RESUMO
Doxorubicin (DOX), a chemotherapy drug widely recognized for its efficacy in cancer treatment, unfortunately, has significant nephrotoxic effects leading to kidney damage. This study explores the nephroprotective potential of Phosphocreatine (PCr) in rats, specifically examining its influence on Nrf2 (Nuclear factor erythroid 2-related factor 2) and PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) pathways, its role in apoptosis inhibition, and effectiveness in preserving mitochondrial function. The research employed in vivo experiments in rats, focusing on PCr's capacity to protect renal function against doxorubicin-induced damage. The study entailed evaluating Nrf2 and PGC-1α pathway activation, apoptosis rates, and mitochondrial health in renal tissues. A significant aspect of this research was the use of high-resolution respirometry (HRR) to assess the function of isolated kidney mitochondria, providing in-depth insights into mitochondrial bioenergetics and respiratory efficiency under the influence of PCr and doxorubicin. Results demonstrated that PCr treatment significantly enhanced the activation of Nrf2 and PGC-1α pathways, reduced apoptosis, and preserved mitochondrial structure in doxorubicin-affected kidneys. Observations included upregulated expression of Nrf2 and PGC-1α target genes, stabilization of mitochondrial membranes, and a notable improvement in cellular antioxidant defense, evidenced by the activities of enzymes like superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) This study positions phosphocreatine as a promising agent in mitigating doxorubicin-induced kidney damage in rats. The findings, particularly the insights from HRR on isolated kidney mitochondria, highlight PCr's potential in enhancing mitochondrial function and reducing nephrotoxic side effects of chemotherapy. These encouraging results pave the way for further research into PCr's applications in cancer treatment, aiming to improve patient outcomes by managing chemotherapy-related renal injuries.
Assuntos
Apoptose , Doxorrubicina , Rim , Mitocôndrias , Fator 2 Relacionado a NF-E2 , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fosfocreatina , Doxorrubicina/toxicidade , Animais , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Apoptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Masculino , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fosfocreatina/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/tratamento farmacológico , Nefropatias/patologiaRESUMO
Diabetic retinopathy (DR) stands as a prevalent complication of diabetes mellitus, causing damage to the delicate retinal capillaries and potentially leading to visual impairment. While the exact underlying cause of DR remains elusive, compelling research suggests that mitochondrial energy deficiency and the excessive generation of reactive oxygen species (ROS) play pivotal roles in its pathogenesis. Recognizing that controlling hyperglycemia alone fails to reverse the defects in retinal mitochondria induced by diabetes, current strategies seek to restore mitochondrial function as a means of safeguarding against DR. To address this pressing issue, a comprehensive study was undertaken to explore the potential of phosphocreatine (PCr) in bolstering mitochondrial bioenergetics and providing protection against DR via modulation of the JAK2/STAT3 signaling pathway. Employing rat mitochondria and RGC-5 cells, the investigation meticulously assessed the impact of PCr on ROS production, mitochondrial membrane potential, as well as the expression of crucial apoptotic and JAK2/STAT3 signaling pathway proteins, utilizing cutting-edge techniques such as high-resolution respirometry and western blotting. The remarkable outcomes revealed that PCr exerts a profound protective influence against DR by enhancing mitochondrial function and alleviating diabetes-associated symptoms and biochemical markers. Notably, PCr administration resulted in an upregulation of antiapoptotic proteins, concomitant with a downregulation of proapoptotic proteins and the JAK2/STAT3 signaling pathway. These significant findings firmly establish PCr as a potential therapeutic avenue for combating diabetic retinopathy. By augmenting mitochondrial function and exerting antiapoptotic effects via the JAK2/STAT3 signaling pathway, PCr demonstrates promising efficacy both in vivo and in vitro, particularly in counteracting the oxidative stress engendered by hyperglycemia. In summary, our study sheds light on the potential of PCr as an innovative therapeutic strategy for diabetic retinopathy. By bolstering mitochondrial function and exerting protective effects via the modulation of the JAK2/STAT3 signaling pathway, PCr holds immense promise in ameliorating the impact of DR in the face of oxidative stress induced by hyperglycemia.
