It has been shown that the high expression of human epididymis protein 4(HE4)in most lung cancers is related to the poor prognosis of patients,but the mechanism of pathological transformation of HE4 in lung cancer is ...It has been shown that the high expression of human epididymis protein 4(HE4)in most lung cancers is related to the poor prognosis of patients,but the mechanism of pathological transformation of HE4 in lung cancer is still unclear.The current study is expected to clarify the function and mechanism of HE4 in the occurrence and metastasis of lung adenocarcinoma(LUAD).Immunoblotting evaluated HE4 expression in lung cancer cell lines and biopsies,and through analysis of The Cancer Genome Atlas(TCGA)dataset.Frequent HE4 overexpression was demonstrated in LUAD,but not in lung squamous cell carcinoma(LUSC),indicating that HE4 can serve as a biomarker to distinguish between LUAD and LUSC.HE4 knockdown significantly inhibited cell growth,colony formation,wound healing,and invasion,and blocked the G1-phase of the cell cycle in LUAD cell lines through inactivation of the EGFR signaling downstream including PI3K/AKT/mTOR and RAF/MAPK pathways.The first-line EGFR inhibitor gefitinib and HE4 shRNA had no synergistic inhibitory effect on the growth of lung adenocarcinoma cells,while the third-line EGFR inhibitor osimertinib showed additive anti-proliferative effects.Moreover,we provided evidence that HE4 regulated EGFR expression by transcription regulation and protein interaction in LUAD.Our findings suggest that HE4 positively modulates the EGFR signaling pathway to promote growth and invasiveness in LUAD and highlight that targeting HE4 could be a novel strategy for LUAD treatment.展开更多
As an important pattern recognition receptor(PRR)in the innate immune system,C-type lectin plays an important role in the innate immune process of invertebrates.Two C-type lectins Sp CTL-C and Sp CTL-D were characteri...As an important pattern recognition receptor(PRR)in the innate immune system,C-type lectin plays an important role in the innate immune process of invertebrates.Two C-type lectins Sp CTL-C and Sp CTL-D were characterized from mud crab(Scylla paramamosain).The predicted Sp CTL-C and Sp CTL-D proteins both contain a single carbohydrate-recognition domain(CRD)with key motif Gln-Pro-Ala(QPA)and Met-Pro-Ala(MPA),respectively.Sp CTL-C and Sp CTL-D transcripts distributed in all examined tissues,and the expression level was the highest in hepatopancreas.As PRR,the purifi ed recombinant proteins r Sp CTL-C and r Sp CTL-D have high affi nity for three kinds of pathogen-associated molecular patterns(PAMPs):β-glucan,lipopolysaccharide,and peptidoglycan.Besides,r Sp CTL-D can bind to all nine microorganisms tested,while r Sp CTL-C can bind to seven microorganisms except for Staphylococcus aureus and Micrococcus luteus.Both r Sp CTL-C and r Sp CTL-D showed agglutination activity towards fungi Pichia pastoris and Saccharomyces cerevisiae.However,r Sp CTL-C and r Sp CTL-D exhibited diff erent antimicrobial activities:r Sp CTL-D has a certain inhibitory eff ect on the growth of Vibrio fl uvialis and M.luteus,while r Sp CTL-C has no obvious inhibitory activity.The results show that r Sp CTL-C and r Sp CTL-D had better phagocytosis-promoting eff ect on M.luteus than the negative control.Meanwhile,both r Sp CTL-C and r Sp CTL-D had certain encapsulation-promoting activity.Collectively,two C-type lectins with novel key motifs make an important impact as PRR in immune response towards pathogens.At the same time,they play diff erent functions in the innate immunity of mud crab S.paramamosain.展开更多
The management of bacterial infections is becoming a major clinical challenge due to the rapid evolution of antibiotic resistant bacteria.As an excellent candidate to overcome antibiotic resistance,antimicrobial pepti...The management of bacterial infections is becoming a major clinical challenge due to the rapid evolution of antibiotic resistant bacteria.As an excellent candidate to overcome antibiotic resistance,antimicrobial peptides(AMPs)that are produced from the synthetic and natural sources demonstrate a broad-spectrum antimicrobial activity with the high specificity and low toxicity.These peptides possess distinctive structures and functions by employing sophisticated mechanisms of action.This comprehensive review provides a broad overview of AMPs from the origin,structural characteristics,mechanisms of action,biological activities to clinical applications.We finally discuss the strategies to optimize and develop AMP-based treatment as the potential antimicrobial and anticancer therapeutics.展开更多
