Silicosis is one of the most serious occupational diseases in China and dates back to centuries ago. In this study, we successfully established a rat model of silicosis by intratracheal silica injection for 28 days an...Silicosis is one of the most serious occupational diseases in China and dates back to centuries ago. In this study, we successfully established a rat model of silicosis by intratracheal silica injection for 28 days and determined hydroxyproline levels to evaluate collagen metabolism in lung homogenates. Oxidative stress status was evaluated by detecting catalase and glutathione peroxidase activities.展开更多
Objective:To observe the expression levels of the main molecules of peroxiredoxins (Prdxs) protein family (Prdx1, Prdx2, Prdx4 and Prdx6) in women with postmenopausal osteoporosis (PMOP), and to analyze their clinical...Objective:To observe the expression levels of the main molecules of peroxiredoxins (Prdxs) protein family (Prdx1, Prdx2, Prdx4 and Prdx6) in women with postmenopausal osteoporosis (PMOP), and to analyze their clinical diagnostic values.Methods: Patients diagnosed with PMOP in Hubei Provincial Hospital of Traditional Chinese Medicine and Wuhan Hospital of Traditional Chinese Medicine from May 2016 to March 2018 were included as the study group (72 cases), postmenopausal women with normal bone mineral density (BMD) in the same period were also collected as the control group (51 cases). Levels of Prdx1, Prdx2, Prdx4 and Prdx6 in plasma were determined by ELISA. mRNA levels of Prdx1, Prdx2, Prdx4 and Prdx6 in peripheral blood mononuclear cells (PBMC) were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The correlations between Prdxs and clinical parameters were analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic values of Prdxs for PMOP.Results: Prdx1, Prdx4 and Prdx6 levels in the study group were significantly lower than those in the control group (P<0.05). The mRNA expression levels of Prdx1 and Prdx6 of PBMC in the study group were significantly lower than those in the control group (P<0.05). Several Prdxs protein levels (plasma) or mRNA levels (PBMC) in the study group were significantly correlated with lipid levels or inflammatory markers levels (P<0.05). The area under the curve (AUC) of plasma Prdx6 for diagnosing PMOP was 0.794 (95% CI =0.714-0.874). And the AUC of mRNA relative expression of Prdx6 in PBMC for diagnosing PMOP was 0.725 (95% CI =0.635-0.814).Conclusion: The decreased expression of Prdxs protein family (especially Prdx1 and Prdx6) is closely related to the incidence of PMOP, and the decreased Prdxs protein family may promote the occurrence of osteoporosis through the abnormal lipid metabolism pathway and the increased systemic inflammation pathway. The detections of Prdx6 levels in plasma and PBMC are of good diagnostic values for PMOP.展开更多
Colorectal cancer(CRC)remains a major global health challenge,with high recurrence and mortality despite advances in surgery,chemotherapy,and immunotherapy.The study by He et al identifies a novel mechanism by which p...Colorectal cancer(CRC)remains a major global health challenge,with high recurrence and mortality despite advances in surgery,chemotherapy,and immunotherapy.The study by He et al identifies a novel mechanism by which peroxiredoxin 1(Prdx1)inhibits CRC progression through induction of pyroptosis,a pro-inflammatory form of programmed cell death.Traditionally viewed as an intracellular antioxidant that protects tumors from oxidative stress,Prdx1 assu-mes a paradoxical immunogenic role when released extracellularly as a damageassociated molecular pattern.Using patient samples,recombinant protein assays,and murine xenograft models,the authors demonstrate that Prdx1 activates the NOD-,LRR-and pyrin domain-containing protein 3 inflammasome/caspase-1/gasdermin D pathway,triggering membrane pore formation,tumor cell lysis,and release of interleukin-1β/interleukin-18.This cascade not only halts tumor proliferation,invasion,and migration but may also enhance anti-tumor immune surveillance.The study’s strengths include rigorous mechanistic validation,clinical cohort data,inhibitor-based causal proof,and in vivo confirmation.However,questions remain regarding the upstream receptor for Prdx1,heterogeneity across CRC subtypes,and the balance between therapeutic benefit and inflammatory toxicity.By establishing Prdx1-induced pyroptosis as a driver of tumor suppression,this work advances a promising paradigm in CRC therapy,linking cell death to immune activation and pointing toward future biomarker-driven,pyroptosis-based interventions.展开更多
