Clinicopathological correlation of insulin-like growth factor binding protein 3 and their death receptor in patients with gastric cancer.

Background and purpose: The insulin-like growth factor binding protein 3 (IGFBP-3) and its novel death receptor (IGFBP-3R) have been exhibited to have tumor suppressor effects. Despite their prognostic value in some cancers, they have not been elucidated in gastric cancer. Experimental approach: We collected 68 samples from patients with gastric cancer. IGFBP-3 and IGFBP-3R expression levels were evaluated with quantitative real-time polymerase chain reaction (RT-PCR) and western blotting in patients. The relationship between prognostic factors and IGFBP-3/IGFBP-3R expression was also evaluated. Findings/Results: Our results showed that IGFBP-3 and IGFBP-3R expression was reduced significantly in tumor tissues. We found that there was an association between the reduction of IGFBP-3 with lymph node metastasis and tumor-node-metastasis (TNM) staging. Besides, IGFBP-3R expression was associated with tumor size, lymph node metastasis, differentiation, and TNM classification. Interestingly, we presented that the downregulation of IGFBP-3R was stage-dependent. In survival analysis, our findings showed that low levels of IGFBP-3R mRNA expression exhibited a close correlation with survival rate. Conclusion and implications: The findings of this study showed that the expression levels of IGFBP-3 and IGFBP-3R are valuable prognostic factors. Despite the potential of IGFBP-3, IGFBP-3R plays a significant role as a prognostic factor in gastric cancer. However, these findings need to be developed and confirmed by further studies.

Targeting androgen receptor (AR) with a synthetic peptide increases apoptosis in triple negative breast cancer and AR-expressing prostate cancer cell lines.

BACKGROUND: The androgen receptor (AR) has been studied as an approach to cancer therapy. AIMS: We used human breast cancer-derived cells with high, low, and very low expression levels of AR, in addition to prostate cancer-derived LNCaP and DU-145 cells as a positive and negative controls to examine apoptosis caused by a synthetic peptide that targets ARs. METHODS AND RESULTS: The peptide was produced to inhibit AR transactivation in breast cancer cell lines. We then measured cell viability, caspase-3 activity, and the ratio of Bax/Bcl-2. The findings indicated that the peptide (100-500 nM) in the presence of dihydrotestosterone (DHT) reduced cell growth in cells with high and low expression level of AR (p < .001), but not in cells with very low levels of AR. Treatment with 100-500 nM of peptide activated caspase-3 and increased the ratio of Bax/Bcl-2 in cells with high and low expression levels of AR. Also, increasing concentrations of the peptide (100-500 nM) reduced BrdU incorporation in the presence of DHT and promoted apoptosis in cells with high and low expression levels of AR (p < .001). CONCLUSION: The findings indicate the peptide significantly increased apoptosis in cancer cells.

New Association Between Diabetes Mellitus and Pancreatic Cancer.

BACKGROUND: Diabetes mellitus is a global issue that has affected the lives of many people all over the world. This disorder, which is also called the mother of all diseases, possesses high pathogenicity and results in the emergence of many disorders. One of the known correlated diseases is pancreatic cancer which can be accompanied by diabetes mellitus. Therefore, finding the association between these diseases and common genes is urgent. OBJECTIVE: In this study, in order to survey the relationship between diabetes mellitus and pancreatic cancer, the common genes of these disorders were analyzed by bioinformatics tools. METHODS: For this purpose, we screened 17 shared genes from microarray data downloaded from the Gene Expression Omnibus (GEO) database. In addition, the relationship between identified genes was constructed by STRING and DAVID tools. RESULTS: In total, 112 genes were identified to be differentially expressed. Among these, 17 genes were found to be common, including two genes that were down-regulated and others that were upregulated. Other analyses showed that most of the genes were enriched in Vibrio cholera infection and the mTOR signaling pathway. The biological processes of such genes included oxygen and gas transport, phagosome acidification, and GTPase activity. CONCLUSION: In this study, 17 common genes that had not previously been considered in diabetes and pancreatic cancer were screened, which can be further considered for clinical approaches and in vitro studies.