Cell death is an essential biological process for physiological growth and development.Three classical forms of cell death—apoptosis,autophagy,and necrosis—display distinct morphological features by activating speci...Cell death is an essential biological process for physiological growth and development.Three classical forms of cell death—apoptosis,autophagy,and necrosis—display distinct morphological features by activating specific signaling pathways.With recent research advances,we have started to appreciate that these cell death processes can cross-talk through interconnecting,even overlapping,signaling pathways,and the final cell fate is the result of the interplay of different cell death programs.This review provides an insight into the independence of and associations among these three types of cell death and explores the significance of cell death under the specific conditions of human diseases,particularly neurodegenerative diseases and cancer.展开更多
Kidney fibrosis is an inevitable result of various chronic kidney diseases(CKDs)and significantly contributes to end-stage renal failure.Currently,there is no specific treatment available for renal fibrosis.ELA13(amin...Kidney fibrosis is an inevitable result of various chronic kidney diseases(CKDs)and significantly contributes to end-stage renal failure.Currently,there is no specific treatment available for renal fibrosis.ELA13(amino acid sequence:RRCMPLHSRVPFP)is a conserved region of ELABELA in all vertebrates;however,its biological activity has been very little studied.In the present study,we evaluated the therapeutic effect of ELA13 on transforming growth factor-β1(TGF-β1)-treated NRK-52E cells and unilateral ureteral occlusion(UUO)mice.Our results demonstrated that ELA13 could improve renal function by reducing creatinine and urea nitrogen content in serum,and reduce the expression of fibrosis biomarkers confirmed by Masson staining,immunohistochemistry,real-time polymerase chain reaction(RT-PCR),and western blot.Inflammation biomarkers were increased after UUO and decreased by administration of ELA13.Furthermore,we found that the levels of essential molecules in the mothers against decapentaplegic(Smad)and extracellular signal-regulated kinase(ERK)pathways were reduced by ELA13 treatment in vivo and in vitro.In conclusion,ELA13 protected against kidney fibrosis through inhibiting the Smad and ERK signaling pathways and could thus be a promising candidate for anti-renal fibrosis treatment.展开更多
Osteoarthritis and psoriasis arthritis are two degenerative forms of arthritis that share similar yet also different manifestations at the histological,cellular,and clinical levels.Rheumatologists have marked them as ...Osteoarthritis and psoriasis arthritis are two degenerative forms of arthritis that share similar yet also different manifestations at the histological,cellular,and clinical levels.Rheumatologists have marked them as two entirely distinct arthropathies.Given recent dis-coveries in disease initiation and progression,potential mechanisms,cellular signaling path-ways,and ongoing clinical therapeutics,there are now more opportunities for discovering osteoarthritis drugs.This review summarized the osteoarthritis and psoriasis arthritis signaling pathways,crosstalk between BMP,WNT,TGF-β,VEGF,TLR,and FGF signaling pathways,bio-markers,and anatomical pathologies.Through bench research,we demonstrated that regen-erative medicine is a promising alternative for treating osteoarthritis by highlighting significant scientific discoveries on entheses,multiple signaling blockers,and novel molecules such as immunoglobulin new antigen receptors targeted for potential drug evaluation.Furthermore,we offered valuable therapeutic approaches with a multidisciplinary strategy to treat patients with osteoarthritis or psoriasis arthritis in the coming future in the clinic.展开更多
Increasing evidence highlight tachykinin receptors as a prominent player in hematological malignancy.We previously revealed the proto-oncogenic role of neurokinin-1 receptor(NK-1R)in acute myeloid leukemia(AML),1 wher...Increasing evidence highlight tachykinin receptors as a prominent player in hematological malignancy.We previously revealed the proto-oncogenic role of neurokinin-1 receptor(NK-1R)in acute myeloid leukemia(AML),1 whereas the role of neurokinin-2 receptor(NK-2R)has not been elucidated.Herein,we found NK-2R was significantly up-regulated in AML patients in The Cancer Genome Atlas databases.This result was further confirmed in blood from AML patients and a range of human leukemia cells.Then,we verified that blocking NK-2R by SR48968 markedly promoted cell death in human myeloid leukemia without cytotoxicity to normal cells.Mechanically,we uncovered that SR48968 induced cytotoxicity through necroptosis mediated by calcium overload-driven reactive oxygen species(ROS)accumulation.In summary,our results propose that NK-2R antagonist SR48968 may be used as a new therapeutic approach for myeloid leukemia.展开更多
