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1.
J Med Virol ; 96(5): e29628, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38682568

RESUMO

This study evaluated the potential for antibody-dependent enhancement (ADE) in serum samples from patients exposed to Middle East respiratory syndrome coronavirus (MERS-CoV). Furthermore, we evaluated the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination on ADE in individuals with a MERS infection history. We performed ADE assay in sera from MERS recovered and SARS-CoV-2-vaccinated individuals using BHK cells expressing FcgRIIa, SARS-CoV-2, and MERS-CoV pseudoviruses (PVs). Further, we analyzed the association of ADE to serum IgG levels and neutralization. Out of 16 MERS patients, nine demonstrated ADE against SARS-CoV-2 PV, however, none of the samples demonstrated ADE against MERS-CoV PV. Furthermore, out of the seven patients exposed to SARS-CoV-2 vaccination after MERS-CoV infection, only one patient (acutely infected with MERS-CoV) showed ADE for SARS-CoV-2 PV. Further analysis indicated that IgG1, IgG2, and IgG3 against SARS-CoV-2 S1 and RBD subunits, IgG1 and IgG2 against the MERS-CoV S1 subunit, and serum neutralizing activity were low in ADE-positive samples. In summary, samples from MERS-CoV-infected patients exhibited ADE against SARS-CoV-2 and was significantly associated with low levels of neutralizing antibodies. Subsequent exposure to SARS-CoV-2 vaccination resulted in diminished ADE activity while the PV neutralization assay demonstrated a broadly reactive antibody response in some patient samples.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Anticorpos Facilitadores , COVID-19 , Imunoglobulina G , Coronavírus da Síndrome Respiratória do Oriente Médio , SARS-CoV-2 , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Anticorpos Antivirais/sangue , SARS-CoV-2/imunologia , Imunoglobulina G/sangue , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Pessoa de Meia-Idade , Masculino , Feminino , Testes de Neutralização , Adulto , Vacinas contra COVID-19/imunologia , Antígenos Virais/imunologia , Animais , Idoso , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação
2.
Nutrients ; 15(19)2023 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-37836560

RESUMO

Breast cancer (BC) is the most common malignancy, and conventional medicine has failed to establish efficient treatment modalities. Conventional medicine failed due to lack of knowledge of the mechanisms that underpin the onset and metastasis of tumors, as well as resistance to treatment regimen. However, Complementary and Alternative medicine (CAM) modalities are currently drawing the attention of both the public and health professionals. Our study examined the effect of a super-combination (SC) of crude extracts, which were isolated from three selected Qatari medicinal plants, on the proliferation, motility and death of BC cells. Our results revealed that SC attenuated cell growth and caused the cell death of MDA-MB-231 cancer cells when compared to human normal neonatal fibroblast cells. On the other hand, functional assays showed that SC reduced BC cell migration and invasion, respectively. SC-inhibited cell cycle and SC-regulated apoptosis was most likely mediated by p53/p21 pathway and p53-regulated Bax/BCL-2/Caspace-3 pathway. Our ongoing experiments aim to validate these in vitro findings in vivo using a BC-Xenograft mouse model. These findings support our hypothesis that SC inhibited BC cell proliferation and induced apoptosis. These findings lay the foundation for further experiments, aiming to validate SC as an effective chemoprevention and/or chemotherapeutic strategy that can ultimately pave the way towards translational research/clinical trials for the eradication of BC.


