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Metastasis of colorectal cancer (CRC) is a leading cause of mortality among CRC patients. Elevated COX-2 and PD-L1 expression in colon cancer tissue has been linked to distant metastasis of tumor cells. Although COX-2 inhibitors and immune checkpoint inhibitors demonstrate improved anti-tumor efficacy, their toxicity and variable therapeutic effects in individual patients raise concerns. To address this challenge, it is vital to identify traditional Chinese medicine components that modulate COX-2 and PD-1/PD-L1: rosmarinic acid (RA) exerts striking inhibitory effect on COX-2, while ginsenoside Rg1 (GR) possesses the potential to suppress the binding of PD-1/PD-L1. In this study we investigated whether the combination of RA and GR could exert anti-metastatic effects against CRC. MC38 tumor xenograft mouse model with lung metastasis was established. The mice were administered RA (100 mg·kg-1·d-1, i.g.) alone or in combination with GR (100 mg·kg-1·d-1, i.p.). We showed that RA (50, 100, 150 µM) or a COX-2 inhibitor Celecoxib (1, 3, 9 µM) concentration-dependently inhibited the migration and invasion of MC38 cells in vitro. We further demonstrated that RA and Celecoxib inhibited the metastasis of MC38 tumors in vitro and in vivo via interfering with the COX-2-MYO10 signaling axis and inhibiting the generation of filopodia. In the MC38 tumor xenograft mice, RA administration significantly decreased the number of metastatic foci in the lungs detected by Micro CT scanning; RA in combination with GR that had inhibitory effect on the binding of PD-1 and PD-L1 further suppressed the lung metastasis of colon cancer. Compared to COX-2 inhibitors and immune checkpoint inhibitors, RA and GR displayed better safety profiles without disrupting the tissue structures of the liver, stomach and colon, offering insights into the lower toxic effects of clinical traditional Chinese medicine against tumors while retaining its efficacy.
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Neoplasias do Colo , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Antígeno B7-H1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Ácido Rosmarínico , Celecoxib/farmacologia , Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
BACKGROUND: One critical component of the immune system that prevents breast cancer cells from forming distant metastasis is natural killer (NK) cells participating in immune responses to tumors. Ginsenoside Rh2 (GRh2) as one of the major active ingredients of ginseng has been employed in treatment of cancers, but the function of GRh2 in modulating the development of breast cancer remains elusive. PURPOSE: This study was to dissect the effect of GRh2 against breast cancer and its potential mechanisms associated with NK cells, both in vitro and in vivo. METHODS: MDA-MB-231 and 4T1 cells were used to establish in situ and hematogenous mouse models. MDA-MB-231 and MCF-7 were respectively co-cultured with NK92MI cells or primary NK cells in vitro. Anti-tumor efficacy of GRh2 was verified by immunohistochemistry (IHC), Cell Counting Kit-8 (CCK8), high resolution micro-computed tomography (micro-CT) scanning of lungs and hematoxylin and eosin (H&E) staining. Lactate dehydrogenase (LDH) cytotoxicity assay, flow cytometry, in vivo depletion of NK cells, enzyme-linked immunosorbent assay (ELISA), western blot, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunofluorescence and cell transfection were performed for investigating the anti-tumor mechanisms of GRh2. Molecular docking, microscale thermophoresis (MST) and cellular thermal shift assay (CETSA) were employed to determine the binding between endoplasmic reticulum protein 5 (ERp5) and GRh2. RESULTS: We demonstrated that GRh2 exerted prominent impacts on retarding the growth and metastasis of breast cancer through boosting the cytotoxic function of NK cells, as validated by the elevated release of perforin, granzyme B and interferon-γ (IFN-γ). Mechanistical studies revealed that GRh2 was capable of diminishing the expression of ERp5 and GRh2 directly bound to ERp5 in MDA-MB-231 cells as well as on a recombinant protein level. GRh2 prevented the formation of soluble MICA (sMICA) and upregulated the expression level of MICA in vivo and in vitro. Importantly, the reduced lung metastasis of breast cancer by GRh2 was almost abolished upon the depletion of NK cells. Moreover, GRh2 was able to insert into the binding pocket of ERp5 directly. CONCLUSION: We firstly demonstrated that GRh2 played a pivotal role in augmenting NK cell activity by virtue of modulating the NKG2D-MICA signaling axis via directly binding to ERp5, and may be further optimized to a therapeutic agent for the treatment of breast cancer.
