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1.
Lipids Health Dis ; 23(1): 201, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38937844

RESUMO

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a prevalent chronic liver condition. However, the potential therapeutic benefits and underlying mechanism of nicotinate-curcumin (NC) in the treatment of NASH remain uncertain. METHODS: A rat model of NASH induced by a high-fat and high-fructose diet was treated with nicotinate-curcumin (NC, 20, 40 mg·kg- 1), curcumin (Cur, 40 mg·kg- 1) and metformin (Met, 50 mg·kg- 1) for a duration of 4 weeks. The interaction between NASH, Cur and Aldo-Keto reductase family 1 member B10 (AKR1B10) was filter and analyzed using network pharmacology. The interaction of Cur, NC and AKR1B10 was analyzed using molecular docking techniques, and the binding energy of Cur and NC with AKR1B10 was compared. HepG2 cells were induced by Ox-LDL (25 µg·ml- 1, 24 h) in high glucose medium. NC (20µM, 40µM), Cur (40µM) Met (150µM) and epalrestat (Epa, 75µM) were administered individually. The activities of ALT, AST, ALP and the levels of LDL, HDL, TG, TC and FFA in serum were quantified using a chemiluminescence assay. Based on the changes in the above indicators, score according to NAS standards. The activities of Acetyl-CoA and Malonyl-CoA were measured using an ELISA assay. And the expression and cellular localization of AKR1B10 and Acetyl-CoA carboxylase (ACCα) in HepG2 cells were detected by Western blotting and immunofluorescence. RESULTS: The results of the animal experiments demonstrated that NASH rat model induced by a high-fat and high-fructose diet exhibited pronounced dysfunction in liver function and lipid metabolism. Additionally, there was a significant increase in serum levels of FFA and TG, as well as elevated expression of AKR1B10 and ACCα, and heightened activity of Acetyl-CoA and Malonyl-CoA in liver tissue. The administration of NC showed to enhance liver function in rats with NASH, leading to reductions in ALT, AST and ALP levels, and decrease in blood lipid and significant inhibition of FFA and TG synthesis in the liver. Network pharmacological analysis identified AKR1B10 and ACCα as potential targets for NASH treatment. Molecular docking studies revealed that both Cur and NC are capable of binding to AKR1B10, with NC exhibiting a stronger binding energy to AKR1B10. Western blot analysis demonstrated an upregulation in the expression of AKR1B10 and ACCα in the liver tissue of NASH rats, accompanied by elevated Acetyl-CoA and Malonyl-CoA activity, and increased levels of FFA and TG. The results of the HepG2 cell experiments induced by Ox-LDL suggest that NC significantly inhibited the expression and co-localization of AKR1B10 and ACCα, while also reduced levels of TC and LDL-C and increased level of HDL-C. These effects are accompanied by a decrease in the activities of ACCα and Malonyl-CoA, and levels of FFA and TG. Furthermore, the impact of NC appears to be more pronounced compared to Cur. CONCLUSION: NC could effectively treat NASH and improve liver function and lipid metabolism disorder. The mechanism of NC is related to the inhibition of AKR1B10/ACCα pathway and FFA/TG synthesis of liver.


Assuntos
Aldo-Ceto Redutases , Curcumina , Hepatopatia Gordurosa não Alcoólica , Triglicerídeos , Curcumina/farmacologia , Curcumina/análogos & derivados , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Humanos , Células Hep G2 , Aldo-Ceto Redutases/metabolismo , Ratos , Masculino , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Acetil-CoA Carboxilase/metabolismo , Aldeído Redutase/metabolismo , Aldeído Redutase/antagonistas & inibidores , Dieta Hiperlipídica/efeitos adversos , Simulação de Acoplamento Molecular , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metformina/farmacologia , Ratos Sprague-Dawley , Modelos Animais de Doenças , Rodanina/análogos & derivados , Tiazolidinas
2.
Int J Mol Sci ; 24(20)2023 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-37894840

RESUMO

Endothelial cells (ECs) form the inner linings of blood vessels, and are directly exposed to endogenous hazard signals and metabolites in the circulatory system. The senescence and death of ECs are not only adverse outcomes, but also causal contributors to endothelial dysfunction, an early risk marker of atherosclerosis. The pathophysiological process of EC senescence involves both structural and functional changes and has been linked to various factors, including oxidative stress, dysregulated cell cycle, hyperuricemia, vascular inflammation, and aberrant metabolite sensing and signaling. Multiple forms of EC death have been documented in atherosclerosis, including autophagic cell death, apoptosis, pyroptosis, NETosis, necroptosis, and ferroptosis. Despite this, the molecular mechanisms underlying EC senescence or death in atherogenesis are not fully understood. To provide a comprehensive update on the subject, this review examines the historic and latest findings on the molecular mechanisms and functional alterations associated with EC senescence and death in different stages of atherosclerosis.