Assuntos
Neoplasias da Mama , Plantas Medicinais , Recém-Nascido , Humanos , Animais , Camundongos , Feminino , Neoplasias da Mama/metabolismo , Proteína Supressora de Tumor p53 , Linhagem Celular Tumoral , Apoptose , Proliferação de Células , Movimento Celular
3.
Artigo em Inglês | MEDLINE | ID: mdl-37252376

RESUMO

Breast cancer (BC) is the most common malignancy worldwide and has a poor prognosis, because it begins in the breast and disseminates to lymph nodes and distant organs. While invading, BC cells acquire aggressive characteristics from the tumor microenvironment through several mechanisms. Thus, understanding the mechanisms underlying the process of BC cell invasion can pave the way towards the development of targeted therapeutics focused on metastasis. We have previously reported that the activation of CD44 receptor with its major ligand hyaluronan (HA) promotes BC metastasis to the liver in vivo. Next, a gene expression profiling microarray analysis was conducted to identify and validate CD44-downstream transcriptional targets mediating its pro-metastatic function from RNA samples collected from Tet CD44-induced versus control MCF7-B5 cells. We have already validated a number of novel CD44-target genes and published their underlying signaling pathways in promoting BC cell invasion. From the same microarray analysis, Integrin subunit beta 1 binding protein 1 (ITGB1BP1) was also identified as a potential CD44-target gene that was upregulated (2-fold) upon HA activation of CD44. This report will review the lines of evidence collected from the literature to support our hypothesis, and further discuss the possible mechanisms linking HA activation of CD44 to its novel potential transcriptional target ITGB1BP1.

4.
Nutrients ; 15(7)2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-37049499

RESUMO

Drug resistance is a well-known and significant obstacle in the battle against cancer, rendering chemotherapy treatments often ineffective. To improve the effectiveness of chemotherapy, researchers are exploring the use of natural molecules that can enhance its ability to kill cancer cells and limit their spread. Docosahexaenoic acid (DHA), a lipid found in marine fish, has been shown to enhance the cytotoxicity of various anti-cancer drugs in vitro and in vivo. While the combined use of chemotherapeutic drugs with DHA demonstrated promising preliminary results in clinical trials, there is still a significant amount of information to be discovered regarding the precise mechanism of action of DHA. As the biological pathways involved in the chemosensitization of already chemoresistant MCF-7 cells are still not entirely unraveled, in this study, we aimed to investigate whether DHA co-treatment could enhance the ability of the chemotherapy drug doxorubicin to inhibit the growth and invasion of MCF-7 breast cancer cells (MCF-7/Dox) that had become resistant to the drug. Upon treating MCF-7/Dox cells with DHA or DHA-doxorubicin, it was observed that the DHA-doxorubicin combination effectively enhanced cancer cell death by impeding in vitro propagation and invasive ability. In addition, it led to an increase in doxorubicin accumulation and triggered apoptosis by arresting the cell cycle at the G2/M phase. Other observed effects included a decrease in the multi-drug resistance (MDR) carrier P-glycoprotein (P-gp) and TG2, a tumor survival factor. Augmented quantities of molecules promoting apoptosis such as Bak1 and caspase-3 and enhanced lipid peroxidation were also detected. Our findings in the cell model suggest that DHA can be further investigated as a natural compound to be used alongside doxorubicin in the treatment of breast cancer that is unresponsive to chemotherapy.


Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Animais , Feminino , Células MCF-7 , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Doxorrubicina/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/metabolismo , Apoptose , Linhagem Celular Tumoral
5.
J Infect Public Health ; 16(5): 808-815, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36996614

RESUMO

Seasonal influenza viruses may lead to severe illness and mortality in patients with comorbidities, including Diabetes Mellitus (DM). Vaccination against influenza in DM patients may reduce influenza incidence and severity. Before the emergence of the COVID-19 pandemic, influenza infections were the most prevalent respiratory infections in Qatar. Still, reports about influenza prevalence and vaccine efficacy in DM patients have not been reported. This study aimed to analyze influenza prevalence among other respiratory infections and assess influenza vaccine efficacy in DM patients in Qatar. Statistical analysis was performed on data obtained from Hamad Medical Corporation (HMC) database for patients that visited the emergency department (ED) with respiratory-like illnesses. The analysis was done for the period between January 2016 to December 2018. Among 17,525 patients who visited HMC-ED with clinical symptoms of respiratory infections, 2611(14.9%) were reported to have DM. Among DM patients, influenza was the most prevalent respiratory pathogen at 48.9%. Influenza virus A (IVA) was the most circulating type, contributing to 38.4%, followed by IVB contributing to 10.4% of total respiratory infections. Among the typed IVA-positive cases, 33.4% were H1N1, and 7.7% were H3N2. A significant decrease in influenza infections was reported in vaccinated DM patients (14.5%) when compared to non-vaccinated patients (18.9%) (p-value = 0.006). However, there was no significant relaxation in the clinical symptoms among vaccinated DM patients compared to their non-vaccinated counterparts. In conclusion, influenza was the most common etiology for respiratory viral infection among diabetic patients at the leading healthcare provider in Qatar. Although vaccination reduced the incidence rate among DM patients, it was less effective in preventing symptoms. Further studies on a larger cohort and for a more extended period are required to investigate influenza prevalence and vaccine efficacy among DM patients.


