RESUMO
BACKGROUND: Recurrence and metastasis are the main causes of disease deterioration in colorectal cancer (CRC) patients, yet efficient therapeutic strategies are lacking. Natural compounds for efficient antitumour therapeutics are becoming increasingly prominent. Kaempferol, one of the main components of flavonoids in plants, displays a variety of pharmacological activities. Our preliminary experiments suggested that kaempferol could inhibit CRC metastasis and is significantly associated with the ß-catenin signalling pathway. Moreover, we also defined the regulatory roles of JMJD2C in ß-catenin signalling in our previous work. PURPOSE: This study aims to reveal the mechanism by which kaempferol inhibits CRC progression and regulates the JMJD2C/ß-catenin signalling pathway. METHODS: The migratory capabilities of CRC cells after kaempferol intervention were measured by scratch wound healing and transwell assays. Circ_0000345 knockdown CRC stable cell lines were generated by lentivirus infection. The possible mechanism of kaempferol on circ_0000345 was verified by molecular-protein docking and verification program cellular thermal shift assay (CETSA). A dual luciferase reporter gene assay was carried out for the targeting relationship among circ_0000345, miR-205-5p and JMJD2C. Fluorescence in situ hybridization (FISH) was performed to determine the expression of circ_0000345 in tumour tissues. A pulmonary metastatic model of CRC in vitro was built to assess the antimetastatic effect and mechanism of kaempferol in vivo. RESULTS: In vitro, kaempferol inhibits the ability to migrate of CRC cells by reducing the activation of the JMJD2C/ß-catenin signalling pathway. MiR-205-5p is a key bridge for kaempferol to inhibit the expression of JMJD2C. The function of miR-205-5p is impeded by circ_0000345, which shows higher expression levels in human metastatic CRC tissues than nonmetastatic CRC tissues, and its formation is regulated by the RNA-binding proteins HNRNPK and HNRNPL. Mechanistically, kaempferol physically interacts with HNRNPK and HNRNPL to suppress JMJD2C by downregulating the expression of circ_0000345. In vivo, kaempferol suppresses CRC lung metastasis. Kaempferol inhibits the activation of JMJD2C/ß-catenin signalling through reducing the expression of circ_0000345 in the CRC lung metastasis model. CONCLUSION: Circ_0000345 enhances activation of the JMJD2C/ß-catenin signalling pathway through miR-205-5p to promote CRC metastasis. Kaempferol inhibits CRC metastasis through the circ_0000345-mediated JMJD2C/ß-catenin signalling pathway, and this effect is influenced as a direct consequence of the binding of kaempferol with HNRNPK and HNRNPL. This provides promising therapeutic and/or adjuvant agents for advanced CRC and sheds light on the multifaceted role of phytomedicine in cancer.
Assuntos
Neoplasias Colorretais , Histona Desmetilases com o Domínio Jumonji , Quempferóis , beta Catenina , Quempferóis/farmacologia , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , beta Catenina/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , RNA Circular/metabolismo , RNA Circular/genética , Transdução de Sinais/efeitos dos fármacos , Camundongos Nus , Camundongos Endogâmicos BALB C , Masculino , MicroRNAs/metabolismo , MicroRNAs/genética , Camundongos , Simulação de Acoplamento MolecularRESUMO
Covalent organic frameworks (COFs) have promising applications in enhanced phototherapy. However, COFs that can sustainably play a role in phototherapy without continuous irradiation are extremely scarce. Herein, we report the fabrication of porphyrin-anthracene multifunctional COFs (Por-DPA) for sustainable photosterilization and bacterial-infected wound healing. A porphyrin photosensitizer, as one of the monomers, was used to provide photothermal and photodynamic activities under irradiation. An anthracene derivative, a good chemical source of singlet oxygen (1O2), was selected as another monomer to capture 1O2 and release it continuously via cycloreversion in the dark. The prepared Por-DPA COF prevents the self-aggregation quenching of the photosensitizer and thermal damage caused by continuous exposure to external light sources. Besides, Por-DPA exhibits good photothermal conversion performance and efficient 1O2 production capacity through dual pathways of photosensitization and cycloreversion. The developed sustainable photosterilization platform not only has good bactericidal effects on Escherichia coli and Staphylococcus aureus, but also promotes wound healing without obvious side effects, and is expected to be a novel efficient bactericide.
