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Colorectal cancer is one of the most leading death-causing cancers in the world. Vernodalin, a cytotoxic sesquiterpene, has been reported to possess anticancer properties against human breast cancer cells. We aimed to examine the anticancer mechanism of vernodalin on human colon cancer cells. Vernodalin was used on human colon cancer cells, HT-29 and HCT116. The cytotoxicity of vernodalin on human colon cancer cells was determined through in vitro 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay. Small interfering RNA was used to analyze the cascade activation of mitogen-activated protein kinase (MAPK) pathway, c-Jun N-terminal kinase (JNK) in HT-29, and HCT116 cells against vernodalin treatment. The protein expressions of caspase 3, Bcl-2, and Bax were examined through Western blot analysis. Immunoblot analysis on the JNK, ERK, and p38 MAPK pathways showed increased activation due to vernodalin treatment. It was proven from the JNK and p38 inhibition test that both pathways are significantly activated by vernodalin to induce apoptosis. Our results, collectively, showed the apoptosis-induced anticancer mechanism of vernodalin on human colon cancer cells that was mediated through the activation of JNK pathway and apoptotic regulator proteins. These results suggest that vernodalin could be developed as a potent chemotherapeutic agent for human colorectal cancer treatment.
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Apoptose/efeitos dos fármacos , MAP Quinase Quinase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ativação Enzimática , Células HCT116 , Células HT29 , Humanos , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos/farmacologiaRESUMO
Carcinogenesis, a multi-step phenomenon, characterized by alterations at genetic level and affecting the main intracellular pathways controlling cell growth and development. There are growing number of evidences linking oncogenes to the induction of malignancies, especially breast cancer. Modulations of oncogenes lead to gain-of-function signals in the cells and contribute to the tumorigenic phenotype. These signals yield a large number of proteins that cause cell growth and inhibit apoptosis. Transcription factors such as STAT, p53, NF-κB, c-JUN and FOXM1, are proteins that are conserved among species, accumulate in the nucleus, bind to DNA and regulate the specific genes targets. Oncogenic transcription factors resulting from the mutation or overexpression following aberrant gene expression relay the signals in the nucleus and disrupt the transcription pattern. Activation of oncogenic transcription factors is associated with control of cell cycle, apoptosis, migration and cell differentiation. Among different cancer types, breast cancer is one of top ten cancers worldwide. There are different subtypes of breast cancer cell-lines such as non-aggressive MCF-7 and aggressive and metastatic MDA-MB-231 cells, which are identified with distinct molecular profile and different levels of oncogenic transcription factor. For instance, MDA-MB-231 carries mutated and overexpressed p53 with its abnormal, uncontrolled downstream signalling pathway that account for resistance to several anticancer drugs compared to MCF-7 cells with wild-type p53. Appropriate enough, inhibition of oncogenic transcription factors has become a potential target in discovery and development of anti-tumour drugs against breast cancer. Plants produce diverse amount of organic metabolites. Universally, these metabolites with biological activities are known as "natural products". The chemical structure and function of natural products have been studied since 1850s. Investigating these properties leaded to recognition of their molecular effects as anticancer drugs. Numerous natural products extracted from plants, fruits, mushrooms and mycelia, show potential inhibitory effects against several oncogenic transcription factors in breast cancer. Natural compounds that target oncogenic transcription factors have increased the number of candidate therapeutic agents. This review summarizes the current findings of natural products in targeting specific oncogenic transcription factors in breast cancer.
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Produtos Biológicos/farmacologia , Neoplasias da Mama/metabolismo , Fatores de Transcrição/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Humanos , MicroRNAsRESUMO
Brewers' rice is one of abundant agricultural waste products in the rice industry. The present study is designed to investigate the potential of brewers' rice to inhibit the development of aberrant crypt foci (ACF) in colon of azoxymethane (AOM)-treated rats. The effects on the attenuation of hepatic toxicity and kidney function enzymes were also evaluated. Male Sprague-Dawley rats were randomly divided into five groups: (G1) normal; (G2) AOM alone; and (G3), (G4), and (G5), which were AOM fed with 10%, 20%, and 40% (w/w) of brewers' rice, respectively. The rats in group 2-5 were injected intraperitoneally with AOM (15 mg/kg body weight) once weekly for two weeks. After 8 weeks of treatment,the total number of ACF/colon and the number of ACF in the distal and middle colon were significantly reduced in all treatment groups compared to G2 (p<0.05). Brewers' rice decreased the number of ACF with dysplastic morphology in a dose-dependent manner. Alkaline phosphatase (ALP) level in G5 was significantly lower compared to the G2 (p<0.05). In conclusion, this study found the potential value of brewers' rice in reducing the risk of cancer susceptibility in colon.
