Chronic,unresolved inflammation correlates with persistent hepatic injury and fibrosis,ultimately progressing to hepatocellular carcinoma(HCC).Bisdemethoxycurcumin(BDMC)demonstrates therapeutic potential against HCC,y...Chronic,unresolved inflammation correlates with persistent hepatic injury and fibrosis,ultimately progressing to hepatocellular carcinoma(HCC).Bisdemethoxycurcumin(BDMC)demonstrates therapeutic potential against HCC,yet its mechanism in preventing hepatic"inflammation-carcinoma transformation"remains incompletely understood.In the current research,clinical HCC specimens underwent analysis using hematoxylin-eosin(H&E)staining and immunohistochemistry(IHC)to evaluate the expression of fibrosis markers,M2 macrophage markers,and CXCL12.In vitro,transforming growth factor-β1(TGF-β1)-induced LX-2 cells and a co-culture system of LX-2,THP-1,and HCC cells were established.Cell functions underwent assessment through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT),flow cytometry,and Transwell assays.Reverse transcription-quantitative polymerase chain reaction(RT-qPCR),Western blotting and immunofluorescence evaluated the differential expression of molecules.The interaction betweenβ-catenin/TCF4 and CXCL12 was examined using co-immunoprecipitation(Co-IP),dual luciferase,and chromatin immunoprecipitation(ChIP)assays.A DEN-induced rat model was developed to investigate BDMC’s role in liver fibrosis-associated HCC(LFAHCC)development in vivo.Our results showed that clinical HCC tissues exhibited elevated fibrosis and enriched M2 macrophages.BDMC delayed liver fibrosis progression to HCC in vivo.BDMC inhibited the inflammatory microenvironment induced by activated hepatic stellate cells(HSCs).Furthermore,BDMC suppressed M2 macrophage-induced fibrosis and HCC cell proliferation and metastasis.Mechanistically,BDMC repressed TCF4/β-catenin complex formation,thereby reducing CXCL12 transcription in LX-2 cells.Moreover,CXCL12 overexpression reversed BDMC’s inhibitory effect on macrophage M2 polarization and its mediation of fibrosis,as well as HCC proliferation and metastasis.BDMC significantly suppressed LFAHCC development through CXCL12 in rats.In conclusion,BDMC inhibited LFAHCC progression by reducing M2 macrophage polarization through suppressingβ-catenin/TCF4-mediated CXCL12 transcription.展开更多
Objective To investigate the effects of bisdemethoxycurcumin （BDMC） on non-small cell lung cancer （NSCLC） cell line, A549, and the highly metastatic lung cancer 95D cells. Methods CCK-8 assay was used to assess th...Objective To investigate the effects of bisdemethoxycurcumin （BDMC） on non-small cell lung cancer （NSCLC） cell line, A549, and the highly metastatic lung cancer 95D cells. Methods CCK-8 assay was used to assess the effect of BDMC on cytotoxicity. Flow cytometry was used to evaluate apoptosis. Western blot analysis, electron microscopy, and quantification of GFP-LC3 punctuates were used to test the effect of BDMC on autophagy and apoptosis of lung cancer cells. Results BDMC inhibited the viability of NSCLC cells, but had no cytotoxic effects on lung small airway epithelial cells （SAECs）. The apoptotic cell death induced by BDMC was accompanied with the induction of autophagy in NSCLC cells. Blockage of autophagy by the autophagy inhibitor 3-methyladenine （3-MA） repressed the growth inhibitory effects and induction of apoptosis by BDMC. In addition, BDMC treatment significantly decreased smoothened （SMO） and the transcription factor glioma-associated oncogene 1 （G1il） expression. Furthermore, depletion of Gill by siRNA and cyclopamine （a specific SMO inhibitor） induced autophagy. Conclusion Aberrant activation of Hedgehog （Hh） signaling has been implicated in several human cancers, including lung cancers. The present findings provide direct evidence that BDMC-induced autophagy plays a pro-death role in NSCLC, in part, by inhibiting Hedgehog signaling.展开更多