Wnt signaling executes an indispensable performance in osteoblast differentiation,bone development,homeostasis,and remodeling.Wnt signals trigger the intracellular Wnt signaling cascade to initiate regulating the impl...Wnt signaling executes an indispensable performance in osteoblast differentiation,bone development,homeostasis,and remodeling.Wnt signals trigger the intracellular Wnt signaling cascade to initiate regulating the implication of b-catenin in the bone environment.Going through the novel discoveries done via high-throughput sequencing technologies on ge-netic mouse models,we highlighted the significant contribution of Wnt ligands,co-receptors,inhibitors,their related skeletal phenotypes in mouse models and the similar bone disorders clinically observed in human beings.Moreover,the crosstalk between Wnt signaling pathway and BMP,TGF-b,FGF,Hippo,Hedgehog,Notch and PDGF signaling pathways is thoroughly demonstrated to be the underlying gene regulatory network that orchestrates osteoblast dif-ferentiation and bone development.We also introspected the significance of Wnt signaling transduction in the reorganization of cellular metabolism by stimulating glycolysis,glutamine catabolism,and fatty acid oxidation in osteoblast-lineage cells that display an important reg-ulatory arbor in the cellular bioenergetics of the bone.Throughout this evaluation,most to date therapeutical approaches towards osteoporosis and other bone maladies found in human beings,are formulated with an aspiration to holistically revamp the present clinical applica-tions involving various monoclonal antibodies therapies that lack specificity,efficacy,and safety into more requisite advanced therapeutics that satisfy these three requirements for further clinical considerations.Conclusively,our review provides comprehensive scientific findings related to the fundamental significance of Wnt signaling cascades in skeletal system and the underlying gene regulatory network with other signaling pathways enlightening re-searchers with the possibility to further integrate the identified target molecules into thera-peutic strategies for skeletal disorders treatment in the clinic.展开更多
Peptide drug development has made great progress in the last decade thanks to new production,modification,and analytic technologies.Peptides have been produced and modified using both chemical and biological methods,t...Peptide drug development has made great progress in the last decade thanks to new production,modification,and analytic technologies.Peptides have been produced and modified using both chemical and biological methods,together with novel design and delivery strategies,which have helped to overcome the inherent drawbacks of peptides and have allowed the continued advancement of this field.展开更多
The modification of 3D printed porous titanium(Ti),especially for the internal pore structure,is critical and has received more attention to promoting its osteogenesis for clinical use.Ultra-violet(UV)responsive chito...The modification of 3D printed porous titanium(Ti),especially for the internal pore structure,is critical and has received more attention to promoting its osteogenesis for clinical use.Ultra-violet(UV)responsive chitosan(CSMA),as an injectable filling material,was firstly incorporated into porous Ti,and then CSMA was in-situ mineralized by carbon oxide(CO_(2))diffusion(CSMA/CaCO_(3)).Their physical-chemical and biological properties were investigated in vitro.CaCO_(3) crystals within CSMA hydrogels were successfully deposited into pores of porous Ti,which exhibited favorable biocompatibility.Ti implants filled with CSMA/CaCO_(3) promoted adhesion and proliferation of bone mesenchymal stem cells(BMSCs).Moreover,Ti implant filled CSMA/CaCO_(3) hydrogels could increase alkaline phosphatase(ALP)activities,up-regulate osteopontin(OPN)and osteocalcin(OCN)expression levels,and enhance extracellular mineralization.3D printed porous Ti filled with mineralized UV-responsive chitosan hydrogel could promote proliferation and osteogenesis of BMSCs,and have great potential for the modification of porous Ti implants in bone tissue engineering.展开更多