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Ginsenosídeos , Células Matadoras Naturais , Neoplasias , Animais , Camundongos , Simulação de Acoplamento Molecular , Microtomografia por Raio-X , Neoplasias/tratamento farmacológicoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Based on the notion of traditional Chinese medicine, the theory of invigorating the circulation of blood is a prominent treatment for cancer in clinic. Therefore, Salvia miltiorrhiza Bunge, as a representative of Chinese medicine of invigorating the circulation of blood, has been proved to be an effective medicinal herb for treating cancer. AIM OF THE STUDY: To clarify the anti-cancer effect of Salvia miltiorrhiza Bunge aqueous extract (SMAE) on colorectal cancer (CRC) and investigate whether the therapeutic effect of SMAE was mediated by attenuating the infiltration of tumor-associated macrophages (TAMs) into the tumor microenvironment (TME). MATERIALS AND METHODS: High-performance liquid chromatography (HPLC) was used for determined the main compounds of SMAE. MC38 cells were subcutaneously injected into the mice to establish the mouse model of CRC. Tumor growth curve was detected by tumor volume measurement. The model group received distilled water irrigation once a day. SMAE-treated group received 5 g/kg or 10 g/kg SMAE once a day. Anti-PD-L1 treated group received 5 mg/kg anti-PD-L1 once every three days. Protein expression of Cox2 and PD-L1 was determined by Western blot assay. The secretion levels of PGE2, IL-1ß, IL-6, MCP-1, and GM-CSF were evaluated through ELISA. The mRNA expression of CSF1, CCL2, CXCL1, CXCL2, and CXCL3 was measured by using RT-qPCR. Staining of Ki67, TUNEL and Caspase3 was used to investigate cell proliferation and apoptosis. Immunohistochemical staining was used to determine CD8+ T cell distribution. H&E staining was used to confirm histopathological changes. The expressions of F4/80 and CD68 were measured by flow cytometry to identify macrophages in tumors and lymph nodes. The number of CD8+ T cells and the expression of PD-1, IFN-γ, and Granzyme B (GZMB) were determined by flow cytometry. RESULTS: SMAE significantly retarded the growth of MC38 mouse colorectal cancer. SMAE strikingly inhibited the expression of Cox2 and impaired the secretion of PGE2 in tumors, contributing to the attenuated intra-tumoral infiltration of TAMs via Cox2/PGE2 cascade. Meanwhile, SMAE augmented anti-tumor immunity by the elevated proportion of IFN-γ+ CD8+ T cells and GZMB+ CD8+ T cells, which decreased the tumor load. Furthermore, the combination of SMAE and anti-PD-L1 showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in MC38 xenograft model. CONCLUSIONS: SMAE attenuated the infiltration of TAMs into tumors and synergized with anti-PD-L1 to treat CRC via modulating Cox2/PGE2 cascade.
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Neoplasias Colorretais , Salvia miltiorrhiza , Salvia , Camundongos , Humanos , Animais , Macrófagos Associados a Tumor , Dinoprostona , Linfócitos T CD8-Positivos , Modelos Animais de Doenças , Neoplasias Colorretais/tratamento farmacológico , Imunoterapia , Água , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
As a famous herbal medicine in China and Asia, ginseng (Panax ginseng C. A. Meyer) is also known as the "King of All Herbs" and has long been used in medicine and healthcare. In addition to the obvious biological activities of ginsenosides, ginseng polysaccharides (GPs) exhibit excellent antitumor, antioxidant stress, and immunomodulatory effects. In particular, GPs can exert an antitumor effect and is a potential immunomodulator. However, due to the complexity and diversity in the structures and components of GPs, their specific physicochemical properties, and underlying mechanisms remain unclear. In this article, we have summarized the factors influencing the antitumor activity of GPs and their mechanism of action, including the stimulation of the immune system, regulation of the gut microbiota, and direct action on tumor cells.
