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1.
Front Microbiol ; 15: 1395634, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38952445

RESUMO

Introduction: Alterations in the gut microbiome and bile acid metabolism are known to play a role in the development and progression of colon cancer. Medicinal plants like Astragalus mongholicus Bunge and Curcuma aromatica Salisb. (AC) have shown preferable therapeutic effect on cancer therapy, especially digestive tract tumors like colon cancer. However, the precise mechanisms of AC inhibiting colon cancer, particularly in relation to the gut microbiome and bile acid dynamics, are not fully understood. Methods: Our research aimed to investigate the anti-tumor properties of AC in mice with CT26 colon cancer and further investigate its underlying mechanism via intestinal microbiota. The size and pathological changes of solid tumors in colon cancer are used to evaluate the inhibitory effect of AC on colon cancer. Metagenomics and 16s rRNA gene sequencing were employed to clarify the dysbiosis in the gut microbiome of colon cancer and its impact on colon cancer. The levels of bile acids (BAs) in the feces of mice from each group were measured using UPLC-Qtrap-MS/MS. Results: AC effectively suppressed the growth of colon cancer and reduced histological damage. Notably, AC treatment led to changes in the gut microbiome composition, with a decrease in pathogenic species like Citrobacter and Candidatus_Arthromitus, and an increase in beneficial microbial populations including Adlercreutzia, Lachnospiraceae_UCG-001, and Parvibacter. Additionally, AC altered bile acid profiles, resulting in a significant decrease in pro-carcinogenic bile acids such as deoxycholic acid (DCA) and lithocholic acid (LCA), while increasing the concentration of the cancer-inhibitory bile acid, ursodeoxycholic acid (UDCA). Tracking and analyzing the data, AC may mainly upregulate FabG and baiA genes by increasing the relative abundance of Adlercreutzia and Parvibacter bacteria, which promoting the metabolism of pro-carcinogenic LCA. Discussion: These findings provide strong evidence supporting the role of AC in regulating gut microbiome-mediated bile acid metabolism, which is crucial in impeding the progression of colon cancer.

2.
Phytomedicine ; 132: 155824, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38941816

RESUMO

BACKGROUND: Colorectal cancer (CRC) is one of the most common causes of cancer-related mortality and significantly impairs quality of life. Astragali Radix-Curcumae Rhizoma (AC) is widely employed in the treatment of CRC in Chinese medicine, but the precise mechanisms remain unclear. PURPOSE: This study aimed to elucidate the mechanisms by which AC inhibits CRC progression. METHODS: The active components of AC were identified using UPLC-MS/MS analysis. An orthotopic transplantation colorectal tumor model was established in BALB/c mice using the CT26-Lucifer cell line to evaluate the effects of AC. Tumor volumes were monitored using IVIS imaging technology. Histological examination of tumor morphology was performed with hematoxylin and eosin (H&E) staining. Transcriptomic sequencing of mouse tumor samples was conducted to identify critical pathways and molecular targets. The impact of AC on cell viability and migration was assessed using CCK-8 and wound healing assays, respectively. To investigate the effects of AC on CRC cells, an in vitro hypoxic model was established using cobalt chloride (CoCl2), a hypoxia inducer. HIF-2α overexpression was achieved by constructing stable lentiviral vectors. Key targets identified from RNA-seq, such as c-Myc, Ki-67, ß-catenin, cleaved caspase 3, CD133, and CD44, were evaluated using western blotting, qRT-PCR, and immunofluorescence assays. Epithelial-Mesenchymal Transition (EMT) and spheroid cloning assays were employed to evaluate phenotypic changes in cancer stem cells. RESULTS: Twelve components of AC were identified. AC effectively inhibited CRC progression in vivo. Transcriptomic analysis highlighted hypoxic signaling as a significantly enriched pathway, implicating its role in suppressing CRC progression by AC. In the hypoxic model, AC inhibited the proliferation and migration of CRC cells in vitro. Furthermore, AC reduced cancer stemness by downregulating stemness markers, inhibiting EMT, and decreasing tumor sphere formation. The downregulation of hypoxic responses and the shift in stemness by AC involved attenuation of HIF-2α and WNT/ß-catenin signaling. CONCLUSION: This study provides the first evidence that AC reduces the stemness of CRC and the inhibition of the transition of CRC to stem-like cells by AC is closely related to the downregulation of the HIF-2α/ß-catenin pathway, especially under hypoxic conditions.

