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1.
SLAS Technol ; 29(4): 100146, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38844139

RESUMO

Rheumatoid arthritis (RA), a chronic inflammatory condition that affects persons between the ages of 20 and 40, causes synovium inflammation, cartilage loss, and joint discomfort as some of its symptoms. Diagnostic techniques for RA have traditionally been split into two main categories: imaging and serological tests. However, significant issues are associated with both of these methods. Imaging methods are costly and only helpful in people with obvious symptoms, while serological assays are time-consuming and require specialist knowledge. The drawbacks of these traditional techniques have led to the development of novel diagnostic approaches. The unique properties of nanomaterials make them well-suited as biosensors. Their compact dimensions are frequently cited for their outstanding performance, and their positive impact on the signal-to-noise ratio accounts for their capacity to detect biomarkers at low detection limits, with excellent repeatability and a robust dynamic range. In this review, we discuss the use of nanomaterials in RA theranostics. Scientists have recently synthesized, characterized, and modified nanomaterials and biomarkers commonly used to enhance RA diagnosis and therapy capabilities. We hope to provide scientists with the promising potential that nanomaterials hold for future theranostics and offer suggestions on further improving nanomaterials as biosensors, particularly for detecting autoimmune disorders.

2.
Front Pharmacol ; 13: 906625, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935871

RESUMO

Pancreatic cancer is amongst the most lethal malignancies, while its poor prognosis could be associated with promotion of autophagy and the tumor immune microenvironment. Studies have confirmed the pro-tumorigenic nature of the cathelicidin family of peptide LL-37 in several types of cancer. However, at higher doses, LL-37 exerts significant cytotoxicity against gastrointestinal cancer cells. In our study, we investigated the anti-tumorigenic potential of LL-37 in pancreatic cancer and the underlying mechanisms. Our results have shown that LL-37 inhibited the growth of pancreatic cancer both in vitro and in vivo. Mechanistic studies have demonstrated that LL-37 induced DNA damage and cell cycle arrest through induction of reactive oxygen species (ROS). Further study indicates that LL-37 suppressed autophagy in pancreatic cancer cells through activation of mTOR signaling, leading to more accumulation of ROS production and induction of mitochondrial dysfunctions. With combined treatment of LL-37 with the mTOR inhibitor rapamycin, LL-37-induced ROS production and cancer cell growth inhibition were attenuated. Subsequent in vivo study has shown that LL-37 downregulated the immunosuppressive myeloid-derived suppressor cells and M2 macrophages while upregulated the anti-cancer effectors CD8+ and CD4+ T cells in the tumor microenvironment. By using an in vitro co-culture system, it was shown that promotion of M2 macrophage polarization would be suppressed by LL-37 with inhibition of autophagy, which possessed significant negative impact on cancer growth. Taken together, our findings implicate that LL-37 could attenuate the development of pancreatic cancer by suppressing autophagy and reprogramming of the tumor immune microenvironment.

3.
Am J Cancer Res ; 12(7): 3242-3258, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35968328

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a prominent type of pancreatic cancer. We have recently unveiled that the anti-tumor adjuvant calycosin concurrently possesses growth-inhibitory and pro-metastatic potential in PDAC development by regulating transforming growth factor ß (TGF-ß), which plays dual roles as both tumor suppressor and tumor promoter. Hence, we are interested to explore if the pro-metastatic property of the drug could be attenuated for effective treatment of PDAC. Through network pharmacology, MUC1 had been identified as the most common drug target of herbal Astragalus constituents (including calycosin) in treating PDAC. Following MUC1 gene silencing, the drug effects of calycosin on migratory activity, growth and metabolic regulation of PDAC cells were assessed by using immunofluorescence microscopy, quantitative real-time polymerase chain reaction (qRT-PCR), Western immunoblotting, co-immunoprecipitation (Co-IP), wound healing assay and flow cytometry, respectively. Through in vivo experiments, we further validated the working relationship between MUC1 and TGF-ß. Results have elucidated that MUC1 gene suppression could switch off the migratory and pro-metastatic drive of calycosin while retaining its growth-inhibitory power by inducing apoptosis and cell cycle arrest, as well as facilitating autophagy and metabolic regulation. The underlying mechanism involves downregulation of TGF-ß that acts via modulation of AMP-activated protein kinase (AMPK), Sirtuin 1 (Sirt1) and fibroblast growth factor 21 (FGF21) signaling. These findings have provided new insights in the safe and target-specific treatment of PDAC.