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Breast cancer is the most commonly diagnosed cancer in the world, and metastasis is often the main cause of death in breast cancer patients. Salvia miltiorrhiza -Ginseng (SG) herb pair is clinically used for the treatment of cardiovascular diseases and cancers. However, the pharmacological action of this pair on breast cancer is yet unclear. In this study, a spontaneous metastasis model of breast cancer was constructed to assess the therapeutic value of SG. After administration of different doses of SG, the results showed that although it did not significantly inhibit tumor growth, high-dose SG administration could inhibit tumor metastasis. Then, based on systematic pharmacology combined with Gene Expression Omnibus (GEO) database, potential targets of drugs were identified such as vascular endothelial growth factor A (VEGFA), matrix metalloproteinase (MMP9), prostaglandin endoperoxide synthase2 (PTGS2), etc. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analysis revealed that these targets were related to cytokine-mediated signaling pathway, cell migration and other biological processes and signaling pathways such as PI3K/Akt, etc. The systematic pharmacology analysis showed that SG effectively inhibited the VEGFA and MMP9-mediated biological events such as angiogenesis, epithelial-mesenchymal transition (EMT) and impaired tumor metastasis. Overall, our research aimed to provide new ideas for the treatment of breast cancer lung metastasis in traditional Chinese medicine.
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Antineoplásicos , Neoplasias da Mama , Medicamentos de Ervas Chinesas , Panax , Salvia miltiorrhiza , Humanos , Feminino , Salvia miltiorrhiza/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Panax/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Antineoplásicos/farmacologia , Medicina Tradicional Chinesa , ChinaRESUMO
Polysaccharide is a kind of macromolecule polymer composed of monosaccharides connected by glycosidic bonds. Traditional Chinese medicine (TCM), composed of various bioactive ingredients, is usually rich in polysaccharides. In recent years, extensive research on TCM polysaccharides has demonstrated their pharmacological effects. Polysaccharides can hardly be catabolized by enzymes encoded by the human genome but can be degraded to absorbable metabolites by bacteria inhabiting the colon. Hence, the gut microbiota plays a vital role in degrading TCM polysaccharides into short-chain fatty acids (SCFAs) which exert physiological functions locally and systemically. Besides, TCM polysaccharides can also modulate the composition and activities of the gut microbiota by promoting the growth of beneficial bacteria and inhibiting the colonization of pathogenic bacteria, ultimately restoring gut homeostasis and improving human health. In this review, we discuss the extraction and pharmacological effects of TCM polysaccharides, various functions of the gut microbiota, and the interactions between TCM polysaccharides and the gut microbiota, illuminating the mechanisms of TCM polysaccharides modulating host physiology via the gut microbiota. To firmly establish the clinical efficacy of TCM polysaccharides, further high-quality studies especially clinical trials are needed. Generally, discussion on the interplay between TCM polysaccharides and the gut microbiota is expected to elucidate their application prospects and inspire new thoughts in the development of TCM.
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Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Humanos , Medicina Tradicional Chinesa , Polissacarídeos/farmacologia , Polissacarídeos/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , BactériasRESUMO
Metastasis is the leading cause of death in melanoma patients. Aerobic glycolysis is a common metabolic feature in tumor and is closely related to cell growth and metastasis. Kaempferol (KAM) is one of the active ingredients in the total flavonoids of Chinese traditional medicine Sparganii Rhizoma. Studies have shown that it interferes with the cell cycle, apoptosis, angiogenesis and metastasis of tumor cells, but whether it can affect the aerobic glycolysis of melanoma is still unclear. Here, we explored the effects and mechanisms of KAM on melanoma metastasis and aerobic glycolysis. KAM inhibited the migration and invasion of A375 and B16F10 cells, and reduced the lung metastasis of melanoma cells. Extracellular acidification rates (ECAR) and glucose consumption were obviously suppressed by KAM, as well as the production of ATP, pyruvate and lactate. Mechanistically, the activity of hexokinase (HK), the first key kinase of aerobic glycolysis, was significantly inhibited by KAM. Although the total protein expression of HK2 was not significantly changed, the binding of HK2 and voltage-dependent anion channel 1 (VDAC1) on mitochondria was inhibited by KAM through AKT/GSK-3ß signal pathway. In conclusion, KAM inhibits melanoma metastasis via blocking aerobic glycolysis of melanoma cells, in which the binding of HK2 and VDAC1 on mitochondria was broken.