Ferroptosis is a form of regulated cell death, characterized by excessive membrane lipid peroxidation in an iron-and ROS-dependent manner. Celastrol, a natural bioactive triterpenoid extracted from Tripterygium wilfor...Ferroptosis is a form of regulated cell death, characterized by excessive membrane lipid peroxidation in an iron-and ROS-dependent manner. Celastrol, a natural bioactive triterpenoid extracted from Tripterygium wilfordii, shows effective anti-fibrotic and anti-inflammatory activities in multiple hepatic diseases. However, the exact molecular mechanisms of action and the direct protein targets of celastrol in the treatment of liver fibrosis remain largely elusive. Here, we discover that celastrol exerts anti-fibrotic effects via promoting the production of reactive oxygen species(ROS) and inducing ferroptosis in activated hepatic stellate cells(HSCs). By using activity-based protein profiling(ABPP) in combination with bio-orthogonal click chemistry reaction and cellular thermal shift assay(CETSA), we show that celastrol directly binds to peroxiredoxins(PRDXs), including PRDX1, PRDX2, PRDX4 and PRDX6,through the active cysteine sites, and inhibits their anti-oxidant activities. Celastrol also targets to heme oxygenase 1(HO-1) and upregulates its expression in activated-HSCs. Knockdown of PRDX1, PRDX2,PRDX4, PRDX6 or HO-1 in HSCs, to varying extent, elevated cellular ROS levels and induced ferroptosis. Taken together, our findings reveal the direct protein targets and molecular mechanisms via which celastrol ameliorates hepatic fibrosis, thus supporting the further development of celastrol as a promising therapeutic agent for liver fibrosis.展开更多
Chloroplast 2-Cys peroxiredoxins （2-Cys Prxs） are efficiently reduced by NADPH Thioredoxin reductase C （NTRC）. To investigate the effect of light/darkness on NTRC function, the content of abundant plastidial enzym...Chloroplast 2-Cys peroxiredoxins （2-Cys Prxs） are efficiently reduced by NADPH Thioredoxin reductase C （NTRC）. To investigate the effect of light/darkness on NTRC function, the content of abundant plastidial enzymes, Rubisco, glutamine synthetase （GS）, and 2-Cys Prxs was analyzed during two consecutive days in Arabidopsis wild-type and ntrc mutant plants. No significant difference of the content of these proteins was observed during the day or the night in wildtype and mutant plants. NTRC deficiency caused a lower content of fully reduced 2-Cys Prxs, which was undetectable in darkness, suggesting that NTRC is the most important pathway for 2-Cys Prx reduction, probably the only one during the night. Arabidopsis contains two plastidial 2-Cys Prxs, A and B, for which T-DNA insertion lines were characterized showing the same phenotype as wild-type plants. Two-dimensional gel analysis of leaf extracts from these mutants allowed the identification of basic and acidic isoforms of 2-Cys Prx A and B. In-vitro assays and mass spectrometry analysis showed that the acidic isoform of both proteins is produced by overoxidation of the peroxidatic Cys residue to sulfinic acid. 2-Cys Prx overoxidation was lower in the NTRC mutant. These results show the important function of NTRC to maintain the redox equilibrium of chloroplast 2-Cys Prxs.展开更多
