(Grant No.CSTB2023NSCQ-BHX0011)the Young Excellent Science and Technology Talent Project of the First Affiliated Hospital of Chongqing Medical University(Grant No.ZYRC2022-05).
文摘Subcellular mitochondria serve as sensors for energy metabolism and redox balance, and the dynamic regulation of functional and dysfunctional mitochondria plays a crucial role in determining cells' fate. Selective removal of dysfunctional mitochondria at the subcellular level can provide chondrocytes with energy to prevent degeneration, thereby treating osteoarthritis. Herein, to achieve an ideal subcellular therapy, cartilage affinity peptide (WYRGRL)-decorated liposomes loaded with mitophagy activator (urolithin A) were integrated into hyaluronic acid methacrylate hydrogel microspheres through microfluidic technology, named HM@WY-Lip/UA, that could efficiently target chondrocytes and selectively remove subcellular dysfunctional mitochondria. As a result, this system demonstrated an advantage in mitochondria function restoration, reactive oxygen species scavenging, cell survival rescue, and chondrocyte homeostasis maintenance through increasing mitophagy. In a rat post-traumatic osteoarthritis model, the intra-articular injection of HM@WY-Lip/UA ameliorated cartilage matrix degradation, osteophyte formation, and subchondral bone sclerosis at 8 weeks. Overall, this study indicated that HM@WY-Lip/UA provided a protective effect on cartilage degeneration in an efficacious and clinically relevant manner, and a mitochondrial-oriented strategy has great potential in the subcellular therapy of osteoarthritis.
基金supported by the National Natural Science Foundation of China(No.81874001)the Program for Youth Innovation in Future Medicine of Chongqing Medical University(China)(No.W0086).
文摘Bladder cancer (BC) is one of the most common malignant tumors in the urinary system.Due to the poor prognosis and high mortality rate of the disease,it is urgent to develop new drugs with high efficacy and low toxicity to treat BC.Echinatin (Ecn) is a bioactive natural flavonoid oflicorice that has attracted special attention for its promising anti-tumor potential.Herein,we explored the inhibitory effects of Echinatin on BC cells and probed the possible molecular mechanism.We found that Ecnin vitro inhibited the proliferation,migration,and invasion,arrested the cell cycle at the G2/M phase,and promoted apoptosis in BC cells.Besides,Ecn had no notable cytotoxicity towards human normal cells.We subsequently confirmed that Ecn restrained xenograft tumor growth and metastasis of BC cells in vivo .Mechanistically,Ecn activated the p38 signaling pathway but inactivated the Wnt/β-catenin signaling pathway,while over-expression of β-catenin and the p38 inhibitor both attenuated the inhibitory effects of Ecn on BC cells.Remarkably,Ecn combined with cisplatin (DDP) or gemcitabine (Gem) had synergistic inhibitory effects on BC cells.In summary,our results validate that Ecn inhibits the tumor growth of human BC cells via p38 and Wnt/β-catenin signaling pathways.More meaningfully,our results suggest a potential strategy to enhance DDP- or Gem-induced inhibitory effects on BC cells by combining with Ecn.
基金supported by the National Key Research and Development Program of China(2020YFA0908200)the National Natural Science Foundation of China(81873998,32101104 and 81972069)Shanghai Jiao Tong University“Medical and Research”Program(ZH2018ZDA04).
文摘Lipid-based boundary layers formed on liposome-containing hydrogels can facilitate lubrication.However,these boundary layers can be damaged by shear,resulting in decreased lubrication.Here,a shear-responsive boundary-lubricated drug-loaded hydrogel is created by incorporating celecoxib(CLX)-loaded liposomes within dynamic covalent bond-based hyaluronic acid(HA)hydrogels(CLX@Lipo@HA-gel).The dynamic cross-linked network enables the hydrogel to get restructured in response to shear,and the HA matrix allows the accumulation of internal liposome microreservoirs on the sliding surfaces,which results in the formation of boundary layers to provide stable lubrication.Moreover,hydration shells formed surrounding the hydrogel can retard the degradation process,thus helping in sustaining lubrication.Furthermore,in vitro and in vivo experiments found that CLX@Lipo@HA-gels can maintain anabolic-catabolic balance,alleviate cartilage wear,and attenuate osteoarthritis progression by delivering CLX and shear-responsive boundary lubrication.Overall,CLX@Lipo@HA-gels can serve as shear-responsive boundary lubricants and drug-delivery vehicles to alleviate friction-related diseases like osteoarthritis.
基金The present research was supported by the National Natural Science Foundation of China(No.81874001)the Natural Science Foundation Project of Chongqing Science and Technology Commission(No.cstc2017jcyjAX0196).
文摘Although there are many therapeutic strategies such as surgery and chemotherapy,the prognosis of osteosarcoma(OS)is still far from being satisfactory.It is urgent to develop more effective,tolerable and safe drugs for the treatment of OS.In the present study,we investigated the anti-OS activity of Alantolactone(ALT),a natural eucalyptone sesquiterpene lactone mainly exists in Inula helenium,and probed the possible mechanism involved.We demonstrated that ALT significantly inhibited cell proliferation of various human OS cell lines while had relative lower cytotoxicity against normal cells.Then,we validated that ALT reduced migration,decreased invasion possibly through reversing epithelial mesenchymal transition(EMT)process and suppressing Matrix metalloproteinases(MMPs).Moreover,we confirmed that ALT promoted apoptosis and arrested cell cycle at G2/M phase of human OS cells in vitro.In addition,we confirmed that ALT restrained tumor growth and metastasis of OS 143 cells in a xenograft model in vivo.Mechanistically,ALT inhibited the activity of Wnt/β-catenin and p38,ERK1/2 and JNK Mitogen Activated Protein Kinases(MAPKs)signal pathway.Notably,the combination of ALT and Wnt/β-catenin inhibitor,as well as the combination of ALT and MAPKs inhibitors resulted in a synergistically effect on inhibiting the proliferation,migration and invasion of OS cells.Collectively,our results validate the ALT may inhibit proliferation,metastasis and promotes apoptosis of human OS cells possibly through suppressing Wnt/β-Catenin and MAPKs signaling pathways.