Radiation therapy is considered the most effective non-surgical treatment for brain tumors.However,there are no available treatments for radiation-induced brain injury.Bisdemethoxycurcumin(BDMC)is a demethoxy derivati...Radiation therapy is considered the most effective non-surgical treatment for brain tumors.However,there are no available treatments for radiation-induced brain injury.Bisdemethoxycurcumin(BDMC)is a demethoxy derivative of curcumin that has anti-proliferative,anti-inflammatory,and anti-oxidant properties.To determine whether BDMC has the potential to treat radiation-induced brain injury,in this study,we established a rat model of radiation-induced brain injury by administe ring a single 30-Gy vertical dose of irradiation to the whole brain,followed by intraperitoneal injection of 500μL of a 100 mg/kg BDMC solution every day for 5 successive weeks.Our res ults showed that BDMC increased the body weight of rats with radiation-induced brain injury,improved lea rning and memory,attenuated brain edema,inhibited astrocyte activation,and reduced oxidative stress.These findings suggest that BDMC protects against radiationinduced brain injury.展开更多
Background：Bisdemethoxycurcumin （BDMC） is an active component of curcumin and a chemotherapeutic agent,which has been suggested to inhibit tumor growth,invasion and metastasis in multiple cancers.But its contributi...Background：Bisdemethoxycurcumin （BDMC） is an active component of curcumin and a chemotherapeutic agent,which has been suggested to inhibit tumor growth,invasion and metastasis in multiple cancers.But its contribution and mechanism of action in invasion and metastasis of non-small cell lung cancer （NSCLC） are not very clear.Therefore,we tried to study the effects of BDMC on regulation of epithelial-to-mesenchymal transition （EMT）,which is closely linked to tumor cell invasion and metastasis.Methods：In this study,we first induced transforming growth factor-βl （TGF-β1） mediated EMT in highly metastatic lung cancer 95D cells.Thereafter,we studied the effects of BDMC on invasion and migration of 95D cells.In addition,EMT markers expressions were also analyzed by western blot and immunofluorescence assays.The contribution of Wnt inhibitory factor-1 （WIF-1） in regulating BDMC effects on TGF-β1 induced EMT were further analyzed by its overexpression and small interfering RNA knockdown studies.Results：It was observed that BDMC inhibited the TGF-β1 induced EMT in 95D cells.Furthermore,it also inhibited the Wnt signaling pathway by upregulating WIF-1 protein expression.In addition,WIF-1 manipulation studies further revealed that WIF-1 is a central molecule mediating BDMC response towards TGF-β1 induced EMT by regulating cell invasion and migration.Conclusions：Our study concluded that BDMC effects on TGF-β1 induced EMT in NSCLC are mediated through WIF-1 and elucidated a novel mechanism of EMT regulation by BDMC.展开更多
Background: Curcuminoids are promising cancer chemopreventive agents. Curcumin, demethoxycurcumin(DMC) and bisdemethoxycurcumin(BDMC) are the major bioactive curcuminoids in turmeric. However, comprehensive metabolic ...Background: Curcuminoids are promising cancer chemopreventive agents. Curcumin, demethoxycurcumin(DMC) and bisdemethoxycurcumin(BDMC) are the major bioactive curcuminoids in turmeric. However, comprehensive metabolic studies of these three curcuminoids are still limited.Objective: To identify the metabolites of curcumin, DMC and BDMC in rats after oral administration of solid lipid nanoparticles(SLNs).Methods: Male Sprague-Dawley rats(250 ± 20 g, body weight) were randomly divided into 4 groups(n=3), and were orally administered with curcumin-SLN, DMC-SLN, BDMC-SLN, or blank-SLN, respectively. Plasma samples(500 μL) via the angular vein were collected at 1, 2 and 4 h post dosing, and the urine and feces samples were collected at 0–12 h and 12–24 h post-intake. An HPLC-DAD-ESI-MSnmethod was developed to identify the metabolites. The structures of phase II metabolites were further confirmed by enzyme hydrolysis.Results: A total of 34 metabolites were identified in rats plasma, urine, and feces. Most of them were phase II metabolites, including glucuronide conjugates and sulfate conjugates. Among them, the glucuronide conjugates were the major metabolites in rats plasma. In the meanwhile, the three parent curcuminoids were detected in high amounts in the urine and feces samples.Conclusion: The possible metabolic pathways of curcuminoids in rats were proposed.展开更多
基金supported by the National Natural Science Foundation of China(No.81904182)the Training Program for Excellent Young Innovators of Changsha(No.kq2209020)+1 种基金the Excellent Youth Project of Hunan University of Chinese Medicine(No.2022XJB006)the Excellent Youth Project of Natural Science Foundation of Heilongjiang Province(No.YQ2022H015).
