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BACKGROUND: Scutellaria barbata D. Don (SB), commonly known as Ban Zhi Lian and firstly documented by Shigong Chen, is a dried whole plant that has been studied for its therapeutic effects on breast cancer, colon cancer, and prostate cancer. Among its various compounds, scutellarin (SCU) has been demonstrated with anti-tumor effects. PURPOSE: This study aimed to evaluate the effects of SB water extract (SBW) and scutellarin on breast cancer stem cells (BCSCs), and to investigate their potential therapeutic effects on breast tumors in mice. METHODS: BCSCs were enriched from human breast cancer cells (MDA-MB-231 and MDA-MB-361) and their characteristics were analyzed. The effects of varying concentrations of SBW and scutellarin on cell viability, proliferation, self-renewal, and migration abilities were studied, along with the underlying mechanisms. The in vivo anti-tumor effects of scutellarin were further evaluated in SCID/NOD mice. Firstly, mice were inoculated with naïve BCSCs and subjected to treatment with scutellarin or vehicle. Secondly, BCSCs were pre-treated with scutellarin or vehicle prior to inoculation into mice. RESULTS: The derived BCSCs expressed CD44, CD133 and ALDH1, but not CD24, indicating that BCSCs have been successfully induced from both MDA-MB-231 and MDA-MB-361 cells. Both SBW and scutellarin reduced the viability, proliferation, sphere and colony formation, and migration of BCSCs. In mice with tumors derived from naïve BCSCs, scutellarin significantly reduced tumor growth, expression of proliferative (Ki67) and stem cell markers (CD44), and lung metastasis. In addition, pre-treatment with scutellarin also slowed tumor growth. Western blot results suggested the involvement of Wnt/ß-catenin, NF-κB, and PTEN/Akt/mTOR signaling pathways underlying the inhibitory effects of scutellarin. CONCLUSION: Our study demonstrated for the first time that both SB water extract and scutellarin could reduce the proliferation and migration of BCSCs in vitro. Scutellarin was shown to possess novel inhibitory activities in BCSCs progression. These findings suggest that Scutellaria barbata water extract, in particular, scutellarin, may have potential to be further developed as an adjuvant therapy for reducing breast cancer recurrence.
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Apigenina , Neoplasias da Mama , Proliferação de Células , Glucuronatos , Camundongos Endogâmicos NOD , Células-Tronco Neoplásicas , Scutellaria , Animais , Apigenina/farmacologia , Scutellaria/química , Glucuronatos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos SCID , Antineoplásicos Fitogênicos/farmacologia , Camundongos , Extratos Vegetais/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Receptores de Hialuronatos/metabolismoRESUMO
Four common Patrinia species, including P. heterophylla, P. monandra, P. scabiosifolia and P. villosa, have been documented as herbal medicines with various clinical applications, such as anti-cancer, anti-diarrhea and sedative. However, the authentication of medicinal Patrinia species poses a problem, particularly with the processed herbal materials. This study aimed to systematically authenticate the four medicinal Patrinia species in the market using morphological and chemical characterization, as well as DNA markers. We found the species identity authenticated by traditional morphologies were in good agreement with both chemical and molecular results. The four species showed species-specific patterns in chromatographic profiles with distinct chemical markers. We also revealed the power of complete chloroplast genomes in species authentication. The sequences of targeted loci, namely atpB, petA, rpl2-rpl23 and psaI-ycf4, contained informative nucleotides for the species differentiation. Our results also facilitate authentication of medicinal Patrinia species using new DNA barcoding markers. To the best of our knowledge, this is the first report on the application of morphology, chemical fingerprinting, complete chloroplast genomes and species-specific Insertion-Deletions (InDels) in differentiating Patrinia species. This study reported on the power of a systematic, multidisciplinary approach in authenticating medicinal Patrinia species.