4.
Phytomedicine ; 106: 154406, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36029643

RESUMO

BACKGROUND: Pancreatic cancer has been characterized by poor prognosis, early metastasis and dissatisfactory treatment outcome. The high basal level of autophagy in tumor cells leads to chemoresistance and tumor progression. Thus, it is imminent to explore novel effective chemotherapeutic adjuvants to increase patients' survival rate. Isoliquiritigenin (ISL) is a bioactive flavonoid obtained from the Traditional Chinese herbal medicine Glycyrrhiza glabra, and it possesses a broad range of pharmacological effects. In this study, the anti-cancer effect of ISL in pancreatic cancer treatment and the underlying mechanism are investigated. METHODS: MTT assay, colony formation and EdU analysis were performed to explore the growth inhibition of ISL on pancreatic cancer cells. Apoptosis were analyzed using TUNEL and flow cytometry. The formations of autophagosomes were analyzed by immunofluorescence microscopy and transmission electron microscopy. RFP-GFP-LC3B probe was applied to detect the autophagy flux. To assess the structural interaction of ISL with p38 protein, molecular docking assays were performed. The molecular mechanism was elucidated by using western immunoblotting. Subsequently, the inhibition of ISL on tumor growth was determined in vivo using pancreatic tumor mice model. RESULTS: ISL inhibited pancreatic cancer cell growth and induced apoptosis, both in vitro and in vivo. ISL caused accumulation of autophagosome through blockade of late stage autophagic flux. Moreover, autophagy inducer rapamycin enhanced ISL-evoked cell growth inhibition and promoted apoptosis, while inhibition of autophagosome formation by siAtg5 attenuated ISL-induced apoptosis. It is remarkable that ISL synergistically sensitized the cytotoxic effect of gemcitabine and 5-fluorouracil on pancreatic cancer cells as both drugs induced autophagy. Molecular docking analysis has indicated that ISL acted by direct targeting of p38 MAPK, which was confirmed by ISL-induced phosphorylation of p38. The autophagy flux induced by p38 inhibitor SB203580 was blocked by ISL, with further increasing toxicity of ISL in pancreatic cancer cells. CONCLUSION: The results have revealed that ISL inhibited pancreatic cancer progression by blockade of autophagy through p38 MAPK signaling.


Assuntos
Chalconas , Medicamentos de Ervas Chinesas , Neoplasias Pancreáticas , Animais , Apoptose , Autofagia , Linhagem Celular Tumoral , Chalconas/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Fluoruracila/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Neoplasias Pancreáticas/tratamento farmacológico , Sirolimo/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno
5.
Antioxidants (Basel) ; 11(7)2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35883840

RESUMO

Oxidative stress could lead to a variety of body dysfunctions, including neurodegeneration and cancer, which are closely associated with intracellular signal transducers such as reactive oxygen species (ROS). It has been suggested that ROS is the upstream regulator of autophagy, and that it provides a negative feedback regulation to remove oxidative damage. Defects in the ROS-autophagic redox homeostasis could lead to the increased production of ROS and the accumulation of damaged organelles that in turn promote metabolic reprogramming and induce tumorigenesis. One significant characteristic of pancreatic cancer is the reprogramming of cellular energy metabolism, which facilitates the rapid growth, invasiveness, and the survival of cancer cells. Thus, the rectification of metabolic dysfunction is essential in therapeutic cancer targeting. Isoliquiritigenin (ISL) is a chalcone obtained from the plant Glycyrrhiza glabra, which is a powdered root licorice that has been consumed for centuries in different regions of the world. ISL is known to be a natural antioxidant that possesses diversified functions, including redox regulation in cells. This review contains discussions on the herbal source, biological properties, and anticancer potential of ISL. This is the first time that the anticancer activities of ISL in pancreatic cancer has been elucidated, with a coverage of the involvement of antioxidation, metabolic redox regulation, and autophagy in pancreatic cancer development. Furthermore, some remarks on related compounds of the isoflavonoid biosynthetic pathway of ISL will also be discussed.

