Muramidase-released protein(MRP)is now being recognized as a critical indicator of the virulence and pathogenicity of Streptococcus suis(S.suis).However,the identification of viable therapeutics for S.suis infection w...Muramidase-released protein(MRP)is now being recognized as a critical indicator of the virulence and pathogenicity of Streptococcus suis(S.suis).However,the identification of viable therapeutics for S.suis infection was hindered by the absence of an explicit mechanism for MRP-actuated inflammation.Dihydroartemisinin(DhA)is an artemisinin derivative with potential anti-inflammatory activity.The modulatory effect of DhA on the inflammatory response mediated by the virulence factor MRP remains obscure.This research aimed to identify the signaling mechanism by which MRP triggers the innate immune response in mouse spleen and cultured macrophages.With the candidate mechanism in mind,we investigated DhA for its ability to dampen the pro-inflammatory response induced by MRP.The innate immune response in mice was drastically triggered by MRP,manifesting as splenic and systemic inflammation with splenomegaly,immune cell infiltration,and an elevation in pro-inflammatory cytokines.A crucial role for Toll-like receptor 4(TLR4)in coordinating the MRP-mediated inflammatory response via nuclear factor-kappa B(NF-kB)activation was revealed by TLR4 blockade.In addition,NFkB-dependent transducer and activator of transcription 3(STAT3)and mitogen-activated protein kinases(MAPKs)activation was required for the inflammatory signal transduction engendered by MRP.Intriguingly,we observed an alleviation effect of DhA on the MRP-induced immune response,which referred to the suppression of TLR4-mediated actuation of NF-kB-STAT3/MAPK cascades.The inflammatory response elicited by MRP is relevant to TLR4-dependent NF-kB activation,followed by an increase in the activity of STAT3 or MAPKs.DhA mitigates the inflammation process induced by MRP via blocking the TLR4 cascade,highlighting the therapeutic potential of DhA in targeting S.suis infection diseases.展开更多
Conjugative transfer of antibiotic resistance genes(ARGs)by plasmids is an important route for ARG dissemination.An increasing number of antibiotic and nonantibiotic compounds have been reported to aid the spread of A...Conjugative transfer of antibiotic resistance genes(ARGs)by plasmids is an important route for ARG dissemination.An increasing number of antibiotic and nonantibiotic compounds have been reported to aid the spread of ARGs,highlighting potential challenges for controlling this type of horizontal transfer.Development of conjugation inhibitors that block or delay the transfer of ARG-bearing plasmids is a promising strategy to control the propagation of antibiotic resistance.Although such inhibitors are rare,they typically exhibit relatively high toxicity and low efficacy in vivo and their mechanisms of action are inadequately understood.Here,we studied the effects of dihydroartemisinin(DHA),an artemisinin derivative used to treat malaria,on conjugation.DHA inhibited the conjugation of the IncI2 and IncX4 plasmids carrying the mobile colistin resistance gene(mcr-1)by more than 160-fold in vitro in Escherichia coli,and more than two-fold(IncI2 plasmid)in vivo in a mouse model.It also suppressed the transfer of the IncX3 plasmid carrying the carbapenem resistance gene bla_(NDM-5)by more than twofold in vitro.Detection of intracellular adenosine triphosphate(ATP)and proton motive force(PMF),in combination with transcriptomic and metabolomic analyses,revealed that DHA impaired the function of the electron transport chain(ETC)by inhibiting the tricarboxylic acid(TCA)cycle pathway,thereby disrupting PMF and limiting the availability of intracellular ATP for plasmid conjugative transfer.Furthermore,expression levels of genes related to conjugation and pilus generation were significantly down-regulated during DHA exposure,indicating that the transfer apparatus for conjugation may be inhibited.Our findings provide new insights into the control of antibiotic resistance and the potential use of DHA.展开更多
Background:Dihydroartemisinin(DHA)is reported to be a potential anticancer agent,and the mechanisms underlying the effects of DHA on diffuse large B cell lymphoma however are still obscure.This study aimed to assess t...Background:Dihydroartemisinin(DHA)is reported to be a potential anticancer agent,and the mechanisms underlying the effects of DHA on diffuse large B cell lymphoma however are still obscure.This study aimed to assess the antitumor effect of DHA on diffuse large B cell lymphoma cells and to determine the potential underlying mechanisms of DHA-induced cell apoptosis.Methods:Here,the Cell Counting Kit 8 assay was conducted to study cell proliferation.We performed Annexin V-FITC/propidium iodide staining,real-time polymerase chain reaction,and western blot analysis to analyze cell apoptosis and potential molecular mechanisms.Results:The results showed that DHA substantially suppressed cell proliferation and induced cell apoptosis in vitro in a time-and concentration-dependent fashion.Moreover,STAT3 activity could be inhibited after stimulation with DHA.Conclusion:These results imply that the underlying anti-tumoral effect of DHA may increase apoptosis in diffuse large B cell lymphoma cells via the STAT3 signaling pathway.In addition,DHA might be an effective drug for diffuse large B cell lymphoma therapy.展开更多