文摘Chronic,unresolved inflammation correlates with persistent hepatic injury and fibrosis,ultimately progressing to hepatocellular carcinoma(HCC).Bisdemethoxycurcumin(BDMC)demonstrates therapeutic potential against HCC,yet its mechanism in preventing hepatic"inflammation-carcinoma transformation"remains incompletely understood.In the current research,clinical HCC specimens underwent analysis using hematoxylin-eosin(H&E)staining and immunohistochemistry(IHC)to evaluate the expression of fibrosis markers,M2 macrophage markers,and CXCL12.In vitro,transforming growth factor-β1(TGF-β1)-induced LX-2 cells and a co-culture system of LX-2,THP-1,and HCC cells were established.Cell functions underwent assessment through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT),flow cytometry,and Transwell assays.Reverse transcription-quantitative polymerase chain reaction(RT-qPCR),Western blotting and immunofluorescence evaluated the differential expression of molecules.The interaction betweenβ-catenin/TCF4 and CXCL12 was examined using co-immunoprecipitation(Co-IP),dual luciferase,and chromatin immunoprecipitation(ChIP)assays.A DEN-induced rat model was developed to investigate BDMC’s role in liver fibrosis-associated HCC(LFAHCC)development in vivo.Our results showed that clinical HCC tissues exhibited elevated fibrosis and enriched M2 macrophages.BDMC delayed liver fibrosis progression to HCC in vivo.BDMC inhibited the inflammatory microenvironment induced by activated hepatic stellate cells(HSCs).Furthermore,BDMC suppressed M2 macrophage-induced fibrosis and HCC cell proliferation and metastasis.Mechanistically,BDMC repressed TCF4/β-catenin complex formation,thereby reducing CXCL12 transcription in LX-2 cells.Moreover,CXCL12 overexpression reversed BDMC’s inhibitory effect on macrophage M2 polarization and its mediation of fibrosis,as well as HCC proliferation and metastasis.BDMC significantly suppressed LFAHCC development through CXCL12 in rats.In conclusion,BDMC inhibited LFAHCC progression by reducing M2 macrophage polarization through suppressingβ-catenin/TCF4-mediated CXCL12 transcription.
基金supported by a grant from the National Science Foundation(Grant number 81102857)
文摘Objective To investigate the effects of bisdemethoxycurcumin （BDMC） on non-small cell lung cancer （NSCLC） cell line, A549, and the highly metastatic lung cancer 95D cells. Methods CCK-8 assay was used to assess the effect of BDMC on cytotoxicity. Flow cytometry was used to evaluate apoptosis. Western blot analysis, electron microscopy, and quantification of GFP-LC3 punctuates were used to test the effect of BDMC on autophagy and apoptosis of lung cancer cells. Results BDMC inhibited the viability of NSCLC cells, but had no cytotoxic effects on lung small airway epithelial cells （SAECs）. The apoptotic cell death induced by BDMC was accompanied with the induction of autophagy in NSCLC cells. Blockage of autophagy by the autophagy inhibitor 3-methyladenine （3-MA） repressed the growth inhibitory effects and induction of apoptosis by BDMC. In addition, BDMC treatment significantly decreased smoothened （SMO） and the transcription factor glioma-associated oncogene 1 （G1il） expression. Furthermore, depletion of Gill by siRNA and cyclopamine （a specific SMO inhibitor） induced autophagy. Conclusion Aberrant activation of Hedgehog （Hh） signaling has been implicated in several human cancers, including lung cancers. The present findings provide direct evidence that BDMC-induced autophagy plays a pro-death role in NSCLC, in part, by inhibiting Hedgehog signaling.