Assuntos
Diabetes Mellitus , Retinopatia Diabética , Hiperglicemia , Doenças Mitocondriais , Animais , Ratos , Retinopatia Diabética/tratamento farmacológico , Fosfocreatina/farmacologia , Fosfocreatina/uso terapêutico , Espécies Reativas de Oxigênio , Apoptose , Hiperglicemia/tratamento farmacológico , Transdução de SinaisRESUMO
Oleanolic acid (3ß-hydroxyolean-12-en-28-oic acid, OA) is a kind of pentacyclic triterpene, which widely distributes in nature. OA possesses a powerful anti-cancer effect; however, its low solubility limits its bioavailability and application. In this study, a new OA derivative, K73-03, was used to determine its effect on liver cancer cells and detailed molecular mechanisms. Here, we show that K73-03 may lead to the disorder of mitochondria in HepG2 cells, leading to excessive ROS production and apoptosis in cells. Meanwhile, K73-03 could induce cell apoptosis by inhibiting JAK2/STAT3 pathway and NF-κB/P65 pathway. Collectively, this study may provide a preliminary basis for further cancer treatment of hepatocellular carcinoma.
RESUMO
Emodin is a natural compound found in several traditional Chinese medicines, including Rheum palmatum and Polygonum cuspidatum. Recent studies have shown that emodin exhibits potent anticancer effects against a variety of cancer types, including liver, breast, lung, and colon cancer. Emodin's anticancer effects are mediated through several mechanisms, including inhibition of cell proliferation, induction of apoptosis, and suppression of tumor angiogenesis and metastasis. In this review, we provide an overview of recent research progress and new perspectives on emodin's anticancer effect. We summarize the current understanding of the molecular mechanisms underlying emodin's anticancer activity, including its effects on signaling pathways such as the PI3K/Akt, MAPK, and NF-[Formula: see text]B pathways. We also discuss the potential of emodin as a therapeutic agent for cancer treatment, including its use in combination with conventional chemotherapeutic drugs and as a sensitizer for radiotherapy. Furthermore, we highlight recent advances in the development of emodin derivatives and their potential as novel anticancer agents. Finally, we discuss the challenges and opportunities for the translation of emodin's anticancer properties into clinical applications, including the need for further preclinical and clinical studies to evaluate its safety and efficacy. In conclusion, emodin represents a promising natural compound with potent anticancer properties, and its potential as a therapeutic agent for cancer treatment warrants further investigation. This review provides a comprehensive overview of the current research progress and new perspectives on emodin's anticancer effects, which may facilitate the development of novel therapeutic strategies for cancer treatment.
RESUMO
Diabetes mellitus (DM) is a complex disease with alarming worldwide health implications and high mortality rates, largely due to its complications such as cardiovascular disease, nephropathy, neuropathy, and retinopathy. Recent research has shown that procyanidins (PC), a type of flavonoid, have strong antioxidant and free radical elimination effects, and may be useful in improving glucose metabolism, enhancing pancreatic islet cell activity, and decreasing the prevalence of DM complications. This review article presents a systematic search for peer-reviewed articles on the use of PC in the treatment of DM, without any language restrictions. The article also discusses the potential for PC to sensitise DM medications and improve their efficacy. Recent in vivo and in vitro studies have demonstrated promising results in improving the biological activity and bioavailability of PC for the treatment of DM. The article concludes by highlighting the potential for novel materials and targeted drug delivery methods to enhance the pharmacokinetics and bioactivity of PC, leading to the creation of safer and more effective anti-DM medications in the future.