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Patrinia , Plantas Medicinais , Patrinia/química , Plantas Medicinais/genética , Plantas Medicinais/químicaRESUMO
OBJECTIVE: To investigate the in vivo immunomodulatory and anti-tumor mechanisms of the combined treatment of novel Four-Herb formula (4HF) and doxorubicin in triple-negative breast cancer (TNBC). METHODS: Murine-derived triple-negative mammary carcinoma cell line, 4T1 cells, was cultured and inoculated into mouse mammary glands. Sixty-six mice were randomly assigned into 6 groups (n=11 in ench): naïve, control, LD 4HF (low dose 4HF), HD 4HF (high dose 4HF), LD 4HF + D (low dose and doxorubicin), and D (doxorubicin). Apart from the naïve group, each mouse received subcutaneous inoculation with 5 × 105 4T1 cells resuspended in 100 µL of normal saline in the mammary fat pads. Starting from the day of tumor cell inoculation, tumors were grown for 6 days. The LD and HD groups received daily oral gavage of 658 and 2,630 mg/kg 4HF, respectively. The LD 4HF+D group received daily oral gavage of 658 mg/kg 4HF and weekly intraperitoneal injection of doxorubicin (5 mg/kg). The D group received weekly intraperitoneal injections of doxorubicin (5 mg/kg). The treatment naïve mice received daily oral gavage of 0.2 mL double distilled water and 0.1 mL normal saline via intraperitoneal injection once a week. The control group received daily oral gavage of 0.2 mL double-distilled water. The treatment period was 30 days. At the end of treatment, mice organs were harvested to analyze immunological activities via immunophenotyping, gene and multiplex analysis, histological staining, and gut microbiota analysis. RESULTS: Mice treated with the combination of 4HF and doxorubicin resulted in significantly reduced tumor and spleen burdens (P<0.05), altered the hypoxia and overall immune lymphocyte landscape, and manipulated gut microbiota to favor the anti-tumor immunological activities. Moreover, immunosuppressive genes, cytokines, and chemokines such as C-C motif chemokine 2 and interleukin-10 of tumors were significantly downregulated (P<0.05). 4HF-doxorubicin combination treatment demonstrated synergetic activities and was most effective in activating the anti-tumor immune response (P<0.05). CONCLUSION: The above results provide evidence for evaluating the immune regulating mechanisms of 4HF in breast cancer and support its clinical significance in its potential as an adjunctive therapeutic agent or immune supplement.
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Neoplasias , Solução Salina , Animais , Camundongos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Terapia Combinada , Imunidade , Água , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológicoRESUMO
Introduction: The plant Patrinia villosa Juss. (PV) has long been used as a medicinal herb for treating intestinal disorders. Pharmacological activities such as anti-oxidation, anti-inflammation, and anti-cancer effects of compounds isolated from PV have been reported, but these bioactive compounds were not derived from PV water extract (PVW). Therefore, in the present study, we aimed to identify the active component(s) of PVW which exhibit inhibitory activities in colon cancer cells viability and migration. Methods: Human colon cancer HCT116 cells were treated with the isolated compounds of PVW and then subjected to MTT and transwell migration assays. Results: Our results showed that an active compound in PVW, 8,9-didehydro-7-hydroxydolichodial (DHD) inhibited cell viability of HCT116 cells, with IC50 value at 6.1 ± 2.2 µM. Interestingly, DHD was not detected in the herbal material of PV. Further investigation revealed that DHD is in fact a heat-generated compound derived from a natural compound present in PV, namely valerosidate. Valerosidate also reduced cell viability in HCT116 cells, with IC50 value at 22.2 ± 1.1 µM. Moreover, both DHD (2.75 µM) and valerosidate (10.81 µM) suppressed cell migration in HCT116 cells, with inhibitory rates at 74.8% and 74.6%, respectively. In addition, western blot results showed that DHD (5.5 µM) could significantly increase p53 expression by 34.8% and PTEN expression by 13.9%, while valerosidate (21.6 µM) could increase expressions of p53 and PTEN by 26.1% and 34.6%, respectively in HCT116 cells after 48 h treatment. Discussion: Taken together, this is the first report that a naturally-occurring valerosidate present in PV could actually transform to DHD by thermal hydrolysis, and both compounds exhibited inhibitory effects on cell viability and migration in HCT116 cells via increasing the expressions of tumor suppressors (p53 and PTEN). Our findings demonstrated that valerosidate is present in raw herb PV but not in PVW, while DHD is present in PVW rather than in raw herb PV. This difference in chemical profiles of raw herb and boiled water extract of PV may affect the anti-cancer activity, and hence further investigations are warranted.