Problem Statement: Malaria’s global impact necessitates effective treatments, like dihydroartemisinin-piperaquine (DHA/PQP), though safety concerns, notably drug-induced cardiotoxicity (DICT), persist. A knowledge ga...Problem Statement: Malaria’s global impact necessitates effective treatments, like dihydroartemisinin-piperaquine (DHA/PQP), though safety concerns, notably drug-induced cardiotoxicity (DICT), persist. A knowledge gap exists regarding DHA/PQP’s cardiac effects, warranting a comprehensive investigation. Approach: This study aimed to assess KROSH (DHA/PQP) impact on albino rat heart histology, examining structural changes and potential cardiotoxicity. 40 albino rats were grouped by KROSH dosage and duration, monitored for weight changes, and heart tissues were examined using hematoxylin and eosin (H & E) staining. Statistical analysis compared to control and treated groups. Results: KROSH administration led to varying rat weight effects, yet not statistically significant. Histological analysis revealed dose and duration-dependent cardiac tissue alterations, including distortion, adipose deposits, artery hypertrophy, fibrosis, and necrosis. These contrasts with prior research documenting DHA/PQP’s non-toxic effects. Conclusion/Recommendation: This study highlights potential KROSH (DHA/PQP) cardiotoxicity concerns through histological changes, underscoring the need for further research into underlying mechanisms and human health implications. Given DHA/PQP’s wide use, these findings should inform safety evaluations and administration practices.展开更多
Dihydroartemisinin(DHA),a first-line antimalarial drug,has demonstrated great anticancer effects in many types of tumors,including liver cancer,glioblastoma,and pancreatic cancer.Due to its abilities to induce program...Dihydroartemisinin(DHA),a first-line antimalarial drug,has demonstrated great anticancer effects in many types of tumors,including liver cancer,glioblastoma,and pancreatic cancer.Due to its abilities to induce programmed cell death(PCD;apoptosis,autophagy and ferroptosis),inhibit tumor metastasis and angiogenesis,and modulate the tumor microenvironment,DHA could become an antineoplastic agent in the foreseeable future.However,the therapeutic efficacy of DHA is compromised owing to its inherent disadvantages,including poor stability,low aqueous solubility,and short plasma halflife.To overcome these drawbacks,nanoscale drug delivery systems(NDDSs),such as polymeric nanoparticles(NPs),liposomes,and metal-organic frameworks(MOFs),have been introduced to maximize the therapeutic efficacy of DHA in either single-drug or multidrug therapy.Based on the beneficial properties of NDDSs,including enhanced stability and solubility of the drug,prolonged circulation time and selective accumulation in tumors,the outcomes of DHA-loaded NDDSs for cancer therapy are significantly improved compared to those of free DHA.This reviewfirst summarizes the current understanding of the anticancer mechanisms of DHA and then provides an overview of DHA-including nanomedicines,aiming to provide inspiration for further application of DHA as an anticancer drug.展开更多
AIM: To determine if topical instillation of dihydroartemisinin (DHA) inhibits corneal neovascularization (NV) in rats and to investigate the role of the extracellular regulated kinases (ERK) 1/2 and p38 pathways in t...AIM: To determine if topical instillation of dihydroartemisinin (DHA) inhibits corneal neovascularization (NV) in rats and to investigate the role of the extracellular regulated kinases (ERK) 1/2 and p38 pathways in this process. O METHODS: Suture-induced corneal NV was produced in rats and the eyes were topically treated with different concentrations of DHA (20mg/L, 10mg/L or 5mg/L) or normal saline 4 times a day for 7 days. The corneal NV was quantified as the proportion of NV area to the whole cornea. Western blot was used to determine the expressions of vascular endothelial growth factor (VEGF) and the phosphorylation status of VEGF receptor-2, ERK1/2 and p38 in the corneas. Immunofluorescent staining was used to determine the expressions of phospho-ERK1/2 and phospho-p38 in the corneal tissues from the eyes treated with 20 mg/L DHA (DHA group) or normal saline (control group). RESULTS: The proportion of corneal NV area in the eyes treated with normal saline or DHA at dosages of 20mg/L, 10mg/L or 5mg/L was (23.74 +/- 3.00)%, (15.73 +/- 2.88)%, (19.53 +/- 2.42)%, and (23.38 +/- 2.79)%, respectively. In the eyes treated with 20mg/L or 10mg/L DHA, the corneal NV area was significantly reduced when compared to that in eyes with normal saline (P < 0.05). Western blot analyses revealed that 20mg/L DHA significantly inhibited the expressions of VEGF and phospho-VEGFR-2. Both 20mg/L and 10mg/L DHA inhibited the expressions of phospho-ERK1/2 and phospho-p38. Immunofluorescent staining further demonstrated that 20mg/L DHA lowered the Expression levels of phospho-ERK1/2 and phospho-p38 in the corneas with suture-induced NV. O CONCLUSION: Suture-induced NV in rat corneas was significantly inhibited by topical treatment with 20mg/L and 10mg/L DHA. The results suggest that the effects could be partially dependent on the DHA-mediated inhibitions of the ERK1/2 and p38 pathways.展开更多