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Focos de Criptas Aberrantes/prevenção & controle , Neoplasias Colorretais/prevenção & controle , Oryza , Focos de Criptas Aberrantes/induzido quimicamente , Focos de Criptas Aberrantes/patologia , Alanina Transaminase/sangue , Animais , Azoximetano , Peso Corporal , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/patologia , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-DawleyRESUMO
Colorectal cancer (CRC) is now perceived as a multistep process characterized by the accumulation of genetic alterations in oncogenes and tumor suppressor genes. Plant-derived compounds are receiving considerable attention for their potential role in reducing cancer risk. Luteolin, a bioflavonoid present in many fruits and vegetables, possesses antioxidant, anti-inflammatory and antiproliferative properties. This study was designed to investigate the possible role of luteolin administration on Phase 1 and 2 enzymes and NF-E2-related factor 2 (Nrf2)/keap1 pathway. Male Balb/C mice were divided into four groups: normal control, Azoxymethane (AOM)-induced, AOM-induced and luteolin treated, normal control treated with luteolin. CRC was induced by administration of AOM (15 mg/kg body weight) intraperitoneally (i.p.) once a week for three weeks. Luteolin administration (1.2 mg/kg body weight/day) significantly alleviated Phase1 enzymes in colon and liver, it increased the levels of phase 2 enzymes. Luteolin modulates the expressions of GST-α, µ and also the expression of Nrf2. Collectively, results of our hypothesis show that luteolin is a novel candidate for treating CRC.
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Azoximetano/toxicidade , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Luteolina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/genéticaRESUMO
The present study describes a method for the preparation of green titanium dioxide (TiO2) nanoparticles from the peel of Solanum tuberosum, commonly known as potato, and the potato peel being a kitchen waste. The green synthesized TiO2 (G- TiO2) nanoparticles were characterized using UV-visible spectroscopy, dynamic light scattering, scanning electron microscopy, TEM, XRD, and FTIR spectroscopy. The photocatalytic activity of the G- TiO2 nanoparticles was also shown using the dye bromophenol blue. To explore the biocompatibility of the G- TiO2, the cell viability in normal as well as cancer cells was assessed. Further, the in vivo toxicity of the G- TiO2 nanoparticles was assessed using zebrafish embryos. The novelty of the present invention is to utilize kitchen waste for a useful purpose for the synthesis of titanium dioxide nanoparticles which is known to have UV light scavenging properties. Moreover, the potato peel is a natural antioxidant and possesses a skin-lightening effect. A combination of the potato peel extract and titanium dioxide prepared using the extract will have a combinatorial effect for protecting UV light exposure to the skin and lightening the skin colour.
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Nanopartículas , Solanum tuberosum , Animais , Peixe-Zebra , Nanopartículas/química , Titânio/farmacologia , Titânio/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , CatáliseRESUMO
Inositol hexaphosphate (IP6), or phytic acid is a natural dietary ingredient and has been described as a "natural cancer fighter", being an essential component of nutritional diets. The marked anti-cancer effect of IP6 has resulted in our quest for an understanding of its mechanism of action. In particular, our data provided strong evidence for the induction of apoptotic cell death, which may be attributable to the up-regulation of Bax and down-regulation of Bcl-xl in favor of apoptosis. In addition, the up-regulation of caspase-3 and -8 expression and activation of both caspases may also contribute to the apoptotic cell death of human colorectal adenocarcinoma HT-29 cells when exposed to IP6. Collectively, this present study has shown that rice bran IP6 induces apoptosis, by regulating the pro- and anti-apoptotic markers; Bax and Bcl-xl and via the activation of caspase molecules (caspase-3 and -8).