Assuntos
Complicações do Diabetes , Diabetes Mellitus Tipo 2 , Proantocianidinas , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proantocianidinas/farmacologia , Proantocianidinas/uso terapêutico , Cicatrização , Complicações do Diabetes/complicações , GlucoseRESUMO
Background Cancer remains a critical global health challenge and a leading cause of mortality. Flavonoids found in fruits and vegetables have gained attention for their potential anti-cancer properties. Fisetin, abundantly present in strawberries, apples, onions, and other plant sources, has emerged as a promising candidate for cancer prevention. Epidemiological studies linking a diet rich in these foods to lower cancer risk have sparked extensive research on fisetin's efficacy. Objective This review aims to comprehensively explore the molecular mechanisms of fisetin's anticancer properties and investigate its potential synergistic effects with other anticancer drugs. Furthermore, the review examines the therapeutic and preventive effects of fisetin against various cancers. Methods A systematic analysis of the available scientific literature was conducted, including research articles, clinical trials, and review papers related to fisetin's anticancer properties. Reputable databases were searched, and selected studies were critically evaluated to extract essential information on fisetin's mechanisms of action and its interactions with other anticancer drugs. Results Preclinical trials have demonstrated that fisetin inhibits cancer cell growth through mechanisms such as cell cycle alteration, induction of apoptosis, and activation of the autophagy signaling pathway. Additionally, fisetin reduces reactive oxygen species levels, contributing to its overall anticancer potential. Investigation of its synergistic effects with other anticancer drugs suggests potential for combination therapies. Conclusion Fisetin, a bioactive flavonoid abundant in fruits and vegetables, exhibits promising anticancer properties through multiple mechanisms of action. Preclinical trials provide a foundation for further exploration in human clinical trials. Understanding fisetin's molecular mechanisms is vital for developing novel, safe, and effective cancer prevention and treatment strategies. The potential synergy with other anticancer drugs opens new avenues for combination therapies, enhancing cancer management approaches and global health outcomes.
RESUMO
Phosphocreatine (PCr) has been shown to have a cardio-protective effect during cardiopulmonary resuscitation (CPR). However, little is known about its impact on atherosclerosis. In this study, we first evaluated the pharmacological effects of PCr on antioxidative defenses and mitochondrial protection against hydrogen peroxide (H2O2) induced human umbilical vascular endothelial cells (HUVECs) damage. Then we investigated the hypolipidemic and antioxidative effects of PCr on hyperlipidemic rat model. Via in vitro studies, H2O2 significantly reduced cell viability and increased apoptosis rate of HUVECs, while pretreatment with PCr abolished its apoptotic effect. PCr could reduce the generation of ROS induced by H2O2. Moreover, PCr could increase the activity of SOD and the content of NO, as well as decrease the activity of LDH and the content of MDA. PCr could also antagonize H2O2-induced up-regulation of Bax, cleaved-caspase3, cleaved-caspase9, and H2O2-induced down-regulation of Bcl-2 and p-Akt/Akt ratio. In addition, PCr reduced U937 cells' adhesion to H2O2-stimulated HUVECs. Via in vivo study, PCr could decrease MDA, TC, TG and LDL-C levels in hyperlipidemic rats. Finally, different-concentration PCr could increase the leaching of TC, HDL, and TG from fresh human atherosclerotic plaques. In conclusion, PCr could suppress H2O2-induced apoptosis in HUVECs and reduce hyperlipidemia through inhibiting ROS generation and modulating dysfunctional mitochondrial system, which might be an effective new therapeutic strategy to further prevent atherosclerosis.
Assuntos
Aterosclerose , Células Endoteliais , Humanos , Animais , Ratos , Peróxido de Hidrogênio , Fosfocreatina/farmacologia , Fosfocreatina/uso terapêutico , Proteínas Proto-Oncogênicas c-akt , Espécies Reativas de Oxigênio , Antioxidantes/farmacologia , Apoptose , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controleRESUMO
Pyruvate dehydrogenase complex (PDH) is an important complex of three enzymes that transforms pyruvate into acetyl-CoA, subsequently entering the tricarboxylic acid (TCA) cycle to produce ATP and electron donors. As a key regulator of energy and metabolic homeostasis, PDH is considered a potential therapeutic target of many diseases. On the other hand, the relationship between PDH and obesity is not clear. In this study, peripheral blood of Pdha1fl/flLyz2-Cre and C57BL/6 mice fed a high-fat diet (HFD) was collected and subjected to extensive transcriptome sequencing. Differentially expressed genes (DEGs) were identified. Enrichment of functions and signaling pathways analyses were performed based on Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the genes selected from RNA sequencing (RNA-seq). Eventually, we found that Pdha1fl/flLyz2-Cre mice were more susceptible to HFD-induced obesity. A total of 302 up-regulated genes and 30 down-regulated genes were screened that were differentially expressed between Pdha1fl/flLyz2-Cre mice fed the HFD and the control groups. Furthermore, we verified that significant transcriptional changes in the genes Sgstm1, Ncoa4, Rraga, Slc3a2, Usp15, Gabarapl2, Wipi1, Sh3glb1, Mtmr3, and Cd36 were consistent with the results obtained from RNA-seq analysis. In summary, this study preliminarily established that there is a close relationship between Pdha1 and obesity and revealed the possible downstream pathways and target genes involved, laying a good foundation for the further study of Pdha1 function in the future.