Peroxiredoxins （Prx） catalyse the reduction of hydrogen peroxide （H2O2） and, in association with catalases and other peroxidases, may participate in signal transduction by regulating intercel ular H2O2 concentrati...Peroxiredoxins （Prx） catalyse the reduction of hydrogen peroxide （H2O2） and, in association with catalases and other peroxidases, may participate in signal transduction by regulating intercel ular H2O2 concentration that in turn can control gene transcription and cel signaling. Using virus-induced-gene-silencing （VIGS）, 2-Cys Peroxiredoxin （2CysPrx） family and type-II Peroxiredoxin B （PrxI B） gene were silenced in Nicotiana benthamiana, to study the impact that the loss of function of each Prx would have in the antioxidant system under control （22℃） and severe heat stress conditions （48 ℃）. The results showed that both Prxs, although in different organel es, influence the regeneration of ascorbate to a significant extent, but with different purposes. 2CysPrx affects abscisic acid （ABA） biosynthesis through ascorbate, while PrxIIB does it probably;through the xanthophyl cycle. Moreover, 2CysPrx is key in H2O2 scavenging and in consequence in the regulation of ABA signal-ing downstream of reactive oxygen species and PrxIIB provides an important assistance for H2O2 peroxisome scavenges.展开更多
Most redox-regulated chloroplast enzymes are reduced during the day and oxidized during the night.While the reduction mechanism of light-dependent enzymes is well known,the mechanism mediating their oxidation in the d...Most redox-regulated chloroplast enzymes are reduced during the day and oxidized during the night.While the reduction mechanism of light-dependent enzymes is well known,the mechanism mediating their oxidation in the dark remains unknown.The thiol-dependent peroxidases,2-Cys peroxiredoxins (Prxs),play a key role in light-dependent reduction of chloroplast enzymes.Prxs transfer reducing equivalents of thiols to hydrogen peroxide,suggesting the participation of these peroxidases in enzyme oxidation in the dark.Here,we have addressed this issue by analyzing the redox state of well-known redox-regulated chloroplast enzymes in response to darkness in Arabidopsis thaliana mutants deficient in chloroplastlocalized Prxs (2-Cys Prxs A and B,Prx ⅡE,and Prx Q).Mutant plants lacking 2-Cys Prxs A and B,and plants overexpressing NADPH-dependent thioredoxin (Trx) reductase C showed delayed oxidation of chloroplast enzymes in the dark.In contrast,the deficiencies of Prx ⅡE or Prx Q exerted no effect.In vitro assays allowed the reconstitution of the pathway of reducing equivalents from reduced fructose 1,6-bisphosphatase to hydrogen peroxide mediated by Trxs and 2-Cys Prxs.Taken together,these results suggest that 2-Cys Prxs participate in the short-term oxidation of chloroplast enzymes in the dark.展开更多
BACKGROUND Damage associated molecular patterns(DAMPs)are vital for the immunogenic cell death of cancer cells and can enhance the anti-tumor activity of immune cells in colorectal cancer(CRC).Peroxiredoxin 1(Prdx1),a...BACKGROUND Damage associated molecular patterns(DAMPs)are vital for the immunogenic cell death of cancer cells and can enhance the anti-tumor activity of immune cells in colorectal cancer(CRC).Peroxiredoxin 1(Prdx1),an important DAMP,is highly expressed in various tumor tissues including CRC.However,the role of Prdx1 in CRC remains unknown.AIM To investigate the effect and mechanisms of Prdx1 on CRC.METHODS Patients diagnosed with CRC in our medical center were included in this study to verify the expression of Prdx1 in cancer tissues.Recombinant Prdx1(rPrdx1)was used to stimulate RKO and SW480 colon cancer cells.The cell survival rate,migration,proliferation and invasion ability were assessed.Transmission electron microscopy,TUNEL assay,lactate dehydrogenase release assay,and Western blot were used to determine the effect of Prdx1 on pyroptosis.NLRP3 inflammasome inhibitor and gasdermin D(GSDMD)inhibitor were used to explore the mechanism of Prdx1-induced pyroptosis.RESULTS The mRNA and protein levels of Prdx1 were significantly increased in the tumor tissues of patients with CRC.rPrdx1 inhibited the viability,proliferation,migration and invasion of RKO and SW480 colon cancer cells.Further study found that rPrdx1 inhibited the malignant biological behaviors of CRC cells by inducing pyroptosis rather than apoptosis and necroptosis.Mechanistically,rPrdx1 induces pyroptosis of CRC cells by activating the NLRP3 inflammasome/GSDMD pathway.CONCLUSION Prdx1 induces pyroptosis by activating the NLRP3 inflammasome/GSDMD pathway,thereby inhibiting the malignant biological behavior of RKO and SW480 colon cancer cells.展开更多