Objective:To evaluate the inhibitory effect of dihydroartemisinin on neuroblastoma cell line SH-SY5 Y,explore the possible mechanism of dihydroartemisinin against neuroblastoma cells.Methods:The cell viability of dihy...Objective:To evaluate the inhibitory effect of dihydroartemisinin on neuroblastoma cell line SH-SY5 Y,explore the possible mechanism of dihydroartemisinin against neuroblastoma cells.Methods:The cell viability of dihydroartemisinin treated SH-SY5 Y cells was examined by MTT assay and morphology of cells was observed by using inverted microscope.Cell cycle was examined with flowcytometry assay,then cyclin D1 and caspase-3 proteins expression was detected by ELISA and western blotting assay.Results:MTT analysis results showed that cell viability significantly decreased after exposure to 0.05,0.50,5.00 and 50.00 mmol/L dihydroartemisinin in a dose-dependent manner,and the lower density of cells was observed in treated groups.The number of cells in sub-G1 phase was increased after treatment with different doses of dihydroartemisinin compared with the control group.The expression of cyclin D1 protein was decreased,while the expression of caspase-3 protein was increased in treated group.Conclusions:Dihydroartemisinin could inhibit the proliferation through stopping the cell cycle and inducing the apoptosis in neuroblastoma SH-SY5 Y cells.展开更多
Objective:To investigate the activity of anti-malarial dihydroartemisinin (DHA) on tumor growth, lymphangiogenesis, nodal and lung metastasis and survival in mice bearing Lewis lung carcimoma (LLC). Methods: The model...Objective:To investigate the activity of anti-malarial dihydroartemisinin (DHA) on tumor growth, lymphangiogenesis, nodal and lung metastasis and survival in mice bearing Lewis lung carcimoma (LLC). Methods: The models of C57BL/6 mice transplantation tumors were established via subcutaneous injection of LLC cells and divided into 4 groups: control group, DHA group, DHA+ferrous sulfate (FS) group and FS group, with 25 mice in each group. Tumor volumes and weights, nodal and lung metastasis, and survival were monitored. Tumor lymphatic microvessel density (LMVD) was determined by lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) immnohistochemistry. After LLC cells were treated with DHA or DHA+FS, protein and mRNA levels of vascular endothelial growth factor (VEGF) -C were evaluated by Western blotting and real time quantitative RT-PCR, respectively. Results: Oral administration of DHA or DHA+FS inhibited lymph node and lung metastasis, and prolonged survival. However, no significant tumor growth retardation effect was observed when mice were treated with DHA alone. The inhibited tumor metastasis was related to the decreased LMVD in the peritumoral regions, but not in the intratumoral regions. DHA significantly down-regulated the expression of VEGF-C protein and mRNA in LLC cells. Conclusion: DHA effectively inhibits LLC transplantation tumor lymphangiogenesis, nodal and lung metastasis, and may be a promising chemotherapeutic agent for controlling lung cancer metastasis by decreasing VEGF-C expression.展开更多
Acute kidney injury(AKI)is an important factor for the occurrence and development of CKD.The protective effect of dihydroartemisinin on AKI and and reported mechanism have not been reported.In this study,we used two a...Acute kidney injury(AKI)is an important factor for the occurrence and development of CKD.The protective effect of dihydroartemisinin on AKI and and reported mechanism have not been reported.In this study,we used two animal models including ischemia-reperfusion and UUO,as well as a high-glucose-stimulated HK-2 cell model,to evaluate the protective effect of dihydroartemisinin on premature senescence of renal tubular epithelial cells in vitro and in vivo.We demonstrated that dihydroartemisinin improved renal aging and renal injury by activating autophagy.In addition,we found that co-treatment with chloroquine,an autophagy inhibitor,abolished the anti-renal aging effect of dihydroartemisinin in vitro.These findings suggested that activation of autophagy/elimination of senescent cell might be a useful strategy to prevent AKI/UUO induced renal tubular senescence and fibrosis.展开更多