3.
J Neuroinflammation ; 21(1): 159, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38898454

RESUMO

A significant decrease in estrogen levels puts menopausal women at high risk for major depression, which remains difficult to cure despite its relatively clear etiology. With the discovery of abnormally elevated inflammation in menopausal depressed women, immune imbalance has become a novel focus in the study of menopausal depression. In this paper, we examined the characteristics and possible mechanisms of immune imbalance caused by decreased estrogen levels during menopause and found that estrogen deficiency disrupted immune homeostasis, especially the levels of inflammatory cytokines through the ERα/ERß/GPER-associated NLRP3/NF-κB signaling pathways. We also analyzed the destruction of the blood-brain barrier, dysfunction of neurotransmitters, blockade of BDNF synthesis, and attenuation of neuroplasticity caused by inflammatory cytokine activity, and investigated estrogen-immuno-neuromodulation disorders in menopausal depression. Current research suggests that drugs targeting inflammatory cytokines and NLRP3/NF-κB signaling molecules are promising for restoring homeostasis of the estrogen-immuno-neuromodulation system and may play a positive role in the intervention and treatment of menopausal depression.


Assuntos
Estrogênios , Menopausa , Humanos , Feminino , Menopausa/imunologia , Menopausa/metabolismo , Estrogênios/metabolismo , Animais , Depressão/imunologia , Depressão/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais/fisiologia , Citocinas/metabolismo
4.
Zhongguo Zhong Yao Za Zhi ; 49(4): 1044-1051, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38621911

RESUMO

The animal and cell models were used in this study to investigate the mechanism of Astragali Radix-Curcumae Rhizoma(HQEZ) in inhibiting colon cancer progression and enhancing the efficacy of 5-fluorouracil(5-FU) by regulating hypoxia-inducible factors and tumor stem cells. The animal model was established by subcutaneous transplantation of colon cancer HCT116 cells in nude mice, and 24 successfully modeled mice were randomized into model, 5-FU, HQEZ, and 5-FU+HQEZ groups. The tumor volume was measured every two days. Western blot was employed to measure the protein levels of epidermal growth factor receptor(EGFR), dihydropyrimidine dehydrogenase(DPYD), and thymidylate synthase(TYMS), the key targets of the hypoxic core region, as well as the hypoxia-inducible factors HIF-1α and HIF-2α and the cancer stem cell surface marker CD133 and SRY-box transcription factor 2(SOX2). The results of animal experiments showed that HQEZ slowed down the tumor growth and significantly increased the tumor inhibition rate of 5-FU. Compared with the model group, HQEZ significantly down-regulated the protein levels of EGFR and DPYD, and 5-FU+HQEZ significantly down-regulated the protein levels of EGFR and TYMS in tumors. Compared with the model group, HQEZ significantly down-regulated the protein levels of HIF-1α, HIF-2α, SOX2, and CD133 in the hypoxic core region. Compared with the 5-FU group, 5-FU+HQEZ lowered the protein levels of HIF-1α, HIF-2α, and SOX2. The cell experiments showed that the protein le-vels of HIF-1α and HIF-2α in HCT116 cells elevated significantly after low oxygen treatment. Compared with 5-FU(1.38 µmol·L~(-1)) alone, HQEZ(40 mg·mL~(-1)) and 5-FU+HQEZ significantly down-regulated the protein levels of HIF-1α, HIF-2α, and TYMS. In conclusion, HQEZ can inhibit the expression of hypoxia-responsive molecules in colon cancer cells and reduce the properties of cancer stem cells, thereby enhancing the therapeutic effect of 5-FU on colon cancer.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Neoplasias do Colo , Camundongos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Camundongos Nus , Fluoruracila/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Hipóxia , Receptores ErbB , Células-Tronco Neoplásicas , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Linhagem Celular Tumoral
5.
Invest Ophthalmol Vis Sci ; 65(4): 33, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38648040

RESUMO

Purpose: The cGAS-STING pathway has been shown to be an important mediator of inflammation. There is emerging evidence of the importance of this signaling cascade in a variety of inflammatory diseases settings. Here, we present evidence that the mitochondrial DNA (mtDNA) damage-mediated cGAS-STING pathway plays an important role in the induction of inflammation in environmental dry eye (DE). Methods: RT-qPCR and Western blot were used to assess the induction of the cGAS-STING pathway and inflammatory cytokines in environmental DE mouse model, primary human corneal epithelial cells (pHCECs), and patients with DE. RNA sequencing was used to determine mRNA expression patterns of high osmotic pressure (HOP)-stimulated pHCECs. mtDNA was detected with electron microscopy, flow cytometry, and immunofluorescent staining. mtDNA was isolated and transfected into pHCECs for evaluating the activation of the cGAS-STING pathway. Results: The expression levels of cGAS, STING, TBK1, IRF3, and IFNß were significantly increased in an environmental DE model and HOP-stimulated pHCECs. The STING inhibitor decreased the expression of inflammatory factors in DE. An upregulation of STING-mediated immune responses and IRF3 expression mediated by TBK1 were observed in the HOP group. HOP stimulation induced mitochondrial oxidative damage and the leakage of mtDNA into the cytoplasm. Then, mtDNA activated the cGAS-STING pathway and induced intracytoplasmic STING translocated to the Golgi apparatus. Finally, we also found activated cGAS-STING signaling in the human conjunctival blot cell of patients with DE. Conclusions: Our findings suggest that the cGAS-STING pathway is activated by recognizing cytoplasmic mtDNA leading to STING translocation, further exacerbating the development of inflammation in environmental DE.