Colorectal cancer(CRC)is a lethal malignancy with a high mortality rate due to its low immunogenicity,the strong immunosuppressive milieu and poor drug permeability.To overcome these obstacles,a cascade synergistic na...Colorectal cancer(CRC)is a lethal malignancy with a high mortality rate due to its low immunogenicity,the strong immunosuppressive milieu and poor drug permeability.To overcome these obstacles,a cascade synergistic nanosystem(denoted as R837/ICG@Lip)was developed via self-assembly of heater indocyanine green(ICG)and toll-like receptor-7 agonist imiquimod(R837)into thermosensitive liposome for simultaneous induction of immunogenic cell death(ICD)and reversing of suppressive tumor microenvironment.The obtained nanoparticles exhibited NIR-triggered drug release,good photothermal conversion efficiency and phototoxicity towards CT26 colorectal cancer cells.In vivo results reveal that the R837/ICG@Lip could be effectively accumulated in CT26 subcutaneous tumors and the draining lymph nodes.More importantly,R837/ICG@Lip-mediated low-temperature photothermal therapy triggers ICD,promotes the maturation of host dendritic cells(DCs),and subsequently amplifies adaptive antitumor T-cell responses,resulting in‘Cold to Hot'transition.Besides directly affecting immune cells,the secretion of some immune-related cytokines further indirectly boosted anti-cancer immunity.After combining with the indoleamine 2,3-dioxygenase(IDO)inhibitor,the systemic antitumor immune response was further augmented,achieving best tumor inhibition effects.Thus,low-temperature mediated photoimmunotherapy targeting multiple antitumor immune pathways boost synergistic antitumor immunity of tolerance tumors.展开更多
In a recent paper in Cell Metabolism,Xu et al.provide new insights whether and how caspase-4/11 involves in pyroptotic cell death implicated in noninfective diseases.They discovered a novel mechanism of GSDME-dependen...In a recent paper in Cell Metabolism,Xu et al.provide new insights whether and how caspase-4/11 involves in pyroptotic cell death implicated in noninfective diseases.They discovered a novel mechanism of GSDME-dependent pyroptosis,which was induced by mitochondrial permeability transition(MPT)-activated Apaf-1/caspase-4 pyroptosome assembly.1 These findings provide important implications for understanding the pathogenesis of cholestatic liver failure(Fig.1).展开更多
Annexin A1,a well-known endogenous anti-inflammatory mediator,plays a critical role in a variety of pathological processes.Fibrosis is described by a failure of tissue regeneration and contributes to the development o...Annexin A1,a well-known endogenous anti-inflammatory mediator,plays a critical role in a variety of pathological processes.Fibrosis is described by a failure of tissue regeneration and contributes to the development of many diseases.Accumulating evidence supports that Annexin A1 participates in the progression of tissue fibrosis.However,the fundamental mechanisms by which Annexin A1 regulates fibrosis remain elusive,and even the functions of Annexin A1 in fibrotic diseases are still paradoxical.This review focuses on the roles of Annexin A1 in the development of fibrosis of lung,liver,heart,and other tissues,with emphasis on the therapy potential of Annexin A1 in fibrosis,and presents future research interests and directions in fibrotic diseases.展开更多
A very recent study by Zhang et al.published in Nature demonstrates that gasdermin E(GSDME,also known as DFNA5)is a tumour suppressor by activating caspaseindependent pyroptosis to enhance anti-tumour immunity.1 In th...A very recent study by Zhang et al.published in Nature demonstrates that gasdermin E(GSDME,also known as DFNA5)is a tumour suppressor by activating caspaseindependent pyroptosis to enhance anti-tumour immunity.1 In the meantime,a study by Wang et al.published in Nature also demonstrates the anti-tumour effect caused by gasdermin A3(GSDMA3)to induce pyroptosis requires both cytotoxic T cells and CD4+T helper cells.2 The authors intriguingly showed that pyroptosis-induced inflammation triggers robust anti-tumour immunity,thus gasdermin is a promising novel therapeutic target for tumour treatment(Fig.1).展开更多
In a recent study published in Nature,Mitchell E.Fane et al.revealed the critical role of the aged microenvironment in the reactivation of melanoma cells from dormancy.1 The authors found that age-induced lung fibrobl...In a recent study published in Nature,Mitchell E.Fane et al.revealed the critical role of the aged microenvironment in the reactivation of melanoma cells from dormancy.1 The authors found that age-induced lung fibroblast secretory changes promoted growth activation of dormant melanoma cells in the lung,and age-induced skin microenvironment changes suppressed melanoma growth but promoted melanoma cell dissemination(Fig.1).展开更多
基金supported by National Natural Science Foundation of China(82272695)the Key Program of Natural Science Foundation of Zhejiang Province(LZ23H160004)National Undergraduate Training Program for Innovation,and Zhejiang Xinmiao Talents Program,China.