Corrigendum to: Association between ABCC8 Ala1369Ser Polymorphism (rs757110 T/G) and Type 2 Diabetes Risk in an Iranian Population: A Case-Control Study.

Due to oversight on the part of the authors, the names of two of the co-authors have been incorrectly published in the article entitled, "Association between ABCC8 Ala1369Ser Polymorphism (rs757110 T/G) and Type 2 Diabetes Risk in an Iranian Population: A Case-Control Study", 2021, Vol. 21, No. 3, pp. 441-447 [1]. The original article can be found online at: https://doi.org/10.2174/1871530320666200713091827. Original: Amin Bakhtiyari, Karimeh Haghani, Salar Bakhtiyari*, Mohammad A. Zaimy, Nooriali Zahed, Ali Gheysarzadeh, Shahram Darabi, Seidali Nahalkhani, Mansour Amraei and Iraj Alipourfard Corrected: Amin Bakhtiyari, Karimeh Haghani, Salar Bakhtiyari*, Mohammad A. Zaimy, Ali Noori-Zadeh, Ali Gheysarzadeh, Shahram Darabi, Ali Seidkhani-Nahal, Mansour Amraei and Iraj Alipourfard.

15-Hydroxy-8(17),13(E)-labdadiene-19-carboxylic acid (HLCA) inhibits proliferation and induces cell cycle arrest and apoptosis in ovarian cancer cells.

AIM: 15-Hydroxy-8(17),13(E)-labdadiene-19-carboxylic acid (HLCA) isolated from Juniperus foetidissima, has been recently identified as an antiproliferative agent; however, the molecular basis of antiproliferative effects of HLCA remains unknown. To investigate it, the current study has emphasized the hypothesis that HLCA induced cell death is a consequence of intracellular reactive oxygen species (ROS) production followed by cell cycle arrest and apoptosis. MAIN METHODS: Human ovarian OVCAR-3 and Caov-4 cells were treated with various concentrations of HLCA (48 h) and the measurement of intracellular ROS was considered. Then, the potential of HLCA in promoting apoptosis was investigated via flow cytometry, western blot, and caspase activity assay. Also, the inhibitory effect of HLCA on the cell cycle was evaluated using flow cytometry and western blot analysis. KEY FINDINGS: We found intracellular (ROS) accumulation in HLCA-treated cells. Subsequent observation of the increment in pro-apoptotic Bax as well as the decrement in antiapoptotic Bcl2 revealed that the HLCA-induced cytotoxicity may be triggered by the intrinsic pathway of apoptosis. Our subsequent experiments suggested that caspase-9 and -3 were activated and led the cells to apoptosis during the process. Cell cycle disruption at the G1 phase via down-regulation of cyclin D1 and Cyclin-dependent kinase 4 (CDK4) was another proved mechanism by which HLCA exerts its antiproliferative effects on the ovarian cell lines, OVCAR-3 and Caov-4, especially at relatively lower concentrations. SIGNIFICANCE: This is the first study that reveals the apoptotic effects of HLCA, suggesting its therapeutic potential as an effective anti-tumor agent. However, further in vivo studies are required to confirm these effects.

Association between ABCC8 Ala1369Ser Polymorphism (rs757110 T/G) and Type 2 Diabetes Risk in an Iranian Population: A Case-Control Study.