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Melanoma , Canal de Ânion 1 Dependente de Voltagem , Linhagem Celular Tumoral , Proliferação de Células , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicólise , Hexoquinase/metabolismo , Humanos , Quempferóis/farmacologia , Melanoma/patologia , Mitocôndrias/metabolismo , Canal de Ânion 1 Dependente de Voltagem/metabolismoRESUMO
Background: The gut-liver axis plays a crucial role in various liver diseases. Therefore, targeting this crosstalk may provide a new treatment strategy for liver diseases. However, the exact mechanism underlying this crosstalk and its impact on drug-induced liver injury (DILI) requires clarification. Aim: This study aimed to investigate the potential mechanism and therapeutic effect of MgIG on MTX-induced liver injury, which is associated with the gut-liver axis and gut microbiota. Methods: An MTX-induced liver injury model was generated after 20-mg/kg/3d MTX application for 30 days. Meanwhile, the treatment group was treated with 40-mg/kg MgIG daily. Histological examination, aminotransferase, and aspartate aminotransferase enzyme levels were estimated to evaluate liver function. Immune cells infiltration and inflammatory cytokines were detected to indicate inflammation levels. Colon histological score, intestinal barrier leakage, and expression of tight junctions were employed to assess the intestinal injury. Bacterial translocation was observed using fluorescent in situ hybridisation, colony-forming unit counting, and lipopolysaccharide detection. Alterations in gut microbial composition were analysed using 16s rDNA sequencing and relative quantitative polymerase chain reaction. Short-chain-fatty-acids and lactic acid concentrations were then utilized to validate changes in metabolites of specific bacteria. Lactobacillus sp. supplement and fecal microbiota transplantation were used to evaluate gut microbiota contribution. Results: MTX-induced intestinal and liver injuries were significantly alleviated using MgIG treatment. Bacterial translocation resulting from the intestinal barrier disruption was considered a crucial cause of MTX-induced liver injury and the therapeutic target of MgIG. Moreover, MgIG was speculated to have changed the gut microbial composition by up-regulating probiotic Lactobacillus and down-regulating Muribaculaceae, thereby remodelling the intestinal barrier and inhibiting bacterial translocation. Conclusion: The MTX-induced intestinal barrier was protected owing to MgIG administration, which reshaped the gut microbial composition and inhibited bacterial translocation into the liver, thus attenuating MTX-related DILI.
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Doença Hepática Crônica Induzida por Substâncias e Drogas , Microbioma Gastrointestinal , Hepatopatias , Humanos , Hepatopatias/microbiologia , Metotrexato/efeitos adversos , Saponinas , TriterpenosRESUMO
The human body and its microbiome constitute a highly delicate system. The gut microbiome participates in the absorption of the host's nutrients and metabolism, maintains the microcirculation, and modulates the immune response. Increasing evidence shows that gut microbiome dysbiosis in the body not only affects the occurrence and development of tumors but also tumor prognosis and treatment. Microbiome have been implicated in tumor control in patients undergoing anti- angiogenesis therapy and immunotherapy. In cases with unsatisfactory responses to chemotherapy, radiotherapy, and targeted therapy, appropriate adjustment of microbes abundance is considered to enhance the treatment response. Here, we review the current research progress in cancer immunotherapy and anti- angiogenesis therapy, as well as the unlimited potential of their combination, especially focusing on how the interaction between intestinal microbiota and the immune system affects cancer pathogenesis and treatment. In addition, we discuss the effects of microbiota on anti-cancer immune response and anti- angiogenesis therapy, and the potential value of these interactions in promoting further research in this field.