6.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207342

RESUMO

The transmembrane glycoprotein mucin 1 (MUC1) is a mucin family member that has different functions in normal and cancer cells. Owing to its structural and biochemical properties, MUC1 can act as a lubricant, moisturizer, and physical barrier in normal cells. However, in cancer cells, MUC1 often undergoes aberrant glycosylation and overexpression. It is involved in cancer invasion, metastasis, angiogenesis, and apoptosis by virtue of its participation in intracellular signaling processes and the regulation of related biomolecules. This review introduces the biological structure and different roles of MUC1 in normal and cancer cells and the regulatory mechanisms governing these roles. It also evaluates current research progress and the clinical applications of MUC1 in cancer therapy based on its characteristics.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma/metabolismo , Mucina-1/metabolismo , Animais , Biomarcadores Tumorais/química , Biomarcadores Tumorais/genética , Carcinoma/diagnóstico , Carcinoma/terapia , Células Epiteliais/metabolismo , Humanos , Mucina-1/química , Mucina-1/genética
7.
Am J Chin Med ; 48(5): 1179-1202, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32668972

RESUMO

Over-expression of calpains in tumor tissues can be associated with cancer progression. Thus, inhibition of calpain activity using specific inhibitors has become a novel approach to control tumor growth. In this study, the anticancer potential of cryptotanshinone in combination with calpain inhibitor had been investigated in colon cancer cells and tumor xenograft. Cryptotanshinone elicited an initial endoplasmic reticular (ER) stress response, whereas prolonged stress would result in the promotion of apoptosis. It was then discovered that cryptotanshinone could cause rapid and sustained increase in cytosolic calcium in colon cancer cells accompanied by early GRP78 overexpression, which could be attenuated by pre-treatment of the calcium chelator BAPTA-AM. Cryptotanshinone also facilitated an early increase in calpain activity, which could be blocked by BAPTA-AM or the calpain inhibitor PD150606. A dynamic interaction between GRP78 and calpain during the action of cryptotanshinone was unveiled. This together with the altered NF-[Formula: see text]B signaling could be abolished by calpain inhibitor. GRP78 knockdown increased the sensitivity of cancer cells to cryptotanshinone-evoked apoptosis and reduction of cancer cell colony formation. Such sensitization of drug action had been confirmed to be p53-dependent by using p53-mutated (HT-29) and p53-deficient (HCT116 p53-∕-) cells. The synergistic antitumor effect of cryptotanshinone and calpain inhibitor was further exhibited in vivo. Taken together, findings in this study exemplify a new chemotherapeutic regimen comprising cryptotanshinone and calpain inhibitor by regulation of calpain and calcium homeostasis. This has provided us with new insights in the search of a potential target-specific neoadjuvant therapy against colon cancer.


Assuntos
Antineoplásicos Fitogênicos , Apoptose/efeitos dos fármacos , Apoptose/genética , Cálcio/metabolismo , Calpaína/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Homeostase/efeitos dos fármacos , Fenantrenos/farmacologia , Fenantrenos/uso terapêutico , Fitoterapia , Proteína Supressora de Tumor p53/metabolismo , Animais , Calpaína/genética , Neoplasias do Colo/genética , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Camundongos Nus , Células Tumorais Cultivadas
8.
Phytomedicine ; 68: 153177, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32106002

RESUMO

BACKGROUND: Calycosin is a bioactive isoflavonoid of the medicinal plant Astragalus membranaceus that exhibits a wide range of pharmacological properties. In the present study, we have attempted to explore the anti-tumorigenic potential of calycosin in pancreatic cancer. METHODS: MTT assay was used to determine cancer cell viability. Cell cycle analysis and detection of apoptosis were performed using flow cytometry. A wound healing assay was employed to study the migratory activity of cancer cells. Western blotting and RT-PCR were used to explore the mechanism by assessing the target proteins and genes. An orthotopic tumor xenograft mouse model was also used to study the drug effects in vivo. RESULTS: Calycosin inhibited the growth of pancreatic cancer cells by inducing p21Waf1/Cip1-induced cell cycle arrest and caspase-dependent apoptosis. Alternatively, it also promoted MIA PaCa-2 cell migration by eliciting epithelial-mesenchymal transition (EMT) and matrix metalloproteinase activation. In vivo study has confirmed that calycosin would provoke the pro-invasive and angiogenic drive and subsequent EMT in pancreatic tumors. Further mechanistic study suggests that induction of the Raf/MEK/ERK pathway and facilitated polarization of M2 tumor-associated macrophage in the tumor microenvironment both contribute to the pro-metastatic potential of calycosin. These events appear to be associated with increased expression of TGF-ß1 at both transcriptional and post-translational levels, which may explain the paradoxical drug actions since TGF-ß has been implicated to play dual roles as both tumor suppressor and tumor promoter in pancreatic cancer development. CONCLUSION: Findings of this study provide innovative insights about the impact of calycosin in pancreatic cancer progression through induction of cell cycle arrest and apoptosis while possessing certain tumor-promoting property by modulation of the tumor microenvironment.