OBJECTIVE: Glucose metabolism increases ATP/ADP ratio within the ß-cells and causes ATP-sensitive K+ (KATP) channel closure and consequently insulin secretion. The enhanced activity of the channel may be a mechanism contributing to the reduced first-phase of insulin secretion observed in T2DM. There is no study to date in the Kurdish ethnic group regarding the relationship between SNP Ala1369Ser (rs757110 T/G) of SUR1 gene and T2DM, and additionally, the results of this association in other populations are inconsistent. Therefore, our aim in this study was to explore the possible association between SNP Ala1369Ser and type 2 diabetes in an Iranian Kurdish ethnic group. METHODS: In this study, we checked out the frequency of alleles and genotypes of SNP Ala1369Ser in T2DM individuals (207 patients; men/women: 106/101) and non-T2DM subjects (201 controls; men/women: 97/104), and their effects on anthropometric, clinical, and biochemical parameters. Genomic DNA was extracted from the leukocytes of blood specimens using a standard method. We amplified the ABCC8 rs757110 polymorphic site (T/G) using a polymerase chain reaction (PCR) method and a designed primer pair. To perform the PCR-RFLP method, the amplicons were subjected to restriction enzymes and the resulting fragments separated by gel electrophoresis. RESULTS: The frequency of the G-allele of Ala1369Ser polymorphism was significantly (0.01) higher in the case group than the control group (19% vs. 9%, respectively). In the dominant model (TT vs. TG+GG), there was a significant relationship between this SNP and an increased risk of T2DM (P = 0.00). T2DM patients with TG+GG genotypes had significantly higher fasting plasma insulin and HOMA-IR than those who had the TT genotype (P = 0.02 and 0.01, respectively). CONCLUSION: Our study is the first study to investigate the association between Ala1369Ser ABCC8 genetic variation and T2DM in the Kurdish population of western Iran. The obtained results clearly show that Ala1369Ser polymorphism of ABCC8 is associated with an increased risk of T2DM in this population.

The Key Role of Akt Protein Kinase in Metabolic-Inflammatory Pathways Cross-Talk: TNF-α Down-Regulation and Improving of Insulin Resistance in HepG2 Cell Line.

BACKGROUND: Elevation of plasma free fatty acids as a principal aspect of type 2 diabetes maintains etiologically insulin insensitivity in target cells. TNF-α inhibitory effects on key insulin signaling pathway elements remain to be verified in insulinresistant hepatic cells. Thus, TNF-α knockdown effects on the key elements of insulin signaling were investigated in the palmitate-induced insulin-resistant hepatocytes. The Akt serine kinase, a key protein of the insulin signaling pathway, phosphorylation was monitored to understand the TNF-α effect on probable enhancing of insulin resistance. METHODS: Insulin-resistant HepG2 cells were produced using 0.5 mM palmitate treatment and shRNA-mediated TNF-α gene knockdown and its down-regulation confirmed using ELISA technique. Western blotting analysis was used to assess the Akt protein phosphorylation status. RESULTS: Palmitate-induced insulin resistance caused TNF-α protein overexpression 1.2-, 2.78, and 2.25- fold as compared to the control cells at post-treatment times of 8 h, 16 h, and 24 h, respectively. In the presence of palmitate, TNF-α expression showed around 30% reduction in TNF-α knockdown cells as compared to normal cells. In the TNF-α down-regulated cell, Akt phosphorylation was approximately 62% more than control cells after treatment with 100 nM insulin in conjugation with 0.5 mM palmitate. CONCLUSIONS: The obtained data demonstrated that TNF-α protein expression reduction improved insulin-stimulated Akt phosphorylation in the HepG2 cells and decreased lipidinduced insulin resistance of the diabetic hepatocytes.

Do Genetic Factors Predispose People to COVID-19: A Review Article.

The pandemic of coronavirus disease 2019 (COVID-19) has become a threat to human life and society. Scientists and clinicians are struggling with the intrusive SARS-CoV-2 virus to enhance their knowledge about its pathogenesis and find an effective medicine and vaccine to combat its complications. Till now, they have learned that this SARS-CoV-2 has not infected all people exposed to this virus, and also severe respiratory illnesses have not been observed in all infected patients. Patients over 65 or with underlying diseases are more vulnerable to develop severe disease. Based on this premise, a highly challenging question is why some people are more susceptible to this virus and others are not. The present study was aimed to review the current information, which explains the broad spectrum of COVID-19 presentation. Here, we discussed how genetic background, immune system, underlying disease, smoking status, as well as age, race, and gender affect COVID-19 susceptibility.