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BACKGROUND: Patrinia villosa, a traditional medicinal herb commonly used for treating intestinal-related diseases, has been commonly prescribed by Chinese medicine practitioners as a key component herb to treat colon cancer, although its anti-tumor effect and mechanisms of action have not been fully elucidated. HYPOTHESIS/PURPOSE: This study aimed to investigate the anti-tumor and anti-metastatic effects of Patrinia villosa aqueous extract (PVW), and its underlying mechanisms. METHOD: The chemical profile of PVW was analysed by high-performance liquid chromatography with photodiode-array detection (HPLC-DAD) method. Cell-based functional assays MTT, BrdU, scratch, and transwell were conducted to evaluate the effects of PVW on human colon cancer HCT116 and murine colon26-luc cells, assessing cytotoxicity, cell proliferation, motility, and migration, respectively. Western blotting was performed to assess the effect of PVW on the expression of key intracellular signaling proteins. In vivo studies were conducted using zebrafish embryos and tumor-bearing mice to evaluate the anti-tumor, anti-angiogenesis, and anti-metastatic effects of PVW in colon cancer. RESULTS: Five chemical markers were identified and quantified in PVW. PVW exhibited significant cytotoxicity and anti-proliferative activity, as well as inhibitory effects on cell motility and migration in both HCT116 and colon 26-luc cancer cells via modulating protein expressions of TGF-ß R1, smad2/3, snail, E-cadherin, FAK, RhoA, and cofilin. PVW (0.01-0.1 mg/ml) could significantly decrease the length of subintestinal vessels of zebrafish embryos through decreasing mRNA expressions of FLT1, FLT4, KDRL, VEGFaa, VEGFc, and Tie1. PVW (> 0.05 mg/ml) also significantly suppressed colon cancer cells migration in the zebrafish embryos. Furthermore, oral administration of PVW (1.6 g/kg) significantly inhibited tumor growth by decreasing the expressions of tumor activation marker Ki-67 and CD 31 in tumor tissues of HCT116 tumor-bearing mice. PVW could also significantly inhibit lung metastasis in colon 26-luc tumor-bearing mice by modulating their tumor microenvironment, including immune cells populations (T cells and MDSCs), levels of cytokines (IL-2, IL-12, and IFN-γ), as well as increasing the relative abundance of gut microbiota. CONCLUSION: This study revealed for the first time the anti-tumor and anti-metastatic effects of PVW through regulation of TGF-ß-smad2/3-E-cadherin, and FAK-cofilin pathways in colon cancer. These findings provide scientific evidence to support the clinical use of P. villosa in patients with colon cancer.
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Neoplasias do Colo , Patrinia , Humanos , Animais , Camundongos , Patrinia/química , Peixe-Zebra , Neoplasias do Colo/tratamento farmacológico , Fator de Crescimento Transformador beta/farmacologia , Caderinas , Movimento Celular , Linhagem Celular Tumoral , Microambiente Tumoral , Proteínas de Peixe-Zebra , Proteína Smad2RESUMO
Ten spirocyclic polycyclic polyprenylated acylphloroglucinols (PPAP), hunascynols A-J (1-10), and 12 known analogs were isolated from the aerial parts of Hypericum ascyron Linn. Compounds 1 and 2, which share a 1,2-seco-spirocyclic PPAP skeleton, could be derived from spirocyclic PPAP, with a common octahydrospiro[cyclohexan-1,5'-indene]-2,4,6-trione core, through a cascade of Retro-Claisen, keto-enol tautomerism, and esterification reactions. Aldolization of normal spirocyclic PPAP yielded 3, which has a caged framework with a 6/5/6/5/6 ring system. The structures of these compounds were determined using spectroscopy and X-ray diffraction. The inhibitory activities of all isolates were tested in three human cancer cell lines and a zebrafish model. Compounds 1 and 2 displayed moderate cytotoxicity against HCT116 cells (IC50 6.87 and 9.86 µM, respectively). The mechanisms of these compounds were evaluated using Western blot assays. Compounds 3 and 5 inhibited the growth of sub-intestinal vessels in zebrafish embryos. Further, the target genes were screened using real-time PCR.