Assuntos
Aterosclerose , Células Endoteliais , Humanos , Células Endoteliais/metabolismo , Senescência Celular/fisiologia , Aterosclerose/metabolismo , Estresse Oxidativo , Transdução de Sinais
3.
Zhongguo Zhong Yao Za Zhi ; 48(10): 2781-2791, 2023 May.
Artigo em Zh | MEDLINE | ID: mdl-37282938

RESUMO

Rosae Radix et Rhizoma is a herbal medicine in a variety of famous Chinese patent medicines, while the quality standard for this medicine remains to be developed due to the insufficient research on the quality of Rosae Radix et Rhizoma from different sources. Therefore, this study comprehensively analyzed the components in Rosae Radix et Rhizoma of different sources from the aspects of extract, component category content, identification based on thin-lay chromatography, active component content determination, and fingerprint, so as to improve the quality control. The results showed that the content of chemical components varied in the samples of different sources, while there was little difference in the chemical composition among the samples. The content of components in the roots of Rosa laevigata was higher than that in the other two species, and the content of components in the roots was higher than that in the stems. The fingerprints of triterpenoids and non-triterpenoids were established, and the content of five main triterpenoids including multiflorin, rosamultin, myrianthic acid, rosolic acid, and tormentic acid in Rosae Radix et Rhizoma was determined. The results were consistent with those of major component categories. In conclusion, the quality of Rosae Radix et Rhizoma is associated with the plant species, producing area, and medicinal parts. The method established in this study lays a foundation for improving the quality standard of Rosae Radix et Rhizoma and provides data support for the rational use of the stem.


Assuntos
Medicamentos de Ervas Chinesas , Plantas Medicinais , Medicamentos de Ervas Chinesas/química , Rizoma/química , Raízes de Plantas/química , Controle de Qualidade
4.
J Cell Physiol ; 236(11): 7853-7873, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34018609

RESUMO

Epidemiological studies have shown that plasma HDL-C levels are closely related to the risk of prostate cancer, breast cancer, and other malignancies. As one of the key carriers of cholesterol regulation, high-density lipoprotein (HDL) plays an important role in tumorigenesis and cancer development through anti-inflammation, antioxidation, immune-modulation, and mediating cholesterol transportation in cancer cells and noncancer cells. In addition, the occurrence and progression of cancer are closely related to the alteration of the tumor microenvironment (TME). Cancer cells synthesize and secrete a variety of cytokines and other factors to promote the reprogramming of surrounding cells and shape the microenvironment suitable for cancer survival. By analyzing the effect of HDL on the infiltrating immune cells in the TME, as well as the relationship between HDL and tumor-associated angiogenesis, it is suggested that a moderate increase in the level of HDL in vivo with consequent improvement of the function of HDL in the TME and induction of intracellular cholesterol efflux may be a promising strategy for cancer therapy.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Mediadores da Inflamação/antagonistas & inibidores , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/uso terapêutico , Neoplasias/tratamento farmacológico , Neovascularização Patológica , Microambiente Tumoral , Animais , HDL-Colesterol/metabolismo , Humanos , Hipolipemiantes/uso terapêutico , Mediadores da Inflamação/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Recombinantes/uso terapêutico , Microambiente Tumoral/imunologia , Regulação para Cima
5.
Acta Pharmacol Sin ; 42(9): 1472-1485, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33303989

