7-Geranyloxcycoumarin enhances radio sensitivity in human prostate cancer cells.

BACKGROUND: Prostate cancer is the second most prevalent and the fifth deadliest cancer among men worldwide. To improve radiotherapy outcome, we investigated the effects of 7-geranyloxycoumarin, also known as auraptene (AUR), on radiation response of prostate cancer cells. METHODS AND RESULTS: PC3 cells were pretreated with 20 and 40 µM AUR for 24, 48 and 72 h, followed by X-ray exposure (2, 4 and 6 Gy). After 72 h recovery, cell viability was determined by alamar Blue assay. Flow cytometric analysis was performed to assess apoptosis induction, clonogenic assay was carried out to investigate clonogenic survival, and the expression of P53, BAX, BCL2, CCND1 and GATA6 was analyzed by quantitative polymerase chain reaction (qPCR). Cell viability assay indicated that toxic effects of radiation was enhanced by AUR, which was also confirmed by increased numbers of apoptotic cells and reduced amount of survival fraction. The qPCR results demonstrated significant induction of P53 and BAX, while the expression of BCL2, GATA6, and CCND1 was significantly downregulated. CONCLUSION: The findings of the present study indicated, for the first time, that AUR improved radio sensitivity in prostate cancer cells, and thus, has the potential to be used in future clinical trials.

The Potential for Natural Products to Overcome Cancer Drug Resistance by Modulation of Epithelial-Mesenchymal Transition.

The acquisition of resistance and ultimately disease relapse after initial response to chemotherapy put obstacles in the way of cancer therapy. Epithelial-mesenchymal transition (EMT) is a biologic process that epithelial cells alter to mesenchymal cells and acquire fibroblast-like properties. EMT plays a significant role in cancer metastasis, motility, and survival. Recently, emerging evidence suggested that EMT pathways are very important in making drug-resistant involved in cancer. Natural products are gradually emerging as a valuable source of safe and effective anticancer compounds. Natural products could interfere with the different processes implicated in cancer drug resistance by reversing the EMT process. In this review, we illustrate the molecular mechanisms of EMT in the emergence of cancer metastasis. We then present the role of natural compounds in the suppression of EMT pathways in different cancers to overcome cancer cell drug resistance and improve tumor chemotherapy. HighlightsDrug-resistance is one of the obstacles to cancer treatment.EMT signaling pathways have been correlated to tumor invasion, metastasis, and drug-resistance.Various studies on the relationship between EMT and resistance to chemotherapy agents were reviewed.Different anticancer natural products with EMT inhibitory properties and drug resistance reversal effects were compared.

PAX2 promoter methylation and AIB1 overexpression promote tamoxifen resistance in breast carcinoma patients.

INTRODUCTION: Disease recurrence is an important obstacle in estrogen receptor positive (ER+) tamoxifen treated breast carcinoma patients. Tamoxifen resistance-related molecular mechanisms are not fully understood. Alteration in DNA methylation which contributes to transcriptional regulation of cancer-related genes plays a crucial role in tamoxifen response. In the present study, the contribution of promoter methylation and mRNA expression of PAX2 and AIB1 in the development of breast carcinoma and tamoxifen refractory was assessed. METHODS: Methylation specific-high resolution melting (MS-HRM) analysis and Real-time quantitative PCR (RT-qPCR) experiment were performed to analyze the promoter methylation and mRNA expression levels of PAX2 and AIB1 genes in 102 breast tumors and adjacent normal breast specimens. RESULTS: We indicated that PAX2 expression is decreased in breast tissues due to hypermethylation in its promoter region. Compared to the adjacent normal tissues, the tumors exhibited significantly lower relative mRNA levels of PAX2 and increased expression of AIB1. Aberrant promoter methylation of PAX2 and overexpression of AIB1 was observed in tamoxifen resistance patients compared to the sensitive ones. Cox regression analysis exhibited that the increased promoter methylation status of PAX2 and overexpression of AIB1 remained as unfavorable identifiers which influence patients' survival independently. CONCLUSIONS: Our results revealed that the aberration in PAX2 promoter methylation and AIB1 overexpression are associated with the tamoxifen response in breast carcinoma patients. Further research is needed to demonstrate the potential of using PAX2 and AIB1 expression and their methylation-mediated regulation as predictive or prognostic biomarkers or as a new target therapy for better disease management.