Assuntos
Dieta Hiperlipídica , Obesidade , Camundongos , Animais , RNA-Seq , Camundongos Endogâmicos C57BL , Obesidade/genética , TranscriptomaRESUMO
The chemotherapeutic drug Doxorubicin is the most commonly prescribed in the world. However, its clinical wide application is limited due to harmful side effects like cardiotoxicity. The cardiotoxic mechanism of DOX is not fully clear, however, it is considered as a potential etiological factor to the generation of ROS and Iron complexes, impairment, Ca2âºhomeostasis, mitochondrial dysfunction, and cell membrane damage. Moreover, it is generally believed that mitochondrial dysfunction plays a central role in the cardiotoxic effect of DOX. Additionally, SIRTs are considered to play an important role, which is activated by small energy molecules to generate energy by stimulation of transcription factors and enzymatic regulation of cardiac energy metabolism. In the heart tissue, SIRT1 and SIRT3 are present in large amounts. This review paper focuses on "DOX mediated cardiomyopathy & cardiomyocytes death" and "The modulation of mitochondrial processes by SIRT1, SIRT3, and DOX". This paper expounds from the following aspects, respectively. 1. A target to mitochondria; (1) ROS overproduction under mitochondrial dysfunction; (2) Lipid peroxidation by oxidative stress after ROS overproduction; (3) Disturbance of calcium homeostasis and mitochondrial permeability transition; 2. SIRTs participate in the process of cardiotoxicity; (1) SIRT1 and toxic myocardial injury; â Over-expression of SIRT1 in toxic myocardial injury; â¡SIRT1 mediated DOX-induced cardiotoxicity; (2) SIRT3 and mitochondrial damage; â A central role of SIRT3 in cardiac metabolism; â¡ Role of SIRT3 in DOX-induced cardiotoxicity; This review is based on SIRTs mediated role in the regulation of mitochondrial function, and evaluates their role on DOX induced cardiotoxicity.
Assuntos
Sirtuína 3 , Sirtuínas , Antibióticos Antineoplásicos/farmacologia , Cardiotoxicidade/metabolismo , Doxorrubicina/efeitos adversos , Humanos , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismo , Sirtuína 3/metabolismo , Sirtuínas/metabolismoRESUMO
Background: We aimed to characterize serine protease inhibitor Kazal type 1 (SPINK1) as a gene signature for the early diagnosis, molecular targeting, and prediction of immune checkpoint blockade (ICB) treatment response of hepatocellular carcinoma (HCC). Methods: The transcriptomics, proteomics, and phenotypic analyses were performed separately or in combination. Results: We obtained the following findings on SPINK1. Firstly, in the transcriptomic training dataset, which included 279 stage I and II tumor samples (out of 1,884 stage I-IV HCC specimens) and 259 normal samples, significantly higher area under curve (AUC) values and increased integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were demonstrated for HCC discrimination in SPINK1-associated models compared with those of alpha-fetoprotein (AFP). The calibration of both SPINK1-related curves fitted significantly better than that of AFP. In the two independent transcriptomic validation datasets, which included 201, 103 stage I-II tumor and 192, 169 paired non-tumor specimens, respectively, the obtained results were consistent with the above-described