RESUMO

Celastrol is a triterpene derived from the traditional Chinese medicine Tripterygium wilfordii Hook f, which displays potential anticancer activity. In the present study, we investigated the anticancer effects of celastrol against clear cell renal cell carcinoma (ccRCC) and the underlying mechanisms. Using Cancer Genome Atlas (TCGA) database and genotype-tissue expression (GTEx) database we conducted a bioinformatics analysis, which showed that the mRNA levels of liver-X receptors α (LXRα) and ATP-binding cassette transporter A1 (ABCA1) in ccRCC tissues were significantly lower than those in adjacent normal tissues. This result was confirmed by immunoblotting analysis of 4 ccRCC clinical specimens, which showed that the protein expression of LXRα and ABCA1 was downregulated. Similar results were obtained in a panel of ccRCC cell lines (786-O, A498, SN12C, and OS-RC-2). In 786-O and SN12C cells, treatment with celastrol (0.25-2.0 µM) concentration-dependently inhibited the cell proliferation, migration, and invasion as well as the epithelial-mesenchymal transition (EMT) process. Furthermore, we demonstrated that celastrol inhibited the invasion of 786-O cells through reducing lipid accumulation; celastrol concentration-dependently promoted autophagy to reduce lipid storage. Moreover, we revealed that celastrol dramatically activated LXRα signaling, and degraded lipid droplets by inducing lipophagy in 786-O cells. Finally, celastrol promoted cholesterol efflux from 786-O cells via ABCA1. In high-fat diet-promoted ccRCC cell line 786-O xenograft model, administration of celastrol (0.25, 0.5, 1.0 mg·kg-1·d-1, for 4 weeks, i.p.) dose-dependently inhibited the tumor growth with upregulated LXRα and ABCA1 protein in tumor tissue. In conclusion, this study reveals that celastrol triggers lipophagy in ccRCC by activating LXRα, promotes ABCA1-mediated cholesterol efflux, suppresses EMT progress, and ultimately inhibits cell proliferation, migration, and invasion as well as tumor growth. Thus, our study provides evidence that celastrol can be used as a lipid metabolism-based anticancer therapeutic approach.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Autofagia/efeitos dos fármacos , Carcinoma de Células Renais/metabolismo , Receptores X do Fígado/metabolismo , Triterpenos Pentacíclicos/farmacologia , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos
6.
Pharmacology ; 106(1-2): 29-36, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32694250

RESUMO

INTRODUCTION: Homeostasis of cholesterol is crucial for cellular function, and dysregulated cholesterol biosynthesis is a metabolic event that can lead to hepatic and cardiovascular abnormalities. OBJECTIVE: The aim of this study was to investigate the effects and mechanisms of domain-associated protein (Daxx) and androgen receptor (AR) on intracellular cholesterol synthesis. METHODS: HepG2 cells were transfected with pCDNA3.1(+)/Daxx plasmid or treated with testosterone propionate to observe the effects of Daxx and AR on intracellular cholesterol levels. Co-immunoprecipitation experiments were performed to identify the interaction between Daxx and AR and to explore the regulatory effects of this interaction on cholesterol synthesis. RESULTS: Our experiments showed that AR promoted cholesterol synthesis and accumulation by activating sterol-regulatory element-binding protein isoform 2. AR-induced cholesterol synthesis was inhibited by Daxx; however, the expression of AR was not affected. Further studies demonstrated the existence of direct binding between Daxx and AR and this interaction was required to suppress AR activity. CONCLUSIONS: The Daxx-mediated antagonism of AR depicts a more complete picture as to how Daxx regulates intracellular cholesterol level and provides a new target for treatment of atherosclerosis.


Assuntos
Colesterol/biossíntese , Proteínas Correpressoras/metabolismo , Chaperonas Moleculares/metabolismo , Receptores Androgênicos/metabolismo , Compostos Azo , Colesterol/análise , Cromatografia Líquida de Alta Pressão , Colorimetria , Células Hep G2 , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Imunoprecipitação , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
7.
Molecules ; 26(21)2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34771018