Assuntos
DNA Mitocondrial , Síndromes do Olho Seco , Proteínas de Membrana , Nucleotidiltransferases , Transdução de Sinais , Animais , Feminino , Humanos , Camundongos , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , DNA Mitocondrial/metabolismo , DNA Mitocondrial/fisiologia , Síndromes do Olho Seco/etiologia , Síndromes do Olho Seco/metabolismo , Epitélio Corneano/metabolismo , Citometria de Fluxo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/fisiologia
6.
Mol Neurobiol ; 61(3): 1318-1330, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37702910

RESUMO

Multiple sclerosis (MS) is a chronic disease that is characterized by demyelination and neuronal damage. Experimental autoimmune encephalomyelitis (EAE) mice are used to model the disease progression of MS and mirror MS-like pathology. Previous researches have confirmed that inhibition of NLRP3 inflammasome significantly alleviated the severity of EAE mice and the demyelination of spinal cord, but its effect on neuronal damage and oligodendrocyte loss in the brain remains unclear. In this study, female C57BL/6 mice were immunized with MOG35-55 and PTX to establish experimental autoimmune encephalomyelitis (EAE) model. MCC950, a selective NLRP3 inflammasome inhibitor, was used to investigate the effect of NLRP3 inflammasome on the pathological changes and glial cell activation in the brain of EAE mice by immunohistochemistry. Our results demonstrated that MCC950 ameliorated the neuronal damage, demyelination, and oligodendrocyte loss in the brain of EAE mice. This protective effect of MCC950 may be attributed to its ability to suppress the activation of glial cells and prevents microglia polarization to M1 phenotype. Our work indicates that inhibition of NLRP3 inflammasome has the therapeutic effects of neuroprotection through immunomodulation and is a promising therapeutic strategy for MS.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Feminino , Animais , Camundongos , Encefalomielite Autoimune Experimental/patologia , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Camundongos Endogâmicos C57BL , Encéfalo/patologia , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
7.
Zhongguo Zhong Yao Za Zhi ; 48(18): 5056-5067, 2023 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-37802848

RESUMO

This study aims to investigate the mechanism of Astragali Radix-Curcumae Rhizoma(HQEZ) in the treatment of gastric cancer based on network pharmacology. Further, the SGC7901 cell model of gastric cancer was employed to validate the efficacy and key targets of the herb pair. Firstly, the CCK-8 assay was employed to evaluate the direct effect of HQEZ on the proliferation of gastric cancer SGC7901 cells. Then, network pharmacology methods were employed to investigate the active ingredients, key targets, and key signaling pathways involved in the treatment of gastric cancer with HQEZ. The results showed that HQEZ contained 18 potential active ingredients, such as quercetin, naringenin, and curcumin. The results of gene ontology(GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment suggested that the main targets of HQEZ in treating gastric cancer were involved in the regulation of protein serine/threonine kinase activity, activation of mitogen-activated protein kinase(MAPK) activity, cysteine-type endopeptidase activity, and negative regulation of protein serine/threonine kinase activity. The hypoxia-inducible factor-1(HIF-1) signaling pathway, ATP-binding cassette(ABC) transporters, cytochrome P450-mediated metabolism of xenobiotics, p53 signaling pathway, and cell apoptosis were key signaling pathways of HQEZ in treating gastric cancer. The cell experiments demonstrated that HQEZ significantly downregulated the expression of ATP-binding cassette subfamily B member 1(ABCB1), epidermal growth factor receptor(EGFR), phosphorylated serine/threonine kinase(p-AKT), hypoxia inducible factor 1 subunit alpha(HIF1A), B-cell lymphoma 2(BCL2), breast cancer susceptibility protein 1(BRCA1), DNA polymerase theta(POLH), ribonucleotide reductase M1(RRM1), and excision repair cross-complementation group 1(ERCC1), and upregulated the expression of tumor protein P53(TP53) and cysteinyl aspartate-specific proteinase(CAPS3). Finally, a multivariate COX regression model was adopted to study the relationship between gene expression and clinical information data of gastric cancer patients in the TCGA database, which demonstrated that the key targets of HQEZ were associated with the poor prognosis in gastric cancer patients. Further feature selection using the LASSO algorithm showed that EGFR, HIF1A, TP53, POLH, RRM1, and ERCC1 were closely associated with the survival of gastric can-cer patients. In conclusion, HQEZ regulates the expression of genes involved in DNA repair, survival, and apoptosis in gastric cancer cells via multiple targets and pathways, assisting the treatment of gastric cancer.