The alleviation of chemotherapy-induced myelosuppression is an integral part of sustained and effective cancer therapy.Although the role of the hematopoietic microenvironment in the regulation of hematopoietic stem/pr...The alleviation of chemotherapy-induced myelosuppression is an integral part of sustained and effective cancer therapy.Although the role of the hematopoietic microenvironment in the regulation of hematopoietic stem/progenitor cells(HSPCs)has been widely studied,no drugs that improve hematopoiesis by targeting and modulating the hematopoietic microenvironment have been used clinically.Here,we show that the active small molecule icaritin(ICT)from the Chinese herb Epimedium brevicornum Maxim effectively alleviates chemotherapy-induced hemocytopenia in both mouse and zebrafish models.We demonstrated that ICT enhanced the number and hematopoietic function of HSPCs and that the beneficial effects of ICT occurred indirectly.Single-cell sequencing analysis confirmed that the target cells of ICT in the bone marrow microenvironment were mesenchymal stromal cells(MSCs).In addition,peroxiredoxin 1(PRDX1)was identified as a direct target of ICT.Furthermore,ICT stimulated MSCs to express the effector molecule C-X-C motif chemokine ligand 12(CXCL12)through the PRDX1-reactive oxygen species(ROS)-mitogen-activated protein kinase(MAPK)signaling axis,thereby increasing the number and function of HSPCs.These results suggest that ICT is a promising compound for achieving targeted modulation of the hematopoietic microenvironment to restore hematopoiesis after chemotherapy.展开更多
基金supported by the Applied Basic Research Program at Hebei Province in China(Grant No.11966120D)
文摘Silicosis is one of the most serious occupational diseases in China and dates back to centuries ago. In this study, we successfully established a rat model of silicosis by intratracheal silica injection for 28 days and determined hydroxyproline levels to evaluate collagen metabolism in lung homogenates. Oxidative stress status was evaluated by detecting catalase and glutathione peroxidase activities.
文摘Objective:To observe the expression levels of the main molecules of peroxiredoxins (Prdxs) protein family (Prdx1, Prdx2, Prdx4 and Prdx6) in women with postmenopausal osteoporosis (PMOP), and to analyze their clinical diagnostic values.Methods: Patients diagnosed with PMOP in Hubei Provincial Hospital of Traditional Chinese Medicine and Wuhan Hospital of Traditional Chinese Medicine from May 2016 to March 2018 were included as the study group (72 cases), postmenopausal women with normal bone mineral density (BMD) in the same period were also collected as the control group (51 cases). Levels of Prdx1, Prdx2, Prdx4 and Prdx6 in plasma were determined by ELISA. mRNA levels of Prdx1, Prdx2, Prdx4 and Prdx6 in peripheral blood mononuclear cells (PBMC) were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The correlations between Prdxs and clinical parameters were analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic values of Prdxs for PMOP.Results: Prdx1, Prdx4 and Prdx6 levels in the study group were significantly lower than those in the control group (P<0.05). The mRNA expression levels of Prdx1 and Prdx6 of PBMC in the study group were significantly lower than those in the control group (P<0.05). Several Prdxs protein levels (plasma) or mRNA levels (PBMC) in the study group were significantly correlated with lipid levels or inflammatory markers levels (P<0.05). The area under the curve (AUC) of plasma Prdx6 for diagnosing PMOP was 0.794 (95% CI =0.714-0.874). And the AUC of mRNA relative expression of Prdx6 in PBMC for diagnosing PMOP was 0.725 (95% CI =0.635-0.814).Conclusion: The decreased expression of Prdxs protein family (especially Prdx1 and Prdx6) is closely related to the incidence of PMOP, and the decreased Prdxs protein family may promote the occurrence of osteoporosis through the abnormal lipid metabolism pathway and the increased systemic inflammation pathway. The detections of Prdx6 levels in plasma and PBMC are of good diagnostic values for PMOP.