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Hypericum , Humanos , Animais , Estrutura Molecular , Hypericum/química , Peixe-Zebra , Linhagem Celular , FloroglucinolRESUMO
Patients with metastatic esophageal squamous cell carcinoma (ESCC) have a grave prognosis with limited life expectancy. Here, a phase II clinical trial was conducted to investigate the effect of Andrographis paniculata (AP) on the palliative care of patients with metastatic ESCC. Patients with metastatic or locally advanced ESCC deemed unfit for surgery, and who have already completed palliative chemotherapy or chemoradiotherapy or are not fit for these treatments, were recruited. These patients were prescribed AP concentrated granules for 4 months. They also received clinical and quality of life assessments for clinical response, as well as positron emission tomography-computed tomography at 3 and 6 months after AP treatment for the assessment of tumor volume. Furthermore, the change in gut microbiota composition after AP treatment was studied. From the results, among the 30 recruited patients, 10 completed the entire course of AP treatment, while 20 received partial AP treatment. Patients who completed the AP treatment achieved significantly longer overall survival periods with the maintenance of the quality of life during the survival period when compared to those who could not complete AP treatment. The treatment effect of AP also contributed to the shift of the overall structure of gut microbiota for ESCC patients towards those of healthy individuals. The significance of this study is the establishment of AP as a safe and effective palliative treatment for patients with squamous cell carcinoma of the esophagus. To the best of our knowledge, this is the first clinical trial of AP water extract in esophageal cancer patients demonstrating its new medicinal use.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Andrographis paniculata , Qualidade de Vida , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologiaRESUMO
Breast cancer is the most commonly diagnosed cancer among women, and its metastasis to distant organs accounts for the majority of death. Eriocalyxin B (Eri B), an ent-kaurane diterpenoid isolating from Isodon eriocalyx var. laxiflora, has previously been reported to have anti-tumor and anti-angiogenic effects in breast cancer. Here, we investigated the effect of Eri B on cell migration and adhesion in triple negative breast cancer (TNBC) cells, as well as aldehyde dehydrogenases 1 family member A1 (ALDH1A1) expression, colony- and sphere-formation in cancer stem cell (CSC) enriched MDA-MB-231 cells. The in vivo anti-metastatic activities of Eri B were determined in 3 different breast tumor-bearing mouse models. Our results indicated that Eri B inhibited TNBC cell migration and adhesion to extracellular matrix proteins, and also reduced ALDH1A1 expression and colony formation in CSC-enriched MDA-MB-231 cells. The metastasis-related pathways, such as epidermal growth factor receptor/ mitogen-activated protein kinase kinases 1/2/ extracellular regulated protein kinase signaling altered by Eri B was firstly shown in MDA-MB-231 cells. The potent anti-metastatic efficacies of Eri B were demonstrated in breast xenograft-bearing mice and syngeneic breast tumor-bearing mice. Gut microbiome analysis results revealed the change in the diversity and composition of microbiome after Eri B treatment, and the potential pathways that are involved in the anti-cancer efficacy of Eri B. In conclusion, Eri B was shown to inhibit breast cancer metastasis in both in vitro and in vivo models. Our findings further support the development of Eri B as an anti-metastatic agent for breast cancer.
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Diterpenos do Tipo Caurano , Diterpenos , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Feminino , Camundongos , Neoplasias de Mama Triplo Negativas/metabolismo , Proliferação de Células , Transdução de Sinais , Diterpenos/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Linhagem Celular Tumoral , Movimento CelularRESUMO
Despite significant advances in the diagnosis and treatment of colorectal cancer (CRC), metastatic colorectal cancer still poses serious threat to CRC patients. The natural gallotannin 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (PGG) has been shown to possess anti-tumor effects on colon cancer cells, but its anti-metastatic effect is yet to be investigated. In this study, the effects of PGG on cell proliferation, colony formation ability, motility, migration were investigated in colon cancer cells using BrdU, colony formation, scratch, and transwell assays, respectively. Western blot assay was used for assessing protein expression. The orthotopic colon tumor-bearing mouse model and human colon cancer metastatic mouse model were employed to evaluate the anti-metastatic effects of PGG. Results showed that PGG exhibited not only anti-proliferative and colony formation inhibitory effects, but also inhibition on cell adhesion, motility, and migration in both HCT116 and colon 26-M01 cells via modulating protein expression of cathepsin B, FAK, cofilin, and epithelial-to-mesenchymal transition related proteins. In addition, PGG (10 or 15 mg/kg, i.p.) could significantly inhibit liver and lung metastasis in colon cancer metastatic mice models. Furthermore, PGG could regulate the populations of T cells, macrophages, and MDSCs, while the levels of IL-2, IL-6, IL-10, IFN-γ, and TNF-α were altered after PGG treatment in metastatic CRC mice. This is the first report of the anti-metastatic effects of PGG by regulating cathepsin B-mediated extracellular matrix dynamics and epithelial-to-mesenchymal transition process in CRC. Our findings suggested that PGG has great potential to be developed as an anti-metastatic agent for metastatic CRC.
