Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death(ICD),making it a promising strategy for clinical application....Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death(ICD),making it a promising strategy for clinical application.Alantolactone(A)was found to augment the anticancer efficacy of paclitaxel(P)at a molar ratio of 1:0.5(P:A)through induction of more potent ICD via modulation of STAT3 signaling pathways.Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents,thereby enhancing multi-drug chemoimmunotherapy.To improve tumor targeting ability and bioavailability of hydrophobic drugs,an amphiphilic prodrug conjugate(HA-PTX)was chemically modified with paclitaxel(PTX)and hyaluronic acid(HA)as a backbone.Based on this concept,CD44-targeted nanodrugs(A@HAP NPs)were developed for co-delivery of A and P in colorectal cancer treatment,aiming to achieve synergistic toxicity-based chemo-immunotherapy.The uniform size and high drug loading capacity of A@HAP NPs facilitated their accumulation within tumors through enhanced permeability and retention effect as well as HA-mediated targeting,providing a solid foundation for subsequent synergistic therapy and immunoregulation.In vitro and in vivo studies demonstrated that A@HAP NPs exhibited potent cytotoxicity against tumor cells while also remodeling the immune-suppressive tumor microenvironment by promoting antigen presentation and inducing dendritic cell maturation,thus offering a novel approach for colorectal cancer chemoimmunotherapy.展开更多
Alantolactone, as the principal constituent oflnula Helenium L, has been shown various pharmacologic activities, such as anti-inflammatory and deworming. In the present study, we developed a high performance liquid ch...Alantolactone, as the principal constituent oflnula Helenium L, has been shown various pharmacologic activities, such as anti-inflammatory and deworming. In the present study, we developed a high performance liquid chromatography （HPLC） method for the determination of alantolactone in rat plasma, and pharmacokinetics of alantolactone was investigated after intravenous and oral administrations to Wistar rats. Separation was achieved on C18 column （4.6 mm×250 mm, 5.0 μm） using a mobile phase consisting of methanol-water （70：30, v/v） at a flow rate of 1.0 mL/min. The wavelength of the ultraviolet detector was set at 239 nm. The excellent linearity was found over a concentration range of 0.08-10 μg/mL （R2 = 0.9998）. The intra- and inter-day precisions were good, and the RSD was lower than 2.27%. The mean absolute recovery of alantolactone in plasma ranged from 88.09% to 95.57%. After intravenous administration, alantolactone showed rapid systemic clearance （CL （0.11±0.014） L/h/kg） and small volume of distribution （Vd （0.71±0.14） L/kg）. The biological half life （t1/2） was 56.24 min. After oral administration, alantolactone showed rapid oral absorption in rats, with a short Tmax of （45.02±0.88） and （45.13±0.39） min for 14 and 28 mg/kg, respectively. The bioavailability of alantolactone in rats was 50.88%, indicating that alantolactone was orally available.展开更多
Psoriasis is a common chronic immune-mediated skin disease characterized by hyperproliferation and aberrant differentiation of keratinocytes and massive infiltration of inflammatory immune cells.Recent studies showed ...Psoriasis is a common chronic immune-mediated skin disease characterized by hyperproliferation and aberrant differentiation of keratinocytes and massive infiltration of inflammatory immune cells.Recent studies showed that Signal Transducer and Activator of Transcription 3(STAT3),which plays an important role in cell survival,proliferation,differentiation,angiogenesis,and immune responses,is constitutively activated in epidermal keratinocytes of human psoriatic skin lesions.In addition,STAT3 promotes the differentiation and expansion of T cells and facilitates cytokine production,thereby exacerbating the condition of psoriasis.Alantolactone(ALT)is a sesquiterpene lactone compound that could selectively suppress STAT3 activation,but its effectiveness and application in psoriasis treatment have not been determined.In this study,we developed ALT loaded chitosan/hyaluronic acid nanoparticles(CHALT),and investigated its therapeutic potential for psoriasis therapy.CHALT effectively abrogated the hyperproliferation by inducing ROS-mediated apoptosis with loss of mitochondrialmembrane potential,and also inhibited IL-6-induced STAT3 signaling activation and inflammatory reaction in HaCaT cell line.In an Imiquimod(IMQ)-induced psoriasis model,the topical treatment of psoriasis lesions with CHALT effectively attenuated the STAT3 hyperactivation within keratinocytes and ameliorated the symptoms of psoriasis.In addition,it was found that CHALT restricted the recruitment of immune cells.These results indicated that ALT-based nanoformulation CHALT holds great potential for psoriasis therapy.展开更多