Assuntos
COVID-19 , Diabetes Mellitus , Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Influenza Humana , Infecções Respiratórias , Humanos , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Vírus da Influenza A Subtipo H3N2 , Prevalência , Catar/epidemiologia , Pandemias , Eficácia de Vacinas , COVID-19/epidemiologia , Infecções Respiratórias/epidemiologia , Estações do Ano , Diabetes Mellitus/epidemiologia
6.
Pharmaceutics ; 15(2)2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36839725

RESUMO

The proteinaceous compounds produced by lactic acid bacteria are called bacteriocins and have a wide variety of bioactive properties. However, bacteriocin's commercial availability is limited due to short stability periods and low yields. Therefore, the objective of this study was to synthesize bacteriocin-derived silver nanoparticles (Bac10307-AgNPs) extracted from Lactobacillus acidophilus (L. acidophilus), which may have the potential to increase the bioactivity of bacteriocins and overcome the hurdles. It was found that extracted and purified Bac10307 had a broad range of stability for both temperature (20-100 °C) and pH (3-12). Further, based on Sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis, its molecular weight was estimated to be 4.2 kDa. The synthesized Bac10307-AgNPs showed a peak of surface plasmon resonance at 430 nm λmax. Fourier transform infrared (FTIR) confirmed the presence of biological moieties, and transmission electron microscopy (TEM) coupled with Energy dispersive X-Ray (EDX) confirmed that AgNPs were spherical and irregularly shaped, with a size range of 9-20 nm. As a result, the Bac10307-AgNPs displayed very strong antibacterial activity with MIC values as low as 8 µg/mL for Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa), when compared to Bac10307 alone. In addition, Bac10307-AgNPs demonstrated promising in vitro antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) (IC50 = 116.04 µg/mL) and in vitro cytotoxicity against human liver cancer cells (HepG2) (IC50 = 135.63 µg/mL), more than Bac10307 alone (IC50 = 139.82 µg/mL against DPPH and 158.20 µg/mL against HepG2). Furthermore, a protein-protein molecular docking simulation study of bacteriocins with target proteins of different biological functions was also carried out in order to ascertain the interactions between bacteriocins and target proteins.

7.
Front Oncol ; 12: 1038121, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36505828

RESUMO

Our tetracycline-off-inducible CD44 expression system previously established in mouse model, revealed that activation of CD44 with its major ligand hyaluronan (HA) promoted breast cancer (BC) metastasis to the liver. To identify the mechanisms that underpin CD44-promoted BC cell invasion, microarray gene expression profiling using RNA samples from (Tet)-Off-regulated expression system of CD44s in MCF7 cells, revealed a set of upregulated genes including, nuclear sirtuin-1 (SIRT1 also known as NAD-dependent deacetylase), an enzyme that requires NAD+ as a cofactor to deacetylate several histones and transcription factors. It stimulates various oncogenic pathways promoting tumorigenesis. This data suggests that SIRT1 is a potential novel transcriptional target of CD44-downstream signaling that promote BC cell invasion/metastasis. This review will discuss the evidence supporting this hypothesis as well as the mechanisms linking SIRT1 to cell proliferation and invasion.