findings. In the proteomic training dataset, which included 98 stage I and II tumor and 165 normal tissue samples, the analyses also revealed better AUCs and increased IDI and NRI in the aforementioned SPINK1-associated settings. A moderate calibration was shown for both SPINK1-associated models relative to the poor results of AFP. Secondly, in the in vitro and/or in vivo murine models, the wet-lab experiments demonstrated that SPINK1 promoted the proliferation, clonal formation, migration, chemoresistance, anti-apoptosis, tumorigenesis, and metastasis of HCC cells, while the anti-SPINK1 antibody inhibited the growth of the cells, suggesting that SPINK1 has "tumor marker" and "targetable" characteristics in the management of HCC. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that SPINK1 was engaged in immunity-related pathways, including T-cell activation. Thirdly, in the transcriptomic analyses of the 368 HCC specimens from The Cancer Genome Atlas (TCGA) cohort, the high abundance of SPINK1 was positively correlated with the high levels of activated tumor-infiltrating CD4+ and CD8+ T lymphocytes and dendritic and natural killer cells, while there were also positive correlations between SPINK1 and immune checkpoints, including PD-1, LAG-3, TIM-3, TIGIT, HAVCR2, and CTLA-4. The ESTIMATE algorithm calculated positive correlations between SPINK1 and the immune and ESTIMATE scores, suggesting a close correlation between SPINK1 and the immunogenic microenvironment within HCC tissues, which may possibly help in predicting the response of patients to ICB therapy. Conclusions: SPINK1 could be a potential biomarker for the early detection, targeted therapy, and prediction of ICB treatment response in the management of HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Detecção Precoce de Câncer , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos , Proteômica , Inibidor da Tripsina Pancreática de Kazal/genética , Inibidor da Tripsina Pancreática de Kazal/metabolismo , Microambiente Tumoral , alfa-FetoproteínasRESUMO
Oleanolic acid (OA) and its derivatives show potent anticancer function. Pancreatic cancer (PC) is the fourth core motive of cancer-related deaths worldwide. Epidermal growth factor receptor (EGFR) has been implicated in PC and has been validated as a therapeutic target. Our study demonstrated that K73-03, an OA derivative, was identified as a potent inhibitor of EGFR by using reverse pharmacophore screening and molecular dynamics simulation assays. Moreover, Western blot analysis showed that K73-03 markedly suppressed the levels of phosphorylated-EGFR (p-EGFR) and phosphorylated-Akt (p-Akt). The inhibitory effect of K73-03 on PC cells was assessed in vitro and in vivo. Mechanistically, K73-03 effectively inhibited the cell proliferation of PC cells, and induced apoptosis and autophagy of ASPC-1 cells in a dose-dependent manner. Additionally, pretreatment with chloroquine, an autophagy inhibitor, significantly inhibited K73-03-induced autophagy and enhanced K73-03-induced apoptotic cell death. K73-03 also strongly repressed ASPC-1 cells xenograft growth in vivo. Thus, all these findings provided new clues about OA analog K73-03 as an effective anticancer agent targeted EGFR against ASPC-1 cells, it is worth further evaluation in the future.