The effect of anti-programmed cell death 1(anti-PD-1)immunotherapy is limited in patients with hepatocellular carcinoma(HCC).Yes-associated protein 1(YAP1)expression increased in liver tumor cells in early HCC,and Akk...The effect of anti-programmed cell death 1(anti-PD-1)immunotherapy is limited in patients with hepatocellular carcinoma(HCC).Yes-associated protein 1(YAP1)expression increased in liver tumor cells in early HCC,and Akkermansia muciniphila abundance decreased in the colon.The response to anti-PD-1 treatment is associated with A.muciniphila abundance in many tumors.However,the interaction between A.muciniphila abundance and YAP1 expression remains unclear in HCC.Here,anti-PD-1 treatment decreased A.muciniphila abundance in the colon,but increased YAP1 expression in the tumor cells by mice with liver tumors in situ.Mechanistically,hepatocyte-specific Yap1 knockout(Yap1^(LKO))maintained bile acid homeostasis in the liver,resulting in an increased abundance of A.muciniphila in the colon.Yap1 knockout enhanced anti-PD-1 efficacy.Therefore,YAP1 inhibition is a potential target for increasing A.muciniphila abundance to promote anti-PD-1 efficacy in liver tumors.Dihydroartemisinin(DHA),acting as YAP1 inhibitor,increased A.muciniphila abundance to sensitize anti-PD-1 therapy.A.muciniphila by gavage increased the number and activation of CD8^(+)T cells in liver tumor niches during DHA treatment or combination with anti-PD-1.Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.展开更多
Artemisinin and its derivatives have emerged as promising therapeutic agents for cancer therapy by endogenous iron-mediated generation of free radicals.However,the enhanced antioxidant defense systems in cancer cells ...Artemisinin and its derivatives have emerged as promising therapeutic agents for cancer therapy by endogenous iron-mediated generation of free radicals.However,the enhanced antioxidant defense systems in cancer cells provide them with resistance to oxidative damage,greatly antagonizing the therapeutic efficacy that relies on inducing oxidative stress.Herein,a metal-organic framework(MOF)-based nanoplatform(CMD)is constructed to disrupt the cellular redox homeostasis and selectively potentiate the cytotoxicity of dihydroartemisinin for cancer therapy.In cancer cells,the copper(II)sites in the MOF nanocarrier of CMD can efficiently weaken the cellular antioxidant capacity by depleting the overexpressed glutathione,simultaneously leading to the decomposition of the framework structure and the release of the encapsulated dihydroartemisinin.As a result,the damaged antioxidant defense system of cancer cells reduces its effect on oxidative stress alleviation and strengthens the therapeutic efficacy of dihydroartemisinin.On contrast,the low concentration of cellular glutathione in normal cells protects them from dihydroartemisinin-induced cytotoxicity by decelerating the drug release.In vivo results demonstrate that CMD could completely suppress the tumor growth in mice and show no evidence of toxicity,providing an effective strategy for the practical usage of dihydroartemisinin in cancer therapy.展开更多
The aim of present study was to evaluate whether diets supplemented with dihydroartemisinin(DHA)could alleviate intestinal inflammatory injury in weaned piglets with intrauterine growth retardation(IUGR).Twelve normal...The aim of present study was to evaluate whether diets supplemented with dihydroartemisinin(DHA)could alleviate intestinal inflammatory injury in weaned piglets with intrauterine growth retardation(IUGR).Twelve normal birth weight(NBW)piglets and 12 piglets with IUGR were fed a basal diet(NBW-CON and IUCR-CON groups),and another 12 piglets with IUGR were fed the basal diet supplemented with DHA at 80 mg/kg(IUGR-DHA group)from 21 to 49 d of age.At 49 d of age,8 piglets with similar body weight in each group were sacrificed.The jejunal and ileal samples were collected for further analysis.The results showed that IUGR impaired intestinal morphology,increased intestinal inflamma-tory response,raised enterocyte apoptosis and reduced enterocyte proliferation and activated trans-membrane toll-like receptor 4(TLR4)/nucleotide-binding and oligomerization domain(NOD)/nuclear factor-kB(NF-kB)signaling pathway.Dihydroartemisinin inclusion ameliorated intestinal morphology,indicated by increased villus height,villus height-to-crypt depth ratio,villus surface area and decreased villus width of piglets with IUGR(P<0.05).Compared with NBW piglets,IUGR piglets supplemented with DHA exhibited higher apoptosis index and caspase-3 expression,and lower proliferation index and proliferating cell nuclear antigen expression in the intestine(P<0.05).Dihydroartemisinin supple-mentation attenuated the intestinal inflammation of piglets with IUGR,indicated by increased concen-trations of intestinal inflammatory cytokines and lipopolysaccharides(P<0.05).In addition,DHA supplementation down-regulated the related mRNA expressions of TLR4/NOD/NF-kB signaling pathway and upregulated mRNA expressions of negative regulators of TLR4 and NOD signaling pathway in the intestine of piglets with IUGR(P<0.05).Piglets in the IUGR-DHA group showed lower protein ex-pressions of TLR4,phosphorylated NF-kB(pNF-kB)inhibitorα,nuclear pNF-kB,and higher protein expression of cytoplasmic pNF-kB in the intestine than those in the IUGR-CON group(P<0.05).In conclusion,DHA supplementation could improve intestinal morphology,regulate enterocyte prolifera-tion and apoptosis,and alleviate intestinal inflammation through TLR4/NOD/NF-kB signaling pathway in weaned piglets with IUGR.展开更多
基金supported by the National Key R&D Program of China(Grant Nos.:2022YFF1100104 and 2022YFF1100102)the National Natural Science Foundation of China(Grant Nos.:31625025,32172749,and 32202701)+1 种基金the 2115 Talent Development Program of China Agricultural University(Grant No.:00109016)the Zhengzhou 1125 Talent Program,China(Grant No.:2016XT016).