Assuntos
Medicamentos de Ervas Chinesas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Proteína Supressora de Tumor p53 , Farmacologia em Rede , Receptores ErbB , Proteínas Serina-Treonina Quinases , Serina , Trifosfato de Adenosina , Simulação de Acoplamento Molecular , Medicamentos de Ervas Chinesas/farmacologia
8.
Ocul Immunol Inflamm ; : 1-9, 2023 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-37163389

RESUMO

PURPOSE: To explore whether circadian clock genes contribute to elicit inflammation in experimental dry eye (EDE). METHODS: RNA sequencing analyzed mRNA expression patterns in EDE model. RT-qPCR and/or Western blot determined the expression of inflammatory factors and circadian genes during EDE. MethylTarget™ assays determined the promoter methylation levels of Per genes in vivo. Per2 or Per3 knockdown assessed their effects on inflammatory factors in vitro. RESULTS: We utilized an intelligently controlled environmental system (ICES) to establish a mouse EDE model. The significant upregulated genes were enriched for circadian rhythms. Therein lied oscillatory and time-dependent upregulation of PER2 and PER3, as well as their promoter hypomethylation during EDE. Silencing PER2 or PER3 significantly decreased inflammatory factor expression and also reversed such increased inflammatory response in azacitidine (AZA) treatment in vitro model. CONCLUSIONS: Our findings suggest that DNA methylation mediated the upregulation of PER2 and PER3, leading to inflammatory response in EDE.

9.
Front Immunol ; 14: 1164278, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37063929

RESUMO

Stroke, especially ischemic stroke, is an important cause of neurological morbidity and mortality worldwide. Growing evidence suggests that the immune system plays an intricate function in the pathophysiology of stroke. Gelsevirine (Gs), an alkaloid from Gelsemium elegans, has been proven to decrease inflammation and neuralgia in osteoarthritis previously, but its role in stroke is unknown. In this study, the middle cerebral artery occlusion (MCAO) mice model was used to evaluate the protective effect of Gs on stroke, and the administration of Gs significantly improved infarct volume, Bederson score, neurobiological function, apoptosis of neurons, and inflammation state in vivo. According to the data in vivo and the conditioned medium (CM) stimulated model in vitro, the beneficial effect of Gs came from the downregulation of the over-activity of microglia, such as the generation of inflammatory factors, dysfunction of mitochondria, production of ROS and so on. By RNA-seq analysis and Western-blot analysis, the JAK-STAT signal pathway plays a critical role in the anti-inflammatory effect of Gs. According to the results of molecular docking, inhibition assay, and thermal shift assay, the binding of Gs on JAK2 inhibited the activity of JAK2 which inhibited the over-activity of JAK2 and downregulated the phosphorylation of STAT3. Over-expression of a gain-of-function STAT3 mutation (K392R) abolished the beneficial effects of Gs. So, the downregulation of JAK2-STAT3 signaling pathway by Gs contributed to its anti-inflammatory effect on microglia in stroke. Our study revealed that Gs was benefit to stroke treatment by decreasing neuroinflammation in stroke as a potential drug candidate regulating the JAK2-STAT3 signal pathway.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Camundongos , Animais , Isquemia Encefálica/metabolismo , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , Microglia/metabolismo , Doenças Neuroinflamatórias , Simulação de Acoplamento Molecular , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Inflamação/metabolismo , Anti-Inflamatórios/uso terapêutico
10.
Invest Ophthalmol Vis Sci ; 63(12): 18, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36374514

RESUMO

Purpose: To assess the role of mitochondrial morphology and adenosine monophosphate-activated protein kinase (AMPK)/mitochondrial fission factor (MFF) in dry eye and the underlying mechanisms. Methods: Immortalized human corneal epithelial cells (HCECs) and primary HCECs were cultured under high osmotic pressure (HOP). C57BL/6 female mice were injected subcutaneously with scopolamine. Quantitative real-time PCR was used to measure mRNA expression. Protein expression was assessed by western blot and immunofluorescence staining. Mitochondrial morphology was observed by confocal microscopy and transmission electron microscopy. Results: First, HOP induced mitochondrial oxidative damage to HCECs, accompanied by mitochondrial fission and increased mitophagy. Then, AMPK/MFF pathway proteins were increased consequent to HOP-induced energy metabolism dysfunction. Interestingly, the AMPK pathway promoted mitochondrial fission and mitophagy by increasing the recruitment of dynamin-related protein 1 (DRP1) to the mitochondrial outer membrane in the HOP group. Moreover, AMPK knockdown attenuated mitochondrial fission and mitophagy due to HOP in HCECs. AMPK activation triggered mitochondrial fission and mitophagy. Mitochondrial fission of HCECs stressed by HOP was mediated via MFF phosphorylation. MFF knockdown reversed mitochondrial fragmentation and mitophagy in HCECs treated with HOP. Inhibition of MFF protected HCECs against oxidative damage, cell death, and inflammation in the presence of HOP. Finally, we detected mitochondrial fission and AMPK pathway activation in vivo. Conclusions: The AMPK/MFF pathway mediates the development of dry eye by positively regulating mitochondrial fission and mitophagy. Inhibition of mitochondrial fission can alleviate oxidative damage and inflammation in dry eye and may provide experimental evidence for treating dry eye.