8.
Mol Immunol ; 152: 172-182, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371813

RESUMO

Antibody-dependent enhancement (ADE) has been associated with severe disease outcomes in several viral infections, including respiratory infections. In vitro and in vivo studies showed that antibody-response to SARS-CoV and MERS-CoV could exacerbate infection via ADE. Recently in SARS CoV-2, the in vitro studies and structural analysis shows a risk of disease severity via ADE. This phenomenon is partially attributed to non-neutralizing antibodies or antibodies at sub-neutralizing levels. These antibodies result in antigen-antibody complexes' deposition and propagation of a chronic inflammatory process that destroys affected tissues. Further, antigen-antibody complexes may enhance the internalization of the virus into cells through the Fc gamma receptor (FcγR) and lead to further virus replication. Thus, ADE occur via two mechanisms; 1. Antibody mediated replication and 2. Enhanced immune activation. Antibody-mediated effector functions are mainly driven by complement activation, and the first complement in the cascade is complement 1q (C1q) which binds to the virus-antibody complex. Reports say that deficiency in circulating plasma levels of C1q, an independent predictor of mortality in high-risk patients, including diabetes, is associated with severe viral infections. Complement mediated ADE is reported in several viral infections such as dengue, West Nile virus, measles, RSV, Human immunodeficiency virus (HIV), and Ebola virus. This review discusses ADE in viral infections and the in vitro evidence of ADE in coronaviruses. We outline the mechanisms of ADE, emphasizing the role of complements, especially C1q in the outcome of the enhanced disease.


Assuntos
COVID-19 , Síndrome Respiratória Aguda Grave , Humanos , Anticorpos Facilitadores , Complemento C1q , Complexo Antígeno-Anticorpo , Anticorpos Antivirais
9.
Front Oncol ; 12: 878034, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35756640

RESUMO

Breast Cancer (BC) is the most common and the major health issue in women worldwide. Metastasis, a multistep process, is the worst aspect of cancer and tumor cell invasion is the defining step. Tumor cell invasion requires cell adhesion molecules (CAMs), and alterations in CAMs is considered as an initiating event in metastasis. Among CAMs, CD44 is a large family of more than 100 isoform, and its precise function was initially controversial in BC. Therefore, we have previously established a (Tet)-off inducible expression system of CD44 in MCF-7 primary BC cell line, and showed that CD44 promoted BC invasion/metastasis both in vitro and in vivo. A microarray gene expression profiling revealed more than 200 CD44-downstream potential transcriptional target genes, mediating its role in BC cell invasion and metastasis. Among these CD44-target genes, the Pre-mRNA cleavage complex 2 protein (PCF11) was upregulated upon the activation of CD44 by its major ligand hyaluronan (HA); This prompted us to hypothesize PCF11 as a potential novel transcriptional target of CD44-promoted BC cell invasion and metastasis. A large body of evidence from the literature supports our hypothesis that CD44 might regulate PCF11 via MAPK/ERK pathway. This review aims to discuss these findings from the literature that support our hypothesis, and further provide possible mechanisms linking CD44-promoted cell invasion through regulation of its potential target PCF11.

10.
Front Nutr ; 9: 882956, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35634400

RESUMO

Breast cancer (BC) is the most common malignant cancer in females worldwide. Drug resistance, toxicity, and the failure of current therapies to completely cure BC has challenged conventional medicine. Consequently, complementary alternative medicine has become popular due to its safety and efficacy. Haematococcus pluvialis (H. pulvialis) is a green microalga living in fresh water, and its crude extract is rich of bioactives, including carotenoids, known to inhibit cancer cell growth. In the present study, we investigated the effects of a methanol crude extract called "T1" of H. pulvialis on cell growth and migration/invasion of the BC cell line MDA-MB-231 in comparison to the fibroblast control cells. TI significantly suppressed BC cell growth, inhibited migration and invasion and induced apoptosis. Interestingly, apoptosis was mediated by a significant loss of mutant p53 protein, and increased Bax/Bcl2 ratio. Our findings support our hypothesis that T1 exerts its anti-cancer effects by inhibiting BC invasion and inducing apoptosis mediated, at least, via the p53/Bax/Bcl2 pathway. Ongoing experiments aim to identify the molecular mechanisms underpinning T1-inhibited BC cell invasion using pre-designed metastasis gene-based array method.