Ellagitannins, promising pharmacological agents for the treatment of cancer stem cells.

Human tumors comprise subpopulations of cells called cancer stem cells (CSCs) that possess stemness properties. CSCs can initiate tumors and cause recurrence, metastasis and are also responsible for chemo- and radio-resistance. CSCs may use signaling pathways similar to normal stem cells, including Notch, JAK/STAT, Wnt and Hedgehog pathways. Ellagitannins (ETs) are a broad group of substances with chemopreventive and anticancer activities. The antitumor activity of ETs and their derivatives are mainly related to their antiinflammatory capacity. They are therefore able to modulate secretory growth factors and pro-inflammatory mediators such as IL-6, TGF-ß, TNF-α, IL-1ß and IFN-γ. Evidence suggests that ETs display their anticancer effect by targeting CSCs and disrupting stem cell signaling. However, there are still few studies in this field. Therefore, high-quality studies are needed to firmly establish the clinical efficacy of the ETs on CSCs. This paper reviews the structures, sources and pharmacokinetics of ETs. It also focuses on the function of ETs and their effects on CSCs-related cytokines and the relationship between ETs and signaling pathways in CSCs.

Association of Interleukin-10 -592 C > A gene polymorphism with coronary artery disease: A case-control study and meta-analysis.

BACKGROUND: Coronary-artery-disease (CAD) is the leading cause of death worldwide, and hence there is a need to identify reliable markers for identifying individuals at high risk of developing CAD. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is associated with an increased risk of developing both atherosclerosis and acute coronary events. The study aimed to explore the association of a genetic variant in IL-10 with the risk of developing CAD and the severity of the disease. To further explore, a systematic review and meta-analysis was performed. The cumulative results of the relationship between IL and 10 -592 C > A polymorphism and CAD in Iranian population have also been presented. METHODS: In this cross sectional study, a total of 948 individuals including 307 healthy controls and 641 patients that among cases, four hundred and fifty-five of the patients had > 50% stenosis (angiogram positive group) and 186 patients had < 50% stenosis (angiogram negative group) were recruited from the Mashhad-Stroke and Heart-Atherosclerotic-Disorders cohort. Genotyping for the IL-10 -592 C > A polymorphism was performed using a PCR-RFLP technique, and statistical analysis undertaken by univariate and multivariate analyses. PubMed, Google Scholar and Scopus were searched for papers related to this polymorphism up to October 2019. The Meta-analysiswas done based on the random effect model using a Meta-analysis. RESULTS: In our study, the frequency of the variant A allele of the IL-10 -592 C > A was significantly higher in CAD patients than the control group (P value = 0.043). Moreover, subjects carrying AA genotype had a significantly higher risk of CAD (OR: 1.8, 95%CI: 1.04-3.16), p = 0.03), compared to those with the wild type genotype. The results of meta-analysis of 9336 cases and 8461 controls did not also show any significant association between IL and 10 -592 C > A and CAD in dominant and recessive genetic models but only in co-dominant model when fix effect was applied. CONCLUSION: Although our research findings support a significant association of genetic polymorphism in the IL10 gene with cardiovascular diseases, this finding cannot be confirmed in meta-analysis. Further functional analysis and evaluation of this marker in a multicenter setting are needed to establish its value as a risk stratification marker.

Antisense Oligonucleotide (AS-ODN) Technology: Principle, Mechanism and Challenges.

Recently, there is a hopefully tremendous interest in antisense therapeutics for clinical purposes. Single-stranded synthetic antisense oligonucleotides (As-ODNs) with monomers of chemically modified 18-21 deoxynucleotides complement the mRNA sequence in target gene. The target gene expression can be blocked because of created cleavage or disability of the mRNA by binding the As-ODNs to cognate mRNA sequences via sequence-specific hybridization. The idea of antisense therapy has become particular concerning that any sequence longer than a minimal number of nucleotides (17 for DNA and 13 for RNA) can be observed only once within the human genome. The mRNA is omnipresent more probably to manipulate compared to DNA, which results in multiple in vitro and in vivo applications for As-ODNs in the field of regulatory mechanisms of biological processes, cancer, viral infections and hereditary impairments. Although, there are uncertain clinical outcomes on the ability of this approach in treatment procedures despite achieving promising findings based on previous investigations. Accordingly, the efficacy, off-target effects, delivery are issues that should be investigated to obtain satisfactory results. In this review, we will explain the mechanism of action of As-ODNs and various types of modifications and their therapeutic purposes.