Assuntos
Síndromes do Olho Seco , Dinâmica Mitocondrial , Feminino , Humanos , Camundongos , Animais , Dinâmica Mitocondrial/genética , Mitofagia , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Mitocondriais/genética , Camundongos Endogâmicos C57BL , Inflamação , Proteínas de Membrana
11.
iScience ; 25(8): 104773, 2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-35992091

RESUMO

Colorectal cancer is one of the most serious tumors and berberine can inhibit the recurrence and transformation of colorectal adenoma into colorectal cancer. However, the direct binding target proteins of berberine in inhibiting colorectal cancer remain unclear. In this study, the chemical proteomics method was used and demonstrated that berberine is directly bound to pyruvate kinase isozyme type M2 (PKM2) in colorectal cancer cells. The triangular N-O-O triangular structure of berberine contributed to hydrophobic interaction with I119 amino acid residues and π-π interaction with F244 amino acid residues of PKM2 protein. Moreover, berberine was shown to inhibit the reprogramming of glucose metabolism and the phosphorylation of STAT3, down regulate the expression of Bcl-2 and Cyclin D1 genes, ultimately inhibiting the progression of colorectal cancer. This study uncovered the direct binding target protein and mechanism of berberine to improve metabolic reprogramming in colorectal cancer, which is helpful to guide the optimization of berberine.

12.
Phytomedicine ; 102: 154217, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35660350

RESUMO

BACKGROUND: Colitis-associated cancer (CAC) is known to be a complex combination of tumor cells, non-tumor cells and a large intestinal flora. The increasing role of intestinal flora in CAC may represent a new approach to improving CAC treatment. Berberine can reduce colorectal adenoma recurrence and inhibit colorectal carcinogenesis. PURPOSE: Berberine has demonstrated efficacy for the control and suppression of CAC. Given the low oral absorption into the blood and large intestinal excretion of berberine, intestinal flora may be one of the important targets of berberine inhibiting the occurrence of colorectal cancer (CRC). The purpose of this study was to investigate the effects of berberine on intestinal flora in CAC mice and its ability to remodel intestinal flora to improve short-chain fatty acid metabolism. STUDY DESIGN AND METHODS: The CAC model in mice was induced by Azoxymethane/Dextran sodium sulfate (AOM/DSS). Berberine was administered daily at doses of 50 and 100 mg/kg, and aspirin was used as the positive control. The effect of berberine on colitis-associated colorectal tumorigenesis was assessed by general imaging, tumor counting, and Ki67 staining. Intestinal flora changes were detected by 16S rDNA sequencing technology. Targeted short-chain fatty acid detection was performed by GC-MS/MS, and Lipopolysaccharide (LPS) levels in feces were quantified with an ELISA kit. The signaling pathway of TLR4/NF-κB P65/IL-6/p-STAT3 was evaluated by Western blotting and immunofluorescence. The expression levels of intestinal barrier functional biomarkers Occludin and ZO-1 were detected by immunohistochemistry. Fecal flora transplantation (FMT) was used to evaluate the effect of intestinal flora in inhibiting inflammatory cancer transformation by berberine. RESULTS: Berberine reduced the number and load of tumors in CAC mice. Berberine remodeled the composition of pathogenic and beneficial bacteria in mice with colitis-associated colorectal tumorigenesis. Berberine treatment resulted in increases in fecal butyric acid, acetic acid and propionic acid levels, but did not alter isobutyric acid, isovaleric acid, valeric acid and caproic acid. In addition, berberine reduced LPS content in feces in mice with colitis-associated colorectal tumorigenesis. Occludin and ZO-1 were upregulated, and the TLR4/p-NF-κB p65/IL-6/p-STAT3 inflammatory-cancer transformation pathway was inhibited with berberine. The FMT results further verified that the berberine-treated intestinal flora was sufficient to alleviate the occurrence of colonic tumors associated with colitis in mice. CONCLUSION: Our study showed that berberine alleviated the colitis-associated colorectal tumorigenesis from three equilibrium levels: (1) Pathogenic and beneficial bacteria; (2) Short-chain fatty acids and LPS produced by intestinal flora; and (3) Inflammatory cancer transformation signaling and intestinal barrier function. This study provided a new approach and experimental basis for the application of berberine in the treatment of CAC in clinical practice.