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Inibidores da Angiogênese/uso terapêutico , Imunoterapia , Microbiota , Neoplasias/terapia , Inibidores da Angiogênese/farmacologia , Carcinogênese/imunologia , Ensaios Clínicos Fase III como Assunto , Terapia Combinada , Dieta , Medicamentos de Ervas Chinesas/farmacologia , Disbiose/imunologia , Disbiose/metabolismo , Humanos , Inibidores de Checkpoint Imunológico , Microbiota/efeitos dos fármacos , Microbiota/imunologia , Microbiota/fisiologia , Neoplasias/irrigação sanguínea , Neoplasias/imunologia , Neoplasias/microbiologia , Probióticos , Simbiose , Evasão TumoralRESUMO
Pathological angiogenesis, as exhibited by aberrant vascular structure and function, has been well deemed to be a hallmark of cancer and various ischemic diseases. Therefore, strategies to normalize vasculature are of potential therapeutic interest in these diseases. Recently, identifying bioactive compounds from medicinal plant extracts to reverse abnormal vasculature has been gaining increasing attention. Tanshinone IIA (Tan IIA), an active component of Salvia miltiorrhiza, has been shown to play significant roles in improving blood circulation and delaying tumor progression. However, the underlying mechanisms responsible for the therapeutic effects of Tan IIA are not fully understood. Herein, we established animal models of HT-29 human colon cancer xenograft and hind limb ischemia to investigate the role of Tan IIA in regulating abnormal vasculature. Interestingly, our results demonstrated that Tan IIA could significantly promote the blood flow, alleviate the hypoxia, improve the muscle quality, and ameliorate the pathological damage after ischemic insult. Meanwhile, we also revealed that Tan IIA promoted the integrity of vascular structure, reduced vascular leakage, and attenuated the hypoxia in HT-29 tumors. Moreover, the circulating angiopoietin 2 (Ang2), which is extremely high in these two pathological states, was substantially depleted in the presence of Tan IIA. Also, the activation of Tie2 was potentiated by Tan IIA, resulting in decreased vascular permeability and elevated vascular integrity. Mechanistically, we uncovered that Tan IIA maintained vascular stability by targeting the Ang2-Tie2-AKT-MLCK cascade. Collectively, our data suggest that Tan IIA normalizes vessels in tumors and ischemic injury via regulating the Ang2/Tie2 signaling pathway.
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Abietanos/farmacologia , Neoplasias do Colo/irrigação sanguínea , Regulação da Expressão Gênica/efeitos dos fármacos , Isquemia/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Receptor TIE-2/antagonistas & inibidores , Proteínas de Transporte Vesicular/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Humanos , Isquemia/metabolismo , Isquemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Longstanding, successful use of combinations of phytopharmaceuticals in traditional Chinese medicine (TCM) has caught the attention of several pharmacologists to natural medicines. However, the development and popularisation of TCM is mainly limited because of the unavailability of reports clarifying the mechanisms of action and pharmacologically active ingredients in such formulations. Previous studies on natural medicines have mostly focused on their dominant components using forward pharmacology which often neglects trace components. It is necessary to assess the pharmacological and therapeutic superiority of many such trace components in comparison with single constituents. PURPOSE: In this study, we aimed to propose a new pharmacological research strategy for TCM. In particular, we presented the possibility that the effective mechanism of action of trace components of TCM is based on synthetic lethality. We sincerely hope to explore this theory further. METHOD: We obtained retrieve published research information related to synthetic lethality, phytochemicals and Chinese medicine from PubMed and Google scholar. Based on the inclusion criteria, 71 studies were selected and discussed in this review. RESULTS: As an interaction among genes, synthetic lethality can amplify co-regulatory biological effects exponentially. Synthetic strategies have been successfully applied for research and development of anti-tumour agents, including poly ADP-ribose polymerase inhibitors and clinical combination of chemotherapeutic agents for efficacy enhancement and toxicity reduction. TCM drugs contain several secondary metabolites to combat environmental stresses, providing a multi-component basis for corresponding synergistic targets. Therefore, we aimed to study whether this method could be used to identify active components present in trace amounts in TCM drugs. Based on a reverse concept of target-component-effect and identified synergistic targets, we explored the mechanisms of action of weakly active components present in trace amounts in TCM drugs to assess combinations of potential synergistic components. CONCLUSION: This pattern of synthetic lethality not only elucidated the mechanisms of action of TCM drugs from a new perspective but also inspired future studies on discovering naturally occurring active components.