文摘Colorectal cancer(CRC)remains a major global health challenge,with high recurrence and mortality despite advances in surgery,chemotherapy,and immunotherapy.The study by He et al identifies a novel mechanism by which peroxiredoxin 1(Prdx1)inhibits CRC progression through induction of pyroptosis,a pro-inflammatory form of programmed cell death.Traditionally viewed as an intracellular antioxidant that protects tumors from oxidative stress,Prdx1 assu-mes a paradoxical immunogenic role when released extracellularly as a damageassociated molecular pattern.Using patient samples,recombinant protein assays,and murine xenograft models,the authors demonstrate that Prdx1 activates the NOD-,LRR-and pyrin domain-containing protein 3 inflammasome/caspase-1/gasdermin D pathway,triggering membrane pore formation,tumor cell lysis,and release of interleukin-1β/interleukin-18.This cascade not only halts tumor proliferation,invasion,and migration but may also enhance anti-tumor immune surveillance.The study’s strengths include rigorous mechanistic validation,clinical cohort data,inhibitor-based causal proof,and in vivo confirmation.However,questions remain regarding the upstream receptor for Prdx1,heterogeneity across CRC subtypes,and the balance between therapeutic benefit and inflammatory toxicity.By establishing Prdx1-induced pyroptosis as a driver of tumor suppression,this work advances a promising paradigm in CRC therapy,linking cell death to immune activation and pointing toward future biomarker-driven,pyroptosis-based interventions.
基金supported by the National Key Research and Development Program of China (2020YFA0908000)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202002,China)+1 种基金the National Natural Science Foundation of China(81903588,81803456,82074098 and 81841001,China)the Fundamental Research Funds for the Central Public Welfare Research Institutes (ZXKT18003 and ZZ15-YQ-063,China)。
文摘Ferroptosis is a form of regulated cell death, characterized by excessive membrane lipid peroxidation in an iron-and ROS-dependent manner. Celastrol, a natural bioactive triterpenoid extracted from Tripterygium wilfordii, shows effective anti-fibrotic and anti-inflammatory activities in multiple hepatic diseases. However, the exact molecular mechanisms of action and the direct protein targets of celastrol in the treatment of liver fibrosis remain largely elusive. Here, we discover that celastrol exerts anti-fibrotic effects via promoting the production of reactive oxygen species(ROS) and inducing ferroptosis in activated hepatic stellate cells(HSCs). By using activity-based protein profiling(ABPP) in combination with bio-orthogonal click chemistry reaction and cellular thermal shift assay(CETSA), we show that celastrol directly binds to peroxiredoxins(PRDXs), including PRDX1, PRDX2, PRDX4 and PRDX6,through the active cysteine sites, and inhibits their anti-oxidant activities. Celastrol also targets to heme oxygenase 1(HO-1) and upregulates its expression in activated-HSCs. Knockdown of PRDX1, PRDX2,PRDX4, PRDX6 or HO-1 in HSCs, to varying extent, elevated cellular ROS levels and induced ferroptosis. Taken together, our findings reveal the direct protein targets and molecular mechanisms via which celastrol ameliorates hepatic fibrosis, thus supporting the further development of celastrol as a promising therapeutic agent for liver fibrosis.