Assuntos
Berberina , Colite , Neoplasias Colorretais , Microbioma Gastrointestinal , Animais , Azoximetano , Berberina/farmacologia , Carcinogênese , Transformação Celular Neoplásica , Colite/induzido quimicamente , Colite/complicações , Colite/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Ácidos Graxos Voláteis , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Ocludina , Espectrometria de Massas em Tandem , Receptor 4 Toll-Like
13.
Phytomedicine ; 102: 154149, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35567995

RESUMO

BACKGROUND: Colorectal cancer (CRC) is an important death-related disease in the world and new therapeutic strategies are urgently needed to reduce mortality. Several studies have demonstrated that emodin, the main ingredient of Rheum palmatum, fights cancer but its potential anti-tumor effect on CRC is still unknown. PURPOSE: The present study is aimed to explore the potential anti-tumor effects of emodin against CRC and the underlying molecular mechanism. METHODS: CRC-related datasets were screened according to filter criteria in the GEO database and TCGA database. By using screened differentially expressed genes, GO, KEGG and survival analysis were carried out. The expressions of ACSL4, VEGFR1, and VEGFR2 were examined by immunohistochemistry and western blot. Then, pcDNA-ACSL4, pcDNA-VEGFR1, and pcDNA-VEGFR2 were used to overexpress ACSL4, VEGFR1, and VEGFR2, while ACSL4 siRNA was used to silence ACSL4 expression in HCT116 cells. CCK-8 assay and transwell migration assay were used to detect the cell proliferation and invasion. A docking simulation assay and an MST assay were performed to explore the potential mode of emodin binding to ACSL4. The HCT116 cells and CRC mouse model were established to investigate the effects of emodin on CRC. RESULTS: The ACSL4, VEGFR1, and VEGFR2 expression were upregulated in CRC tissues and ACSL4 was associated with a shorter survival time in CRC patients. ACSL4 downregulation reduced cell proliferation and invasion, while ACSL4 exhibited a positive correlation with the levels of VEGFR1, VEGFR2, and VEGF. In HCT116 cells, emodin reduced cell proliferation and invasion by inhibiting ACSL4, VEGFR1, and VEGFR2 expression and VEGF secretion. Docking simulation and MST assay confirmed that emodin can directly bind to ACSL4 target. Moreover, ACSL4 overexpression abolished the inhibitory effect of emodin on VEGF secretion and VEGFR1 and VEGFR2 expression, but VEGFR1 and VEGFR2 overexpression did not affect the inhibitory effect of emodin on ACSL4 expression and VEGF secretion. Furthermore, emodin reduced the mortality and tumorigenesis of CRC mice and reduced ACSL4, VEGFR1, VEGFR2 expression, and VEGF content. CONCLUSION: Our findings indicate that emodin inhibits proliferation and invasion of CRC cells and reduces VEGF secretion and VEGFR1 and VEGFR2 expression by inhibiting ACSL4. This emodin-induced pathway offers insights into the molecular mechanism of its antitumor effect and provides a potential therapeutic strategy for CRC.


Assuntos
Coenzima A Ligases , Neoplasias Colorretais , Emodina , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Emodina/farmacologia , Células HCT116 , Humanos , Camundongos , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Artigo em Inglês | MEDLINE | ID: mdl-31275425

RESUMO

Astragalus membranaceus and Curcuma zedoaria, two traditional Chinese medicines, are widely used together in colorectal cancer adjuvant treatment. Many different mechanisms should be involved in the benefit effect of Astragalus membranaceus and Curcuma zedoaria. In this study, we established that the combined extract from Astragalus membranaceus and Curcuma zedoaria (HQEZ) decreased the metastasis ability in colorectal cancer cells (HCT116, a cell line of colorectal carcinoma established from Homo sapiens) in vitro, and the treatment induced the downregulation of EMT signal and decreased CXCR4 expression and the level of ß-catenin. Overexpression of CXCR4 and the administration of the agonist and inhibitor to ß-catenin signal pathway were used to explore the mechanism of Astragalus membranaceus and Curcuma zedoaria in colorectal cancer treatment. The data demonstrated that HQEZ increased the phosphorylation of ß-catenin which related to the degradation of ß-catenin, and it induced the downregulation of EMT signal and CXCR4. It meant that the influence of ß-catenin should be a key event in the antimetastasis effects of Astragalus membranaceus-Curcuma zedoaria in colorectal cancer model. These findings revealed the potential effect and mechanism of Astragalus membranaceus-Curcuma zedoaria in colorectal cancer treatment and provided insight for optimization of the usage.