Alantolactone is a natural compound identified from the roots of Inula helenium L. that has multiple bio-activities. We examined its inhibitory effects on human non-small cell lung cancer（NSCLC） A549 cells. The an-t...Alantolactone is a natural compound identified from the roots of Inula helenium L. that has multiple bio-activities. We examined its inhibitory effects on human non-small cell lung cancer（NSCLC） A549 cells. The an-tiproliferative effect of alantolactone on A549 cells was investigated via MTT[3′-（4,5dimethylthiazol-2-yl）-2,5- diphenyl tetrazolium bromide] assay and its apoptosis-inducing effect was determined by Hoechst staining and flow cytometry. We found that alantolactone significantly inhibited the proliferation of A549 cells and induced morphological changes typical for apoptosis. Flow cytometry analysis indicates dose-dependent cell cycle retardation at G0/G1 and S stages. The results indicate that alantolactone could be an attractive small-molecular natural compound for further development as a therapeutic drug against NSCLC.展开更多
Objective:To explore the effect of alantolactone on thioacetamide-induced liver fibrosis in mice as well as elucidate its underlying mechanism.Methods:Animals were divided into 5 groups:the control,the thioacetamide g...Objective:To explore the effect of alantolactone on thioacetamide-induced liver fibrosis in mice as well as elucidate its underlying mechanism.Methods:Animals were divided into 5 groups:the control,the thioacetamide group(150 mg/kg/twice weekly),the thioacetamide groups treated with alantolactone(5 and 10 mg/kg)or silymarin(50 mg/kg),respectively.All treatments were continued for 6 successive weeks,followed by collection of sera and tissue samples.Biochemical,histological,and immunohistochemical analyses were performed to examine the hepatoprotective effects of alantolactone.Results:Alantolactone ameliorated thioacetamide-induced hepatic impairment and prevented the rise of serum activities of liver enzymes.Its hepatoprotective effect was further confirmed by histological examinations.Moreover,alantolactone lowered the expression of transforming growth factor-beta 1 and alpha-smooth muscle actin,hydroxyproline content as well as COL1A1 mRNA expression.It restored antioxidant balance and inhibited thioacetamide-induced upregulated expression of interleukin-1 beta,interleukin-6,and tumor necrosis factor-alpha,Toll-like receptor 4(TLR4),myeloid differentiation primary response 88(MyD88),and nuclear factor kappa B(NF-κB).Conclusions:Alantolactone protects against thioacetamide-induced liver fibrosis in mice by reducing collagen deposition,oxidative stress,and inflammation.These effects are mediated,at least partly,by the inhibition of TLR4/MyD88/NF-κB axis.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
Oxaliplatin(OXA),a platinum-based chemotherapeutic agent,remains a mainstay in first-line treatments for advanced colorectal cancer(CRC).However,the eventual development of OXA resis-tance represents a significant cli...Oxaliplatin(OXA),a platinum-based chemotherapeutic agent,remains a mainstay in first-line treatments for advanced colorectal cancer(CRC).However,the eventual development of OXA resis-tance represents a significant clinical challenge.In the present study,we demonstrate that the aldo-keto reductase 1C1(AKR1C1)is overexpressed in CRC cells upon acquisition of OXA resistance,evident in OXA-resistant CRC cell lines.We employed genetic silencing and pharmacological inhibition strategies to establish that suppression of AKR1C1 restores OXA sensitivity.Mechanistically,AKR1C1 interacts with and activates the transcription factor STAT3,which upregulates the glutamate transporter EAAT3,thereby elevating intracellular glutathione levels and conferring OXA resistance.Alantolactone,a potent natural product inhibitor of AKR1C1,effectively reverses this chemoresistance,restricting the growth of OXA-resistant CRC cells both in vitro and in vivo.Our findings uncover a critical AKR1C1-dependent mechanism behind OXA resistance and propose a promising combinatorial therapeutic strategy to over-come this resistance in CRC.展开更多
基金supported by Zhejiang Provincial Natural Science Foundation(LYY22H300001,LGF22H150016)Wenzhou Municipal Science and Technology Bureau(Y20210212)+2 种基金Application Basic Research Project of Liaoning Provincial Department of Science and Technology(2023JH2/101700072)Zhejiang Medical Doctor Association(YS2022-2-001)Health innovation talents program(Longfa Kou)from Health Commission of Zhejiang Province.