文摘It has been shown that the high expression of human epididymis protein 4(HE4)in most lung cancers is related to the poor prognosis of patients,but the mechanism of pathological transformation of HE4 in lung cancer is still unclear.The current study is expected to clarify the function and mechanism of HE4 in the occurrence and metastasis of lung adenocarcinoma(LUAD).Immunoblotting evaluated HE4 expression in lung cancer cell lines and biopsies,and through analysis of The Cancer Genome Atlas(TCGA)dataset.Frequent HE4 overexpression was demonstrated in LUAD,but not in lung squamous cell carcinoma(LUSC),indicating that HE4 can serve as a biomarker to distinguish between LUAD and LUSC.HE4 knockdown significantly inhibited cell growth,colony formation,wound healing,and invasion,and blocked the G1-phase of the cell cycle in LUAD cell lines through inactivation of the EGFR signaling downstream including PI3K/AKT/mTOR and RAF/MAPK pathways.The first-line EGFR inhibitor gefitinib and HE4 shRNA had no synergistic inhibitory effect on the growth of lung adenocarcinoma cells,while the third-line EGFR inhibitor osimertinib showed additive anti-proliferative effects.Moreover,we provided evidence that HE4 regulated EGFR expression by transcription regulation and protein interaction in LUAD.Our findings suggest that HE4 positively modulates the EGFR signaling pathway to promote growth and invasiveness in LUAD and highlight that targeting HE4 could be a novel strategy for LUAD treatment.
基金Supported by the National Natural Science Foundation of China(No.31702375)the Fundamental Research Funds of Zhejiang Sci-Tech University(No.2019Q047)。
文摘As an important pattern recognition receptor(PRR)in the innate immune system,C-type lectin plays an important role in the innate immune process of invertebrates.Two C-type lectins Sp CTL-C and Sp CTL-D were characterized from mud crab(Scylla paramamosain).The predicted Sp CTL-C and Sp CTL-D proteins both contain a single carbohydrate-recognition domain(CRD)with key motif Gln-Pro-Ala(QPA)and Met-Pro-Ala(MPA),respectively.Sp CTL-C and Sp CTL-D transcripts distributed in all examined tissues,and the expression level was the highest in hepatopancreas.As PRR,the purifi ed recombinant proteins r Sp CTL-C and r Sp CTL-D have high affi nity for three kinds of pathogen-associated molecular patterns(PAMPs):β-glucan,lipopolysaccharide,and peptidoglycan.Besides,r Sp CTL-D can bind to all nine microorganisms tested,while r Sp CTL-C can bind to seven microorganisms except for Staphylococcus aureus and Micrococcus luteus.Both r Sp CTL-C and r Sp CTL-D showed agglutination activity towards fungi Pichia pastoris and Saccharomyces cerevisiae.However,r Sp CTL-C and r Sp CTL-D exhibited diff erent antimicrobial activities:r Sp CTL-D has a certain inhibitory eff ect on the growth of Vibrio fl uvialis and M.luteus,while r Sp CTL-C has no obvious inhibitory activity.The results show that r Sp CTL-C and r Sp CTL-D had better phagocytosis-promoting eff ect on M.luteus than the negative control.Meanwhile,both r Sp CTL-C and r Sp CTL-D had certain encapsulation-promoting activity.Collectively,two C-type lectins with novel key motifs make an important impact as PRR in immune response towards pathogens.At the same time,they play diff erent functions in the innate immunity of mud crab S.paramamosain.
基金supported by grants from the National Natural Science Foundation of China (81770176)the special support plan for Zhejiang Province High-Level Talents (2019R52011)。
文摘The management of bacterial infections is becoming a major clinical challenge due to the rapid evolution of antibiotic resistant bacteria.As an excellent candidate to overcome antibiotic resistance,antimicrobial peptides(AMPs)that are produced from the synthetic and natural sources demonstrate a broad-spectrum antimicrobial activity with the high specificity and low toxicity.These peptides possess distinctive structures and functions by employing sophisticated mechanisms of action.This comprehensive review provides a broad overview of AMPs from the origin,structural characteristics,mechanisms of action,biological activities to clinical applications.We finally discuss the strategies to optimize and develop AMP-based treatment as the potential antimicrobial and anticancer therapeutics.
基金This work was supported by grants from the National Natural Science Foundation of China(Nos.81770176 and 31470071)the New Century 151 Talent Project of Zhejiang Province,the 521 Talent Foundation of Zhejiang Sci-Tech University,and the Open Foundation from Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province(No.ZJZLSYS004)The funders played no role in the study design,data collection and analysis,decision to publish,or preparation of the manuscript.