The Prevalence of Shiga Toxin-1 in Non-Shigella Dysenteriae Isolates Collected from Diarrhea Samples in Patients, Ahvaz, Iran.

BACKGROUND: Acute diarrhea is a major public health problem, particularly in developing countries. Shigellosis is one of the substantial causative agents of microbial dysentery and still has a remarkable prevalence, particularly in areas with poor hygienic infrastructures. The probable existence of the deadly Shiga toxin (Stx) protein in some Shigella strains would manifest life-threatening clinical symptoms of the infection. METHODS: The aim of this study was to determine the presence of Shigella toxin 1 (Stx1) in isolated from patients with diarrhea. Totally, 227 Shigella species, including 60 S. flexneri, 157 S. sonnei, and 10 S. boydii were collected from diarrheal patients in the tropical infectious diseases research center of Ahvaz, Iran, during 2013-2015. The isolates were collected mostly from the intensive care unit, infectious disease, and surgery settings. The isolates were identified, and the polymerase chain reaction (PCR) was performed to detect the stx gene. RESULTS: The results indicated that none of them encode the stx1 gene. CONCLUSION: Isolates of this study were not capable of stx1 encoding. Future investigations should consider the relations between other Shigella species and Shigella toxin in Iran.

Insulin-like growth factor binding protein 3 chemosensitizes pancreatic ductal adenocarcinoma through its death receptor.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. Gemcitabine and doxorubicin are commonly used as the chemotherapy agents, but most of PDAC tumors eventually acquired resistance to chemotherapy. Accumulating evidence indicates that Insulin-like growth factor binding protein 3 (IGFBP-3) plays a key role against tumor growth but its expression has commonly suppressed. The present study was designed to evaluate IGFBP-3 effects in chemotherapy sensitization of PDAC cells. Here, we report that the re-sensitization of chemoresistant PDAC cells was occurred by IGFBP-3 through recruitment of its death receptor (IGFBP-3R). Using gemcitabine, doxorubicin-resistant PDAC cell lines, we found that IGFBP-3 sensitized chemoresistant cells by activating apoptosis (as evaluated by Bax up-regulation, Bcl-2 down-regulation as well as Caspase-3 and Caspase 8 activation). IGFBP-3R was also found to have higher expression level in resistant AsPc-1 and MIA PaCa-2 cells in comparison to parental cells. IGFBP-3R was also highly expressed in PDAC tumor which exposed to chemotherapy in comparison to un-treated PDAC tumors. In addition, we confirmed our finding by using specific siRNA to knocking down of IGFBP-3R which prevents IGFBP-3 Chemosensitization. Taken together, the present study for the first time indicates the clinical relevance for combining IGFBP-3 with chemotherapy to reduce chemoresistance in PDAC.

The Association Between Gelsolin-like Actin-capping Protein (CapG) Overexpression and Bladder Cancer Prognosis.

PURPOSE: Muscle-invasive bladder cancer (MIBC) is associated with disease progression and metastasis leading to poor prognosis. Current chemotherapy approaches have not adequately increased patient survival. Therefore, in this study, tissue proteome of patients with MIBC was performed to introduce possible protein candidates for bladder cancer prognosis as well as targeted therapy. MATERIALS AND METHODS: After obtaining tumoral and non-tumoral tissues of MIBC patients, and normal bladder tissue of non-bladder cancer patients, two-dimensional gel electrophoresis (2-DE) and liquid chromatography-mass spectrometry (LC-MS/MS) were used to analyze tissue proteome. Gelsolin-like Actin-capping (CAPG) protein was further examined using Real-time PCR and western blot analysis. RESULTS: The 2-DE analysis and LC-MS/MS identified CAPG protein as differentially expressed protein in tumor and non-tumor tissues of bladder cancer compared with normal tissues. Western blot analysis showed the CAPG overexpression in tumor tissues compared with normal tissues in a stage-dependent manner. Correspondingly, Real- time PCR showed a higher mRNA expression in tumoral bladder tissues than normal ones. CAPG mRNA overexpression had significantly a positive relation with tumor size (P = 0.019), the TNM staging (P = 0.001), and tumor differentiation (grade) (P = 0.006). Patients with lower levels of CAPG had higher recurrence-free survival in comparison with patients with higher levels (P = .027). CONCLUSION: CAPG overexpression was correlated with size, stage, grade, and shorter time to recurrence of bladder cancer. Therefore, CAPG overexpression could be related to poor prognosis of bladder cancer. These results suggest that CAPG may be considered as a prognostic factor and also for targeted therapy in bladder cancer. Moreover, it could be concluded that cancerous and noncancerous tissues of MIBC have the same protein expression because 2-DE results showed the CAPG expression in cancer and adjacent cancer tissues of bladder while CAPG was not detectable in normal tissues of bladder.