15.
Integr Cancer Ther ; 18: 1534735418824408, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30762443

RESUMO

Normalizing the disordered tumor vasculature, rather than blocking it, is a novel method for anticancer therapy. Astragali polysaccharide (APS) and curcumin were reported to be active against carcinomas. However, the effect and mechanism of the combination of APS and curcumin on vascular normalization in hepatocellular carcinoma (HCC) was not clear. In the present study, effects of combined APS and curcumin on tumor vascular normalization were evaluated in HepG2 tumor-bearing mice. Photoacoustic tomography (PAT) was performed to observe the morphological structure of tumor vessels in vivo. The microstructure of the tumor vessels was also analyzed through scanning electron microscopy. Additionally, the expression of CD31 and NG2 was analyzed by immunohistochemical staining. Tumor vessels of HepG2 tumor-bearing mice treated with the combination were sparse with uniform growth, morphology rules, and complete vascular walls, which had fewer branches and sprouts. ECs of tumor vessels were arranged regularly and were tightly connected, tending toward normalization. The expression of CD31 was reduced while NG2 was increased significantly by the combination of APS and curcumin. The results indicated that APS and curcumin in combination showed a better effect on inhibiting tumor growth in an orthotopic nude-mouse model of HCC. More important, the combination induced normalization of tumor vascular better than APS or curcumin administration alone, improving the morphological structure of tumor vessels and promoting maturation of tumor vessels. The results of the present study provided a reasonable possibility for combination therapy of APS and curcumin in the treatment of HCC via tumor vascular normalization.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Curcumina/farmacologia , Fabaceae/química , Neoplasias Hepáticas/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Polissacarídeos/farmacologia , Animais , Linhagem Celular Tumoral , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
16.
PLoS One ; 12(11): e0187971, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29121121

RESUMO

Development of multidrug resistance (MDR) is a continuous clinical challenge partially due to the overexpression of P-glycoprotein (P-gp) for chronic myelogenous leukemia (CML) patients. Herein, we evaluated the inhibitory potency of emodin, a natural anthraquinone derivative isolated from Rheum palmatum L, on P-gp in P-gp positive K562/ADM cells. Competition experiments combined with molecular docking analysis were utilized to investigate the binding modes between emodin and binding sites of P-gp. Emodin reversed adriamycin resistance in K562/ADM cells accompanied with the decrease of P-gp protein expression, further increasing the uptake of rhodamine123 in both K562/ADM and Caco-2 cells, indicating the inhibition of P-gp efflux function. Moreover, when incubated with emodin under different conditions where P-gp was inhibited, K562/ADM cells displayed increasing intracellular uptake of emodin, suggesting that emodin may be the potential substrate of P-gp. Importantly, rhodamine 123 could increase the Kintrinsic (Ki) value of emodin linearly, whereas, verapamil could not, implying that emodin competitively bound to the R site of P-gp and noncompetition existed between emodin and verapamil at the M site, in a good accordance with the results of molecular docking that emodin bound to the R site of P-gp with higher affinity. Based on our results, we suggest that emodin might be used to modulate P-gp function and expression.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Emodina/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos Fitogênicos/química , Sítios de Ligação , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Emodina/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Simulação de Acoplamento Molecular
17.
Zhongguo Zhong Yao Za Zhi ; 42(4): 686-695, 2017 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-28959838

RESUMO

The samples of Huangqi injection (HI) were analyzed by liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (LC-TOF-MS), and both positive and negative ion modes were employed to obtain the LC-TOF-MS analysis information of chemical compounds in HI. Then the mass defect filtering (MDF) approach, which was developed based on the previously published articles, was utilized to rapidly screen the astragalosides from the obtained LC-TOF-MS data. Each screened astragaloside was confirmed by the presence of no less than 2 quasi-molecular ions. All the screened astragalosides were then tentatively assigned according to the parent ion and daughter ion information. Finally, a total of 62 astragalosides were screened and characterized from the HI samples, including 15 new detected ones. The identification results indicated that acetylation, hydrogenation, dehydrogenation, methoxylation and hydration might be the major conversion reactions involved in the formation of the astragalosides. The LC-TOF-MS-based MDF approach was proved to be a feasible and efficient tool to screen the chemical constituents in complex matrices such as herbal medicines.


Assuntos
Medicamentos de Ervas Chinesas/química , Saponinas/análise , Astragalus propinquus , Cromatografia Líquida , Plantas Medicinais/química , Espectrometria de Massas em Tandem
18.
Zhongguo Zhong Yao Za Zhi ; 41(4): 748-754, 2016 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-28871705