Assuntos
Isoflavonas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Isoflavonas/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/metabolismo , Células RAW 264.7 , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Mol Sci ; 20(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500132

RESUMO

Parkinson's disease is a progressive neurodegenerative disorder resulting from the degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta. It induces a series of functional modifications in the circuitry of the basal ganglia nuclei and leads to severe motor disturbances. The amino acid glutamate, as an excitatory neurotransmitter, plays a key role in the disruption of normal basal ganglia function regulated through the interaction with its receptor proteins. It has been proven that glutamate receptors participate in the modulation of neuronal excitability, transmitter release, and long-term synaptic plasticity, in addition to being related to the altered neurotransmission in Parkinson's disease. Therefore, they are considered new targets for improving the therapeutic strategies used to treat Parkinson's disease. In this review, we discuss the biological characteristics of these receptors and demonstrate the receptor-mediated neuroprotection in Parkinson's disease. Pharmacological manipulation of these receptors during anti-Parkinsonian processes in both experimental studies and clinical trials are also summarized.


Assuntos
Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Receptores de Glutamato/metabolismo , Animais , Ensaios Clínicos como Assunto , Descoberta de Drogas , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Humanos , Terapia de Alvo Molecular , Neurotransmissores/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Receptores de Glutamato/genética , Transdução de Sinais/efeitos dos fármacos , Substância Negra/metabolismo , Transmissão Sináptica , Resultado do Tratamento
10.
Curr Pharm Des ; 23(27): 3952-3961, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28245762

RESUMO

BACKGROUND: When tumor cells are under hypoxic condition or other forms of oxidative stress, one of the survival mechanisms is to undergo angiogenesis, involving dissemination of existing vessels or neovascularization to antagonize the apoptotic drive and to facilitate migration to secondary sites. METHODS: This paper reveals the pathogenesis of tumor angiogenesis, particularly during hypoxia and other forms of oxidative stress in cancer cells. RESULTS: Following successive invasion of the extracellular matrix (ECM), new blood vessels penetrate and supply nutrients to tumor tissues for growth and metastasis. The metastatic power of cancers is determined by a series of angiogenic and metastatic factors. These factors could allow neoplastic tissues to survive and withstand the stress induced by hypoxia and/or disruption of the ECM, including vascular endothelial growth factor and matrix metalloproteinases that were found to be highly elevated in tumor tissues of colon cancer patients. These aggressive factors could be regulated by cancer signaling pathways such as the phosphatidylinositol 3-kinase/Akt/ mTOR cascade. In fact, mTOR (the mammalian target of rapamycin) acts as a central regulator of many cellular activities involving growth and differentiation through regulation of cell cycle progression, cell size, cell migration and survival, including those in tumor cells. Several novel therapeutic approaches that target the angiogenic drive of cancers have been introduced, including compounds derived from natural products and synthetic chemicals. CONCLUSION: This article highlights the importance of angiogenesis and oxidative stress on the development of advanced and metastatic colon cancers, and provides new insights on alternative and effective treatment options.


Assuntos
Neoplasias do Colo/patologia , Neovascularização Patológica/patologia , Estresse Oxidativo , Inibidores da Angiogênese/farmacologia , Animais , Produtos Biológicos/farmacologia , Neoplasias do Colo/irrigação sanguínea , Neoplasias do Colo/terapia , Progressão da Doença , Desenho de Fármacos , Humanos , Terapia de Alvo Molecular , Metástase Neoplásica , Neovascularização Patológica/terapia , Transdução de Sinais
11.
Am J Chin Med ; 44(3): 579-93, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27109155