文摘Muramidase-released protein(MRP)is now being recognized as a critical indicator of the virulence and pathogenicity of Streptococcus suis(S.suis).However,the identification of viable therapeutics for S.suis infection was hindered by the absence of an explicit mechanism for MRP-actuated inflammation.Dihydroartemisinin(DhA)is an artemisinin derivative with potential anti-inflammatory activity.The modulatory effect of DhA on the inflammatory response mediated by the virulence factor MRP remains obscure.This research aimed to identify the signaling mechanism by which MRP triggers the innate immune response in mouse spleen and cultured macrophages.With the candidate mechanism in mind,we investigated DhA for its ability to dampen the pro-inflammatory response induced by MRP.The innate immune response in mice was drastically triggered by MRP,manifesting as splenic and systemic inflammation with splenomegaly,immune cell infiltration,and an elevation in pro-inflammatory cytokines.A crucial role for Toll-like receptor 4(TLR4)in coordinating the MRP-mediated inflammatory response via nuclear factor-kappa B(NF-kB)activation was revealed by TLR4 blockade.In addition,NFkB-dependent transducer and activator of transcription 3(STAT3)and mitogen-activated protein kinases(MAPKs)activation was required for the inflammatory signal transduction engendered by MRP.Intriguingly,we observed an alleviation effect of DhA on the MRP-induced immune response,which referred to the suppression of TLR4-mediated actuation of NF-kB-STAT3/MAPK cascades.The inflammatory response elicited by MRP is relevant to TLR4-dependent NF-kB activation,followed by an increase in the activity of STAT3 or MAPKs.DhA mitigates the inflammation process induced by MRP via blocking the TLR4 cascade,highlighting the therapeutic potential of DhA in targeting S.suis infection diseases.
基金supported in part by grants from the Laboratory of Lingnan Modern Agriculture Project (NT2021006)National Key Research and Development Program of China (2022YFD1800400)。
文摘Conjugative transfer of antibiotic resistance genes(ARGs)by plasmids is an important route for ARG dissemination.An increasing number of antibiotic and nonantibiotic compounds have been reported to aid the spread of ARGs,highlighting potential challenges for controlling this type of horizontal transfer.Development of conjugation inhibitors that block or delay the transfer of ARG-bearing plasmids is a promising strategy to control the propagation of antibiotic resistance.Although such inhibitors are rare,they typically exhibit relatively high toxicity and low efficacy in vivo and their mechanisms of action are inadequately understood.Here,we studied the effects of dihydroartemisinin(DHA),an artemisinin derivative used to treat malaria,on conjugation.DHA inhibited the conjugation of the IncI2 and IncX4 plasmids carrying the mobile colistin resistance gene(mcr-1)by more than 160-fold in vitro in Escherichia coli,and more than two-fold(IncI2 plasmid)in vivo in a mouse model.It also suppressed the transfer of the IncX3 plasmid carrying the carbapenem resistance gene bla_(NDM-5)by more than twofold in vitro.Detection of intracellular adenosine triphosphate(ATP)and proton motive force(PMF),in combination with transcriptomic and metabolomic analyses,revealed that DHA impaired the function of the electron transport chain(ETC)by inhibiting the tricarboxylic acid(TCA)cycle pathway,thereby disrupting PMF and limiting the availability of intracellular ATP for plasmid conjugative transfer.Furthermore,expression levels of genes related to conjugation and pilus generation were significantly down-regulated during DHA exposure,indicating that the transfer apparatus for conjugation may be inhibited.Our findings provide new insights into the control of antibiotic resistance and the potential use of DHA.
基金supported by the Shandong Provincial Natural Science Foundation of China(ZR2019MH096).