RESUMO

It is necessary to investigate the influence of the rationality of clinical drug use on the benefit and risk factors of traditional Chinese medicine injections. The retrospective survey was based on the medical records and information of 4 950 patients who used Danhong injection in the HIS database of the first affiliated hospital of Nanjing University of Chinese Medicine from 2013 to 2014. The basic statistical methods and associated rules analysis were utilized to analyze the HIS information of these patients, including the basic information, the diagnosis, the department, the dosage, the usage of medication, the drug combination and the adverse reactions. And the rationality analysis of the clinical application of Danhong injection was carried out to investigate relevant factors of the adverse reactions. The results showed that most cases came from the department of cardiology (51.95%) and encephalopathy center (20.67%). In the statistical period, the patients aged above 40 years old accounted for 96.65%. And the two western medicine diagnosis items with the highest confidence level were coronary heart disease and angina pectoris (97.15%), while the three items were coronary heart disease, angina pectoris and hypertension (97.02%). The irrational indications were mainly hypertension (12.93%) and diabetes (4.55%). All of them were diagnosed as blood stasis syndrome by the traditional Chinese medicine. About 98.93% of the single dosage was within the range stipulated on package insert, the duration mainly ranged between 1 and 21 days, and 97.64% of the menstrua contained 0.9% NS and 5% GS. According to the medication records,99.26% were the use of combined drugs, with 8.41 drugs on average. Antiplatelet drugs (72.04%) were the most frequently combined with western medicine, followed by the cholesterol-regulating drugs (64.86%) and the cerebrovascular drugs (60.26%). When used in the combination with antibiotics for the infection, cephalosporin antibiotics were the most frequently applied (8.81%). When used with traditional Chinese medicines, traditional Chinese medicines for activating blood circulation and removing blood stasis or monomer traditional Chinese medicine injections (28.93%) were the dominance, in which Gastrodin injection was the most frequently applied (16.23%). And 12 cases of adverse reactions were reported, with the ADR rate of 0.24%. The indications, solvent compatibility and irrational drug combination may be the potential risk factors for ADRs induced by Danhong injection. Further experiments are required to evaluate the benefits and risks in these three aspects.


Assuntos
Doença das Coronárias/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Hipertensão/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Hospitais Universitários/estatística & dados numéricos , Humanos , Lactente , Injeções , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
19.
Heart Vessels ; 27(4): 411-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22038107

RESUMO

Previous studies have established that Mycobacterium tuberculosis heat shock protein 65 (mHSP65) plays an important role in immune-associated diseases as an autoimmune factor. Some overlapping epitopes of mHSP65 may serve as initiators of both atherosclerosis and other autoimmune-associated diseases. In the present study, atherosclerosis was significantly enhanced in high-cholesterol diet (HCD)-fed New Zealand white rabbits immunized with mHSP65(91-105) compared with PBS-immunized or BSA-immunized rabbits. Immunizing wild-type C57BL/6J mice with mHSP65(91-105) induced the aortic endothelial injury. Although western blot demonstrated that specific antibodies against mHSP65(91-105) can cross-react with recombinant human heat shock protein 60, specific antibodies against mHSP65(91-105) had no direct effects on HUVECs in vitro. Laser scanning confocal microscopy showed that mHSP65(91-105) localized in the cytoplasm of HUVECs, even when HUVECs were heat shocked at 42°C. mHSP65(91-105)-specific splenic cells secreted more IFN-γ than controls. Also, adoptive transfer of mHSP65(91-105)-specific splenic cells can accelerate atherosclerosis in ldlr( -/- ) mice. We can conclude that the (auto)immune response to mHSP65(91-105) accelerates atherosclerosis in animal models, and that the response of Th1 plays an important role in this progress.


Assuntos
Doenças da Aorta/etiologia , Aterosclerose/etiologia , Proteínas de Bactérias/imunologia , Chaperonina 60/imunologia , Epitopos , Mycobacterium tuberculosis/imunologia , Fragmentos de Peptídeos/imunologia , Receptores de LDL/deficiência , Transferência Adotiva , Animais , Doenças da Aorta/genética , Doenças da Aorta/imunologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Western Blotting , Células Cultivadas , Colesterol na Dieta , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/imunologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipercolesterolemia/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Coelhos , Receptores de LDL/genética , Linfócitos T/imunologia , Linfócitos T/transplante , Fatores de Tempo
20.
J Chromatogr Sci ; 48(5): 417-20, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20515539

RESUMO

Capillary electrophoresis (CE) is employed for the first time in a fingerprint analysis of Marsdenia tenacissima. Because the CE method is a new approach to fingerprinting, it is necessary to compare it to the conventional one: high-performance liquid chromatography (HPLC). In HPLC separation, 15 components are separated in 55 min, while in CE separation, 10 stable components are separated by 200 mM boric acid (pH 8.0) containing 10% methanol within 12 min. CE shows better performance in the analysis of Marsdenia tenacissima, which makes its fingerprint in a much lower analysis time than with HPLC. It is further proven that CE can be a feasible and cost-effective method for the development of the fingerprint of Marsdenia tenacissima.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Eletroforese Capilar/métodos , Marsdenia/química , Extratos Vegetais/análise , Eletroforese Capilar/economia
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