The insulin-like growth factor binding protein-3 and its death receptor in pancreatic ductal adenocarcinoma poor prognosis.

Insulin-like growth factor binding protein-3 (IGFBP-3) and its newly discovered death receptor (IGFBP-3R) have been reported to involve in a wide variety of cancers. However, their role in pancreatic ductal adenocarcinoma (PDAC) has not been elucidated yet. Here, 478 pancreatic cancers were screened for primary PDAC tumors. The samples were evaluated using quantitative reverse-transcriptase polymerase chain reaction, western blotting, and immunohistochemistry staining. The results indicated that relative IGFBP-3 mRNA expression and its protein level were reduced stage dependently in the PDAC tumors (p < .001 and p < .05, respectively). The subcellular distribution of IGFBP-3 was mainly nuclear only in Stage 0 + 1 (about 150% compared to adjacent normal tissues [p < .05]). The value for IGFBP-3R messenger RNA (mRNA) and protein were also reduced in tumors in compared to adjacent normal pancreatic tissues (p < .05). The Kaplan-Meier analysis also showed that mRNA expression of IGFBP-3 and IGFBP-3R was positively associated with survival, (p = .001). In addition, there is a strong association between low expression of IGFBP-3 and tumor size (p = .032), the lymphatic invasion (p = .001), the TNM (tumor, node, metastasis) staging (p = .001), tumor differentiation (p = .001), and PNI status (p = .021). Down-regulation of IGFBP-3R was also correlated with the tumor size (p = .01), the lymphatic invasion (p = .012) TNM staging (p = .001), tumor differentiation (p = .021) and PNI status (p = .038). In conclusion, IGFBP-3 and its receptor were down-regulated and their expression was associated with poor prognosis of PDAC.

Over-expression of low-density lipoprotein receptor-related Protein-1 is associated with poor prognosis and invasion in pancreatic ductal adenocarcinoma.

BACKGROUND: Low-density lipoprotein receptor-Related Protein-1 (LRP-1) has been reported to involve in tumor development. However, its role in pancreatic cancer has not been elucidated. The present study was designed to evaluate the expression of LRP-1 in Pancreatic Ductal Adenocarcinoma Cancer (PDAC) as well as its association with prognosis. METHODS: Here, 478 pancreatic cancers were screened for suitable primary PDAC tumors. The samples were analyzed using qRT-PCR, western blotting, and Immunohistochemistry (IHC) staining as well as LRP-1 expression in association with clinicopathological features. RESULTS: The relative LRP-1 mRNA expression was up-regulated in 82.3% (42/51) of the PDAC tumors and its expression (3.72 ±â€¯1.25) was significantly higher than that in pancreatic normal margins (1.0 ±â€¯0.23, P < 0.05). This up-regulation was stage dependent (P < 0.05). A similar pattern of LRP-1 protein expression was discovered (P < 0.05). The high expression of LRP-1 in the PDAC tissues was strongly correlated with the low survival time (P = 0.001), TNM classification (P = 0.001), low differentiations status (P = 0.001), lymphatic invasion (P = 0.01) and Perineural Invasion (PNI) status (P = 0.001). CONCLUSIONS: Our finding for the first time revealed that LRP-1 expression inversely associated with poor prognosis and PNI in PDAC tumor.