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Medicamentos de Ervas Chinesas , Compostos Fitoquímicos , Mutações Sintéticas Letais , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa , Compostos Fitoquímicos/farmacologiaRESUMO
Accumulating evidences implicate that gut microbiota play an important role in the onset and prolongation of fat inflammation and diabetes. Sennoside A, the main active ingredient of Rhizoma Rhei (rhubarb), is widely used for constipation as a kind of anthranoid laxative (e.g., senna). Here, we put forward the hypothesis that the structural alteration of gut microbiota in obesity mice may be involved in the pathogenesis of type 2 diabetes (T2D) which may be ameliorated by Sennoside A. We investigated the appearance of obesity, insulin resistance, host inflammation, and leaky gut phenotype with or without Sennoside A in db/db mice. Horizontal fecal microbiota transplantation (FMT) was used to confirm the critical roles of gut microbiota in the amelioration of the indices in T2D mice after Sennoside A treatment. As a result, we found that Sennoside A administration markedly improved the indices in T2D mice and obesity-related traits including blood glucose level, body weight, lipid metabolism disorder, and insulin resistance. The gut microbiota changed quickly during the onset of T2D in db/db mice, which confirmed the hypothesis that gut microbiota was involved in the pathogenesis of T2D. Sennoside A altered gut microbial composition which might mediate the antiobesogenic effects in T2D remission. Sennoside A also reduced inflammation and increased tight junction proteins in the ileum in gene-deficient mice via gut microbiota alteration. FMT lowered the blood glucose level and improved insulin resistance, corroborating that Sennoside A perhaps exerted its antiobesogenic effects through gut microbiota alteration. Chemical Compounds Studied in This Article. Compounds studied in this article include Sennoside A (PubChem CID: 73111) and metformin hydrochloride (PubChem CID: 14219).
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Laxantes/uso terapêutico , Obesidade/tratamento farmacológico , Senosídeos/uso terapêutico , Animais , Modelos Animais de Doenças , Humanos , Laxantes/farmacologia , Masculino , Camundongos , Senosídeos/farmacologiaRESUMO
BACKGROUND: Radix et Rhizoma Ginseng (thereafter called ginseng) has been used as a medicinal herb for thousands of years to maintain people's physical vitality and is also a non-organ-specific cancer preventive and therapeutic traditional medicine in several epidemiologic and preclinical studies. Owing to few toxic side effects and strong enhancement on body immunity, ginseng has admirable application potential and value in cancer chemoprevention. The study aims at investigating the chemopreventive effects of ginseng on cutaneous carcinoma and the underlying mechanisms. METHODS: The mouse skin cancer model was induced by 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate. Ultraperformance liquid chromatography/mass spectrometry was used for identifying various ginsenosides, the main active ingredients of ginseng. Comprehensive approaches (including network pharmacology, bioinformatics, and experimental verification) were used to explore the potential targets of ginseng. RESULTS: Ginseng treatment inhibited cutaneous carcinoma in terms of initiation and promotion. The content of Rb1, Rb2, Rc, and Rd ginsenosides was the highest in both mouse blood and skin tissues. Ginseng and its active components well maintained the redox homeostasis and modulated the immune response in the model. Specifically, ginseng treatment inhibited the initiation of skin cancer by enhancing T-cell-mediated immune response through upregulating HSP27 expression and inhibited the promotion of skin cancer by maintaining cellular redox homeostasis through promoting nuclear translocation of Nrf2. CONCLUSION: According to the study results, ginseng can be potentially used for cutaneous carcinoma as a chemopreventive agent by enhancing cell-mediated immunity and maintaining redox homeostasis with multiple components, targets, and links.
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Relieving Sore Throat Formula (RSTF) is a formula approved by the China Food and Drug Administration and has been used for the treatment of pharyngitis in clinic for many years. However, the potential pharmacological mechanism still remains unknown. We combined multiple methods including bioinformatics data digging, network pharmacology analysis, and pathway analysis to predict the potential target of RSTF. We verified our in silico prediction results with an in vivo/vitro antibacterial effect test, mouse phagocytic index test, proliferation, transformation, and migration of mouse spleen lymphocytes. Alteration of NF-κB pathway was determined by Western blotting, immunofluorescence, and PCR. The in vivo experiments demonstrated that the RSTF could significantly relieve the symptoms of pharyngitis. A rat saliva secretion test showed that RSTF can effectively relieve the xerostomia symptom. A phenol red excretion test showed that RSTF has an eliminating phlegm effect. A hot plate method and granuloma experiment proved that RSTF also have analgesic and anti-inflammatory effects. In silico prediction demonstrates that 70 active compounds of RSTF were filtered out through ADME screening and 84 putative targets correlated with different diseases. Pathway enrichment analysis showed that the candidate targets were mostly related to the response to bacteria and immunity signalling pathways, which are known contributors to pharyngitis. Experimental results confirmed that RSTF exerted therapeutic effects on pharyngitis mainly by antibacterial effect and downregulation of NF-κB activities. It is demonstrated both in silico and in vivo/vitro that RSTF exerted therapeutic effects on pharyngitis mainly through an antibiotic effect and downregulation of NF-κB signalling pathway.