RESUMO

Excessive nitric oxide (NO) and pro-inflammatory cytokines are produced during the pathogenesis of inflammatory diseases and cancer. It has been demonstrated that anti-inflammation contributes Astragalus membranaceus saponins (AST)'s beneficial effects in combination of conventional anticancer drugs. However, the immunomodulating property of AST has not been well characterized. In this study, we found that AST suppressed lipopolysaccharide (LPS)-induced generation of NO without causing cytotoxicity in the mouse macrophage RAW264.7. The gene and protein overexpression of inducible NO synthase (iNOS) as well as the production of tumor necrosis factor-[Formula: see text], evoked by LPS, was consistently down-regulated by AST. AST also inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and suppressed nuclear factor (NF)-[Formula: see text]B activation and the associated I[Formula: see text]B[Formula: see text] degradation during LPS insult. Furthermore, AST induced growth inhibition in promyelocytic leukemic HL-60 cells and T-lymphocyte leukemic Jurkat cells, but exerted no cytotoxic effects in normal human peripheral blood mononuclear cells (PBMC). It is known that the chemotherapeutic drug 5-FU can suppress the immune system, which can be identified by a reduced white blood cell count and decreased hematocrit, while the combination of AST and 5-FU can reverse the above hematologic toxicities. To summarize, non-cytotoxic concentrations of AST suppress LPS-induced inflammatory responses via the modulation of p38 MAPK signaling and the inhibition of NO and cytokine release. Importantly, AST can alleviate the hematologic side effects of current chemotherapeutic agents. These findings can facilitate the establishment of AST in the treatment of inflammatory diseases and inflammation-mediated tumor development.


Assuntos
Medicamentos de Ervas Chinesas/química , Fatores Imunológicos/farmacologia , Inflamação/etiologia , Lipopolissacarídeos/efeitos adversos , Fitoterapia , Saponinas/farmacologia , Animais , Astragalus propinquus , Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , NF-kappa B/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Saponinas/isolamento & purificação , Saponinas/uso terapêutico , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Am J Chin Med ; 44(1): 1-22, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26916911

RESUMO

Astragalus membranaceus is a major medicinal herb commonly used in many herbal formulations in the practice of traditional Chinese medicine (TCM) to treat a wide variety of diseases and body disorders. Among its diversified clinical applications, the potential use of this herb and its chemical constituents in treatments of inflammatory diseases and cancers has been actively investigated in recent years. Astragalus-based treatments have demonstrated significant amelioration of the toxicity induced by other concurrently administered orthodox drugs (e.g., immunosuppressants and cancer chemotherapeutics). The major components of Astragalus membranaceus are polysaccharides, flavonoids, and saponins. Contemporary use of Astragalus membranaceus mainly focuses on its immunomodulating, anti-oxidant, and anti-inflammatory, as well as anticancer effects. In this paper, we summarize the properties of Astragalus membranaceus and its major constituents in the biological system based on experimental and clinical studies. The antitumorigenic mechanisms of a novel Astragalus saponins extract called AST in treating various gastrointestinal cancers are highlighted. We discuss in detail how the Astragalus herb and AST influence the immune system, modulate various cancer signaling pathways, and interact with specific transcription molecules during protection against gastrointestinal inflammation and cancers. This information could help clinicians and scientists develop novel target-specific and effective therapeutic agents that are deprived of major systemic side effects, so as to establish a better treatment regimen in the battle against inflammatory diseases and cancers of the gut.


Assuntos
Astragalus propinquus , Neoplasias Gastrointestinais/tratamento farmacológico , Inflamação/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios , Antineoplásicos Fitogênicos , Antioxidantes , Astragalus propinquus/química , Flavonoides/química , Flavonoides/isolamento & purificação , Humanos , Fatores Imunológicos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Saponinas/química , Saponinas/isolamento & purificação
13.
BMC Complement Altern Med ; 14: 401, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25319833