RESUMO

Aspirin and curcumin have been reported to be beneficial to anti-aging in a variety of biological models. Here, we synthesized a novel compound, curcumin acetylsalicylate (CA), by combining aspirin and curcumin. We characterized how CA affects the lifespan of Caenorhabditis elegans (C. elegans) worms. Our results demonstrated that CA extended the lifespan of worms in a dose-dependent manner and reached its highest anti-aging effect at the concentration of 20 µM. In addition, CA reduced the deposition of lipofuscin or "age pigment" without affecting the reproductivity of worms. CA also caused a rightward shift of C. elegans lifespan curves in the presence of paraquat-induced (5 mM) oxidative stress or 37 °C acute heat shock. Additionally, CA treatment decreased the reactive oxygen species (ROS) level in C. elegans and increased the expression of downstream genes superoxide dismutase (sod)-3, glutathione S-transferase (gst)-4, heat shock protein (hsp)-16.2, and catalase-1 (ctl-1). Notably, CA treatment resulted in nuclear translocation of the DAF-16 transcription factor, which is known to stimulate the expression of SOD-3, GST-4, HSP-16, and CTL-1. CA did not produce a longevity effect in daf-16 mutants. In sum, our data indicate that CA delayed the aging of C. elegans without affecting reproductivity, and this effect may be mediated by its activation of DAF-16 and subsequent expression of antioxidative genes, such as sod-3 and gst-4. Our study suggests that novel anti-aging drugs may be developed by combining two individual drugs.


Assuntos
Aspirina/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Curcumina/farmacologia , Longevidade/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Caenorhabditis elegans/metabolismo
8.
Zhongguo Zhong Yao Za Zhi ; 46(7): 1813-1821, 2021 Apr.
Artigo em Zh | MEDLINE | ID: mdl-33982486

RESUMO

Prunella vulgaris(PV) is an edible and traditional medicinal herb which has a wide range application in fighting inflammation and oxidative stress, and protecting liver. Now it has been used to treat various types of liver diseases and has significant clinical efficacy. This study aims to investigate the effects of PV on ethanol-induced oxidative stress injury in rats and its metabolic mechanism. The rats were divided into control group, model group, PV group, and VC group. The liver protection of PV was identified by measuring pharmacological indexes such as antioxidant and anti-inflammatory activity. The metabolic mechanism of long-term ethanol exposure and the metabolic regulation mechanism of PV treatment were studied by LS-MS metabonomics. The pharmacological investigation indicated that ethanol could significantly decrease the contents of SOD, GSH-Px, CAT and other antioxidant enzymes in liver and increase the content of MDA. At the same time, PV could significantly reduce the contents of inflammatory factors(TNF-α, IL-6 and IL-1ß) and liver function markers(ALT, AST, ALP) in serum. What's more, long-term ethanol exposure could significantly cause liver injury, while PV could protect liver. Metabolomics based on multiple statistical analyses showed that long-term ethanol exposure could cause significant metabolic disorder, and fatty acids, phospholipids, carnitines and sterols were the main biomarkers. Meanwhile, pathway analysis and enrichment analysis showed that the ß oxidation of branched fatty acids was the main influencing pathway. Also, PV could improve metabolic disorder of liver injury induced by ethanol, and amino acids, fatty acids, and phospholi-pids were the main biomarkers in PV treatment. Metabolic pathway analysis showed that PV mainly regulated metabolic disorder of ethanol-induced liver injury through phenylalanine, tyrosine and tryptophan biosynthetic pathways. This study could provide a new perspective on the hepatoprotective effect of natural medicines, such as PV.


Assuntos
Prunella , Animais , Antioxidantes/metabolismo , Etanol/toxicidade , Fígado/metabolismo , Metabolômica , Estresse Oxidativo , Ratos
9.
Zhongguo Zhong Yao Za Zhi ; 46(24): 6353-6365, 2021 Dec.
Artigo em Zh | MEDLINE | ID: mdl-34994127

RESUMO

In this paper, the newly isolated tannins were sorted after a review of the literature concerning tannins in recent 10 years, and their research progress was summarized in terms of extraction, isolation, pharmacological activity and metabolism. Hydrolysable tannins and condensed tannins are the main structural types. Modern research shows that tannins have many pharmacological effects, such as bacteriostasis, antioxidation, antitumor, antivirus and blood glucose reduction, and have broad development prospects. They are usually extracted by water, ethanol and acetone and isolated and purified by macroporous resin and gel column chromatography. The packings commonly adopted for the column chromatography mainly included Sephadex LH-20, Diaion HP-20, MCI-gel CHP-20 and Toyopearl HW-40. Modern analytical techniques such as nuclear magnetic resonance spectroscopy(NMR), fast atom bombardment mass spectrometry(FAB-MS) and circular dichroism(CD) are generally used for the structural identification of tannins. Howe-ver, their isolation, purification and structural identification are still challenging. It is necessary to use a variety of high-throughput screening methods to explore their pharmacological activities and to explore the material basis responsible for their functions through experiments in vivo.