Serum-based microRNA biomarkers for major depression: MiR-16, miR-135a, and miR-1202.

BACKGROUND: Depression is a common medical condition with a high prevalence leading to emotional abnormality. Despite some drawbacks, depression currently diagnosed using a combination of patient interviews and self-report questionnaires. Recently, there is emerging emphasis to establish biomarkers to diagnosis and clinical management of depression. This case-control study was designed to develop microRNA (miRNA)-based serum biomarker for depression. MATERIALS AND METHODS: In this study, 39 patients with depression and 36 healthy controls were enrolled. Serum miRNAs gene expression was measured using real-time polymerase chain reaction (PCR) analysis; finally, the data represent as the 2-ΔCt followed by further statistical analysis. RESULTS: The serum level of miR-16 was significantly (P < 0.001) down-regulated (mean: 0.9123 and standard deviation [SD]: 0.06) in compared to normal individuals (mean: 1.6848 and SD: 0.09). The concentration of miR-135a was also catastrophically decreased (P < 0.001) in the patients (mean: 1.160 and SD: 0.07) in compared to control (mean: 1.819 and SD: 0.09). The relative miR-1202 expression levels were significantly lower (P < 0.001) in the patients (mean: 0.1755 and SD: 0.01) than in the healthy individuals (mean: 0.2939 and SD: 0.01). The receiver operating characteristic curve analysis indicated the obvious separation between patient and healthy control, with an AUC of 0.75 (95% confidence interval [CI] = 0.642-0.858, P < 0.001), 0.72 (95% CI = 0.607-0.834, P < 0.001), and 0.74 (95% CI = 0.630-0.861, P < 0.001) for miR-16, miR-135a, and miR-1202, respectively. The data suggest that these miRNAs have a potential to be used as a biomarker of depression with sensitivity 77.8% and specificity of 61.5% for miR-16, 94.4% and 41.0% for miR-135a as well as 86.1% and 61.5% for miR-1202, respectively (P < 0.001). CONCLUSION: Our findings showed that these miRNA can be used as a biomarker of depression diagnosis. MiR-135a and miR-1202 exhibited better sensitivity and specificity, respectively.

In silico interaction of insulin-like growth factor binding protein 3 with insulin-like growth factor 1.

Insulin-like growth factor binding protein-3 (IGFBP-3) is a vital protein exist in circulation which interacts with high affinity to insulin-like growth factor (IGFs) altering their activities. Therefore, the interaction between IGFs and IGFBP-3 has a key role altering large spectrum of activities such as cell cycle progression, proliferation and apoptosis. Despite decades of research, the crystal structure of IGFBP-3 has not been identified possibly due to some technical challenge in its crystallizing. The three-dimensional (3D) structure of IGFBP-3 was predicted using homology modeling, Phyre2, and molecular dynamic. Its interaction with IGF-1 was also identified by HADDOCK software. IGFBP-3 has the most identity with other IGFBPs in N and C-domain; however, its linker domain has lower identity. Our data predicted that IGF-1 structurally interacts with N-domain and linker domain of IGFBP-3. Some conserved residues of IGFBP-3 such as Glu33, Arg36, Gly39, Arg60, Arg66, Asn109, and Ile146 interacts with Glu3, Asp12, Phe16, Gly19, Asp20, Arg21, and Glu58 of IGF-1. In addition, our data predict that the linker domain has a loop structure which covers post translational modification and interacts with IGF-1. The phosphorylation of Ser111 in linker domain, which previously has been shown to induce apoptosis make a repulsive force interrupting this interaction to IGF-1, which enables IGFBP-3 to induce apoptosis. The present study suggests that the linker domain has a key role in recognition of IGFBP-3 with IGF-1.

STAT5 reactivation by catechin modulates H2O 2-induced apoptosis through miR-182/FOXO1 pathway in SK-N-MC cells.