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Neoplasias do Colo , Taninos Hidrolisáveis , Fatores de Despolimerização de Actina , Animais , Bromodesoxiuridina , Catepsina B , Linhagem Celular Tumoral , Matriz Extracelular , Glucose , Humanos , Taninos Hidrolisáveis/farmacologia , Taninos Hidrolisáveis/uso terapêutico , Interleucina-10 , Interleucina-2 , Interleucina-6 , Camundongos , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND AND AIM: Esophageal squamous cell carcinoma (ESCC) is the most common histological subtype of esophageal cancer worldwide. Patients with ESCC display an altered esophageal microbiota compared with healthy individuals; however, little is known about the gut microbiota in ESCC. METHODS: Here, we characterized the fecal microbiota of 15 ESCC patients and 16 healthy control subjects using 16S rRNA gene sequencing. RESULTS: After controlling for potential confounders, significant alterations in both taxonomic and functional composition of the gut microbiota in ESCC patients were observed. By contrast, alpha diversity of the gut microbiota did not significantly differ between the cases and controls. We observed an enrichment of potentially pro-inflammatory and/or carcinogenic bacteria, such as Butyricimonas, Veillonella, and Streptococcus, and a depletion of butyrate-producing and/or potentially anti-inflammatory bacteria, such as Butyricicoccus, Lachnospiraceae NK4A136 group, and Eubacterium eligens group, in the gut microbiota of ESCC patients. The log-ratios of Streptococcus to Butyricicoccus and Streptococcus to Lachnospiraceae NK4A136 group of the gut microbiota were identified as potential diagnostic biomarkers for ESCC, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.863 (95% confidence interval: 0.707-1.000) and 0.825 (0.673-0.977), respectively. The diagnostic performance of both microbial biomarkers was validated in another ESCC cohort. CONCLUSIONS: This pilot study has revealed an altered gut microbiota in ESCC patients and has paved the way for large-scale prospective cohort studies to examine the causative relationship between ESCC and gut dysbiosis.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Microbioma Gastrointestinal , Butiratos , Disbiose/microbiologia , Neoplasias Esofágicas/patologia , Humanos , Projetos Piloto , Estudos Prospectivos , RNA Ribossômico 16S/genéticaRESUMO
BACKGROUND: Esophageal cancer (EC) is highly prevalent in Eastern Asia (including China) with high rates of mortality. The metastatic tendency in EC is associated with a poor prognosis. Our previous studies have demonstrated the suppressive effects of Andrographis paniculata water extract (APW) on metastatic esophageal cancer in vitro and in tumor-bearing mice models, as well as illustrated the potential underlying mechanism by transcriptome analysis. HYPOTHESIS: High expressions of several membrane protein tetraspanins were reported to lead to a high risk of metastasis in esophageal cancer in patients. We hypothesized that APW could downregulate the expression of tetraspanin CD81 in esophageal cancer cells and xenografts. METHODS: Human esophageal cancer cells EC109 and KYSE520 were incubated with APW for 24 hours in cell culture, while mice bearing EC109 xenograft tumors were treated with APW for 21 days. The expressions of CD81 in cancer cells and in tumors from mice were evaluated. Molecular docking and microscale thermophoresis analyses were applied to identify the components in APW interacting with CD81. The influence of the identified components on CD81 expression was further evaluated in EC109 cells. RESULTS: APW could significantly suppress the expressions of CD81 in both EC109 and KYSE520 cells in a concentration-dependent manner. Treatment of APW in xenograft-bearing mice reduces the metastasis in lungs, livers, and lymph nodes. The expression of CD81 in xenograft tumors of APW-treated mice was significantly lower than those of untreated control mice. The binding of andrographolide, bisandrographolide A, and bisandrographolide C with CD81 were elucidated by microscale thermophoresis. The suppressive effects of these compounds on the motility of EC109 cells, as well as CD81 protein and mRNA expressions, were further confirmed. CONCLUSION: This is the first time to demonstrate that andrographolide, bisandrographolide A, and bisandrographolide C, which are present in APW, bind to CD81 and suppress its function. These compounds are likely to be responsible for the anti-metastatic activities of APW in esophageal cancer.