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Estruturas Metalorgânicas , Porfirinas , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Estruturas Metalorgânicas/farmacologia , Estruturas Metalorgânicas/química , Porfirinas/farmacologia , Porfirinas/química , Fototerapia , Oxigênio Singlete/metabolismoRESUMO
Adjuvant whole-breast radiotherapy is essential for breast cancer patients who adopted breast-conserving surgery (BCS) to reduce the risk of local recurrences, which however suffer from large-area and highly destructive ionizing radiation-induced adverse events. To tackle this issue, an afterglow/photothermal bifunctional polymeric nanoparticle (APPN) is developed that utilizes nonionizing light for precise afterglow imaging-guided post-BCS adjuvant second near-infrared (NIR-II) photothermal therapy. APPN consists of a tumor cell targeting afterglow agent, which is doped with a NIR dye as an afterglow initiator and a NIR-II light-absorbing semiconducting polymer as a photothermal transducer. Such a design realizes precise afterglow imaging-guided NIR-II photothermal ablation of minimal residual breast tumor foci after BCS, thus achieving complete inhibition of local recurrences. Moreover, APPN enables early diagnosis and treatment of local recurrence after BCS. This study thus provides a nonionizing modality for precision post-BCS adjuvant therapy and early recurrence theranostic.
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Nanopartículas , Medicina de Precisão , Humanos , Fototerapia , Polímeros , Recidiva , Linhagem Celular TumoralRESUMO
The need for adjuvant therapy to inhibit local recurrence after breast-conserving surgery with minimal side effects is great. Adjuvant photothermal therapy (aPTT) has the potential to replace radiotherapy and eliminates its inherent damage to healthy tissues. Herein, we functionalized semiconducting polymer nanoparticles (SPNs) with cRGD-peptide and silicon 2,3-naphthalocyanine bis(trihexylsilyloxide) (NIR775) to target breast cancer and perform aPTT under an ultra-low laser power (0.2 W cm-2) after breast-conserving surgery (BCS). The synthesized RGD-SPNNIR775 showed an excellent photothermal conversion efficiency and biocompatibility and was demonstrated to accumulate in tumors specifically. The BCS could be performed with confidence under the guidance of preoperative and postoperative fluorescence imaging. Notably, the aPTT completely inhibited the local recurrence after the BCS without compromising the cosmetic effect of the BCS. These results indicate the prospect of RGD-SPNNIR775 as a theranostic nanoplatform for efficient aPTT using an ultra-low laser power to control recurrence after BCS.
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Neoplasias da Mama , Nanopartículas , Humanos , Feminino , Terapia Fototérmica , Polímeros/farmacologia , Mastectomia Segmentar/métodos , Neoplasias da Mama/patologia , Adjuvantes Imunológicos , Nanopartículas/uso terapêutico , Lasers , Recidiva , Oligopeptídeos/farmacologiaRESUMO
BACKGROUND: Extracellular vesicles (EVs) contribute greatly to the formation of pre-metastatic niche and tumor metastasis. Our previous study has revealed that tumor-derived ITGBL1 (integrin beta- like 1)-rich EVs activate fibroblasts through the NF-κB signaling to promote colorectal cancer (CRC) metastasis. Targeting ITGBL1-loaded EVs may be a new and effective therapy for treating CRC metastasis. Simultaneously, our preliminary clinical trial has demonstrated that Jianpi Jiedu Recipe (JPJDR) was an ideal alternative traditional Chinese medicine for the prevention and treatment of CRC metastasis. However, the underlying mechanism of JPJDR in the prevention of CRC metastasis is not clear. In this study, we will investigate the regulatory effect of JPJDR on ITGBL1 levels in CRC-derived EVs, and to detect how JPJDR regulate ITGBL1-rich EVs mediated activation of fibroblasts to inhibit CRC metastasis. METHODS: EVs derived from CRC cells with/without JPJDR treatment were obtained by ultracentrifugation, following by characterization with electron microscopy, LM10 nanoparticle characterization system and western blot. The migration and growth of CRC cells were tested by transwell assay, wound healing assay and colony formation assay. The effect of JPJDR on the fibroblasts-activation associated inflammatory factors including IL-6, IL-8 and α-SMA was detected by real-time PCR. The levels of IL-6, IL-8 and α-SMA in the cell culture supernatant were detected by ELISA. The protein expressions of TNFAIP3, ITGBL1, p-NF-κB, IκBα and ß-actin were detected by western blot. Liver metastasis model in mice was established by injecting MC38 single cell suspension into the spleen of mice to observe the effect of JPJDR on CRC liver metastasis. Immunohistochemistry