文摘Cell death is an essential biological process for physiological growth and development.Three classical forms of cell death—apoptosis,autophagy,and necrosis—display distinct morphological features by activating specific signaling pathways.With recent research advances,we have started to appreciate that these cell death processes can cross-talk through interconnecting,even overlapping,signaling pathways,and the final cell fate is the result of the interplay of different cell death programs.This review provides an insight into the independence of and associations among these three types of cell death and explores the significance of cell death under the specific conditions of human diseases,particularly neurodegenerative diseases and cancer.
基金supported by the Zhejiang Provincial Natural Science Foundation of China(No.LD22H310004)the National Natural Science Foundation of China(No.82204492)+2 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2019-I2M-5-074)the Medical Innovation and Development Project of Lanzhou University(No.lzuyxcx-2022-156)the Scientific Research Foundation of Zhejiang Sci-Tech University(No.21042100-Y),China。
文摘Kidney fibrosis is an inevitable result of various chronic kidney diseases(CKDs)and significantly contributes to end-stage renal failure.Currently,there is no specific treatment available for renal fibrosis.ELA13(amino acid sequence:RRCMPLHSRVPFP)is a conserved region of ELABELA in all vertebrates;however,its biological activity has been very little studied.In the present study,we evaluated the therapeutic effect of ELA13 on transforming growth factor-β1(TGF-β1)-treated NRK-52E cells and unilateral ureteral occlusion(UUO)mice.Our results demonstrated that ELA13 could improve renal function by reducing creatinine and urea nitrogen content in serum,and reduce the expression of fibrosis biomarkers confirmed by Masson staining,immunohistochemistry,real-time polymerase chain reaction(RT-PCR),and western blot.Inflammation biomarkers were increased after UUO and decreased by administration of ELA13.Furthermore,we found that the levels of essential molecules in the mothers against decapentaplegic(Smad)and extracellular signal-regulated kinase(ERK)pathways were reduced by ELA13 treatment in vivo and in vitro.In conclusion,ELA13 protected against kidney fibrosis through inhibiting the Smad and ERK signaling pathways and could thus be a promising candidate for anti-renal fibrosis treatment.
文摘Osteoarthritis and psoriasis arthritis are two degenerative forms of arthritis that share similar yet also different manifestations at the histological,cellular,and clinical levels.Rheumatologists have marked them as two entirely distinct arthropathies.Given recent dis-coveries in disease initiation and progression,potential mechanisms,cellular signaling path-ways,and ongoing clinical therapeutics,there are now more opportunities for discovering osteoarthritis drugs.This review summarized the osteoarthritis and psoriasis arthritis signaling pathways,crosstalk between BMP,WNT,TGF-β,VEGF,TLR,and FGF signaling pathways,bio-markers,and anatomical pathologies.Through bench research,we demonstrated that regen-erative medicine is a promising alternative for treating osteoarthritis by highlighting significant scientific discoveries on entheses,multiple signaling blockers,and novel molecules such as immunoglobulin new antigen receptors targeted for potential drug evaluation.Furthermore,we offered valuable therapeutic approaches with a multidisciplinary strategy to treat patients with osteoarthritis or psoriasis arthritis in the coming future in the clinic.
基金the Zhejiang Provincial Natural Science Foundation of China(No.LD22H310004)the“Pioneer”R&D program of Zhejiang,China(No.2022C03005)+1 种基金the National Natural Science Foundation of China(No.81770176,82204492)the Special Support Plan for Zhejiang Province High-Level Talents(China)(No.2019R52011).
文摘Increasing evidence highlight tachykinin receptors as a prominent player in hematological malignancy.We previously revealed the proto-oncogenic role of neurokinin-1 receptor(NK-1R)in acute myeloid leukemia(AML),1 whereas the role of neurokinin-2 receptor(NK-2R)has not been elucidated.Herein,we found NK-2R was significantly up-regulated in AML patients in The Cancer Genome Atlas databases.This result was further confirmed in blood from AML patients and a range of human leukemia cells.Then,we verified that blocking NK-2R by SR48968 markedly promoted cell death in human myeloid leukemia without cytotoxicity to normal cells.Mechanically,we uncovered that SR48968 induced cytotoxicity through necroptosis mediated by calcium overload-driven reactive oxygen species(ROS)accumulation.In summary,our results propose that NK-2R antagonist SR48968 may be used as a new therapeutic approach for myeloid leukemia.