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Antineoplásicos Fitogênicos/química , Oryza/química , Ácido Fítico/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Caspase 8/genética , Caspase 8/metabolismo , Regulação para Baixo/efeitos dos fármacos , Células HT29 , Humanos , Oryza/metabolismo , Ácido Fítico/isolamento & purificação , Ácido Fítico/farmacologia , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMO
Bone regeneration or restoration is a series of well-ordered physiological activities that occur throughout a person's life, they are continuously being repaired and remodeled. A conventional bone repair procedure, such as autograft and allograft bone transplant, has failed to address bone reconstruction disputes and complexity. On the other hand, Tissue Engineering is a potential therapy option for repairing rather than replacing the damaged tissue. Biomaterials in bone tissue engineering (BTE) help pave the way for damaged tissues as an artificial extracellular matrix, facilitating new tissue growth. Collagen-based biomaterials for repair and replacement have inspired much interest in the hunt for versatile biomaterials compatible with human tissue. It is a major organic component of extracellular matrix in bone and has been employed as scaffolding material in BTE for decades. In this review, we documented the role of collagen in BTE, focusing on collagen type I, its crosslinking capability, collagen-based biomaterials, and fabrication methods. It also considers osteoblast citration a critical process in bone formation, a unique perspective for an old relationship.
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Engenharia Tecidual , Alicerces Teciduais , Humanos , Engenharia Tecidual/métodos , Materiais Biocompatíveis , Osso e Ossos , ColágenoRESUMO
AIM: Alzheimer's disease (AD) has been identified as a progressive brain disorder associated with memory dysfunction and the accumulation of ß-amyloid plaques and neurofibrillary tangles of τ protein. Mitochondria is crucial in maintaining cell survival, cell death, calcium regulation, and ATP synthesis. Mitochondrial dysfunction and linked calcium overload have been involved in the pathogenesis of AD. CRM2 (Collapsin response mediator protein-2) is involved in endosomal lysosomal trafficking as well as autophagy, and their reduced level is also a primary culprit in the progression of AD. In addition, Cholinergic neurotransmission and neuroinflammation are two other mechanisms implicated in AD onset and might be protective targets to attenuate disease progression. The microbiota-gut-brain axis (MGBA) is another crucial target for AD treatment. Crosstalk between gut microbiota and brain mutually benefitted each other, dysbiosis in gut microbiota affects the brain functions and leads to AD progression with increased AD-causing biomarkers. Despite the complexity of AD, treatment is only limited to symptomatic management. Therefore, there is an urgent demand for novel therapeutics that target associated pathways responsible for AD pathology. This review explores the role of different mechanisms involved in AD and possible therapeutic targets to protect against disease progression. BACKGROUND: Amidst various age-related diseases, AD is the most deleterious neurodegenerative disorder that affects more than 24 million people globally. Every year, approximately 7.7 million new cases of dementia have been reported. However, to date, no novel disease-modifying therapies are available to treat AD. OBJECTIVE: The aim of writing this review is to highlight the role of key biomarker proteins and possible therapeutic interventions that could play a crucial role in mitigating the ongoing prognosis of Alzheimer's disease. MATERIALS AND METHODS: The available information about the disease was collected through multiple search engines, including PubMed, Science Direct, Clinical Trials, and Google Scholar. RESULTS: Accumulated pieces of evidence reveal that extracellular aggregation of ß-amyloid plaques and intracellular tangles of τ protein are peculiar features of perpetuated Alzheimer's disease (AD). Further, the significant role of mitochondria, calcium, and cholinergic pathways in the pathogenesis of AD makes the respiratory cell organelle a crucial therapeutic target in this neurodegenerative disease. All currently available drugs either delay the clinical damage to cells or temporarily attenuate some symptoms of Alzheimer's disease. CONCLUSION: The pathological features of AD are extracellular deposition of ß-amyloid, acetylcholinesterase deregulation, and intracellular tangles of τ protein. The multifactorial heterogeneity of disease demands more research work in this field to find new therapeutic biological targets.
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Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Proteínas tau , Placa Amiloide , Acetilcolinesterase , Cálcio , Peptídeos beta-Amiloides/metabolismo , Progressão da Doença , Colinérgicos/uso terapêuticoRESUMO
Recently, the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been critically recognized and spread rapidly on this planet. Considerable recognition of SARS-CoV-2 has been known with a range of viruses that are more capable to cause diseases in avian and mammals including humans. The virus was found as a main culprit for major defects in respiratory system and thereby caused severe acute respiratory syndrome disease. This has led to depict the mortality in human population. Nevertheless, compromised reports on SARS-CoV-2 has also shown neurological complications in both central nervous system (CNS) and peripheral nervous system (PNS). This virus has notified with neurological defects as stroke, encephalopathy, cerebral edema, erythema, seizures, meningitis, ischemic, ageusia, loss of smell, myalgia and Guillain Barre Syndrome. In this review, we focused on COVID-19 mediated neurodegeneration and its mechanistic episodes on affected patients. We also discuss the possible available therapeutic interventions with clinically investigated drugs against COVID-19 mediated neurological impairment in patients and experimental in vitro and in vivo research models required for the development of drugs and/or vaccines against COVID-19 mediated neurological complications.