were applied to detect the expression of ITGBL1 and TNFAIP3 in the liver metastatic tissues. Tissue immunofluorescence detection was performed to observe the regulatory effect of JPJDR on the ITGBL1-NF-κB signaling pathway. Cancer-associated fibroblasts (CAFs) in the liver metastatic tissues were sorted and characterized by platelet-derived growth factor receptor ß (PDGFRß) with flow cytometry, following by the detection of inflammatory factors including IL-6, IL-8 and α-SMA using real-time PCR. RESULTS: JPJDR reduced the ITGBL1 levels in CRC cells-derived EVs. JPJDR inhibited the migration and growth of CRC cells via regulating ITGBL1-rich EVs mediated fibroblasts activity. Mechanically, JPJDR decreased fibroblasts activation by regulating ITGBL1-rich EVs mediated TNFAIP3-NF-κB signaling. Further in vivo experiments demonstrated that JPJDR reduced CRC liver metastasis by regulating ITGBL1-rich EVs secretion from CRC and blocked the fibroblasts activation by regulating ITGBL1-TNFAIP3- NF-κB signaling. CONCLUSION: Our research demonstrated that JPJDR preventd CRC liver metastasis via down-regulating CRC-derived ITGBL1-loaded EVs mediated activation of CAFs, providing the experimental evidence for the clinical application of JPJDR in the prevention and treatment of CRC metastasis. More importantly, our study confirmed the great benefits of therapeutic targeting the EVs-mediated metastasis and warranted future clinical validation.
Assuntos
Fibroblastos Associados a Câncer , Neoplasias Colorretais , Vesículas Extracelulares , Neoplasias Hepáticas , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Medicamentos de Ervas Chinesas , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , NF-kappa B/metabolismo , Metástase NeoplásicaRESUMO
BACKGROUND: Nonsmall-cell lung cancer (NSCLC) is the main type of lung cancer, whose morbidity and mortality rank first among malignant tumors. More than 70% of NSCLC patients are diagnosed at locally advanced or advanced stage, missing the best operation period. Chemotherapy and targeted therapy are important means for the treatment of advanced NSCLC, but various side effects seriously affect the curative effect and the life quality of NSCLC patients. Our previous clinical practice has shown that Mufangji Decoction, a classic traditional Chinese medicine, has a significant curative effect in the treatment of NSCLC, but the specific mechanism is not clear. This study intends to explore the potential mechanism of Mufangji Decoction and its active ingredient patchouli alcohol against NSCLC and to provide a scientific basis for the prevention and treatment of NSCLC by traditional Chinese medicine. METHODS: The in vivo and in vitro experiments were performed to evaluate the antitumor effects and investigate the underlying mechanism of Mufangji Decoction and its active ingredient patchouli alcohol. Network pharmacology was applied to analyze the effective ingredients and potential targets or signaling pathways of Mufangji Decoction. RESULTS: Our current study shows that Mufangji Decoction can effectively inhibit the growth of subcutaneous transplantation of NSCLC. The following network pharmacological analysis and in vivo experiment suggest that patchouli alcohol is one of the main active ingredients of Mufangji Decoction and exerts antitumor effects. Further mechanism investigation reveals that the antitumor effect of patchouli alcohol is related to the induction of Akt/mTOR signaling pathway-mediated autophagy in NSCLC cells. CONCLUSION: Mufangji Decoction and its active ingredient patchouli alcohol might exert their antitumor effects in NSCLC partly through regulating Akt/mTOR-mediated autophagy, providing the evidence that traditional Chinese medicine might be a key approach for NSCLC treatment via targeting the Akt/mTOR signal axis.
RESUMO
Cancer occurs in a complex tissue environment, and its progression depends largely on the tumour microenvironment (TME). The TME has a highly complex and comprehensive system accompanied by dynamic changes and special biological characteristics, such as hypoxia, nutrient deficiency, inflammation, immunosuppression and cytokine production. In addition, a large number of cancer-associated biomolecules and signalling pathways are involved in the above bioprocesses. This paper reviews our understanding of the TME and describes its biological and molecular characterization in different stages of cancer development. Furthermore, we discuss in detail the intervention strategies for the critical points of the TME, including chemotherapy, targeted therapy, immunotherapy, natural products from traditional Chinese medicine, combined drug therapy, etc., providing a scientific basis for cancer therapy from the perspective of key molecular targets in the TME.