11.
J Infect Public Health ; 15(4): 412-424, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35339014

RESUMO

Over the past two decades, diabetes mellitus (DM) has been receiving increasing attention among autoimmune diseases. The prevalence of type 1 and type 2 diabetes has increased rapidly and has become one of the leading causes of death worldwide. Therefore, a better understanding of the genetic and environmental risk factors that trigger the onset of DM would help develop more efficient therapeutics and preventive measures. The role and mechanism of respiratory viruses in inducing autoimmunity have been frequently reported. On the other hand, the association of DM with respiratory infections might result in severe complications or even death. Since influenza is the most common respiratory infection, DM patients experience disease severity and increased hospitalization during influenza season. Vaccinating diabetic patients against influenza would significantly reduce hospitalization due to disease severity. However, recent studies also report the role of viral vaccines in inducing autoimmunity, specifically diabetes. This review reports causes of diabetes, including genetic and viral factors, with a special focus on respiratory viruses. We further brief the burden of influenza-associated complications and the effectiveness of the influenza vaccine in DM patients.


Assuntos
Diabetes Mellitus Tipo 2 , Vacinas contra Influenza , Influenza Humana , Infecções Respiratórias , Vírus , Hospitalização , Humanos , Influenza Humana/complicações , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Infecções Respiratórias/complicações , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/prevenção & controle
12.
Molecules ; 27(3)2022 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-35164076

RESUMO

CD44, a cell-adhesion molecule has a dual role in tumor growth and progression; it acts as a tumor suppressor as well as a tumor promoter. In our previous work, we developed a tetracycline-off regulated expression of CD44's gene in the breast cancer (BC) cell line MCF-7 (B5 clone). Using cDNA oligo gene expression microarray, we identified SOD2 (superoxide dismutase 2) as a potential CD44-downstream transcriptional target involved in BC metastasis. SOD2 gene belongs to the family of iron/manganese superoxide dismutase family and encodes a mitochondrial protein. SOD2 plays a role in cell proliferation and cell invasion via activation of different signaling pathways regulating angiogenic abilities of breast tumor cells. This review will focus on the findings supporting the underlying mechanisms associated with the oncogenic potential of SOD2 in the onset and progression of cancer, especially in BC and the potential clinical relevance of its various inhibitors.


Assuntos
Neoplasias da Mama/genética , Receptores de Hialuronatos/genética , Superóxido Dismutase/genética , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/análise , Receptores de Hialuronatos/metabolismo , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Superóxido Dismutase/análise , Superóxido Dismutase/metabolismo , Ativação Transcricional
13.
J Cell Mol Med ; 25(5): 2309-2314, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33486887

RESUMO

Using a validated tetracycline-off-inducible CD44 expression system in mouse model, we have previously demonstrated that the hyaluronan (HA) receptor CD44 promotes breast cancer (BC) metastasis to the liver. To unravel the mechanisms that underpin CD44-promoted BC cell invasion, RNA samples were isolated from two cell models: (a) a tetracycline (Tet)-Off-regulated expression system of the CD44s in MCF-7 cells and; (b) as a complementary approach, the highly metastatic BC cells, MDA-MB-231, were cultured in the presence and absence of 50 µg/mL of HA. Kynureninase (KYNU), identified by Microarray analysis, was up-regulated by 3-fold upon induction and activation of CD44 by HA; this finding suggests that KYNU is a potential novel transcriptional target of CD44-downtstream signalling. KYNU is a pyridoxal phosphate (PLP) dependent enzyme involved in the biosynthesis of NAD cofactors from tryptophan that has been associated with the onset and development of BC. This review will attempt to identify and discuss the findings supporting this hypothesis and the mechanisms linking KYNU cell invasion via CD44.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptores de Hialuronatos/metabolismo , Hidrolases/genética , Hidrolases/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Movimento Celular , Suscetibilidade a Doenças , Desenvolvimento de Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hidrolases/antagonistas & inibidores , Hidrolases/química , Invasividade Neoplásica , Transdução de Sinais , Relação Estrutura-Atividade
14.
J Cell Mol Med ; 24(19): 11477-11488, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32888398