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COVID-19 , SARS-CoV-2 , Animais , COVID-19/complicações , Vacinas contra COVID-19 , Humanos , MamíferosRESUMO
Ulcerative colitis (UC) is a serious health condition and defined as inflammation in the colon. Untreated, UC can develop into colitis-associated cancer (CAC), for which effective medicines are not available. Natural products are a better choice to treat UC by alleviating the inflammation. Caffeic acid phenethyl ester (CAPE) is a phenolic compound and known for its beneficial effects, including antibacterial, anti-inflammatory, anti-diabetic, and anticancer. We aimed to study the effect of CAPE on dextran sulfate sodium (DSS)-induced UC in mouse model. Administration of CAPE to DSS-induced mice protected against colon damage by improving body weight of mice, reducing the weight of spleen, and increased colon length. In addition, administration of CAPE resulted reduced the activity of myeloperoxidase (MPO) and CD68+ positive cells. Furthermore, a significant decrease in the production of key cytokines and the expression of nuclear factor (p65-NF)-κB. Moreover, p65-NF-κB activation was reduced in lipopolysaccharide (LPS)-treated RAW 264.7 macrophage cells from mouse origin. CAPE treatment leads to the reduced expressions of intercellular adhesion molecules (ICAM)-1 and vascular cell adhesion molecules (VCAM), both are key cell adhesion molecules. The results of this study clearly indicate that CAPE can potentially control inflammation in the colon and can be used as a therapy for UC.
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NF-kappa BRESUMO
The most important role of tissue engineering is to develop a biomaterial with a property that mimics the extracellular matrix (ECM) by enhancing the lineage-specific proliferation and differentiation with favorable regeneration property to aid in new tissue formation. Thus, to develop an ideal scaffold for bone repair, we have fabricated a composite nanofiber by the coaxial electrospinning technique. The coaxial electrospun nanofiber contains the core layer, consisting of polyvinyl alcohol (PVA) blended with oregano extract and mesoporous silica nanoparticles (PVA-OE-MSNPs), and the shell layer, consisting of poly-ε-caprolactone blended with collagen and hydroxyapatite (PCL-collagen-HAP). We evaluated the physicochemical properties of the nanofibers using X-ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR). In vitro biocompatibility, cell adhesion, cell viability, and osteogenic potential were evaluated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenlytetrazolium bromide (MTT), calcein AM, and alkaline phosphatase (ALP) activity and Alizarin Red staining in NIH 3T3/MG-63 cells. The results showed that the nanoparticle-incorporated coaxial nanofiber was observed with bead-free, continuous, and uniform fiber morphology with a mean diameter in the range of 310 ± 125 nm. From the biochemical studies, it is observed that the incorporation of nanofiber with HAP and MSNPs shows good swelling property with ideal porosity, biodegradation, and enhanced biomineralization property. In vitro results showed that the scaffolds with nanoparticles have higher cell adhesion, cell viability, ALP activity, and mineralization potential. Thus, the fabricated nanofiber could be an appropriate implantable biomaterial for bone tissue engineering.
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Materiais Revestidos Biocompatíveis , Teste de Materiais , Nanofibras , Osteogênese/efeitos dos fármacos , Dióxido de Silício , Animais , Linhagem Celular , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Avaliação de Medicamentos , Camundongos , Nanofibras/química , Nanofibras/uso terapêutico , Porosidade , Dióxido de Silício/química , Dióxido de Silício/farmacologiaRESUMO
Purpose of Review: Neuropathic pain (NP) has been ubiquitously characterized by lesion and its linked somatosensory system either the central nervous system (CNS) or peripheral nervous system (PNS) This PNS episode is the most prevalent site of NP origin and is found to be associated with afferent nerve fibers carrying pain signals from injured/trauma site to the CNS including the brain. Several kinds of pharmacotherapeutic drugs shuch as analgesics, anti-convulsants, and anti-depressants are being employed for the its possible interventions. The NP has been a great interest to follow different pathophysiological mechanisms which are often considered to correlate with the metabolic pathways and its mediated disease. There is paucity of knowledge to make such mechanism via NP. Recent Finding: Most notably, recent pandemic outbreak of COVID-19 has also been reported in chronic pain mediated diabetes, inflammatory disorders, and cancers. There is an increasing incidence of NP and its complex mechanism has now led to identify the possible investigations of responsible genes and proteins via bioinformatics tools. The analysis might be more instrumental as collecting the genes from pain genetic database, analyzing the variants through differential gene expression (DEG) and constructing the protein-protein interaction (PPI) networks and thereby determining their upregulating and downregulating pathways. Summary: This review sheds a bright light towards several mechanisms at both cellular and molecular level, correlation of NP-mediated disease mechanism and possible cell surface biomarkers (receptors), and identified genes could be more promising for their pharmacological targets.