Glucosamine Reverses P-Glycoprotein-Mediated Multidrug Resistance in the Daunorubicin-Resistant Human Gastric Cancer Cells.

Glucosamine (GlcN) is a natural amino monosaccharide in the human body, and evidence of its anticancer effects is growing. In this study, we aimed to evaluate the effects of GlcN for its cytotoxicity, MDR reversal effects and inhibitory effects on function and expression of P-glycoprotein (P-gp) transporter in the daunorubicin-resistant human gastric cancer cells. Cell viability was measured by MTT assay to evaluate the cytotoxicity and multidrug resistance (MDR) reversal effects of GlcN. The effects of GlcN on function and mRNA expression level of P-gp transporter were assessed by flow cytometry and real-time RT-qPCR, respectively. Our results indicated that GlcN reduced the proliferation of human gastric cancer cell line EPG85-257 and its drug-resistant variant EPG85-257RD in a dose-dependent manner. GlcN (at the concentrations of 0.5 and 1 mM) also enhanced the sensitivity of EPG85-257RDB cells to daunorubicin. The cellular accumulation studies showed that GlcN inhibited efflux activity of P-gp and enhanced the mean fluorescent intensity of Rho123 while ˙it had no effects on P-gp gene expression in these cells. This study suggested that the inhibition of P-gp activity is a novel mechanism of action by which GlcN could reverse MDR in EPG85-257RDB cells.

Selenium nanoparticle as a bright promising anti-nanobacterial agent.

The use of nanotechnology for nanobacteria (or calcifying nanoparticles) treatment is a new creative approach. Use of selenium nanoparticles (SeNPs) as anti-nanobacterial agents might be considered as a bright promising approach due to their critical role in the inhibition of crystal growth and aggregation of calcium oxalate. Hence, in this study, we investigated the probable outcome of SeNPs inhibitory effects on growth of nanobacteria. Fragments of thirty urinary tract stones were chemically analyzed by X-ray diffraction (XRD) and urinary stones Kits for calcifying nanoparticles presence. Then powder of stone fragments were resuspended in Dulbecco's modified Eagle's medium (DMEM), sterilized by filtration and cultured in presence of 1, 5, 30, 60, and 90 µmol/L SeNPs concentrations. Besides, calcifying nanoparticles growth in the culture without SeNPs was measured spectrophotometrically. Also, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses were used, where calcifying nanoparticles formation occurred. Results showed that in the culture without SeNPs, the positive calcifying nanoparticles detection was 60% while after adding SeNPs at 90 µmol/L, not any calcifying nanoparticles were observed. Further confirmation came out when Energy-dispersive X-ray (EDX) analysis showed calcium and phosphate peaks in the culture medium without any SeNPs while in the culture containing 90 µm/L SeNPs a decrease in calcium and other minerals was obvious. Therefore, SeNPs clearly restricted the growth of nanobacteria due to their inhibitory effects on calcium oxalate deposition.

Altered DNA methyltransferases promoter methylation and mRNA expression are associated with tamoxifen response in breast tumors.