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Medicamentos de Ervas Chinesas/uso terapêutico , NF-kappa B/metabolismo , Faringite/tratamento farmacológico , Animais , Antibacterianos/uso terapêutico , Movimento Celular , Proliferação de Células , Celulose/química , Biologia Computacional , Simulação por Computador , Regulação para Baixo , Granuloma/metabolismo , Proteínas Hemolisinas/sangue , Sistema Imunitário , Imunidade Inata , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ácido N-Acetilneuramínico/metabolismo , Fagocitose , Fenolsulfonaftaleína/química , Extratos Vegetais/uso terapêutico , Ratos , Saliva/metabolismo , Transdução de Sinais , Baço/metabolismo , Temperatura , Xerostomia/terapiaRESUMO
Pyruvate kinase M2 (PKM2), playing a central role in regulating aerobic glycolysis, was considered as a promising target for cancer therapy. However, its role in cancer metastasis is rarely known. Here, we found a tight relationship between PKM2 and breast cancer metastasis, demonstrated by the findings that beta-elemene (ß-elemene), an approved drug for complementary cancer therapy, exerted distinct anti-metastatic activity dependent on PKM2. The results indicated that ß-elemene inhibited breast cancer cell migration, invasion in vitro as well as metastases in vivo. ß-Elemene further inhibited the process of aerobic glycolysis and decreased the utilization of glucose and the production of pyruvate and lactate through suppressing pyruvate kinase activity by modulating the transformation of dimeric and tetrameric forms of PKM2. Further analysis revealed that ß-elemene suppressed aerobic glycolysis by blocking PKM2 nuclear translocation and the expression of EGFR, GLUT1 and LDHA by influencing the expression of importin α5. Furthermore, the effect of ß-elemene on migration, invasion, PKM2 transformation, and nuclear translocation could be reversed in part by fructose-1,6-bisphosphate (FBP) and L-cysteine. Taken together, tetrameric transformation and nuclear translocation of PKM2 are essential for cancer metastasis, and ß-elemene inhibited breast cancer metastasis via blocking aerobic glycolysis mediated by dimeric PKM2 transformation and nuclear translocation, being a promising anti-metastatic agent from natural compounds.
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Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Núcleo Celular/metabolismo , Multimerização Proteica , Piruvato Quinase/metabolismo , Sesquiterpenos/farmacologia , Aerobiose , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Cisteína/farmacologia , Receptores ErbB/metabolismo , Feminino , Frutosedifosfatos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 1/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Invasividade Neoplásica , Metástase Neoplásica , Multimerização Proteica/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Major depressive disorder is now becoming a common disease in daily life, and most patients do not have satisfactory treatment outcomes. We herein evaluated the therapeutic effects of Zhile capsule and clarified the molecular mechanism. A rat model of chronic unpredictable mild stress-induced depression was established to assess the antidepressant-like effects of Zhile by using the sucrose preference test, open field test, forced swim test, tail suspension test and HPLC. Systems pharmacology was then performed to unravel the underlying mechanism which was confirmed by western blot, enzyme-linked immunosorbent assay, and qPCR. Zhile alleviated depression-like behaviors by upregulating the cAMP-CREB-BDNF (brain-derived neurotrophic factor) axis to exert neuroprotective effects. It may be beneficial to depressive patients in clinical practice.