RESUMO

Breast cancer (BC) is the most common malignancy and the leading cause of death in women worldwide. Only 5%-10% of mutations in BRCA genes are associated with familial breast tumours in Eastern countries, suggesting the contribution of other genes. Using a microarray gene expression profiling study of BC, we have recently identified BRIP1 (fivefold up-regulation) as a potential gene associated with BC progression in the Omani population. Although BRIP1 regulates DNA repair and cell proliferation, the precise role of BRIP1 in BC cell invasion/metastasis has not been explored yet; this prompted us to test the hypothesis that BRIP1 promotes BC cell proliferation and invasion. Using a combination of cellular and molecular approaches, our results revealed differential overexpression of BRIP1 in different BC cell lines. Functional assays validated further the physiological relevance of BRIP1 in tumour malignancy, and siRNA-mediated BRIP1 knockdown significantly reduced BC cell motility by targeting key motility-associated genes. Moreover, down-regulation of BRIP1 expression significantly attenuated cell proliferation via cell cycle arrest. Our study is the first to show the novel function of BRIP1 in promoting BC cell invasion by regulating expression of various downstream target genes. Furthermore, these findings provide us with a unique opportunity to identify BRIP1-induced pro-invasive genes that could serve as biomarkers and/or targets to guide the design of appropriate BC targeted therapies.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , RNA Helicases/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , RNA Helicases/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Cicatrização
15.
J Cancer ; 11(15): 4521-4533, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32489469

RESUMO

Conventional therapies for cancer treatment have posed many challenges, including toxicity, multidrug resistance and economic expenses. In contrast, complementary alternative medicine (CAM), employing phytochemicals have recently received increased attention owing to their capability to modulate a myriad of molecular mechanisms with a less toxic effect. Increasing evidence from preclinical and clinical studies suggest that phytochemicals can favorably modulate several signaling pathways involved in cancer development and progression. Combinations of phytochemicals promote cell death, inhibit cell proliferation and invasion, sensitize cancerous cells, and boost the immune system, thus making them striking alternatives in cancer therapy. We previously investigated the effect of six phytochemicals (Indol-3-Carbinol, Resveratrol, C-phycocyanin, Isoflavone, Curcumin and Quercetin), at their bioavailable levels on breast cancer cell lines and were compared to primary cell lines over a period of 6 days. This study showed the compounds had a synergestic effect in inhibiting cell proliferation, reducing cellular migration and invasion, inducing both cell cycle arrest and apoptosis. Despite the vast number of basic science and preclinical cancer studies involving phytochemicals, the number of CAM clinical trials in cancer treatment still remains nascent. In this review, we summarize findings from preclinical and clinical studies, including our work involving use of phytochemicals, individually as well as in combination and further discuss the potential of these phytochemicals to pave way to integrate CAM in primary health care.