文摘Chloroplast 2-Cys peroxiredoxins （2-Cys Prxs） are efficiently reduced by NADPH Thioredoxin reductase C （NTRC）. To investigate the effect of light/darkness on NTRC function, the content of abundant plastidial enzymes, Rubisco, glutamine synthetase （GS）, and 2-Cys Prxs was analyzed during two consecutive days in Arabidopsis wild-type and ntrc mutant plants. No significant difference of the content of these proteins was observed during the day or the night in wildtype and mutant plants. NTRC deficiency caused a lower content of fully reduced 2-Cys Prxs, which was undetectable in darkness, suggesting that NTRC is the most important pathway for 2-Cys Prx reduction, probably the only one during the night. Arabidopsis contains two plastidial 2-Cys Prxs, A and B, for which T-DNA insertion lines were characterized showing the same phenotype as wild-type plants. Two-dimensional gel analysis of leaf extracts from these mutants allowed the identification of basic and acidic isoforms of 2-Cys Prx A and B. In-vitro assays and mass spectrometry analysis showed that the acidic isoform of both proteins is produced by overoxidation of the peroxidatic Cys residue to sulfinic acid. 2-Cys Prx overoxidation was lower in the NTRC mutant. These results show the important function of NTRC to maintain the redox equilibrium of chloroplast 2-Cys Prxs.
基金funded by Fundao para a Ciência e Tecnologia (FCT): CBAA (Pest OE/AGR/UI0240/2011)the postdoc grants SFRH/BPD/43898/2008 to PVSFRH/BPD/85767/ 2012 to LC
文摘Peroxiredoxins （Prx） catalyse the reduction of hydrogen peroxide （H2O2） and, in association with catalases and other peroxidases, may participate in signal transduction by regulating intercel ular H2O2 concentration that in turn can control gene transcription and cel signaling. Using virus-induced-gene-silencing （VIGS）, 2-Cys Peroxiredoxin （2CysPrx） family and type-II Peroxiredoxin B （PrxI B） gene were silenced in Nicotiana benthamiana, to study the impact that the loss of function of each Prx would have in the antioxidant system under control （22℃） and severe heat stress conditions （48 ℃）. The results showed that both Prxs, although in different organel es, influence the regeneration of ascorbate to a significant extent, but with different purposes. 2CysPrx affects abscisic acid （ABA） biosynthesis through ascorbate, while PrxIIB does it probably;through the xanthophyl cycle. Moreover, 2CysPrx is key in H2O2 scavenging and in consequence in the regulation of ABA signal-ing downstream of reactive oxygen species and PrxIIB provides an important assistance for H2O2 peroxisome scavenges.
文摘Most redox-regulated chloroplast enzymes are reduced during the day and oxidized during the night.While the reduction mechanism of light-dependent enzymes is well known,the mechanism mediating their oxidation in the dark remains unknown.The thiol-dependent peroxidases,2-Cys peroxiredoxins (Prxs),play a key role in light-dependent reduction of chloroplast enzymes.Prxs transfer reducing equivalents of thiols to hydrogen peroxide,suggesting the participation of these peroxidases in enzyme oxidation in the dark.Here,we have addressed this issue by analyzing the redox state of well-known redox-regulated chloroplast enzymes in response to darkness in Arabidopsis thaliana mutants deficient in chloroplastlocalized Prxs (2-Cys Prxs A and B,Prx ⅡE,and Prx Q).Mutant plants lacking 2-Cys Prxs A and B,and plants overexpressing NADPH-dependent thioredoxin (Trx) reductase C showed delayed oxidation of chloroplast enzymes in the dark.In contrast,the deficiencies of Prx ⅡE or Prx Q exerted no effect.In vitro assays allowed the reconstitution of the pathway of reducing equivalents from reduced fructose 1,6-bisphosphatase to hydrogen peroxide mediated by Trxs and 2-Cys Prxs.Taken together,these results suggest that 2-Cys Prxs participate in the short-term oxidation of chloroplast enzymes in the dark.