Tamoxifen is a standard anti-hormone treatment in estrogen receptor positive breast carcinoma patients. Unfortunately, about 50% of patients relapse during treatment. Promoter hypermethylation contributes to the epigenetic modulation of tamoxifen resistance-related genes. To evaluate the contribution of DNMTs expression and their promoter methylation as diagnostic biomarkers in development of breast malignancy and tamoxifen resistance, the present study was designed and 107 breast tumors and normal breast tissues were recruited. Methylation-specific high-resolution melt curve analysis and quantitative RT-PCR were performed to evaluate DNMTs promoter methylation and mRNA expression, respectively. Our results indicated that DNMT3A and DNMT3B promoters were demethylated in breast tumors as compared to control tissues. The mRNA expression levels of all three DNMTs were significantly increased in tumor specimens in comparison to control tissues (p < 0.05). Among tumor tissues, DNMT3A promoter methylation was significantly higher in tamoxifen sensitive patients (p = 0.001). Overexpression of DNMT3A (p = 0.037) and DNMT3B (p < 0.001) mRNA were observed in tamoxifen resistance group. Multivariate logistic regression analysis indicated that low methylation status of DNMT3A and overexpression of DNMT3B could be as independent predictors of disease recurrence. Multivariate Cox regression analysis, revealed that high methylation status of DNMT3A could be an independent and favorable predictor for disease free survival (p = 0.002) and overall survival (p = 0.026); high expression of DNMT1 (p = 0.03) remained significant and unfavorable predictive factor for overall survival. In conclusion, our data for the first time indicated that low methylation status of DNMT3A promoter and overexpression of DNMT3B could contribute to disease recurrence in tamoxifen-treated breast cancer patients.

Association of tumor necrosis factor-α -308 G/A gene polymorphism with coronary artery diseases: An evidence-based study.

BACKGROUND: Coronary artery disease (CAD) is the leading cause of death worldwide and remains a major health problem, providing the rationale for identification of molecular markers for detection of individuals at high risk of developing CAD. Tumor necrosis factor-α (TNF-α) plays a crucial role in the pathogenesis of CAD. We have therefore explored the association of TNF-α 308 (G/A) gene polymorphism in 903 individuals with/without CAD. METHODS: TNF-α 308 gene polymorphism was analyzed in 903 subjects of whom 222 were healthy controls. Among the 681 patients who were investigated angiographically, 468 had ≧50% stenosis and 213 patients had <50% stenosis. Biochemical profiles (eg, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting blood glucose, and CRP) were evaluated. Associations between TNF-α genotypes with biochemical and anthropometric characteristics were determined. RESULTS: The frequencies of TNF-α-AA or AG genotypes were significantly lower in patients classified as CAD patients with ≥ or <50% obstruction in at least one coronary artery, compared to the control group. We observed that CAD patients with ≥50% stenosis and with AA genotype were associated with higher risk of CAD with OR of 3.56 (95%CI: 1.02-12.41; P=.046) using multivariate analysis. Moreover, we found that TNF-α-308-AA genotype was associated with blood pressure and CRP level in CAD patients, compared to the wild type-genotype. CONCLUSION: Our data showed an association of TNF-α-308G/A polymorphism with CAD patients with ≥50% obstruction, supporting the need for further investigations on the role of TNF-α-308G/A polymorphism with hypertension.

Association of heat shock protein70-2 (HSP70-2) gene polymorphism with obesity.

BACKGROUND: Obesity is a major risk factor of chronic-diseases, including cardiovascular-diseases (CVD). Increasing evidence is showing the association of heat-shock protein (HSP) with type-2 diabetes and CVD; however, there is little data on the relationship between the genetic-polymorphisms of HSP70-2 with obesity. AIM: The present study has investigated the association between 1267HSP70-2 genetic polymorphism and obesity in an Iranian population with 317 subjects. SUBJECTS AND METHODS: Anthropometric parameters and biochemical measurements were measured in all the samples, while genotypes were determined using PCR-RFLP. Univariate/multivariate analyses were conducted to explore the relationship between the genetic-polymorphisms and obesity. RESULTS: The data showed a significant association between 1267HSP70-2 polymorphism in obese subjects, compared to the non-obese group. Moreover, it was observed that this polymorphism was associated with obesity in the CAD + group, which had a high BMI compared to non-obese controls. CONCLUSION: The 1267HSP70-2 polymorphism is associated with obesity in an Iranian population, supporting a possible potential genetic link between obesity and cardiovascular diseases.

Association of neuropeptide Y gene rs16147 polymorphism with metabolic syndrome in patients with documented coronary artery disease.