RESUMO

BACKGROUND: Glucose-regulated proteins (GRP) are induced in the cancer microenvironment to promote tumor survival, metastasis and drug resistance. AST was obtained from the medicinal plant Astragalus membranaceus, which possesses anti-tumor and pro-apoptotic properties in colon cancer cells and tumor xenograft. The present study aimed to investigate the involvement of GRP in endoplasmic reticulum (ER) stress-mediated apoptosis during colon cancer development, with focus on the correlation between AST-evoked regulation of GRP and calpain activation. METHODS: The effects of AST on GRP and apoptotic activity were assessed in HCT 116 human colon adenocarcinoma cells. Calpain activity was examined by using a fluorescence assay kit. Immunofluorescence staining and immunoprecipitation were employed to determine the localization and association between calpains and GRP. GRP78 gene silencing was performed to confirm the importance of GRP in anticancer drug activities. The modulation of GRP and calpains was also studied in nude mice xenograft. RESULTS: ER stress-mediated apoptosis was induced by AST, as shown by elevation in both spliced XBP-1 and CHOP levels, with parallel up-regulation of GRP. The expression of XBP-1 and CHOP continued to increase after the peak level of GRP was attained at 24 h. Nevertheless, the initial increase in calpain activity as well as calpain I and II protein level was gradually declined at later stage of drug treatment. Besides, the induction of GRP was partly reversed by calpain inhibitors, with concurrent promotion of AST-mediated apoptosis. The knockdown of GRP78 by gene silencing resulted in higher sensitivity of colon cancer cells to AST-induced apoptosis and reduction of colony formation. The association between calpains and GRP78 had been confirmed by immunofluorescence staining and immunoprecipitation. Modulation of GRP and calpains by AST was similarly demonstrated in nude mice xenograft, leading to significant inhibition of tumor growth. CONCLUSIONS: Our findings exemplify that calpains, in particular calpain II, play a permissive role in the modulation of GRP78 and consequent regulation of ER stress-induced apoptosis. Combination of calpain inhibitors and AST could exhibit a more pronounced pro-apoptotic effect. These results help to envisage a new therapeutic approach in colon cancer by targeting calpain and GRP.


Assuntos
Astrágalo/química , Calpaína/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Proteínas de Choque Térmico HSP70/genética , Proteínas de Membrana/genética , Extratos Vegetais/administração & dosagem , Saponinas/administração & dosagem , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Calpaína/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/fisiopatologia , Chaperona BiP do Retículo Endoplasmático , Células HCT116 , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
14.
Mol Biosyst ; 10(9): 2305-16, 2014 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-24949573

RESUMO

We recently reported that processed Aconitum carmichaelii Debx (Bai-Fu-Pian in Chinese, BFP) elicits differential toxic responses in rats under various health conditions. The present study aimed to determine the graded toxicity of BFP so as to derive a safe therapeutic rationale in clinical practice. Sensitive and reliable biomarkers of toxicity were also identified, with the corresponding metabolic pathways being unveiled. Thirty male Sprague-Dawley rats were divided into five groups (n = 6) and received oral administration of BFP extract (0.32, 0.64, 1.28 or 2.56 g kg(-1) per day) or an equal volume of drinking water (control) for 15 days. The metabolomic profiles of rat serum were analyzed by liquid chromatography quadruple time-of-flight mass spectrometry (LC-Q-TOF-MS). Linear regression analysis and Ingenuity Pathway Analysis (IPA) were used to elucidate the differentiated altered metabolites and associated network relationships. Results from biochemical and histopathological examinations revealed that BFP could induce prominent toxicity in the heart, liver and kidneys at a dose of 2.56 g kg(-1) per day. Betaine up-regulation and phosphatidylcholine down-regulation were detected in the serum samples of drug-treated groups in a dose-dependent manner. In summary, betaine and phosphatidylcholine could be regarded as sensitive biomarkers for the toxic responses of BFP. Perturbations of RhoA signaling, choline metabolism and free radical scavenging were found to be partly responsible for the toxic effects of the herbal drug. Based on the metabolomics findings, we could establish a safe therapeutic range in the clinical use of BFP, with promising predictions of possible drug toxicity.


Assuntos
Aconitum/efeitos adversos , Betaína/metabolismo , Biomarcadores/metabolismo , Medicamentos de Ervas Chinesas/efeitos adversos , Fosfatidilcolinas/metabolismo , Soro/metabolismo , Animais , Regulação para Baixo/efeitos dos fármacos , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metaboloma/fisiologia , Metabolômica/métodos , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
15.
Nutr Cancer ; 66(4): 662-74, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24660995