Assuntos
Antineoplásicos , Ácido Oleanólico , Neoplasias Pancreáticas , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Cloroquina/farmacologia , Receptores ErbB/metabolismo , Humanos , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias PancreáticasRESUMO
Diabetes mellitus (DM) is a metabolic syndrome, caused by insufficient insulin secretion or insulin resistance (IR). DM enhances oxidative stress and induces mitochondrial function in different kinds of cell types, including pancreatic ß-cells. Our previous study has showed phosphocreatine (PCr) can advance the mitochondrial function through enhancing the oxidative phosphorylation and electron transport ability in mitochondria damaged by methylglyoxal (MG). Our aim was to explore the potential role of PCr as a molecule to protect mitochondria from diabetes-induced pancreatic ß-cell injury with insulin secretion deficiency or IR through dual AKT/IRS-1/GSK-3ß and STAT3/Cyclophilin D (Cyp-D) signaling pathways. MG-induced INS-1 cell viability, apoptosis, mitochondrial division and fusion, the morphology, and function of mitochondria were suppressed. Flow cytometry was used to detect the production of intracellular reactive oxygen species (ROS) and the changes of intracellular calcium, and the respiratory function was measured by oxygraph-2k. The expressions of AKT, IRS-1, GSK-3ß, STAT3, and Cyp-D were detected using Western blot. The result showed that the oxidative stress-related kinases were significantly restored to the normal level after the pretreatment with PCr. Moreover, PCr pretreatment significantly inhibited cell apoptosis, decreased intracellular calcium, and ROS production, and inhibited mitochondrial division and fusion, and increased ATP synthesis damaged by MG in INS-1 cells. In addition, pretreatment with PCr suppressed Cytochrome C, p-STAT3, and Cyp-D expressions, while increased p-AKT, p-IRS-1, p-GSK-3ß, caspase-3, and caspase-9 expressions. In conclusion, PCr has protective effect on INS-1 cells in vitro and in vivo, relying on AKT mediated STAT3/ Cyp-D pathway to inhibit oxidative stress and restore mitochondrial function, signifying that PCr might become an emerging candidate for the cure of diabetic pancreatic cancer ß-cell damage.
Assuntos
Cálcio , Proteínas Proto-Oncogênicas c-akt , Apoptose , Cálcio/metabolismo , Peptidil-Prolil Isomerase F , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/farmacologia , Proteínas Substratos do Receptor de Insulina/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Fosfocreatina/metabolismo , Fosfocreatina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
Oleanolic acid (OA, 3 ß - hydroxyoleanolic acid-12-en-28-oic acid) is a pentacyclic triterpenoid present in many plants. As a new framework for development of semi synthetic triterpenoids, OA is of great significance in the discovery of anticancer drugs. Some of these derivatives, such as CDDO (2-cyano-3,12-dioxooleana-1, 9 (11)-dien-28-oic acid) have been verified in clinical trials, while other derivatives studied previously, such as SZC014, SZC015 and SZC017 (OA derivatives respectively), are also candidate drugs for cancer treatment. This paper reviews the preclinical studies, literature evidence, target analysis and anticancer mechanism of OA and its derivatives. The mechanism of action of its derivatives mainly includes anti-cancer cell proliferation, inducing tumor cell apoptosis, inducing autophagy, regulating cell cycle regulatory proteins, inhibiting vascular endothelial growth, anti angiogenesis, inhibiting tumor cell migration and invasion. In recent years, the molecular mechanism of OA and its derivatives has been elucidated. These effects seem to be mediated by the alterations in a variety of signaling pathways induced by OA and its derivatives. In conclusion, OA and its derivatives are considered as important candidate drugs for the treatment of cancer, indicating that OA and its derivatives have the potential to be used as anticancer drugs in practice.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias/tratamento farmacológico , Ácido Oleanólico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Ácido Oleanólico/análogos & derivados , Transdução de Sinais/efeitos dos fármacosRESUMO
Non-alcoholic steatohepatitis (NASH) is a serious form of non-alcoholic fatty liver disease (NAFLD) characterized by liver steatosis with lobular inflammation, hepatocyte injury and pericellular fibrosis. JBP485 is a hydrophilic dipeptide with protective effects on liver through alleviation of oxidative stress and inhibition of hepatocyte apoptosis and ICAM-1 expression. Vitamin E (VE), as a powerful biological antioxidant, exerts a certain protective effect on cell membranes and lipoproteins from lipid peroxidation. In this study, on the basis of the structural characteristics of two agents, the prodrug form target of JBP485 and VE (JBP485-VE) was designed and synthesized via succinic acid linker. The synthesized compound significantly reduced the degree of inflammation and fibrosis according to hematoxylin-eosin (H&E) and sirius red staining assay for the liver tissue in CCl4-induced NASH mouse model. The clear reduction of TG, T-CHO and ALT, AST content also demonstrated its efficacy in the treatment of NASH. In addition, JBP485-VE also reduced the expression of the inflammatory markers IL-2, IL-17A and malondialdehyde (MDA) in liver tissue, which indicated its higher anti-inflammatory and anti-oxidative stress activity. All these evaluated biological properties suggest that the strategy of prodrug design provided an effective method for the treatment of NASH.