文摘Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death(ICD),making it a promising strategy for clinical application.Alantolactone(A)was found to augment the anticancer efficacy of paclitaxel(P)at a molar ratio of 1:0.5(P:A)through induction of more potent ICD via modulation of STAT3 signaling pathways.Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents,thereby enhancing multi-drug chemoimmunotherapy.To improve tumor targeting ability and bioavailability of hydrophobic drugs,an amphiphilic prodrug conjugate(HA-PTX)was chemically modified with paclitaxel(PTX)and hyaluronic acid(HA)as a backbone.Based on this concept,CD44-targeted nanodrugs(A@HAP NPs)were developed for co-delivery of A and P in colorectal cancer treatment,aiming to achieve synergistic toxicity-based chemo-immunotherapy.The uniform size and high drug loading capacity of A@HAP NPs facilitated their accumulation within tumors through enhanced permeability and retention effect as well as HA-mediated targeting,providing a solid foundation for subsequent synergistic therapy and immunoregulation.In vitro and in vivo studies demonstrated that A@HAP NPs exhibited potent cytotoxicity against tumor cells while also remodeling the immune-suppressive tumor microenvironment by promoting antigen presentation and inducing dendritic cell maturation,thus offering a novel approach for colorectal cancer chemoimmunotherapy.
基金The National Natural Science fund of China(Grant No.31360379)the open fund of the Key Laboratory of the New Animal Drug Project of Gansu Provincethe Key Laboratory of Veterinary Pharmaceutical Development of the Ministry of Agriculture(Grant No.2014)
文摘Alantolactone, as the principal constituent oflnula Helenium L, has been shown various pharmacologic activities, such as anti-inflammatory and deworming. In the present study, we developed a high performance liquid chromatography （HPLC） method for the determination of alantolactone in rat plasma, and pharmacokinetics of alantolactone was investigated after intravenous and oral administrations to Wistar rats. Separation was achieved on C18 column （4.6 mm×250 mm, 5.0 μm） using a mobile phase consisting of methanol-water （70：30, v/v） at a flow rate of 1.0 mL/min. The wavelength of the ultraviolet detector was set at 239 nm. The excellent linearity was found over a concentration range of 0.08-10 μg/mL （R2 = 0.9998）. The intra- and inter-day precisions were good, and the RSD was lower than 2.27%. The mean absolute recovery of alantolactone in plasma ranged from 88.09% to 95.57%. After intravenous administration, alantolactone showed rapid systemic clearance （CL （0.11±0.014） L/h/kg） and small volume of distribution （Vd （0.71±0.14） L/kg）. The biological half life （t1/2） was 56.24 min. After oral administration, alantolactone showed rapid oral absorption in rats, with a short Tmax of （45.02±0.88） and （45.13±0.39） min for 14 and 28 mg/kg, respectively. The bioavailability of alantolactone in rats was 50.88%, indicating that alantolactone was orally available.
基金inancially supported by the National Natural Science Foundation of China (81903551)Zhejiang Province Natural Science Foundation (LQ19H300001)Excellent Young Scientist Training Program fund from Wenzhou Medical University
文摘Psoriasis is a common chronic immune-mediated skin disease characterized by hyperproliferation and aberrant differentiation of keratinocytes and massive infiltration of inflammatory immune cells.Recent studies showed that Signal Transducer and Activator of Transcription 3(STAT3),which plays an important role in cell survival,proliferation,differentiation,angiogenesis,and immune responses,is constitutively activated in epidermal keratinocytes of human psoriatic skin lesions.In addition,STAT3 promotes the differentiation and expansion of T cells and facilitates cytokine production,thereby exacerbating the condition of psoriasis.Alantolactone(ALT)is a sesquiterpene lactone compound that could selectively suppress STAT3 activation,but its effectiveness and application in psoriasis treatment have not been determined.In this study,we developed ALT loaded chitosan/hyaluronic acid nanoparticles(CHALT),and investigated its therapeutic potential for psoriasis therapy.CHALT effectively abrogated the hyperproliferation by inducing ROS-mediated apoptosis with loss of mitochondrialmembrane potential,and also inhibited IL-6-induced STAT3 signaling activation and inflammatory reaction in HaCaT cell line.In an Imiquimod(IMQ)-induced psoriasis model,the topical treatment of psoriasis lesions with CHALT effectively attenuated the STAT3 hyperactivation within keratinocytes and ameliorated the symptoms of psoriasis.In addition,it was found that CHALT restricted the recruitment of immune cells.These results indicated that ALT-based nanoformulation CHALT holds great potential for psoriasis therapy.