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Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Microambiente Tumoral/genética , HumanosRESUMO
α-Linolenic acid is an essential omega-3 fatty acid needed for human health. However, the isolation of high-purity α-linolenic acid from plant resources is challenging. The preparative separation methods of α-linolenic acid by both conventional and pH-zone refining counter current chromatography were firstly established in this work. The successful separation of α-linolenic acid by conventional counter current chromatography was achieved by the optimized solvent system n-heptane/methanol/ water/acetic acid (10:9:1:0.04, v/v), producing 466 mg of 98.98% α-linolenic acid from 900 mg free fatty acid sample prepared from perilla seed oil with linoleic acid and oleic acid as by-products. The scaled-up separation in 45× is efficient without loss of resolution and extension of separation time. The separation of α-linolenic acid by pH-zone refining counter current chromatography was also satisfactory by the solvent system n-hexane/methanol/water (10:5:5, v/v) and the optimized concentration of trifluoroacetic acid 30 mM and NH4 OH 10 mM. The separation can be scaled up in 180× producing 9676.7 mg of 92.79% α-linolenic acid from 18 000 mg free fatty acid sample. pH-zone refining counter current chromatography exhibits a great advantage over conventional counter current chromatography with 20× sample loading capacity on the same column.
Assuntos
Extratos Vegetais/isolamento & purificação , Ácido alfa-Linolênico/isolamento & purificação , Distribuição Contracorrente , Concentração de Íons de Hidrogênio , Extratos Vegetais/química , Óleos de Plantas/química , Ácido alfa-Linolênico/químicaRESUMO
A new bakuchiol compound Δ11-12-hydroxy-12-dimethyl bakuchiol (1), a new flavanone compound 2(S)-6-methoxy-7- hydroxymethylene-4'-hydroxyl-flavanone (8), and two new isoflavanone compounds 4',7-dihydroxy-3'-(6"ß-hydroxy-3â³,7â³-dimethyl-,2â³,7â³-dibutenyl)-geranylisoflavone (9) and 4',7-dihydroxy-3'-(7â³-hydroxy-7â³-methyl-2â³,5â³-dibutenyl)-geranylisoflavone (10) together with eight known compounds (2-7, 11, 12) were isolated from the P. corylifolia. Their structures were elucidated on the basis of spectroscopic and physico-chemical analyses. All the isolates were evaluated for in vitro inhibitory activity against DGAT1/2. Among them, compounds 3, 9 and 10 were found to exhibit selective inhibitory activity on DGAT1 with IC50 values ranging from 93.7⯱â¯1.3 to 96.2⯱â¯1.1⯵M. Compound 1 showed inhibition activity on DGAT1 with IC50 values 73.4⯱â¯1.3⯵M and inhibition of DGAT2 with IC50 value 121.1⯱â¯1.3⯵M.
Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Isoflavonas/isolamento & purificação , Fenóis/isolamento & purificação , Psoralea/química , Estrutura Molecular , Sementes/químicaRESUMO
Four new compounds, erythro-7'E-4-hydroxy-3,3'-dimethoxy-8,5'-oxyneoligna-7'-ene-7,9-diol-9'-al (1), (7S,8S)-4-hydroxy-3,1',3'-trimethoxy-4',7-epoxy-8,5'-neolign-9-ol (5), (7S,8S,7'E)-5-hydroxy-3,3'-dimethoxy-4',7-epoxy-8,5'-neolign-7'-ene-9,9'-diol (6) and (7S,8S,7'E)-5-hydroxy-3,3',9'-trimethoxy-4'-7-epoxy-8,5'-neolign-7'-ene-9-ol (7). Along with four known compounds (2-4, 8) were isolated from the EtOAc-soluble extract of Eleutherococcus senticosus. Their structures were elucidated on the basis of spectroscopic and physicochemical analyses. All the compounds were evaluated for in vitro inhibitory activity against PTP1B, VHR and PP1. Among them, compounds 1-4 and 6-8 were found to exhibit selective inhibitory activity on PTP1B with IC50 values ranging from 17.2±1.6 to 32.7±1.2µM.