Assuntos
Desenho de Fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Peptídeos Cíclicos/farmacologia , Pró-Fármacos/farmacologia , Vitamina E/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Tetracloreto de Carbono , Relação Dose-Resposta a Droga , Fibrose/induzido quimicamente , Fibrose/tratamento farmacológico , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Fígado/efeitos dos fármacos , Camundongos , Estrutura Molecular , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Tamanho do Órgão/efeitos dos fármacos , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade , Vitamina E/síntese química , Vitamina E/químicaRESUMO
Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related mortality worldwide. Nowadays, liver-targeting drug delivery system has been proven as a promising strategy for overcoming HCC. Asialoglycoprotein receptor (ASGPR) is an ideal receptor for liver targeting, which is mainly expressed on hepatocytes. In this study, we developed several novel liver-targeting chitosan nanoparticles to selectively overcome HCC via ASGPR. Chitosan nanoparticles (Gly-CS-VE, Gal-Gly-CS-VE, Gly-CS-DCA, and Gal-Gly-CS-DCA) were prepared by grafting hydrophilic group (glycidol, Gly), hydrophobic group (deoxycholic acid, DCA or vitamin E succinate, VE), and ASGPR recognizing group (galactose, Gal). Subsequently, their characterizations were measured by 1H NMR, FT-IR, TEM, and DLS. Doxorubicin (DOX) was loaded in nanoparticles and released out in a pH-dependent manner. Most importantly, the galactosylated Gal-Gly-CS-VE and Gal-Gly-CS-DCA nanoparticles exhibited significantly stronger in vitro cell internalization, cytotoxicity, anti-migration capabilities and in vivo anticancer efficacies than the corresponding Gly-CS-VE and Gly-CS-DCA nanoparticles, as well as free DOX. Finally, the four chitosan nanoparticles exhibited good biocompatibility without causing any obvious histological damage to the major organs. Overall, the galactosylated chitosan nanoparticles were proven to be promising pharmaceutical formulations for selectively overcoming HCC, with great potential for clinical applications.
Assuntos
Antineoplásicos/farmacologia , Receptor de Asialoglicoproteína/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Doxorrubicina/farmacologia , Neoplasias Hepáticas/patologia , Nanopartículas/química , Animais , Antineoplásicos/administração & dosagem , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Quitosana/química , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Células Hep G2 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Espectroscopia de Infravermelho com Transformada de Fourier , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Gemcitabine (GCB) is a first-line chemotherapeutic drug for pancreatic cancer (PCa). However, the resistance begins developing within weeks of chemotherapy. SPINK1 overexpression enhances resistance to chemotherapy. In a recent study, our laboratory established that the oleanolic acid (OA) derivative, K73-03, had a strong inhibitory effect on a SPINK1 overexpressed PCa cells. PURPOSE: In our current study, we studied the enhancement of GCB inhibitory effect by K73-03, a new novel OA derivative, alone or in combination with GCB on the GCB-resistant PCa cells by mitochondrial damage through regulation of the miR-421/SPINK1. METHODS: We detected the binding between miR-421 and SPINK1-3'-UTR in GCB-resistant PCa cells using Luciferase reporter assays. Cells viability, apoptosis, migration, and mitochondrial damage were investigated. RESULTS: The results demonstrated that the combination of K73-03 and GCB suppressed the growth of AsPC-1 and MIA PaCa-2 cells synergistically, with or without GCB resistance. Mechanistic findings showed that a combination of K73-03 and GCB silences SPINK1 epigenetically by miR-421 up-regulating, which leads to mitochondrial damage and inducing apoptosis in GCB-resistant PCa cells. CONCLUSION: We found an interesting finding that the 73-03 in combination with GCB can improve GCB efficacy and decrease PCa resistance, which induced apoptosis and mitochondrial damage through epigenetic inhibition of SPINK1 transcription by miR-421 up-regulation. This was the first study that used OA derivatives on GCB-resistant PCa cells, so this combined strategy warrants further investigation.