16.
Front Biosci (Elite Ed) ; 12(2): 223-236, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32114459

RESUMO

We have previously characterized the role of p16/Rb in coordinating the early events in UVB-irradiated skin. As an extension to this work, normal melanocytes and mutant p16-inducible melanoma cell models were employed to elucidate further the coordinated molecular mechanisms occurring during early UVB exposure. Our results showed that melanocytes expressed p16 only at a high UVB dose, with undetectable p53. The Bax/Bcl2 ratio increased at higher dose, indicating that the cells had selected apoptosis program. In the wt-p16 melanoma cells, while low UVB dose upregulated p16, the high dose suppressed it, and further abrogated Cdk6 but not Cdk4. Interestingly, while induction of mutant-p16 increased Cdk4, cdk6 and pRb proteins, UVB exposure did not affect this increase. More interestingly, p16 mutant cells increased their resistance to apoptosis at high UVB-dose, associated with decreased Bax and increased Bcl2 expression. Thus, mutant-p16 appears to dictate a deregulation of cell cycle and increased resistance to apoptosis in melanoma cells. Together, the data indicate a deregulation of p16INK4/Rb pathway as an early event in UVB-induced melanomagenesis.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Melanócitos/efeitos da radiação , Melanoma/etiologia , Proteína do Retinoblastoma/metabolismo , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Genes p16 , Humanos , Melanócitos/metabolismo , Raios Ultravioleta/efeitos adversos
17.
Bioprinting ; 182020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32099931

RESUMO

Despite the recent rigorous studies towards a possible cure, cancer still remains as one of the most daunting problems faced by the humanity. Currently utilized two-dimensional cancer models are known to have various insuperable limitations such as insufficient biomimicry of the heterogeneous conditions of tumors and their three-dimensional structures. Discrepancies between the laboratory models and the actual tumor environment significantly impair a thorough comprehension of the carcinogenesis process and development of successful remedies against cancer. Modeling tumor microenvironments through bioprinting poses strong potential to minimize the effects of the aforementioned issues thanks to its freeform nature, adaptability, customizability, scalability and diversity. Numerous research studies involving three-dimensional modeling of various cancer types using bioprinting technologies have been reported, recently. In this review, we provide a broad summary of these studies to help better represent their potential and analyze their contribution to cancer research.

18.
Int J Med Sci ; 17(1): 103-111, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929744

RESUMO

Beyond their role in bone and lung homeostasis, mesenchymal stem cells (MSCs) are becoming popular in cell therapy. Various insults may disrupt the repair mechanisms involving MSCs. One such insult is smoking, which is a major risk factor for osteoporosis and respiratory diseases. Upon cigarette smoke-induced damage, a series of reparatory mechanisms ensue; one such mechanism involves Glycosaminoglycans (GAG). One of these GAGs, namely hyaluronic acid (HA), serves as a potential therapeutic target in lung injury. However, much of its mechanisms of action through its major receptor CD44 remains unexplored. Our previous studies have identified and functionally validated that both cortactin (CTTN: marker of motility) and Survivin (BIRC5: required for cell survival) act as novel HA/CD44-downstream transcriptional targets underpinning cell motility. Here, human MSCs were treated with "Water-pipe" smoke to investigate the effects of cigarette smoke condensate (CSC) on these HA-CD44 novel signaling pathways. Our results show that CSC decreased the expression of both CD44 and its downstream targets CTTN and BIRC5 in MSCs, and that HA reversed these effects. Interestingly, CSC inhibited migration and invasion of MSCs upon CD44-targeted RNAi treatment. This shows the importance of CD44-HA/CTTN and CD44-HA/BIRC5 signaling pathways in MSC motility, and further suggests that these signaling pathways may provide a novel mechanism implicated in migration of MSCs during repair of lung tissue injury. These findings suggest that one should use caution before utilizing MSC from donors with history of smoking, and further pave the way towards the development of targeted therapeutic approaches against CD44-associated diseases.


Assuntos
Fumar Cigarros/efeitos adversos , Cortactina/genética , Receptores de Hialuronatos/genética , Lesão Pulmonar/genética , Survivina/genética , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glicosaminoglicanos/genética , Humanos , Ácido Hialurônico/genética , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/patologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/patologia , Transdução de Sinais/efeitos dos fármacos , Fumar/efeitos adversos
19.
Nutrients ; 11(11)2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31717258