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Andrographis paniculata , Diterpenos , Neoplasias Esofágicas , Extratos Vegetais/química , Tetraspanina 28 , Andrographis paniculata/química , Animais , Linhagem Celular Tumoral , Diterpenos/química , Regulação para Baixo/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Humanos , Camundongos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Extratos Vegetais/farmacologiaRESUMO
Colorectal cancer (CRC), the third most common cancer globally, is associated with intestinal inflammation that leads to poor prognosis. RA-XII, a natural cyclopeptide, has previously been reported to possess anti-tumor activities. Here, the anti-inflammatory activities of RA-XII were investigated in colitis-associated colon cancer mice and a co-culture in vitro model, in which colon cancer cells HCT116 and macrophages RAW264.7 were grown together to mimic the inflammatory microenvironment of CRC. Changes of inflammatory-related molecules and protein expressions in cells were evaluated after RA-XII incubation. Besides, azoxymethane and dextran sulfate sodium-induced colitis-associated colon cancer mice were treated with RA-XII for 24 days, inflammatory parameters and gut microbiome alterations were studied. Our results showed that RA-XII reversed the inflammatory responses of RAW264.7 cells induced by LPS and modulated the protein expressions of AKT, STAT3/p-STAT3, P70S6K, NF-κB and GSK3ß and suppressed the expression of LC3A/B in HCT116 cells in co-culture system. RA-XII treatment restored the colitis damage in colon, reduced colon tumors numbers and decreased inflammatory factors (IL-6, IL-10 and TNF-α). The role of RA-XII on regulating gut microbiome was also demonstrated for the first time. In conclusion, our findings provided new scientific evidence for developing RA-XII as a potent anti-inflammatory agent for CRC.
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Neoplasias Associadas a Colite , Colite , Microbioma Gastrointestinal , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Colite/induzido quimicamente , Colite/complicações , Colite/tratamento farmacológico , Colo/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Peptídeos Cíclicos/farmacologia , Microambiente TumoralRESUMO
Antitumor and antimetastatic effects of the medicinal herb Andrographis paniculata (AP) in esophageal cancer (EC) have been previously reported. In this study, we aimed to uncover the potential functional components and the underlying molecular mechanisms of AP in EC treatment using network pharmacology and experimental validation. Twenty-two potential active AP compounds against EC were revealed, including the antitumor/antiinflammatory compounds panicolin, moslosooflavone, and deoxyandrographiside. Epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), RAC-alpha serine/threonine-protein kinase (AKT1), prostaglandin-endoperoxide synthase 2 (PTGS2), chemokine (C-X-C motif) ligand 8 (CXCL8), phosphatidylinositol 4,5-bisphosphate 3-kinase subunit alpha (PIK3CA), and toll-like receptor 4 (TLR4) were most highly ranked among the predicted targets of AP in EC treatment and may play important roles in the anti-EC effects of AP. KEGG pathway analysis revealed the enrichment of multiple cancer-related pathways and signaling pathways. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting validation showed that overnight treatment with 850.3 µg/ml of AP water extract significantly reduced the mRNA expressions of EGFR and AKT in human EC-109 cells. The presence of panicolin and moslosooflavone in the AP water extract samples were confirmed using LC-MS against reference standards. This study has comprehensively revealed for the first time the potential functional components of AP in EC and explored the underlying molecular mechanisms. Future studies should characterize the potential pharmacological properties of the other highly ranked yet understudied compounds in AP detected.
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Andrographis , Neoplasias Esofágicas , Andrographis paniculata , Receptores ErbB , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Humanos , Farmacologia em Rede , ÁguaRESUMO
Colorectal cancer (CRC) is the third leading cause of cancer death worldwide. Obesity has been proven to be closely related to colorectal carcinogenesis. This review summarized the potential underlying mechanisms linking obesity to CRC in different aspects, including energy metabolism, inflammation, activities of adipokines and hormones. Furthermore, the potential therapeutic targets of obesity-associated CRC were predicted using network-based target analysis, with total predicted pathways not only containing previously reported pathways, but also putative signaling pathways pending for investigation. In addition, the current conventional therapeutic treatment options, plus the potential use of herbs and natural products in the management of obesity-associated CRC were also discussed. Taken together, the aim of this review article is to provide strong theoretical basis for future drug development, particularly herbs and natural products, in obesity-associated CRC.