Assuntos
Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais , Regulação para Cima , Animais , Antidepressivos/farmacologia , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas/metabolismo , Cápsulas , Doença Crônica , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/complicações , Medicamentos de Ervas Chinesas/farmacologia , Elevação dos Membros Posteriores , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Neurotransmissores/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológicoRESUMO
NiaoDuQing (NDQ) granules, a traditional Chinese medicine, has been clinically used in China for over fourteen years to treat chronic kidney disease (CKD). To elucidate the mechanisms underlying the therapeutic benefits of NDQ, we designed an approach incorporating chemoinformatics, bioinformatics, network biology methods, and cellular and molecular biology experiments. A total of 182 active compounds were identified in NDQ granules, and 397 putative targets associated with different diseases were derived through ADME modelling and target prediction tools. Protein-protein interaction networks of CKD-related and putative NDQ targets were constructed, and 219 candidate targets were identified based on topological features. Pathway enrichment analysis showed that the candidate targets were mostly related to the TGF-ß, the p38MAPK, and the erythropoietin (EPO) receptor signaling pathways, which are known contributors to renal fibrosis and/or renal anemia. A rat model of CKD was established to validate the drug-target mechanisms predicted by the systems pharmacology analysis. Experimental results confirmed that NDQ granules exerted therapeutic effects on CKD and its comorbidities, including renal anemia, mainly by modulating the TGF-ß and EPO signaling pathways. Thus, the pharmacological actions of NDQ on CKD symptoms correlated well with in silico predictions.
RESUMO
Accumulating evidence has indicated that garlic consumption may reduce the risk of developing several types of cancer, and extensive studies have revealed the effects of its bioactive component, diallyl trisulï¬de (DATS), on the proliferation and apoptosis of tumor cells. The present study was undertaken to examine whether DATS affects hematogenous metastasis. In view of the dynamic crosstalk interplayed by tumor cells and platelets in hematogenous metastasis, we attempted to demonstrate the role of DATS in the metastatic behavior of MDA-MB-231 human breast cancer cells, which were co-incubated with activated platelets. Indeed, our data indicated that DATS significantly blocked platelet activation and aggregation induced by platelet-activating factor (PAF), and decreased the production of thromboxane B2 (TXB2). It was also found that DATS suppressed the migration and invasion of MDA-MB-231 cells in the presence of platelets activated by PAF in vitro in a dose-dependent manner. Furthermore, our results revealed thaat the release of activated TGF-ß1 in the platelet-tumor cell system was markedly attenuated by DATS. Therefore, our findings strongly suggest that the diverse pharmacological activities of DATS are at least partially reflected by the interruption of the activated platelets-mediated metastasis of breast cancer cells.
Assuntos
Compostos Alílicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Invasividade Neoplásica/prevenção & controle , Inibidores da Agregação Plaquetária/farmacologia , Sulfetos/farmacologia , Compostos Alílicos/química , Apoptose/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Alho/química , Humanos , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Metástase Neoplásica/prevenção & controle , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Sulfetos/químicaRESUMO
Xanthatin, a xanthanolide sesquiterpene lactone isolated from Xanthium strumarium L. (Asteraceae), has prominent anti-tumor activity. Initial mechanism of action studies suggested xanthatin triggered activation of Wnt/ß-catenin. We examined the effects of xanthatin on signaling pathways in A459 lung cancer cells and mouse embryonic fibroblasts to ascertain requirements for xanthatin-induced cell death and tumor growth in xenografts. Genetic inactivation of GSK-3ß, but not the related isoform GSK-3α, compromised xanthatin cytotoxicity while inactivation of ß-catenin enhanced xanthatin-mediated cell death. These data provide insight into how xanthatin and related molecules could be effectively targeted toward certain tumors.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Furanos/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Xanthium/químicaRESUMO
BACKGROUND: Migration and invasion are two crucial steps of tumor metastasis. Blockage of these steps may be an effective strategy to reduce the risk. The objective of the present study was to investigate the effects of diallyl trisulfide (DATS), a natural organosulfuric compound with most sulfur atoms found in garlic, on migration and invasion in triple negative breast cancer (TNBC) cells. Molecular mechanisms underlying the anticancer effects of DATS were further investigated. METHODS AND RESULTS: MDA-MB-231 cells and HS 578t breast cancer cells were treated with different concentrations of DATS. DATS obviously suppressed the migration and invasion of two cell lines and changed the morphological. Moreover, DATS inhibited the mRNA/protein/ enzymes activities of MMP2/9 via attenuating the NF-κB pathway. DATS also inhibited ERK/MAPK rather than p38 and JNK. CONCLUSION: DATS inhibits MMP2/9 activity and the metastasis of TNBC cells, and emerges as a potential anti-cancer agent. The inhibitory effects are associated with down-regulation of the transcriptional activities of NF-κB and ERK/MAPK signaling pathways.