RESUMO

The preventive effect of high-dose (9%) regular-fish oil (FO) against bone loss during aging has been demonstrated, but the effects of a low-dose (1%-4%) of a highly purified concentrated FO (CFO) has not been elucidated. The aim of this study was to determine the dose-dependent effect of a CFO against bone loss in C57BL/6 female mice during aging. Twelve-month old mice were fed with 1% and 4% CFO and 4% safflower oil (SFO) diets, including a group with a 4% regular-FO diet and a group with a lab chow diet for 12 months. Bone mineral density (BMD) was analyzed by dual-energy x-ray absorptiometry (DXA) before and after the dietary intervention. At the end of dietary intervention, bone resorption markers in serum and inflammatory markers in bone marrow and splenocytes and inflammatory signaling pathways in the bone marrow were analyzed. As compared to the 4% SFO control, 4% CFO maintained higher BMD during aging, while 1% CFO offered only a mild benefit. However, the 1% CFO fed group exhibited slightly better BMD than the 4% regular-FO fed group. BMD loss protection by CFO was accompanied by reduced levels of the bone resorption marker, TRAP, and the osteoclast-stimulating-factor, RANKL, without affecting the decoy-receptor of RANKL, osteoprotegerin (OPG). Further, CFO supplementation was associated with an increase in the production of IL-10, IL-12, and IFN-γ and a decrease in the production of TNF-α and IL-6, and the activation of NF-κB, p38 MAPK, and JNK signaling pathways. In conclusion, the supplementation of 4% CFO is very efficient in maintaining BMD during aging, whereas 1% CFO is only mildly beneficial. CFO supplementation starting at middle age may maintain better bone health during aging.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Suplementos Nutricionais/análise , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Osteoporose/prevenção & controle , Fatores Etários , Animais , Conservadores da Densidade Óssea/análise , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Osso e Ossos/fisiopatologia , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/análise , Ácido Eicosapentaenoico/análise , Feminino , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos Endogâmicos C57BL , Osteoporose/diagnóstico por imagem , Osteoporose/metabolismo , Osteoporose/fisiopatologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
FASEB J ; 33(12): 14051-14066, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31661292

RESUMO

Cancer was recently annexed to diabetic complications. Furthermore, recent studies suggest that cancer can increase the risk of diabetes. Consequently, diabetes and cancer share many risk factors, but the cellular and molecular pathways correlating diabetes and colon and rectal cancer (CRC) remain far from understood. In this study, we assess the effect of hyperglycemia on cancer cell aggressiveness in human colon epithelial adenocarcinoma cells in vitro and in an experimental animal model of CRC. Our results show that Nox (NADPH oxidase enzyme) 4-induced reactive oxygen species (ROS) production is deregulated in both diabetes and CRC. This is paralleled by inactivation of the AMPK and activation of the mammalian target of rapamycin (mTOR) C1 signaling pathways, resulting in 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) accumulation, induction of DNA damage, and exacerbation of cancer cell aggressiveness, thus contributing to the genomic instability and predisposition to increased tumorigenesis in the diabetic milieu. Pharmacologic activation of AMPK, inhibition of mTORC1, or blockade of Nox4 reduce ROS production, restore the homeostatic signaling of 8-oxoguanine DNA glycosylase/8-oxodG, and lessen the progression of CRC malignancy in a diabetic milieu. Taken together, our results identify the AMPK/mTORC1/Nox4 signaling axis as a molecular switch correlating diabetes and CRC. Modulating this pathway may be a strategic target of therapeutic potential aimed at reversing or slowing the progression of CRC in patients with or without diabetes.-Mroueh, F. M., Noureldein, M., Zeidan, Y. H., Boutary, S., Irani, S. A. M., Eid, S., Haddad, M., Barakat, R., Harb, F., Costantine, J., Kanj, R., Sauleau, E.-A., Ouhtit, A., Azar, S. T., Eid, A. H., Eid, A. A. Unmasking the interplay between mTOR and Nox4: novel insights into the mechanism connecting diabetes and cancer.


Assuntos
NADPH Oxidase 4/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Antibióticos Antineoplásicos/farmacologia , Glicemia , Células CACO-2 , Dano ao DNA , Diabetes Mellitus Experimental , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NADPH Oxidase 4/genética , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Regulação para Cima
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