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Produtos Biológicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Obesidade/tratamento farmacológico , Fitoterapia , Animais , Neoplasias Colorretais/etiologia , Humanos , Obesidade/complicaçõesRESUMO
Herba Patriniae (HP) are medicinal plants commonly used in colorectal cancer (CRC) patients. In this study, network pharmacology was used to predict the active components and key signaling pathways of HP in CRC. Patrinia heterophylla, one type of HP, was chosen for validation of the network pharmacology analysis. The phytochemical profile of Patrinia heterophylla water extract (PHW) was determined by UHPLC-MS. MTT, RT-PCR, and Western blot assays were performed to evaluate the bioactivities of PHW in colon cancer cells. Results showed that 15 potentially active components of HP interacted with 28 putative targets of CRC in the compound-target network, of which asperglaucide had the highest degree. Furthermore, the ErbB signaling pathway was identified as the pathway mediated by HP with the most potential against CRC. Both RT-PCR and Western blot results showed that PHW significantly downregulated the mRNA and protein levels of EGFR, PI3K, and AKT in HCT116 cells. Asperglaucide, present in PHW, exhibited an anti-migratory effect in HCT116 cells, suggesting that it could be an active component of PHW in CRC treatment. In conclusion, this study has provided the first scientific evidence to support the use of PHW in CRC and paved the way for further research into the underlying mechanisms of PHW against CRC.
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Neoplasias Colorretais/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Adenocarcinoma/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Dipeptídeos/farmacologia , Descoberta de Drogas/métodos , Receptores ErbB/metabolismo , Proteína Forkhead Box O1/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Medicina Tradicional Chinesa , Patrinia/química , Plantas Medicinais/químicaRESUMO
High prevalence rates of methicillin-resistant Staphylococcus aureus (MRSA) and lack of effective antibacterial treatments urge discovery of alternative therapeutic modalities. The advent of antibacterial photodynamic therapy (aPDT) is a promising alternative, composing rapid, nonselective cell destruction without generating resistance. We used a panel of clinically relevant MRSA to evaluate hypericin (Hy) and pheophobide a (Pa)-mediated PDT with clinically approved methylene blue (MB). We translated the promising in vitro anti-MRSA activity of selected compounds to a full-thick MRSA wound infection model in mice (in vivo) and the interaction of aPDT innate immune system (cytotoxicity towards neutrophils). Hy-PDT consistently displayed lower minimum bactericidal concentration (MBC) values (0.625-10 µM) against ATCC RN4220/pUL5054 and a whole panel of community-associated (CA)-MRSA compared to Pa or MB. Interestingly, Pa-PDT and Hy-PDT topical application demonstrated encouraging in vivo anti-MRSA activity (>1 log10 CFU reduction). Furthermore, histological analysis showed wound healing via re-epithelization was best in the Hy-PDT group. Importantly, the dark toxicity of Hy was significantly lower (p < 0.05) on neutrophils compared to Pa or MB. Overall, Hy-mediated PDT is a promising alternative to treat MRSA wound infections, and further rigorous mechanistic studies are warranted.
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BACKGROUND: Ulcerative colitis is a subtype of inflammatory bowel disease, characterized by relapsing inflammation in the gastrointestinal tract with limited treatment options. Previous studies suggested that the natural compound tricin, a flavone isolated from rice bran, could suppress chemically-induced colitis in mice, while our recent study also demonstrated the anti-metastatic effect of tricin in colon tumor-bearing mice. HYPOTHESIS/PURPOSE: Here we further investigated the underlying mechanism of the inhibitory effects of tricin on lipopolysaccharides-activated macrophage RAW264.7 cells and explored the efficacy of tricin in acute colitis mouse model induced by 4.5% dextran sulfate sodium (DSS) for 7 days. METHODS: Tricin (75, 100, and 150 mg/kg) or the positive control drug sulfasalazine (200 mg/kg) were orally administered to mice for 7 days. Stool consistency scores, stool blood scores, and body weight were recorded daily. Disease activity index (DAI) was examined on day 7, and colon tissues were collected for biochemical analyses. The fecal microbiome of colitis mice after tricin treatment was characterized for the first time in this study using 16S rDNA amplicon sequencing. RESULTS: Results showed that tricin (50 µM) remarkably reduced nitric oxide production in lipopolysaccharides-activated RAW264.7 cells and the anti-inflammatory activity of tricin was shown to act through the NF-κB pathway. Besides, tricin treatment at 150 mg/kg significantly reversed colon length reduction, reduced myeloperoxidase activities and DAI scores, as well as restored the elevated myeloid-derived suppressive cells population in acute colitis mice. The influence from DSS on gut microbiota, such as the increased population of Proteobacteria phylum and Ruminococcaceae family, was shown to be relieved after tricin treatment. CONCLUSION: Our present study firstly demonstrated that tricin ameliorated acute colitis by improving colonic inflammation and modulating gut microbiota profile, which supports the potential therapeutic use of tricin for colitis treatment.
Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa , Colite , Flavonas , Macrófagos/citologia , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite Ulcerativa/tratamento farmacológico , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Flavonas/farmacologia , Flavonoides/farmacologia , Camundongos , NF-kappa B/metabolismo , Células RAW 264.7RESUMO
The immune modulating effects of selected herbs deserve careful studies to gain evidence-based support for their further development. We have been working hard on many items of medicinal herbs to gain insight into their immunomodulatory effects relevant to cancer treatment in particular, while infection control is not excluded. Nine of them have been selected to give the results of our exploration on their biological, particularly immunomodulatory activities. Since Hong Kong people especially favor one medicinal mushroom, viz. Coriolus versicolor, a number of clinical trials using Coriolus for cancer-related studies are included in this review. While immune modulation platforms are being built for relevant studies, a brief account on the research targets and related procedures are given.
Assuntos
Agaricales/química , Antineoplásicos/farmacologia , Fatores Imunológicos/farmacologia , Plantas Medicinais/química , Antineoplásicos/uso terapêutico , Hong Kong , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologiaRESUMO
Although the in vivo metabolic pathways of scutellarin, a traditional Chinese medicine, have been investigated via different liquid chromatography techniques, studies on the distribution and location of scutellarin within organ tissue sections have not been reported. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) can generate in situ spatial distribution profiles for scutellarin and its metabolites in a kidney section. However, the direct detection of a small molecule (m/z < 600) using conventional matrices often results in ion suppression and matrix interferences. In this study, we demonstrated a novel methodology using MALDI-MSI for the in situ spatial localization of scutellarin and its metabolites in kidney tissues by applying a binary matrix of graphene oxide (GO) and caffeic acid (CA). The results indicated that the binary matrix (GO/CA) significantly improved the detection efficiency of scutellarin and its metabolites with relatively high sensitivity, selectivity and reproducibility on tissue sections. This methodology was successfully applied to map scutellarin and its metabolites with MALDI-MSI in mouse kidney tissues. Specifically, scutellarin and scutellarein were found to be located in the cortex and medulla regions of the kidney with relatively high abundance, whereas the remaining metabolites appeared in the cortex with low abundance. We believe that the novel imaging methodology may also be used for the studies of cancerous tissues and inform the development of the future therapies of kidney tumors.
Assuntos
Rim , Animais , Apigenina , Ácidos Cafeicos , Glucuronatos , Grafite , Camundongos , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
The plant Scutellaria barbata (SB) is commonly used as herbal medicines for treating cancer. The present pre-clinical study aimed to validate the Chinese Pharmacopoeia (CP) recommended dosages of SB water extract (SBW) in treating colon tumors. The content of chemical marker scutellarin in SBW was quantified using UPLC. Mice bearing human HCT116 xenografts or murine colon26 tumors received oral administration of SBW or scutellarin for 4 weeks. Results showed that SBW (615 and 1,230 mg/kg) and scutellarin (7 mg/kg) treatments significantly reduced human xenograft weights by 28.7, 36.9 and 28.8%, respectively. Lung metastasis area could be ameliorated after SBW (615 mg/kg) and scutellarin (7 mg/kg) treatments by 23.4 and 29.5%, respectively. Expressions of colon cancer metastasis-related proteins E-cadherin, Tspan 8 and CXCR4, as well as Src kinase in tumors were first shown to be regulated by SBW. Furthermore, in murine colon26 tumor-bearing mice, SBW (615 mg/kg) and scutellarin (7 mg/kg) treatments reduced the orthotopic tumor burden by 94.7% and lung metastatic tumor burden by 94.1%, respectively. Our findings provided evidences that SBW (at the mouse equivalent dosages to clinical dosages recommended by CP) could exert anti-tumor and anti-metastatic effects in colon cancer animal models.