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Nanoparticle research is fascinating and getting hold of consequences due to the wide variety of applications in the biomedical field. Green synthesis of nanoparticles is a cost-effective and eco-friendly approach. It can be synthesised using fungi, algae, plant, yeast, bacteria, microbial enzymes etc. Our current research study focuses on the green synthesis of silver nanoparticles using seed extract of Cassia tora. The colour change from yellow to red colour confirms the formation of silver nanoparticles. The synthesised silver nanoparticles were characterised by Ultraviolet-Visible spectroscopy, Fourier-transform infrared (FTIR), X-ray diffraction analysis (XRD), Scanning Electron Microscopy (SEM) and antibacterial efficacy against three different strains were analysed. The surface plasmon resonance of synthesised AgNPs using Cassia tora seed extract shows maximum absorption peak at 423 nm in UV-visible spectroscopy. X-ray diffraction displays the crystalline nature of synthesised AgNPs and they exhibited four distinct peaks at 36.69°, 42.92°, 63.27° and 76.46°. The particle size of synthesised AgNPs observed through SEM was found to be 55.80 nm, 58.97 nm, 61.06 nm, 63.26 nm and 64.80 nm. S.aureus exhibited maximum zone of inhibition of 12 mm and 13 mm when treated with 25 and 50 µl of the synthesised nanoparticles. Thus, the green synthesised silver nanoparticle using Cassia tora seed extract proved to possess strong anti-bacterial activity.
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Antibacterianos , Cassia/química , Nanopartículas Metálicas/química , Extratos Vegetais/química , Sementes/química , Prata , Staphylococcus aureus/crescimento & desenvolvimento , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Química Verde , Prata/química , Prata/farmacologiaRESUMO
In recent years, inflammatory mediators have been considered a possible key for nonsteroidal anti-inflammatory drugs (NSAID's). NSAID's have been known as most promising medication against inflammation and its mediated pain. Inflammation could be recognize as a systemic adaptive stimulation triggered by detrimental stimuli as pathogenic attack and endogenous signals mediated injury inside the cells. In addition, there has been an inflammatory key mechanism involved in disease state. NSAIDs have been compromisingly recommended for targeting specific proteins and/or inflammatory-mediated enzymes including cyclooxygenases (COX). This subsequently inhibits the prostaglandins at the site of inflammation. For the past decades, two forms of the COX enzyme have been implicated as COX-1 expressed in cells and tissues and other COX-2 selectively triggered via proinflammatory cytokines at the site of inflammation and/or injury. In addition, NSAID's have also been implicated for the inhibition of NF-κB pathways, and other relevant proteins considered potent candidates for these drugs. NF-κB has been identified a classical proinflammatory signaling pathway. It has been recognized as a primary target for novel anti-inflammatory drugs. In our results, reports are being confirmed via the probable effects of NSAID's on inflammatory-mediated switches. Several studies were considered to enquire the possible interactions of NSAID's and inflammatory hub. Nevertheless, the exact mechanism is still debatable. In our study, NSAID's and their targeted proteins or molecules caused a convincing pattern. For improvised perception, the binding affinity of NSAID's with inflammatory-mediated proteins was quantified using a molecular docking tool. In addition, we have depicted the complex juncture of hydrogen bonding in targeted proteins with NSAID's. Our in silico investigations have revealed NSAID's as the powerful armor against COX-2- and NF-κB-mediated inflammation.