文摘Background:Dihydroartemisinin(DHA)is reported to be a potential anticancer agent,and the mechanisms underlying the effects of DHA on diffuse large B cell lymphoma however are still obscure.This study aimed to assess the antitumor effect of DHA on diffuse large B cell lymphoma cells and to determine the potential underlying mechanisms of DHA-induced cell apoptosis.Methods:Here,the Cell Counting Kit 8 assay was conducted to study cell proliferation.We performed Annexin V-FITC/propidium iodide staining,real-time polymerase chain reaction,and western blot analysis to analyze cell apoptosis and potential molecular mechanisms.Results:The results showed that DHA substantially suppressed cell proliferation and induced cell apoptosis in vitro in a time-and concentration-dependent fashion.Moreover,STAT3 activity could be inhibited after stimulation with DHA.Conclusion:These results imply that the underlying anti-tumoral effect of DHA may increase apoptosis in diffuse large B cell lymphoma cells via the STAT3 signaling pathway.In addition,DHA might be an effective drug for diffuse large B cell lymphoma therapy.
文摘Problem Statement: Malaria’s global impact necessitates effective treatments, like dihydroartemisinin-piperaquine (DHA/PQP), though safety concerns, notably drug-induced cardiotoxicity (DICT), persist. A knowledge gap exists regarding DHA/PQP’s cardiac effects, warranting a comprehensive investigation. Approach: This study aimed to assess KROSH (DHA/PQP) impact on albino rat heart histology, examining structural changes and potential cardiotoxicity. 40 albino rats were grouped by KROSH dosage and duration, monitored for weight changes, and heart tissues were examined using hematoxylin and eosin (H & E) staining. Statistical analysis compared to control and treated groups. Results: KROSH administration led to varying rat weight effects, yet not statistically significant. Histological analysis revealed dose and duration-dependent cardiac tissue alterations, including distortion, adipose deposits, artery hypertrophy, fibrosis, and necrosis. These contrasts with prior research documenting DHA/PQP’s non-toxic effects. Conclusion/Recommendation: This study highlights potential KROSH (DHA/PQP) cardiotoxicity concerns through histological changes, underscoring the need for further research into underlying mechanisms and human health implications. Given DHA/PQP’s wide use, these findings should inform safety evaluations and administration practices.
基金supported by the National Natural Science Foundation of China[51922111]the Science and Technology Development Fund,Macao SAR[File no.0124/2019/A3]Guangdong-Hong Kong-Macao Joint Laboratory of Optoelectronic and Magnetic Functional Materials[2019B121205002].
文摘Dihydroartemisinin(DHA),a first-line antimalarial drug,has demonstrated great anticancer effects in many types of tumors,including liver cancer,glioblastoma,and pancreatic cancer.Due to its abilities to induce programmed cell death(PCD;apoptosis,autophagy and ferroptosis),inhibit tumor metastasis and angiogenesis,and modulate the tumor microenvironment,DHA could become an antineoplastic agent in the foreseeable future.However,the therapeutic efficacy of DHA is compromised owing to its inherent disadvantages,including poor stability,low aqueous solubility,and short plasma halflife.To overcome these drawbacks,nanoscale drug delivery systems(NDDSs),such as polymeric nanoparticles(NPs),liposomes,and metal-organic frameworks(MOFs),have been introduced to maximize the therapeutic efficacy of DHA in either single-drug or multidrug therapy.Based on the beneficial properties of NDDSs,including enhanced stability and solubility of the drug,prolonged circulation time and selective accumulation in tumors,the outcomes of DHA-loaded NDDSs for cancer therapy are significantly improved compared to those of free DHA.This reviewfirst summarizes the current understanding of the anticancer mechanisms of DHA and then provides an overview of DHA-including nanomedicines,aiming to provide inspiration for further application of DHA as an anticancer drug.
基金Science and Technology Planning Projects of Guangdong Province,China (No.2008B080703037,No. 2008B080703042)
文摘AIM: To determine if topical instillation of dihydroartemisinin (DHA) inhibits corneal neovascularization (NV) in rats and to investigate the role of the extracellular regulated kinases (ERK) 1/2 and p38 pathways in this process. O METHODS: Suture-induced corneal NV was produced in rats and the eyes were topically treated with different concentrations of DHA (20mg/L, 10mg/L or 5mg/L) or normal saline 4 times a day for 7 days. The corneal NV was quantified as the proportion of NV area to the whole cornea. Western blot was used to determine the expressions of vascular endothelial growth factor (VEGF) and the phosphorylation status of VEGF receptor-2, ERK1/2 and p38 in the corneas. Immunofluorescent staining was used to determine the expressions of phospho-ERK1/2 and phospho-p38 in the corneal tissues from the eyes treated with 20 mg/L DHA (DHA group) or normal saline (control group). RESULTS: The proportion of corneal NV area in the eyes treated with normal saline or DHA at dosages of 20mg/L, 10mg/L or 5mg/L was (23.74 +/- 3.00)%, (15.73 +/- 2.88)%, (19.53 +/- 2.42)%, and (23.38 +/- 2.79)%, respectively. In the eyes treated with 20mg/L or 10mg/L DHA, the corneal NV area was significantly reduced when compared to that in eyes with normal saline (P < 0.05). Western blot analyses revealed that 20mg/L DHA significantly inhibited the expressions of VEGF and phospho-VEGFR-2. Both 20mg/L and 10mg/L DHA inhibited the expressions of phospho-ERK1/2 and phospho-p38. Immunofluorescent staining further demonstrated that 20mg/L DHA lowered the Expression levels of phospho-ERK1/2 and phospho-p38 in the corneas with suture-induced NV. O CONCLUSION: Suture-induced NV in rat corneas was significantly inhibited by topical treatment with 20mg/L and 10mg/L DHA. The results suggest that the effects could be partially dependent on the DHA-mediated inhibitions of the ERK1/2 and p38 pathways.