Assuntos
Proantocianidinas , Taninos , China , Taninos Hidrolisáveis , Medicina Tradicional Chinesa
10.
J Membr Biol ; 253(2): 101-108, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32140737

RESUMO

As a member of the kinesin-3 family, kinesin family member 16B (KIF16B) has a characteristic PhoX homology (PX) domain that binds to membranes containing phosphatidylinositol-3-phosphate (PI(3)P) and moves along microtubule filaments to the plus end via a process regulated by coiled coils in the stalk region in various cell types. The physiological function of KIF16B supports the transport of intracellular cargo and the formation of endosomal tubules. Ras-related protein (Rab) coordinates many steps of membrane transport and are involved in the regulation of KIF16B-mediated vesicle trafficking. Data obtained from clinical research suggest that KIF16B has a potential effect on the disease processes in intellectual disability, abnormal lipid metabolism, and tumor brain metastasis. In this review, we summarize recent advances in the structural and physiological characteristics of KIF16B as well as diseases associated with KIF16B disorders, and speculating its role as a potential adaptor for intracellular cholesterol trafficking.


Assuntos
Cinesinas/química , Cinesinas/metabolismo , Microtúbulos/metabolismo , Domínios e Motivos de Interação entre Proteínas , Animais , Proteínas de Transporte/metabolismo , Membrana Celular/metabolismo , Suscetibilidade a Doenças , Humanos , Espaço Intracelular/metabolismo , Ligação Proteica , Transporte Proteico , Relação Estrutura-Atividade
11.
Hepatology ; 69(6): 2489-2501, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30672601

RESUMO

Aldo-keto reductase family 1 member B10 (AKR1B10) is a secretory protein overexpressed in hepatocellular carcinoma (HCC). We aimed to evaluate AKR1B10 as a serum marker for detection of HCC. Herein, we conducted a cohort study that consecutively enrolled 1,244 participants from three independent hospitals, including HCC, healthy controls (HCs), benign liver tumors (BLTs), chronic hepatitis B (CHB), and liver cirrhosis (LC). Serum AKR1B10 was tested by time-resolved fluorescent assays. Data were plotted for receiver operating characteristic (ROC) curve analyses. Alpha-fetoprotein (AFP) was analyzed for comparison. An exploratory discovery cohort demonstrated that serum AKR1B10 increased in patients with HCC (1,567.3 ± 292.6 pg/mL; n = 69) compared with HCs (85.7 ± 10.9 pg/mL; n = 66; P < 0.0001). A training cohort of 519 participants yielded an optimal diagnostic cutoff of serum AKR1B10 at 267.9 pg/mL. When ROC curve was plotted for HCC versus all controls (HC + BLT + CHB + LC), serum AKR1B10 had diagnostic parameters of the area under the curve (AUC) 0.896, sensitivity 72.7%, and specificity 95.7%, which were better than AFP with AUC 0.816, sensitivity 65.1%, and specificity 88.9%. Impressively, AKR1B10 showed promising diagnostic potential in early-stage HCC and AFP-negative HCC. Combination of AKR1B10 with AFP increased diagnostic accuracy for HCC compared with AKR1B10 or AFP alone. A validation cohort of 522 participants confirmed these findings. An independent cohort of 68 patients with HCC who were followed up showed that serum AKR1B10 dramatically decreased 1 day after operation and was nearly back to normal 3 days after operation. Conclusion: AKR1B10 is a potent serum marker for detection of HCC and early-stage HCC, with better diagnostic performance than AFP.


Assuntos
Membro B10 da Família 1 de alfa-Ceto Redutase/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Adulto , Biomarcadores Tumorais , Biópsia por Agulha , Carcinoma Hepatocelular/diagnóstico , Estudos de Casos e Controles , China , Feminino , Hospitais Universitários , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Curva ROC , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
12.
Cell Commun Signal ; 18(1): 119, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32746850

RESUMO

Exosomes have been considered as novel and potent vehicles of intercellular communication, instead of "cell dust". Exosomes are consistent with anucleate cells, and organelles with lipid bilayer consisting of the proteins and abundant lipid, enhancing their "rigidity" and "flexibility". Neighboring cells or distant cells are capable of exchanging genetic or metabolic information via exosomes binding to recipient cell and releasing bioactive molecules, such as lipids, proteins, and nucleic acids. Of note, exosomes exert the remarkable effects on lipid metabolism, including the synthesis, transportation and degradation of the lipid. The disorder of lipid metabolism mediated by exosomes leads to the occurrence and progression of diseases, such as atherosclerosis, cancer, non-alcoholic fatty liver disease (NAFLD), obesity and Alzheimer's diseases and so on. More importantly, lipid metabolism can also affect the production and secretion of exosomes, as well as interactions with the recipient cells. Therefore, exosomes may be applied as effective targets for diagnosis and treatment of diseases. Video abstract.