基金Supported by the National Natural Science Foundation of China,No.82302454Natural Science Foundation of Hunan Province,No.2025JJ60797,No.2025JJ60734 and No.2022JJ40718Guangdong Basic and Applied Basic Research Foundation,No.2022A1515111063.
文摘BACKGROUND Damage associated molecular patterns(DAMPs)are vital for the immunogenic cell death of cancer cells and can enhance the anti-tumor activity of immune cells in colorectal cancer(CRC).Peroxiredoxin 1(Prdx1),an important DAMP,is highly expressed in various tumor tissues including CRC.However,the role of Prdx1 in CRC remains unknown.AIM To investigate the effect and mechanisms of Prdx1 on CRC.METHODS Patients diagnosed with CRC in our medical center were included in this study to verify the expression of Prdx1 in cancer tissues.Recombinant Prdx1(rPrdx1)was used to stimulate RKO and SW480 colon cancer cells.The cell survival rate,migration,proliferation and invasion ability were assessed.Transmission electron microscopy,TUNEL assay,lactate dehydrogenase release assay,and Western blot were used to determine the effect of Prdx1 on pyroptosis.NLRP3 inflammasome inhibitor and gasdermin D(GSDMD)inhibitor were used to explore the mechanism of Prdx1-induced pyroptosis.RESULTS The mRNA and protein levels of Prdx1 were significantly increased in the tumor tissues of patients with CRC.rPrdx1 inhibited the viability,proliferation,migration and invasion of RKO and SW480 colon cancer cells.Further study found that rPrdx1 inhibited the malignant biological behaviors of CRC cells by inducing pyroptosis rather than apoptosis and necroptosis.Mechanistically,rPrdx1 induces pyroptosis of CRC cells by activating the NLRP3 inflammasome/GSDMD pathway.CONCLUSION Prdx1 induces pyroptosis by activating the NLRP3 inflammasome/GSDMD pathway,thereby inhibiting the malignant biological behavior of RKO and SW480 colon cancer cells.
基金funded by the National Natural Science Foundation of China(82141203,82374086,and 82274172)the Shanghai Municipal Science and Technology Major Project(ZD2021CY001)+2 种基金the Three-year Action Plan for Shanghai TCM Development and Inheritance Program(ZY(2021-2023)-0401)the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(ZYYCXTDD-202004)the Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine(2023YZZ02).
文摘The alleviation of chemotherapy-induced myelosuppression is an integral part of sustained and effective cancer therapy.Although the role of the hematopoietic microenvironment in the regulation of hematopoietic stem/progenitor cells(HSPCs)has been widely studied,no drugs that improve hematopoiesis by targeting and modulating the hematopoietic microenvironment have been used clinically.Here,we show that the active small molecule icaritin(ICT)from the Chinese herb Epimedium brevicornum Maxim effectively alleviates chemotherapy-induced hemocytopenia in both mouse and zebrafish models.We demonstrated that ICT enhanced the number and hematopoietic function of HSPCs and that the beneficial effects of ICT occurred indirectly.Single-cell sequencing analysis confirmed that the target cells of ICT in the bone marrow microenvironment were mesenchymal stromal cells(MSCs).In addition,peroxiredoxin 1(PRDX1)was identified as a direct target of ICT.Furthermore,ICT stimulated MSCs to express the effector molecule C-X-C motif chemokine ligand 12(CXCL12)through the PRDX1-reactive oxygen species(ROS)-mitogen-activated protein kinase(MAPK)signaling axis,thereby increasing the number and function of HSPCs.These results suggest that ICT is a promising compound for achieving targeted modulation of the hematopoietic microenvironment to restore hematopoiesis after chemotherapy.