基金Supported by the National Natural Science Foundation of China(NO.81201671,NO.81202953 and NO.81202031)
文摘Objective:To evaluate the inhibitory effect of dihydroartemisinin on neuroblastoma cell line SH-SY5 Y,explore the possible mechanism of dihydroartemisinin against neuroblastoma cells.Methods:The cell viability of dihydroartemisinin treated SH-SY5 Y cells was examined by MTT assay and morphology of cells was observed by using inverted microscope.Cell cycle was examined with flowcytometry assay,then cyclin D1 and caspase-3 proteins expression was detected by ELISA and western blotting assay.Results:MTT analysis results showed that cell viability significantly decreased after exposure to 0.05,0.50,5.00 and 50.00 mmol/L dihydroartemisinin in a dose-dependent manner,and the lower density of cells was observed in treated groups.The number of cells in sub-G1 phase was increased after treatment with different doses of dihydroartemisinin compared with the control group.The expression of cyclin D1 protein was decreased,while the expression of caspase-3 protein was increased in treated group.Conclusions:Dihydroartemisinin could inhibit the proliferation through stopping the cell cycle and inducing the apoptosis in neuroblastoma SH-SY5 Y cells.
文摘Objective:To investigate the activity of anti-malarial dihydroartemisinin (DHA) on tumor growth, lymphangiogenesis, nodal and lung metastasis and survival in mice bearing Lewis lung carcimoma (LLC). Methods: The models of C57BL/6 mice transplantation tumors were established via subcutaneous injection of LLC cells and divided into 4 groups: control group, DHA group, DHA+ferrous sulfate (FS) group and FS group, with 25 mice in each group. Tumor volumes and weights, nodal and lung metastasis, and survival were monitored. Tumor lymphatic microvessel density (LMVD) was determined by lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) immnohistochemistry. After LLC cells were treated with DHA or DHA+FS, protein and mRNA levels of vascular endothelial growth factor (VEGF) -C were evaluated by Western blotting and real time quantitative RT-PCR, respectively. Results: Oral administration of DHA or DHA+FS inhibited lymph node and lung metastasis, and prolonged survival. However, no significant tumor growth retardation effect was observed when mice were treated with DHA alone. The inhibited tumor metastasis was related to the decreased LMVD in the peritumoral regions, but not in the intratumoral regions. DHA significantly down-regulated the expression of VEGF-C protein and mRNA in LLC cells. Conclusion: DHA effectively inhibits LLC transplantation tumor lymphangiogenesis, nodal and lung metastasis, and may be a promising chemotherapeutic agent for controlling lung cancer metastasis by decreasing VEGF-C expression.
基金the National Natural Science Foundation of China(No.81700559)the Natural Science Foundation of Hubei Province(No.2021CFB360)the Program for Jiangsu Province Innovative Research Team.
文摘Acute kidney injury(AKI)is an important factor for the occurrence and development of CKD.The protective effect of dihydroartemisinin on AKI and and reported mechanism have not been reported.In this study,we used two animal models including ischemia-reperfusion and UUO,as well as a high-glucose-stimulated HK-2 cell model,to evaluate the protective effect of dihydroartemisinin on premature senescence of renal tubular epithelial cells in vitro and in vivo.We demonstrated that dihydroartemisinin improved renal aging and renal injury by activating autophagy.In addition,we found that co-treatment with chloroquine,an autophagy inhibitor,abolished the anti-renal aging effect of dihydroartemisinin in vitro.These findings suggested that activation of autophagy/elimination of senescent cell might be a useful strategy to prevent AKI/UUO induced renal tubular senescence and fibrosis.
基金the National Natural Science Foundation of China(No.81873112)Science and Technology Project of Hebei Education Department(No.ZD2022120)for the economic support.