Assuntos
Exossomos/metabolismo , Metabolismo dos Lipídeos , Animais , Humanos , Lipídeos/biossíntese , Modelos Biológicos
13.
J Cell Physiol ; 234(12): 21436-21449, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31054175

RESUMO

Obesity is well-known as the second factor for tumorigenesis after smoking and is bound up with the malignant progression of several kinds of cancers, including esophageal cancer, liver cancer, colorectal cancer, kidney cancer, and ovarian cancer. The increased morbidity and mortality of obesity-related cancer are mostly attributed to dysfunctional adipose tissue. The possible mechanisms connecting dysfunctional adipose tissue to high cancer risk mainly focus on chronic inflammation, obesity-related microenvironment, adipokine secretion disorder, and browning of adipose tissue, and so forth. The stromal vascular cells in adipose tissue trigger chronic inflammation through secreting inflammatory factors and promote cancer cell proliferation. Hypertrophic adipose tissues lead to metabolic disorders of adipocytes, such as abnormal levels of adipokines that mediate cancer progression and metastasis. Cancer patients often show adipose tissue browning and cancerous cachexia in an advanced stage, which lead to unsatisfied chemotherapy effect and poor prognosis. However, increasing evidence has shown that adipose tissue may display quite opposite effects in cancer development. Therefore, the interaction between cancers and adipose tissue exert a vital role in mediates adipose tissue dysfunction and further leads to cancer progression. In conclusion, targeting the dysfunction of adipose tissue provides a promising strategy for cancer prevention and therapy.


Assuntos
Tecido Adiposo/patologia , Carcinogênese/patologia , Neoplasias/patologia , Animais , Progressão da Doença , Humanos , Inflamação/patologia
14.
Biochem Biophys Res Commun ; 514(1): 92-97, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31023527

RESUMO

Hepatic autophagy plays an important role in lipid metabolism, especially in nonalcoholic fatty liver disease. The relationship between Oleate acid and autophagy is not yet clear. In this work, using mouse epithelial cell hepa1c1c7, we investigated the role of Oleate acid on autophagy and explored its potential mechanisms. The exposure of hepatic cells to Oleate acid resulted in a significant reduction of LC3 accumulation together with enhancement of p62 protein expression and the mRNA levels of ATG7 and BECN1 were reduced as well. Mechanistically, the inhibitory effects of Oleate acid on rapamycin-induced autophagy were completely blocked by treatment with dominant negative p38α and p38 inhibitor SB203580. Furthermore, ATF-2, downstream of p38, was activated by Oleate treatment. Oleate treatment also inhibited the ULK1 promoter and decreased the ULK1 mRNA level. Our data therefore suggest that Oleate activated the ATF-2 via p38 kinase which inhibited the ULK1 via binding to ULK1 promoter, and eventually the rapamycin-induced autophagy was suppressed.


Assuntos
Autofagia , Hepatócitos/citologia , Ácido Oleico/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Linhagem Celular , Regulação para Baixo , Hepatócitos/metabolismo , Fígado/citologia , Fígado/metabolismo , Camundongos , Regiões Promotoras Genéticas
15.
Pharmacology ; 103(5-6): 282-290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30808828