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Inibidores de Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/química , Simulação de Acoplamento Molecular , NF-kappa B , Linhagem Celular , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , NF-kappa B/químicaRESUMO
In the present study, we investigated the effects of conditioned media (CM) collected from the cancer cell lines (K562, MCF-7, and HeLa) on peripheral blood mononuclear cells (PBMCs) isolated from the healthy human blood. The soluble factors in the CM are probably responsible for the differential mRNA expressions of Foxp3, Helios, Neuropilin- 1 (NRP-1), and glycoprotein A repetitions predominant (GARP), along with IFN-γ and TGF-ß in PBMCs cultured with cancer cells CM. The PBMCs cultured with CM of K562 showed increased expression of Foxp3, Helios, NRP-1, GARP, IFN-γ, and TGF-ß compared to PBMCs cultured with CM of MCF-7 and HeLa cells. In addition, the intracellular staining on PBMCs cultured with CM from cell lines were also evaluated for CD4, CD25, Foxp3, Helios, and NRP-1 by multicolor flow cytometry. The expression of CD4+CD25+Foxp3+, CD4+Helios+Foxp3+ and CD+NRP-1+Foxp3+ showed retarded cell population compared to control PBMCs. Our data suggest that soluble factors in CM of cancer cells may trigger the immune response in PBMCs resulting in a systematic response. Further research could lead to the identification of specific soluble factors that are involved in trafficking of cells into the immune cascades, which could be a safe and promising strategy for targeting human cancers.
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Expressão Gênica , Interferon gama/genética , Leucócitos Mononucleares/metabolismo , Fator de Crescimento Transformador beta/genética , Meios de Cultivo Condicionados , Células HeLa , Humanos , Interferon gama/metabolismo , Células K562 , Células MCF-7 , Fator de Crescimento Transformador beta/metabolismoRESUMO
Colorectal carcinogenesis (CRC) imposes a major health burden in developing countries. It is the third major cause of cancer deaths. Despite several treatment strategies, novel drugs are warranted to reduce the severity of this disease. Adenomatous polyps in the colon are the major culprits in CRC and found in 45% of cancers, especially in patients 60 years of age. Inflammatory polyps are currently gaining attention in CRC, and a growing body of evidence denotes the role of inflammation in CRC. Several experimental models are being employed to investigate CRC in animals, which include the APCmin/+ mouse model, Azoxymethane, Dimethyl hydrazine, and a combination of Dextran sodium sulphate and dimethyl hydrazine. During CRC progression, several signal transduction pathways are activated. Among the major signal transduction pathways are p53, Transforming growth factor beta, Wnt/ß-catenin, Delta Notch, Hippo signalling, nuclear factor erythroid 2-related factor 2 and Kelch-like ECH-associated protein 1 pathways. These signalling pathways collaborate with cell death mechanisms, which include apoptosis, necroptosis and autophagy, to determine cell fate. Extensive research has been carried out in our laboratory to investigate these signal transduction and cell death mechanistic pathways in CRC. This review summarizes CRC pathogenesis and the related cell death and signal transduction pathways.
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INTRODUCTION: Colorectal cancer (CRC) is common, with a worldwide incidence estimated at more than 1 million cases annually. Therefore, the search for agents for CRC treatment is highly warranted. Inositol-6 phosphate (IP6) is enriched in rice bran and possesses many beneficial effects. In the present study the effect of IP6 on autophagy-mediated death by modulating the mTOR pathway in HT-29 colon cancer cells was studied. MATERIAL AND METHODS: Autophagy was assessed by acridine orange (AO) staining, transmission electron microscopy, and western blotting to detect LC3-II and Beclin 1. Akt/mTOR signaling protein expression was also analyzed by western blotting. Apoptosis was analyzed by annexin V staining. RESULTS: Incubation of cells with IP6 resulted in downregulation of the p-Akt at 3h. Along with that confocal microscopic analysis of p-AKT, IP6 administration resulted that a diminished expression of p-Akt. mTOR pathway regulates autophagy and incubation with IP6 to HT-29 cells showed decreased expression of p-70S6Kinase, 4-EBP-1 in a time-dependent manner. Inositol-6 phosphate (10 µg/ml, 24 and 48 h) induced autophagic vesicles, as confirmed by AO staining and transmission electron microscopy. We also found increased expression of LC3-II and Beclin 1 in a time-dependent manner after incubation with IP6. Furthermore, IP6 induced apoptosis, as revealed by annexin V staining. CONCLUSIONS: Our results clearly indicate that IP6 induces autophagy by inhibiting the Akt/mTOR pathway.