基金supported by grants by Zhejiang Qianjiang Talent Program(No.21040040-E)the Department of Sci-Tech of Zhejiang Province(No.LGF19H140002)+4 种基金a startup grant from Zhejiang Sci-Tech University(No.18042290-Y,2021Q031)funds from National Natural Science Foundation of China(No.81900806,81400489)the basic Public Welfare Planning Project of Zhejiang Province(No.LGD20C040001)Jiaxing Science Technology Foundation(No.2020AY10001)Jiaxing Key Laboratory of Animal Model Generation and Precise Synthesis of New Drug Leads。
文摘Wnt signaling executes an indispensable performance in osteoblast differentiation,bone development,homeostasis,and remodeling.Wnt signals trigger the intracellular Wnt signaling cascade to initiate regulating the implication of b-catenin in the bone environment.Going through the novel discoveries done via high-throughput sequencing technologies on ge-netic mouse models,we highlighted the significant contribution of Wnt ligands,co-receptors,inhibitors,their related skeletal phenotypes in mouse models and the similar bone disorders clinically observed in human beings.Moreover,the crosstalk between Wnt signaling pathway and BMP,TGF-b,FGF,Hippo,Hedgehog,Notch and PDGF signaling pathways is thoroughly demonstrated to be the underlying gene regulatory network that orchestrates osteoblast dif-ferentiation and bone development.We also introspected the significance of Wnt signaling transduction in the reorganization of cellular metabolism by stimulating glycolysis,glutamine catabolism,and fatty acid oxidation in osteoblast-lineage cells that display an important reg-ulatory arbor in the cellular bioenergetics of the bone.Throughout this evaluation,most to date therapeutical approaches towards osteoporosis and other bone maladies found in human beings,are formulated with an aspiration to holistically revamp the present clinical applica-tions involving various monoclonal antibodies therapies that lack specificity,efficacy,and safety into more requisite advanced therapeutics that satisfy these three requirements for further clinical considerations.Conclusively,our review provides comprehensive scientific findings related to the fundamental significance of Wnt signaling cascades in skeletal system and the underlying gene regulatory network with other signaling pathways enlightening re-searchers with the possibility to further integrate the identified target molecules into thera-peutic strategies for skeletal disorders treatment in the clinic.
基金This work was supported by Zhejiang Provincial Natural Science Foundation of China under Grant No.LD22H310004,the National Natural Science Foundation of China(No.81770176)the"Pioneer"and"Leading Goose"R&D Program of Zhejiang(No.2022C03005)+2 种基金the special support plan for Zhejiang Province high-level talents(No.2019R52011)the Zhejiang Provincial Natural Science Foundation of China under Grant No.LQ20H300005Program of Xinmiao Talents in Zhejiang Province(2021R406062).
文摘Peptide drug development has made great progress in the last decade thanks to new production,modification,and analytic technologies.Peptides have been produced and modified using both chemical and biological methods,together with novel design and delivery strategies,which have helped to overcome the inherent drawbacks of peptides and have allowed the continued advancement of this field.
基金financially supported partly by the Zhejiang Provincial Natural Science Foundation of China(No.LY20E010006)partly by the Fundamental Research Funds for the Central Universities(No.WK9110000152)+1 种基金partly by the Key Research and Development Plan of Anhui Province(No.20194a0720097)partly by the National Natural Science Foundation of China(Nos.51502265 and 81701033).
文摘The modification of 3D printed porous titanium(Ti),especially for the internal pore structure,is critical and has received more attention to promoting its osteogenesis for clinical use.Ultra-violet(UV)responsive chitosan(CSMA),as an injectable filling material,was firstly incorporated into porous Ti,and then CSMA was in-situ mineralized by carbon oxide(CO_(2))diffusion(CSMA/CaCO_(3)).Their physical-chemical and biological properties were investigated in vitro.CaCO_(3) crystals within CSMA hydrogels were successfully deposited into pores of porous Ti,which exhibited favorable biocompatibility.Ti implants filled with CSMA/CaCO_(3) promoted adhesion and proliferation of bone mesenchymal stem cells(BMSCs).Moreover,Ti implant filled CSMA/CaCO_(3) hydrogels could increase alkaline phosphatase(ALP)activities,up-regulate osteopontin(OPN)and osteocalcin(OCN)expression levels,and enhance extracellular mineralization.3D printed porous Ti filled with mineralized UV-responsive chitosan hydrogel could promote proliferation and osteogenesis of BMSCs,and have great potential for the modification of porous Ti implants in bone tissue engineering.