It has been suggested that oxidative stress-induced apoptosis is a major contributing factor in the pathogenesis of Alzheimer's and Parkinson's diseases. However, the molecular mechanism of the oxidative stress-associated apoptosis is far to be elucidated. Herein, we investigated whether STAT5, which is involved in many signaling pathways, is affected by oxidative stress. Previously, it has been shown that STAT5 is a direct activator of miR-182 which is in turn a robust inhibitor of FOXO1. Our results showed that oxidative stress inactivated STAT5 may be in a JAK2-independent manner. Thus, under oxidative stress and miR-182 down-regulation, FOXO1 has the opportunity to be translated leading to FOXO1 over-expression. Finally, pro-apoptotic gene targets of FOXO1 e.g., Bim and Bax are up-regulated leading to apoptosis. To further confirm such events, we also demonstrated that Catechin, a well-known natural antioxidant, partially restored both the STAT5 activation and miR-182 expression resulting in cell survival. To the best of our knowledge, this is the first study demonstrating that STAT5/miRNA-182 negatively regulates FOXO1 in response to oxidative stress.

Inhibition of H2O2-induced cell death through FOXO1 modulation by EUK-172 in SK-N-MC cells.

It has been suggested that excess accumulation of reactive oxygen species, termed oxidative stress, may lead to neuronal death resulting in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. In oxidative stress-induced cell death numerous transcription factors are thought to be involved. One of them is Forkhead box protein O1 (FOXO1) that governs many genes involved in oxidative stress resistance, DNA repair, cell cycle arrest, proliferation and apoptosis. Apparently, FOXO1 activity is tightly linked to post translational modifications including phosphorylation and acetylation, which are modulated by many factors such as oxidative stress. Reactive oxygen species, as the major players in oxidative stress, guide FOXO1 nuclear localization at least by simultaneous c-Jun N-terminal kinase (JNK) activation and Akt/PKB activity suppression. Here, we showed that a synthetic salen-manganese derivative (EUK-172) with strong catalase activity reduced oxidative stress evident through marked reduction in intracellular reactive oxygen species, protein carbonylation and lipid peroxidation. In addition, our results indicated that EUK-172 not only reduced the FOXO1 protein content, but also it inhibited FOXO1 nuclear translocation in H(2)O(2)-exposed SK-N-MC cells. These events attenuated caspase-3 activity and bax/Bcl-2 ratio leading to higher viability of the H(2)O(2)-treated SK-N-MC cells.

Syntheses and structure-activity relationships of seven manganese-salen derivatives as anti-amyloidogenic and fibril-destabilizing agents against hen egg-white lysozyme aggregation.

Accumulation of intra- and/or extracellular misfolded proteins as amyloid fibrils is a key hallmark in more than 20 amyloid-related diseases. In that respect, blocking or reversing amyloid aggregation via the use of small compounds is considered as two useful approaches in hampering the development of these diseases. In this research, we have studied the ability of different manganese-salen derivatives to inhibit amyloid self-assembly as well as to dissolve amyloid aggregates of hen egg-white lysozyme, as an in vitro model system, with the aim of investigating their structure-activity relationships. By coupling several techniques such as thioflavin T and anilinonaphthalene-8-sulfonic acid fluorescence, congo red absorbance, far-UV circular dichroism, and transmission electron microscopy, we demonstrated that all compounds possessed anti-amyloidogenic activities and were capable of dispersing the fibrillar aggregates. In addition, MTT assay of the treated SK-N-MC cells with the preformed fibrils formed in the presence of compounds at a drug-to-protein molar ratio of 5:1, indicated a significant increase in the viability of cells, compared to the fibrils formed in the absence of each of the compounds. Our spectroscopy, electron microscopy, and cellular studies indicated that EUK-15, with a methoxy group at the para position (group R(5)), had higher activity to either inhibit or disrupt the ß-sheet structures relative to other compounds. On the basis of these results, it can be concluded that in addition to aromatic rings of each of the derivatives, the type and position of the side group(s) contribute to lower lysozyme fibril accumulation.