基金Supported by the Natural Science Foundation of Jilin Province China(No.20090461)
文摘Alantolactone is a natural compound identified from the roots of Inula helenium L. that has multiple bio-activities. We examined its inhibitory effects on human non-small cell lung cancer（NSCLC） A549 cells. The an-tiproliferative effect of alantolactone on A549 cells was investigated via MTT[3′-（4,5dimethylthiazol-2-yl）-2,5- diphenyl tetrazolium bromide] assay and its apoptosis-inducing effect was determined by Hoechst staining and flow cytometry. We found that alantolactone significantly inhibited the proliferation of A549 cells and induced morphological changes typical for apoptosis. Flow cytometry analysis indicates dose-dependent cell cycle retardation at G0/G1 and S stages. The results indicate that alantolactone could be an attractive small-molecular natural compound for further development as a therapeutic drug against NSCLC.
文摘Objective:To explore the effect of alantolactone on thioacetamide-induced liver fibrosis in mice as well as elucidate its underlying mechanism.Methods:Animals were divided into 5 groups:the control,the thioacetamide group(150 mg/kg/twice weekly),the thioacetamide groups treated with alantolactone(5 and 10 mg/kg)or silymarin(50 mg/kg),respectively.All treatments were continued for 6 successive weeks,followed by collection of sera and tissue samples.Biochemical,histological,and immunohistochemical analyses were performed to examine the hepatoprotective effects of alantolactone.Results:Alantolactone ameliorated thioacetamide-induced hepatic impairment and prevented the rise of serum activities of liver enzymes.Its hepatoprotective effect was further confirmed by histological examinations.Moreover,alantolactone lowered the expression of transforming growth factor-beta 1 and alpha-smooth muscle actin,hydroxyproline content as well as COL1A1 mRNA expression.It restored antioxidant balance and inhibited thioacetamide-induced upregulated expression of interleukin-1 beta,interleukin-6,and tumor necrosis factor-alpha,Toll-like receptor 4(TLR4),myeloid differentiation primary response 88(MyD88),and nuclear factor kappa B(NF-κB).Conclusions:Alantolactone protects against thioacetamide-induced liver fibrosis in mice by reducing collagen deposition,oxidative stress,and inflammation.These effects are mediated,at least partly,by the inhibition of TLR4/MyD88/NF-κB axis.
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.
基金supported by the National Natural Science Foundation of China(Grant Nos.82204758 and 82073402).
文摘Oxaliplatin(OXA),a platinum-based chemotherapeutic agent,remains a mainstay in first-line treatments for advanced colorectal cancer(CRC).However,the eventual development of OXA resis-tance represents a significant clinical challenge.In the present study,we demonstrate that the aldo-keto reductase 1C1(AKR1C1)is overexpressed in CRC cells upon acquisition of OXA resistance,evident in OXA-resistant CRC cell lines.We employed genetic silencing and pharmacological inhibition strategies to establish that suppression of AKR1C1 restores OXA sensitivity.Mechanistically,AKR1C1 interacts with and activates the transcription factor STAT3,which upregulates the glutamate transporter EAAT3,thereby elevating intracellular glutathione levels and conferring OXA resistance.Alantolactone,a potent natural product inhibitor of AKR1C1,effectively reverses this chemoresistance,restricting the growth of OXA-resistant CRC cells both in vitro and in vivo.Our findings uncover a critical AKR1C1-dependent mechanism behind OXA resistance and propose a promising combinatorial therapeutic strategy to over-come this resistance in CRC.