BACKGROUND AND AIMS: There have been few epidemiological studies that have investigated genetic susceptibility to cardiovascular risk associated with the prevalence of metabolic syndrome (MetS). Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). Therefore, the aim of this study was to investigate the association between the NPY gene rs16147 polymorphism and the presence of MetS in a well defined group of Iranian subjects with angiographically-defined CAD. METHODS: A cross-sectional study design was used in which a total of 364 patients were recruited; 143 patients with MetS and 221 without MetS were genotyped using the ARMS-PCR technique. Logistic regression analyses were performed to determine the odds ratios (ORs) for the association of specific genotypes with the presence of MetS and related phenotypes. RESULTS: The frequency of the variant G allele of the NPY gene was significantly higher in CAD patients without MetS (p = 0.032). Compared to the AA genotype of the NPY gene, individuals carrying the GG genotype had a reduced risk of MetS (OR = 0.51, 95% CI = 0.27-0.95, p = 0.034). CONCLUSION: The rs16147 polymorphism may be associated with presence of MetS among subjects with documented CAD. Carriage of NPY A allele in patients with CAD is associated with a higher prevalence of MetS.

Lack of an association between a functional polymorphism in the neuropeptide Y gene promoter and the presence of coronary artery disease in an Iranian population.

BACKGROUND/AIMS: Several genetic factors have been identified that may contribute to the risk of coronary artery disease (CAD). Variants of the neuropeptide Y (NPY) gene, whose products play an important role in regulating several physiological functions, have been associated with the risk of CAD in some populations. The purpose of this study was to investigate the relationship between the NPY gene rs16147 polymorphism and the presence of CAD in an Iranian population. METHODS: DNA samples of 922 subjects, including 433 with angiographically defined CAD (CAD+), 196 without angiographically defined significant CAD (CAD-) and 293 controls, were genotyped using polymerase chain reaction based on the amplification-refractory mutation system. Logistic regression analyses were performed to assess the association of rs16147 genotypes with the presence of significant CAD. RESULTS: Although logistic regression analysis indicated that the NPY polymorphism rs16147 was nominally associated with an increased risk of CAD (p < 0.05), after adjustment for confounding factors, there was no evidence for any significantly increased or decreased risk of CAD with this polymorphism. However, in stratified analyses, the C allele was significantly associated with a reduced risk of CAD in males and subjects who were <50 years of age. CONCLUSIONS: This study suggests that the rs16147 polymorphism in the NPY gene may not be a potential contributor to the risk of CAD in an Iranian population.

Assessment of protective effects of glucosamine and N-acetyl glucosamine against DNA damage induced by hydrogen peroxide in human lymphocytes.

The antigenotoxic activity of glucosamine (GlcN) and N-acetylglucosamine (GlcNAc) in human peripheral lymphocytes exposed to oxidative stress was investigated. Human lymphocytes were treated with different concentrations of these aminosugars (0, 2.5, 5, 10, 20 and 40 mM) and 25 µM H2O2 simultaneously and evaluated by single cell gel electrophoresis technique (Comet assay). The single cells were analyzed using "TriTek Cometscore version 1.5" software and the data were presented as % DNA in tail. Both GlcN and GlcNAc at examined concentrations (2.5, 5, 10, 20 and 40 mM) did not reveal any genotoxicity compared to the vehicle control (PBS). Glucosamine at all concentrations (2.5, 5, 10, 20 and 40 mM) showed a significant protective activity (% DNA in tail ranging from 16.07 ± 0.85 to 5.47 ± 0.26, p < 0.001) against H2O2 induced DNA damage (% DNA in tail = 38 ± 0.65) while its N-acetylated analog only indicated a slight DNA protection at concentration of 40 mM (% DNA in tail = 33.4 ± 1.17, p < 0.01). We concluded that GlcN at tested concentrations exhibited potent antigenotoxic effect and its protection activity might be related to the presence of 2-NH2 moiety in its chemical backbone.

Investigation of the effects of curcumin on serum cytokines in obese individuals: a randomized controlled trial.