RESUMO

Our previous study had demonstrated that Astragalus saponins (AST) could reduce the side effects of orthodox chemotherapeutic drugs, while concurrently promote antitumor activity. In the present study, we attempted to investigate the potential synergistic anticarcinogenic effects of AST and a vinca alkaloid vinblastine (VBL). Reduced expression of key proangiogenic and metastatic factors including VEGF, bFGF, metalloproteinase (MMP)-2, and MMP-9 was detected in VBL-treated colon cancer cells, with further downregulation by combined VBL/AST treatment. Subsequently, VBL or AST decreased LoVo cell invasiveness, with further reduction when the drugs were cotreated. Significant growth inhibition and cell cycle arrest at G2/M phase were achieved by either drug treatment with apparent synergistic effects. VBL-induced apoptosis was confirmed but found to be unrelated to induction of the novel apoptotic protein NSAID-activated gene 1. In vivo study in tumor xenograft indicates that combined VBL/AST treatment resulted in sustained regression of tumor growth, with attenuation of the neutropenic and anemic effects of VBL. In addition, downregulation of proangiogenic and proliferative factors was also visualized, with boosting effect by combined drug treatment. These findings have provided evidence that AST combined with adjuvant chemotherapeutics like VBL could alleviate cancer development through diversified modes of action, including the regulation of angiogenesis.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Astrágalo/química , Extratos Vegetais/farmacologia , Saponinas/farmacologia , Vimblastina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Regulação para Baixo , Sinergismo Farmacológico , Inativação Gênica , Células HCT116 , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Nus , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Curr Med Chem ; 21(21): 2346-56, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24524767

RESUMO

Cancer cells can express specific membrane proteins, which act as biomarkers for chemotherapeutic targeting. Functional peptides possess unique properties that will ensure efficacy, selectivity, specificity and low toxicity when used as therapeutic agents. Therapeutic peptides have been derived in treatment of cancers through improvement of cellular uptake, drug targeting and vaccine development. Peptides from natural source have been used for chemoprevention and therapy of various cancers. These include peptides derived from food, marine products, venom components and other animal constituents. Besides, chemically- and recombinantly-synthesized peptides have also been produced and extensively studied in contemporary applications. Improvement of tumor targeting is essential for chemotherapeutic development. This can be achieved through enhancement of intracellular delivery and/or increased specific binding affinity to cancer cells by pore-forming and cytotoxic peptides. Cytotoxic peptides such as the Bcl-2 family members can induce receptor-specific binding to tumor cells and promote apoptosis by targeting lipid membranes. This approach has some limitations in targeting, penetration and localization within tumors. Cell-penetrating peptides (CPPs) belong to a new class of tumor-targeting peptides that can facilitate internalization of tumor markers and/or chemotherapeutic drugs. In order to overcome the problem of serum instability in classical CPPs (e.g. Tat), newer classes of CPPs has been recently introduced. Nevertheless, some cyclized CPPs can further enhance cellular uptake and binding selectivity when compared to activities of their linear counterpart, especially when treating chemoresistant tumors. This review compiles the use of effective tumor-targeting peptides including novel CPPs that represents new therapeutic strategies for the treatment of cancers.


Assuntos
Antineoplásicos/uso terapêutico , Produtos Biológicos/uso terapêutico , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Peptídeos/uso terapêutico , Animais , Antineoplásicos/síntese química , Humanos , Peptídeos/síntese química
17.
Curr Pharm Des ; 20(7): 1082-96, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23782147

RESUMO

Ulcerative colitis (UC) and Crohn's disease (CD) constitute the two major groups of idiopathic disorders in inflammatory bowel disease (IBD). Environmental factors, genetic factors and immune responses have been considered as the major etiology of IBD. Despite the diversified pathogenesis of the disease, no guaranteed curative therapeutic regimen has been developed so far. This review summarizes the knowledge on the pathophysiology and current treatment approaches of IBD. Since IBD is caused by excessive and tissue- disruptive inflammatory reactions of the gut wall, down-regulation of the immune responses may allow the damaged mucosa to heal and reset the physiological functions of the gut back to normal. Current pharmacotherapy through modulation of neutrophil-derived factors, cytokines, adhesion molecules and reactive oxygen/nitrogen metabolites has been utterly described. Categories of treatment modalities include corticosteroids, aminosalicylates, immunomodulators, antibiotics, probiotics, and a series of unique novel agents. The use of anti-tumor necrosis factor monoclonal antibody (Infliximab), recombinant anti-inflammatory cytokines and related gene therapy has been covered. In addition, discussions on dietary supplementation and heparin treatment are also included. The anti-inflammatory and immunoregulatory potential of investigational agents such as nicotine and the filtered protective compounds from tobacco smoke, as well as active herbal medicinal compounds were tested in our previous experimental works, whereas promising findings have been presented here. With the discovery of novel target-oriented agents, more effective and relatively harmless approaches of IBD therapy could be established to achieve a curative outcome. Indeed, more experimental and clinical studies are needed to confirm the relevance of these therapies.