文摘The effect of anti-programmed cell death 1(anti-PD-1)immunotherapy is limited in patients with hepatocellular carcinoma(HCC).Yes-associated protein 1(YAP1)expression increased in liver tumor cells in early HCC,and Akkermansia muciniphila abundance decreased in the colon.The response to anti-PD-1 treatment is associated with A.muciniphila abundance in many tumors.However,the interaction between A.muciniphila abundance and YAP1 expression remains unclear in HCC.Here,anti-PD-1 treatment decreased A.muciniphila abundance in the colon,but increased YAP1 expression in the tumor cells by mice with liver tumors in situ.Mechanistically,hepatocyte-specific Yap1 knockout(Yap1^(LKO))maintained bile acid homeostasis in the liver,resulting in an increased abundance of A.muciniphila in the colon.Yap1 knockout enhanced anti-PD-1 efficacy.Therefore,YAP1 inhibition is a potential target for increasing A.muciniphila abundance to promote anti-PD-1 efficacy in liver tumors.Dihydroartemisinin(DHA),acting as YAP1 inhibitor,increased A.muciniphila abundance to sensitize anti-PD-1 therapy.A.muciniphila by gavage increased the number and activation of CD8^(+)T cells in liver tumor niches during DHA treatment or combination with anti-PD-1.Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.
基金the Program of Science and Technology Development Plan of Jilin Province of China(No.20200201099JC)the National Natural Science Foundation of China(Nos.21871249 and 22105197).
文摘Artemisinin and its derivatives have emerged as promising therapeutic agents for cancer therapy by endogenous iron-mediated generation of free radicals.However,the enhanced antioxidant defense systems in cancer cells provide them with resistance to oxidative damage,greatly antagonizing the therapeutic efficacy that relies on inducing oxidative stress.Herein,a metal-organic framework(MOF)-based nanoplatform(CMD)is constructed to disrupt the cellular redox homeostasis and selectively potentiate the cytotoxicity of dihydroartemisinin for cancer therapy.In cancer cells,the copper(II)sites in the MOF nanocarrier of CMD can efficiently weaken the cellular antioxidant capacity by depleting the overexpressed glutathione,simultaneously leading to the decomposition of the framework structure and the release of the encapsulated dihydroartemisinin.As a result,the damaged antioxidant defense system of cancer cells reduces its effect on oxidative stress alleviation and strengthens the therapeutic efficacy of dihydroartemisinin.On contrast,the low concentration of cellular glutathione in normal cells protects them from dihydroartemisinin-induced cytotoxicity by decelerating the drug release.In vivo results demonstrate that CMD could completely suppress the tumor growth in mice and show no evidence of toxicity,providing an effective strategy for the practical usage of dihydroartemisinin in cancer therapy.
基金supported by the National Natural Science Foundation of China(no.31601948)the Fundamental Research Funds for the Central Universities(no.KJQN201935)
文摘The aim of present study was to evaluate whether diets supplemented with dihydroartemisinin(DHA)could alleviate intestinal inflammatory injury in weaned piglets with intrauterine growth retardation(IUGR).Twelve normal birth weight(NBW)piglets and 12 piglets with IUGR were fed a basal diet(NBW-CON and IUCR-CON groups),and another 12 piglets with IUGR were fed the basal diet supplemented with DHA at 80 mg/kg(IUGR-DHA group)from 21 to 49 d of age.At 49 d of age,8 piglets with similar body weight in each group were sacrificed.The jejunal and ileal samples were collected for further analysis.The results showed that IUGR impaired intestinal morphology,increased intestinal inflamma-tory response,raised enterocyte apoptosis and reduced enterocyte proliferation and activated trans-membrane toll-like receptor 4(TLR4)/nucleotide-binding and oligomerization domain(NOD)/nuclear factor-kB(NF-kB)signaling pathway.Dihydroartemisinin inclusion ameliorated intestinal morphology,indicated by increased villus height,villus height-to-crypt depth ratio,villus surface area and decreased villus width of piglets with IUGR(P<0.05).Compared with NBW piglets,IUGR piglets supplemented with DHA exhibited higher apoptosis index and caspase-3 expression,and lower proliferation index and proliferating cell nuclear antigen expression in the intestine(P<0.05).Dihydroartemisinin supple-mentation attenuated the intestinal inflammation of piglets with IUGR,indicated by increased concen-trations of intestinal inflammatory cytokines and lipopolysaccharides(P<0.05).In addition,DHA supplementation down-regulated the related mRNA expressions of TLR4/NOD/NF-kB signaling pathway and upregulated mRNA expressions of negative regulators of TLR4 and NOD signaling pathway in the intestine of piglets with IUGR(P<0.05).Piglets in the IUGR-DHA group showed lower protein ex-pressions of TLR4,phosphorylated NF-kB(pNF-kB)inhibitorα,nuclear pNF-kB,and higher protein expression of cytoplasmic pNF-kB in the intestine than those in the IUGR-CON group(P<0.05).In conclusion,DHA supplementation could improve intestinal morphology,regulate enterocyte prolifera-tion and apoptosis,and alleviate intestinal inflammation through TLR4/NOD/NF-kB signaling pathway in weaned piglets with IUGR.