BACKGROUND: Obesity is a disorder often accompanied by a heightened state of systemic inflammation and immunoactivation. The present randomized crossover trial aimed to investigate the efficacy of curcumin, a bioactive polyphenol with established anti-inflammatory and immunomodulatory effects, on the serum levels of a panel of cytokines and mediators in obese individuals. METHODS: Thirty obese individuals were randomized to receive curcumin at a daily dose of 1 g or a matched placebo for 4 weeks. Following a 2-week wash-out period, each group was assigned to the alternate treatment regimen for another 4 weeks. Serum samples were collected at the start and end of each study period. Serum levels of IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, VEGF, IFNγ, EGF, MCP-1, and TNF α were measured using a multiplex Biochip Array Technology based method. RESULTS: Mean serum IL-1ß (P = 0.042), IL-4 (P = 0.008), and VEGF (P = 0.01) were found to be significantly reduced by curcumin therapy. In contrast, no significant difference was observed in the concentrations of IL-2, IL-6, IL-8, IL-10, IFNγ, EGF, and MCP-1. CONCLUSIONS: The findings of the present trial suggested that curcumin may exert immunomodulatory effects via altering the circulating concentrations of IL-1ß, IL-4, and VEGF.

Inhibition of melanoma cell migration and invasion by natural coumarin auraptene through regulating EMT markers and reducing MMP-2 and MMP-9 activity.

Melanoma, the most invasive form of skin cancer, shows a rising incidence trend in industrial countries. Since the main reason for the failure of current therapeutic approaches against melanoma is metastasis, there is a great interest in introducing effective natural agents to combat melanoma cell migration and invasion. Auraptene (AUR) is the most abundant coumarin derivative in nature with valuable pharmaceutical effects. In this study, we aimed to investigate whether AUR could induce inhibitory effects on the migration and invasion of melanoma cells. B16F10 melanoma cells were treated with different concentrations of AUR and the viability of cells was evaluated by alamarBlue assay. Then, cells were treated with 20 µM AUR, and wound healing, invasion, and adhesion assays were carried out. In addition, the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9 was assessed by gelatin zymography and the expression of genes related to epithelial-mesenchymal transition (EMT) was investigated by qPCR. Finally, the interactions between AUR and MMPs were stimulated by molecular docking. Findings revealed that AUR significantly reduced the migration and invasion of B16F10 cells while improved their adhesion. Furthermore, results of gelatin zymography indicated that AUR suppressed the activity of MMP-2 and MMP-9, and qPCR revealed negative regulatory effect of AUR on the expression of mesenchymal markers including fibronectin and N-cadherin. In addition, molecular docking verified the interactions between AUR and the active sites of wild-type and mutant MMP-2 and MMP-9. Accordingly, AUR could be considered as a potential natural agent with inhibitory effects on the migration and invasion of melanoma cells for future preclinical studies.

Galbanic acid suppresses melanoma cell migration and invasion by reducing MMP activity and downregulating N-cadherin and fibronectin.

High mortality rate of melanoma is due to the metastasis of malignant cells. Galbanic acid (GBA) is a natural sesquiterpene coumarin with valuable pharmaceutical activities. Our study aimed to investigate whether GBA can affect the migration, invasion, and adhesion of melanoma cells. The survival rate of B16F10 cells was measured using the alamarBlue assay. Scratch, adhesion, and invasion assays were performed to determine the effect of GBA on metastatic behavior of cells. Moreover, gelatin zymography was done to assess the activity of MMP-2 and MMP-9, and qRT-PCR was used to investigate the effect of GBA on the expression of candidate genes. Based on the results of alamarBlue assay, 40 µM GBA was chosen as the optimum concentration for all tests. Our findings indicated that GBA significantly decreased the invasion and migration of B16F10 cells while enhancing their adhesion ability. In addition, gelatin zymography demonstrated that GBA reduced the enzymatic activity of MMP-2 and MMP-9. Moreover, qRT-PCR revealed that GBA reduced the expression of N-cadherin and fibronectin. Current findings demonstrated, for the first time, that GBA inhibited the migration and invasion of melanoma cells via reducing the activity of MMP-2 and MMP-9 and downregulating N-cadherin and fibronectin expression. Accordingly, GBA could be suggested as a potential therapeutic agent for the treatment of melanoma.

Glucosamine alleviates scopolamine induced spatial learning and memory deficits in rats.