RESUMO

BACKGROUND/AIMS: Hypoxia can induce cell injury in cardiomyocytes and further lead to cardiovascular diseases. Genistein (Gen), the predominant isoflavone found in soy products, has shown protective effects on cardiovascular system. The aim of the present study was to investigate the cardioprotective effect of Gen against chemical hypoxia-induced injury. METHODS: Cobalt chloride (CoCl2) was administrated to trigger chemical hypoxia in H9c2 cardiomyocytes. Cell proliferation was detected by using MTT assay. The expression level of hypoxia-related proteins (hypoxia-inducible factor [HIF]-1α and Notch-1) and apoptosis-related proteins (B cell lymphoma [Bcl]-2, Bax, and caspase-3) were evaluated by Western blot analysis. RESULTS: In response to hypoxia, cell viability was reduced dramatically, whereas the expression of HIF-1α was upregulated. Hypoxia also induced cardiomyocytes apoptosis by reducing the ratio of Bcl-2/Bax and increasing expression of caspase-3. Interestingly, Gen attenuated CoCl2-induced cell death and suppressed HIF-1α expression, as well as upregulated the expression of Notch-1. Furthermore, Gen could antagonize CoCl2-induced apoptosis through upregulating Bcl-2/Bax ratio and inhibiting caspase-3 expression. CONCLUSIONS: Gen prevents chemical hypoxia-induced cell apoptosis through inhibition of the mitochondrial apoptotic pathway, exerting protective effects on H9c2 cardiomyocytes.


Assuntos
Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Genisteína/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Animais , Western Blotting , Cardiotônicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cobalto/toxicidade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Miócitos Cardíacos/patologia , Ratos , Regulação para Cima/efeitos dos fármacos
16.
Molecules ; 24(22)2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31752145

RESUMO

Curcumin is an anticancer agent, but adverse effects and low bioavailability are its main drawbacks, which drives efforts in chemical modifications of curcumin. This study evaluated antiproliferative activity and cancer cell selectivity of a curcumin derivative, curcumin nicotinate (CN), in which two niacin molecules were introduced. Our data showed that CN effectively inhibited proliferation and clonogenic growth of colon (HCT116), breast (MCF-7) and nasopharyngeal (CNE2, 5-8F and 6-10B) cancer cells with IC50 at 27.7 µM, 73.4 µM, 64.7 µM, 46.3 µM, and 31.2 µM, respectively. In cancer cells, CN induced apoptosis and cell cycle arrest at G2/M phase through a p53-mediated mechanism, where p53 was activated, p21 and pro-apoptotic proteins Bid and Bak were upregulated, and PARP was cleaved. In non-transformed human mammary epithelial cells MCF10A, CN at 50 µM had no cytotoxicity and p53 was not activated, but curcumin at 12.5 µM activated p53 and p21 and inhibited MCF10A cell growth. These data suggest that CN inhibits cell growth and proliferation through p53-mediated apoptosis and cell cycle arrest with cancer cell selectivity.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Curcumina/análogos & derivados , Niacina/análogos & derivados , Proteína Supressora de Tumor p53/metabolismo , Proliferação de Células/efeitos dos fármacos , Curcumina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Células MCF-7 , Niacina/farmacologia
17.
Molecules ; 24(9)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035334

RESUMO

As part of our continual efforts to exploit 'Tujia Ethnomedicine' for their pharmacophoric functionalities, we herein investigated Kadsura heteroclita collected from a deep Wulin mountain area in northern Hunan province. The current study resulted in the isolation of three new sesquiterpenes: 6α,9α,15-trihydroxycadinan-4-en-3-one (1), (+)-3,11,12-trihydroxycalamenene (2), (-)-3,10,11,12-tetrahydroxy-calamenene (3), along with four known sesquiterpenes (4-7), and a cytochalasin H (8). Their chemical structures were elucidated by 1D-, and 2D-NMR spectroscopy, and HRESI-MS, CD spectrometry. The antioxidant, and cytotoxic activities of the compounds were evaluated. Compound 8 exhibited a strong antioxidant effect with an IC50 value of 3.67 µM on isolated human polymorphonuclear cells or neutrophils.


Assuntos
Kadsura/química , Extratos Vegetais/química , Caules de Planta/química , Sesquiterpenos/química , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Sesquiterpenos Policíclicos , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia
18.
Sheng Li Xue Bao ; 71(2): 235-247, 2019 Apr 25.
Artigo em Zh | MEDLINE | ID: mdl-31008483

RESUMO

Vascular remodeling is a significant pathological characteristic of hypertension, which is regulated by complex regulatory networks. The vascular remodeling may be adaptive initially, however it becomes maladaptive and decompensation eventually and further compromises target organ function, leading to hypertensive cardiovascular complications. This review focuses on the role and mechanisms of vascular remodeling in the pathogenesis and progression of hypertension and its complications. Moreover, the strategies of syndrome differentiation of traditional Chinese medicine application provide clinical and theoretical evidences for hypertensive vascular remodeling therapy. A better understanding of underlying signaling pathways, therapeutic targets in vascular remodeling, as well as screening of active ingredients from traditional Chinese medicine may be able to provide some effective approaches for vascular protection in hypertensive diseases.