基金supported by the National Natural Science Foundation of China(Nos.32271469 and U1904206)Fujian Provincial Science and Technology Cooperation Project(No.20210002)Zhejiang Provincial Natural Science Foundation of China(No.LY18C100002)。
文摘Colorectal cancer(CRC)is a lethal malignancy with a high mortality rate due to its low immunogenicity,the strong immunosuppressive milieu and poor drug permeability.To overcome these obstacles,a cascade synergistic nanosystem(denoted as R837/ICG@Lip)was developed via self-assembly of heater indocyanine green(ICG)and toll-like receptor-7 agonist imiquimod(R837)into thermosensitive liposome for simultaneous induction of immunogenic cell death(ICD)and reversing of suppressive tumor microenvironment.The obtained nanoparticles exhibited NIR-triggered drug release,good photothermal conversion efficiency and phototoxicity towards CT26 colorectal cancer cells.In vivo results reveal that the R837/ICG@Lip could be effectively accumulated in CT26 subcutaneous tumors and the draining lymph nodes.More importantly,R837/ICG@Lip-mediated low-temperature photothermal therapy triggers ICD,promotes the maturation of host dendritic cells(DCs),and subsequently amplifies adaptive antitumor T-cell responses,resulting in‘Cold to Hot'transition.Besides directly affecting immune cells,the secretion of some immune-related cytokines further indirectly boosted anti-cancer immunity.After combining with the indoleamine 2,3-dioxygenase(IDO)inhibitor,the systemic antitumor immune response was further augmented,achieving best tumor inhibition effects.Thus,low-temperature mediated photoimmunotherapy targeting multiple antitumor immune pathways boost synergistic antitumor immunity of tolerance tumors.
基金This work was supported by a grant from the National Natural Science Foundation of China(No.81770176).
文摘In a recent paper in Cell Metabolism,Xu et al.provide new insights whether and how caspase-4/11 involves in pyroptotic cell death implicated in noninfective diseases.They discovered a novel mechanism of GSDME-dependent pyroptosis,which was induced by mitochondrial permeability transition(MPT)-activated Apaf-1/caspase-4 pyroptosome assembly.1 These findings provide important implications for understanding the pathogenesis of cholestatic liver failure(Fig.1).
基金This work was supported by the National Natural Science Foundation of China(No.81770176)the Special Support Plan for Zhejiang Province High-level Talents(No.2019R52011)+1 种基金the Zhejiang Provincial Natural Science Foundation of China(No.LD22H310004)the Scientific Research Foundation of Zhejiang Sci-Tech University(No.21042100-Y).
文摘Annexin A1,a well-known endogenous anti-inflammatory mediator,plays a critical role in a variety of pathological processes.Fibrosis is described by a failure of tissue regeneration and contributes to the development of many diseases.Accumulating evidence supports that Annexin A1 participates in the progression of tissue fibrosis.However,the fundamental mechanisms by which Annexin A1 regulates fibrosis remain elusive,and even the functions of Annexin A1 in fibrotic diseases are still paradoxical.This review focuses on the roles of Annexin A1 in the development of fibrosis of lung,liver,heart,and other tissues,with emphasis on the therapy potential of Annexin A1 in fibrosis,and presents future research interests and directions in fibrotic diseases.
基金supported by grants from the National Natural Science Foundation of China(No.81770176)the Fundamental Research Funds of Zhejiang Sci-Tech University(No.2019Y001).
文摘A very recent study by Zhang et al.published in Nature demonstrates that gasdermin E(GSDME,also known as DFNA5)is a tumour suppressor by activating caspaseindependent pyroptosis to enhance anti-tumour immunity.1 In the meantime,a study by Wang et al.published in Nature also demonstrates the anti-tumour effect caused by gasdermin A3(GSDMA3)to induce pyroptosis requires both cytotoxic T cells and CD4+T helper cells.2 The authors intriguingly showed that pyroptosis-induced inflammation triggers robust anti-tumour immunity,thus gasdermin is a promising novel therapeutic target for tumour treatment(Fig.1).
基金This work was supported by the Zhejiang Provincial Natural and Science Foundation of China under Grant No.LD22H310004.
文摘In a recent study published in Nature,Mitchell E.Fane et al.revealed the critical role of the aged microenvironment in the reactivation of melanoma cells from dormancy.1 The authors found that age-induced lung fibroblast secretory changes promoted growth activation of dormant melanoma cells in the lung,and age-induced skin microenvironment changes suppressed melanoma growth but promoted melanoma cell dissemination(Fig.1).