基金supported by the National Natural Science Foundation of China,No.82002400(to GJZ)Scientific Research Project of Hu nan Health Committee,No.20201911and No.20200469(both to ZJX)+2 种基金Scientific Research Project of Hunan Health Committee,No.20211411761(to HMW)the Natural Science Foundation of Hunan Province,No.2020JJ5512(to GJZ)a grant from Clinical Medical Technology Innovation Guidance Project in Hunan Province,No.2020SK51822(to ZJX)。
文摘Radiation therapy is considered the most effective non-surgical treatment for brain tumors.However,there are no available treatments for radiation-induced brain injury.Bisdemethoxycurcumin(BDMC)is a demethoxy derivative of curcumin that has anti-proliferative,anti-inflammatory,and anti-oxidant properties.To determine whether BDMC has the potential to treat radiation-induced brain injury,in this study,we established a rat model of radiation-induced brain injury by administe ring a single 30-Gy vertical dose of irradiation to the whole brain,followed by intraperitoneal injection of 500μL of a 100 mg/kg BDMC solution every day for 5 successive weeks.Our res ults showed that BDMC increased the body weight of rats with radiation-induced brain injury,improved lea rning and memory,attenuated brain edema,inhibited astrocyte activation,and reduced oxidative stress.These findings suggest that BDMC protects against radiationinduced brain injury.
文摘Background：Bisdemethoxycurcumin （BDMC） is an active component of curcumin and a chemotherapeutic agent,which has been suggested to inhibit tumor growth,invasion and metastasis in multiple cancers.But its contribution and mechanism of action in invasion and metastasis of non-small cell lung cancer （NSCLC） are not very clear.Therefore,we tried to study the effects of BDMC on regulation of epithelial-to-mesenchymal transition （EMT）,which is closely linked to tumor cell invasion and metastasis.Methods：In this study,we first induced transforming growth factor-βl （TGF-β1） mediated EMT in highly metastatic lung cancer 95D cells.Thereafter,we studied the effects of BDMC on invasion and migration of 95D cells.In addition,EMT markers expressions were also analyzed by western blot and immunofluorescence assays.The contribution of Wnt inhibitory factor-1 （WIF-1） in regulating BDMC effects on TGF-β1 induced EMT were further analyzed by its overexpression and small interfering RNA knockdown studies.Results：It was observed that BDMC inhibited the TGF-β1 induced EMT in 95D cells.Furthermore,it also inhibited the Wnt signaling pathway by upregulating WIF-1 protein expression.In addition,WIF-1 manipulation studies further revealed that WIF-1 is a central molecule mediating BDMC response towards TGF-β1 induced EMT by regulating cell invasion and migration.Conclusions：Our study concluded that BDMC effects on TGF-β1 induced EMT in NSCLC are mediated through WIF-1 and elucidated a novel mechanism of EMT regulation by BDMC.
基金supported by the National Natural Science Foundation of China(Grant No.81222054 and 81302742)State Administration of Traditional Chinese Medicine(No.201307002)the Key Research Project of Department of Education of Sichuan(11ZA005)
文摘Background: Curcuminoids are promising cancer chemopreventive agents. Curcumin, demethoxycurcumin(DMC) and bisdemethoxycurcumin(BDMC) are the major bioactive curcuminoids in turmeric. However, comprehensive metabolic studies of these three curcuminoids are still limited.Objective: To identify the metabolites of curcumin, DMC and BDMC in rats after oral administration of solid lipid nanoparticles(SLNs).Methods: Male Sprague-Dawley rats(250 ± 20 g, body weight) were randomly divided into 4 groups(n=3), and were orally administered with curcumin-SLN, DMC-SLN, BDMC-SLN, or blank-SLN, respectively. Plasma samples(500 μL) via the angular vein were collected at 1, 2 and 4 h post dosing, and the urine and feces samples were collected at 0–12 h and 12–24 h post-intake. An HPLC-DAD-ESI-MSnmethod was developed to identify the metabolites. The structures of phase II metabolites were further confirmed by enzyme hydrolysis.Results: A total of 34 metabolites were identified in rats plasma, urine, and feces. Most of them were phase II metabolites, including glucuronide conjugates and sulfate conjugates. Among them, the glucuronide conjugates were the major metabolites in rats plasma. In the meanwhile, the three parent curcuminoids were detected in high amounts in the urine and feces samples.Conclusion: The possible metabolic pathways of curcuminoids in rats were proposed.