Assuntos
Hipertensão/fisiopatologia , Hipertensão/terapia , Medicina Tradicional Chinesa , Remodelação Vascular , Humanos , Transdução de Sinais
19.
Zhongguo Zhong Yao Za Zhi ; 44(3): 509-517, 2019 Feb.
Artigo em Zh | MEDLINE | ID: mdl-30989916

RESUMO

Idiosyncratic hepatotoxicity of Polygonum multiflorum has attracted a great attention in the world. The most toxic part of idiosyncratic hepatotoxicity was screened by MTT assay and flow cytometry, which was the 50% ethanol elute by macroporous adsorptive resins from alcohol-extraction of P. multiflorum. The fingerprints were collected by HPLC from 50% ethanol elute of crude and processed P. multiflorum from different habitats, then 14 common peaks were determined. Spectrum-toxicity relationship was analyzed by rough set theory(RST). Two main chemical components were predicted for idiosyncratic hepatotoxicity, in which TSG was the greater contributor. Idiosyncratic hepatotoxicity of TSG was tested in vitro, and the results indicated that TSG was the most important constituent contributed to idiosyncratic hepatotoxicity of P. multiflorum. The study showed the discovery of the main chemical components for idiosyncratic hepatotoxicity, and RST was effective for analyzing the spectrum-toxicity relationship, which could be a new method used in the effective/toxic constituents field of traditional Chinese medicine.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas/efeitos adversos , Fallopia multiflora/química , Compostos Fitoquímicos/efeitos adversos , Cromatografia Líquida de Alta Pressão , Humanos , Medicina Tradicional Chinesa
20.
Mol Carcinog ; 57(10): 1300-1310, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29846015

RESUMO

Aldo-keto reductase 1B10 (AKR1B10) is upregulated in breast cancer and promotes tumor growth and metastasis. However, little is known of the molecular mechanisms of action. Herein we report that AKR1B10 activates lipid second messengers to stimulate cell proliferation. Our data showed that ectopic expression of AKR1B10 in breast cancer cells MCF-7 promoted lipogenesis and enhanced levels of lipid second messengers, including phosphatidylinositol bisphosphate (PIP2), diacylglycerol (DAG), and inositol triphosphate (IP3). In contrast, silencing of AKR1B10 in breast cancer cells BT-20 and colon cancer cells HCT-8 led to decrease of these lipid messengers. Qualitative analyses by liquid chromatography-mass spectrum (LC-MS) revealed that AKR1B10 regulated the cellular levels of total DAG and majority of subspecies. This in turn modulated the phosphorylation of protein kinase C (PKC) isoforms PKCδ (Thr505), PKCµ (Ser744/748), and PKCα/ßII (Thr638/641) and activity of the PKC-mediated c-Raf/MEK/ERK signaling cascade. A pan inhibitor of PKC (Go6983) blocked ERK1/2 activation by AKR1B10. In these cells, phospho-p90RSK, phospho-MSK, and Cyclin D1 expression was increased by AKR1B10, and pharmacological inhibition of the ERK signaling cascade with MEK1/2 inhibitors U0126 and PD98059 eradicated induction of phospho-p90RSK, phospho-MSK, and Cyclin D1. In breast cancer cells, AKR1B10 promoted the clonogenic growth and proliferation of breast cancer cells in two-dimension (2D) and three-dimension (3D) cultures and tumor growth in immunodeficient female nude mice through activation of the PKC/ERK pathway. These data suggest that AKR1B10 stimulates breast cancer cell growth and proliferation through activation of DAG-mediated PKC/ERK signaling pathway.


Assuntos
Membro B10 da Família 1 de alfa-Ceto Redutase/metabolismo , Neoplasias da Mama/metabolismo , Diglicerídeos/metabolismo , Sistemas do Segundo Mensageiro , Membro B10 da Família 1 de alfa-Ceto Redutase/genética , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Lipogênese , Sistema de Sinalização das MAP Quinases , Células MCF-7 , Camundongos Nus , Proteína Quinase C/metabolismo , Transplante Heterólogo , Carga Tumoral
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