INTRODUCTION AND OBJECTIVE: Beneficial effects of glucosamine in spatial learning and memory impairment induced by scopolamine has been evaluated in rats by using Morris water maze. METHODS: Male Wistar rats were randomly divided into control, scopolamine and scopolamine plus glucosamine groups. All injections were given in 5 consecutive days and 30min after each injection, the rats were tested in the Morris water maze test. Escape latency and path length to reach the hidden platform were subjected to analysis of variance [ANOVA]. RESULTS: The rats treated with scopolamine showed increased escape latency and path length to reach the hidden platform compared to control group (P<0.001). Both escape latency and traveled path length to reach the hidden platform in glucosamine treated animals (1 and 2g/kg) were significantly lower (P<0.05 to P<0.001) than in the scopolamine group. CONCLUSION: The results of this study showed that the glucosamine can inhibit scopolamine-induced impairments of spatial learning and memory in rats. Glucosamine might offer a promise in either the prevention or the treatment of neurodegenerative diseases such as Alzheimer's disease.

Improving the efficacy of peptide vaccines in cancer immunotherapy.

Peptide vaccines have shown great potential in cancer immunotherapy by targeting tumor antigens and activating the patient's immune system to mount a specific response against cancer cells. However, the efficacy of peptide vaccines in inducing a sustained immune response and achieving clinical benefit remains a major challenge. In this review, we discuss the current status of peptide vaccines in cancer immunotherapy and strategies to improve their efficacy. We summarize the recent advancements in the development of peptide vaccines in pre-clinical and clinical settings, including the use of novel adjuvants, neoantigens, nano-delivery systems, and combination therapies. We also highlight the importance of personalized cancer vaccines, which consider the unique genetic and immunological profiles of individual patients. We also discuss the strategies to enhance the immunogenicity of peptide vaccines such as multivalent peptides, conjugated peptides, fusion proteins, and self-assembled peptides. Although, peptide vaccines alone are weak immunogens, combining peptide vaccines with other immunotherapeutic approaches and developing novel approaches such as personalized vaccines can be promising methods to significantly enhance their efficacy and improve the clinical outcomes for cancer patients.

Tamoxifen resistance induction results in the upregulation of ABCG2 expression and mitoxantrone resistance in MCF-7 breast cancer cells.

Cancer endocrine therapy can promote evolutionary dynamics and lead to changes in the gene expression profile of tumor cells. We aimed to assess the effect of tamoxifen (TAM)-resistance induction on ABCG2 pump mRNA, protein, and activity in ER + MCF-7 breast cancer cells. We also evaluated if the resistance to TAM leads to the cross-resistance toward mitoxantrone (MX), a well-known substrate of the ABCG2 pump. The ABCG2 mRNA and protein expression were compared in MCF-7 and its TAM-resistant derivative MCF-7/TAMR cells using RT-qPCR and western blot methods, respectively. Cross-resistance of MCF-7/TAMR cells toward MX was evaluated by the MTT method. Flow cytometry was applied to compare ABCG2 function between cell lines using MX accumulation assay. ABCG2 mRNA expression was also analyzed in tamoxifen-sensitive (TAM-S) and tamoxifen-resistant (TAM-R) breast tumor tissues. The levels of ABCG2 mRNA, protein, and activity were significantly higher in MCF-7/TAMR cells compared to TAM-sensitive MCF-7 cells. MX was also less toxic in MCF-7/TAMR compared to MCF-7 cells. ABCG2 was also upregulated in tissue samples obtained from TAM-R cancer patients compared to TAM-S patients. Prolonged exposure of ER + breast cancer cells to the active form of TAM and clonal evolution imposed by the selective pressure of the drug can lead to higher expression of the ABCG2 pump in the emerged TAM-resistant cells. Therefore, in choosing a sequential therapy for a patient who develops resistance to TAM, the possibility of the cross-resistance of the evolved tumor to chemotherapy drugs that are ABCG2 substrates should be considered. Prolonged exposure of MCF-7 breast cancer cells to tamoxifen can cause resistance to it and an increase in the expression of the ABCG2 mRNA and protein levels in the cells. Tamoxifen resistance can lead to cross-resistance to mitoxantrone.