Assuntos
Doenças Inflamatórias Intestinais , Terapia de Alvo Molecular , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Humanos , Sistema Imunitário/efeitos dos fármacos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/fisiopatologia , Probióticos
18.
Artigo em Inglês | MEDLINE | ID: mdl-23533509

RESUMO

Hand-foot-and-mouth disease (HFMD), with poorly understood pathogenesis, has become a major public health threat across Asia Pacific. In order to characterize the metabolic changes of HFMD and to unravel the regulatory role of clinical intervention, we have performed a metabolomics approach in a clinical trial. In this study, metabolites profiling was performed by liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) platform from the HFMD clinical patient samples. The outcome of this study suggested that 31 endogenous metabolites were mainly involved and showed marked perturbation in HFMD patients. In addition, combination therapy intervention showed normalized tendency in HFMD patients in differential pathway. Taken together, these results indicate that metabolomics approach can be used as a complementary tool for the detection and the study of the etiology of HFMD.

19.
Curr Pharm Des ; 19(1): 48-66, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22950499

RESUMO

A prominent group of effective cancer chemopreventive drugs has been derived from natural products having low toxicity while possessing apparent benefit in the disease process. It is plausible that there are multiple target molecules critical to cancer cell survival. Herbal terpenoids have demonstrated excellent target-specific anti-neoplastic functions by suppression of cell proliferation and induction of apoptosis. Transcriptional molecules in the NF-κB, MEK/ERK and PI3K/Akt/mTOR pathways are important molecular targets of chemotherapy that play distinctive roles in modulating the apoptosis cascades. It is recently suggested that NSAID-activated gene (NAG-1), a novel proapoptotic protein, is the upstream anti-carcinogenic target of NSAIDs, PPAR ligands and herbal chemotherapeutic agents that triggers some of the events mentioned above. Besides, angiogenesis, oxidative stress as well as inflammation are important factors that contribute to the development and metastasis of cancer, which could be actively modulated by novel agents of plant origin. The aim of the present review is to discuss and summarize the contemporary use of herbal therapeutics and phytochemicals in the treatment of human cancers, in particular that of the colon. The major events and signaling pathways in the carcinogenesis process being potentially modulated by natural products and novel herbal compounds will be evaluated, with emphasis on some terpenoids. Advances in eliciting the precise cellular and molecular mechanisms during the anti-tumorigenic process of novel herbal therapeutics will be of imperative clinical significance to increase the efficacy and reduce prominent adverse drug effects in cancer patients through target-specific therapy.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Inflamação/patologia , Fitoterapia/métodos , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Produtos Biológicos/efeitos adversos , Produtos Biológicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias Gastrointestinais/patologia , Humanos , Inflamação/tratamento farmacológico , Terapia de Alvo Molecular , Fitoterapia/efeitos adversos , Extratos Vegetais/efeitos adversos , Extratos Vegetais/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
20.
J Proteome Res ; 12(1): 513-24, 2013 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-23205644

RESUMO

Radix aconiti lateralis praeparata (Baifupian) has received great attention because of its excellent therapeutic effects as well as the associated adverse drug reactions. According to the traditional Chinese medicine (TCM) principle, Baifupian should only be used in patients with TCM "kidney-yang" deficiency pattern, a clinical state that can be mimicked by hydrocortisone induction in rats. This study aimed to decipher the differential toxic responses of Baifupian in healthy and hydrocortisone-pretreated rats based on serum metabolic profiles. Drug-treated rats received Baifupian intragastrically at the dose of 1.28 g/kg/day for 15 days. Serum metabolic profiles were obtained by using the LC-Q-TOF-MS technique. Our results show that Baifupian could induce severe toxicity in the heart, liver, and kidneys of healthy rats. These drug-induced toxic reactions were largely alleviated in hydrocortisone-pretreated animals. Changes of metabolic profiles in drug-treated healthy and hydrocortisone-pretreated rats were demonstrated, involving oxidative phosphorylation, amino acid and lipid metabolism as characterized by altered phosphate, betaine, and phosphatidyl choline. These metabolic alterations could be responsible at least in part for the differential toxic responses of Baifupian under various health conditions. This study provides a new paradigm for better understanding of the risks and limitations when using potentially toxic herbs in clinical applications.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Medicamentos de Ervas Chinesas/efeitos adversos , Medicina Tradicional Chinesa , Metaboloma/genética , Aconitum/química , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Hidrocortisona/administração & dosagem , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Espectrometria de Massas , Ratos , Deficiência da Energia Yang/sangue , Deficiência da Energia Yang/metabolismo
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