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The growth and lectin production of Ganoderma applanatum, a white rot fungus, was optimized in broth cultures. The fungus was found to have a higher growth rate and higher lectin activity when grown in a medium adjusted to pH 6.5 at 26°C under stationary conditions. Expression of lectin activity started in 5-day-old mycelial culture; maximum activity was expressed after the 15th day of incubation. Among the various carbon and nitrogen sources tested, the carbon source sucrose and the nitrogen source yeast extract support maximum growth and lectin production. Lectin from G. applanatum was purified by ammonium sulfate precipitation and ion exchange chromatography. The purified fraction revealed a single band with a molecular weight of 35.0 kDa. Moreover, carbohydrates such as mannitol, glucose, sucrose, maltose, mannose, galactose, sorbose, and fructose were found to inhibit the hemagglutinating activity of the lectin. The purified lectins from G. applanatum contain cytotoxic and proapoptotic activities against HT-29 colon adenocarcinoma cells.
Assuntos
Antineoplásicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Ganoderma/química , Lectinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbono/metabolismo , Linhagem Celular Tumoral , Senescência Celular , Cromatografia por Troca Iônica , Neoplasias do Colo , Ensaios de Seleção de Medicamentos Antitumorais , Testes de Hemaglutinação , Humanos , Concentração de Íons de Hidrogênio , Lectinas/química , Lectinas/isolamento & purificação , Nitrogênio/metabolismo , TemperaturaRESUMO
Microtubule Targeting Agents (MTAs) induce cell death through mitotic arrest, preferentially affecting rapidly dividing cancer cells over slowly proliferating normal cells. Previously, we showed that Methyl 2-(-5-fluoro-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (MBIC) acts as a potential MTA. In this study, we demonstrated that MBIC exhibits greater toxicity towards non-aggressive breast cancer cell-line, MCF-7 (IC50 = 0.73 ± 0.0 µM) compared to normal fibroblast cell-line, L-cells (IC50 = 59.6 ± 2.5 µM). The IC50 of MBIC against the aggressive breast cancer cell-line, MDA-MB-231 was 20.4 ± 0.2 µM. We hypothesized that the relatively high resistance of MDA-MB-231 cells to MBIC is associated with p53 mutation. We investigated p53 and three of its downstream proteins: survivin, cyclin dependent kinase (Cdk1) and cyclin B1. Following treatment with MBIC, survivin co-immunoprecipitated with caspases with higher affinity in MDA-MB-231 compared to MCF-7 cells. Furthermore, silencing survivin caused a 4.5-fold increase in sensitivity of MDA-MB-231 cells to MBIC (IC50 = 4.4 ± 0.3). In addition, 4 weeks of MBIC administration in MDA-MB-231 cells inoculated BALB/c nude mice resulted in 79.7% reduction of tumor volume compared to the untreated group with no severe sign of toxicity. Our results demonstrated MBIC has multiple anti-tumor actions and could be a potential drug in breast cancer therapy.
Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Ácidos Carboxílicos/uso terapêutico , Proteínas Inibidoras de Apoptose/metabolismo , Microtúbulos/metabolismo , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzimidazóis/química , Benzimidazóis/farmacologia , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina B/genética , Ciclina B/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Proteínas Inibidoras de Apoptose/genética , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Interferente Pequeno/genética , Survivina , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Phytometabolites are functional elements derived from plants and most of them exhibit therapeutic characteristics such as anti-cancer, anti-inflammatory and anti-oxidant effects. Phytometabolites exert their anti-cancer effect by targeting multiple signaling pathways. One of the remarkable phenomena targeted by phytometabolites is the Warburg effect. The Warburg effect describes the observation that cancer cells exhibit an increased rate of glycolysis and aberrant redox activity compared to normal cells. This phenomenon promotes further cancer development and progression. Recent observations revealed that some phytometabolites could target metabolic-related enzymes (e.g. Hexokinase, Pyruvate kinase M2, HIF-1) in cancer cells, with little or no harm to normal cells. Since hyper-proliferation of cancer cells is fueled by higher cellular metabolism, phytometabolites targeting these metabolic pathways can create synergistic crosstalk with induced apoptotic pathways and sensitize cancer cells to chemotherapeutic agents. In this review, we discuss phytometabolites that target the Warburg effect and the underlying molecular mechanism that leads to tumor growth suppression.