Development a novel nano-platform for Thrombolysis acceleration by Thrombin sensitive polymer-peptide hybrid nancapsules.

According to the importance of time in treatment of thrombosis disorders, faster than current treatments are required. For the first time, this research discloses a novel strategy for rapid dissolution of blood clots by encapsulation of a fibrinolytic (Reteplase) into a Thrombin sensitive shell formed by polymerization of acrylamide monomers and bisacryloylated peptide as crosslinker. Degradability of the peptide units in exposure to Thrombin, creates the Thrombin-sensitive Reteplase nanocapsules (TSRNPs) as a triggered release system. Accelerated thrombolysis was achieved by combining three approaches including: deep penetration of TSRNPs into the blood clots, changing the clot dissolution mechanism by altering the distribution pattern of TSRNPs to 3D intra-clot distribution (based on the distributed intra-clot thrombolysis (DIT) model) instead of peripheral and unidirectional distribution of unencapsulated fibrinolytics and, enzyme-stimulated release of the fibrinolytic. Ex-vivo study was carried out by an occluded tube model that mimics in-vivo brain stroke as an emergency situation where faster treatment in short time is a golden key. In in vivo, efficacy of the developed formulation was confirmed by PET scan and laser Doppler flowmetry (LDF). As the most important achievements, 40.0 ± 0.7 (n = 3) % and 37.0 ± 0.4 (n = 3) % reduction in the thrombolysis time (faster reperfusion) were observed by ex-vivo and in-vivo experiments, respectively. Higher blood flow and larger digestion mass of clot at similar times in comparison to non-encapsulated Reteplase were observed that means more effective thrombolysis by the developed strategy.

Using chitosan-coated magnetite nanoparticles as a drug carrier for opioid delivery against breast cancer.

Over the past decades, opium derivatives have been discovered as new anticancer agents. In our study, Fe3O4 superparamagnetic nanoparticles (SPIONs) decorated with chitosan were loaded with papaverine or noscapine to surmount drug delivery-related obstacles. Modifying the magnetic nanoparticles (MNP) surface with polymeric materials such as chitosan prevents oxidation and provides a site for drug linkage, which renders them a great drug carrier. The obtained systems were characterized by DLS (20-40 nm were achieved for MNPs and drug- loaded MNPs), TEM (spherical with average size of 11-20 nm) FTIR, XRD, and VSM (71.3 - 42.8 emu/g). Contrary to noscapine, papaverine-MNPs attenuated 4T1 murine breast cancer cell proliferation (11.50 ± 1.74 µg/mL) effectively compared to the free drug (62.35 ± 2.88 µg/mL) while sparing L-929 fibroblast cells (138.14 ± 4.38 µg/mL). Furthermore, SPION and SPION-chitosan displayed no cytotoxic activity. Colony-formation assay confirmed the long-term cytotoxicity of nanostructures. Both developed formulations promoted ROS production accompanied by late apoptotic cell death. The biocompatible nanoparticle exerted an augmenting effect to deliver papaverine to metastatic breast cancer cells.

The Impact of Cancer-Associated Fibroblasts on Drug Resistance, Stemness, and Epithelial-Mesenchymal Transition in Bladder Cancer: A Comparison between Recurrent and Non-Recurrent Patient-Derived CAFs.

This study comparatively evaluated the possible effects of recurrent and non-recurrent patient-derived Cancer-Associated Fibroblasts (CAFs-R and -NR) on the bladder cancer cell line, EJ138. Both groups of CAFs increased cisplatin resistance and altered cell cycle distribution alongside induced resistance to apoptosis. Later, the scratch assay confirmed the cell migration-inducing effects of CAFs on cells. Nonetheless, only CAFs-R managed to increase sphere-formation and clonogenic levels in EJ138 cells, which were later validated by upregulating pluripotency transcription factors. Besides, CAFs-R also affected the expression levels of some of the EMT markers. Our study suggests that CAFs-R had stronger pro-tumorigenic effects on EJ138 cells.

Dual drug delivery system based on layered double hydroxides/carboxymethyl cellulose-poly ethylene oxide bionanocomposite electrospun fibrous mats: Fabrication, characterization, in-vitro and in-vivo studies.

The main goal of the present project was to design and develop ibuprofen (IBU) and layered double hydroxides-vancomycin (LDH-VAN) nanohybrid loaded bionanocomposite fibrous mats to increase the wound healing rate. Thus, first, LDH-VAN nanohybrid particles was synthesized by in-situ incorporation of VAN into the Mg-Al-LDH interlayers during the co-precipitation of hydroxides. Then, LDH-VAN/IBU/CMC-PEO bionanocomposite fibrous mats were fabricated by electrospinning technique. Test samples were examined XRD, SEM, TEM, TGA, and FTIR. In vitro drug release test was performed in the phosphate buffer solution (pH = 7.4) to prove the efficiency of the fabricated bionanocomposite fibrous mats as a sustained-release carrier for both VAN and IBU. All the fabricated bionanocomposite fibrous mats did not displayed any significant cytotoxicity on NIH/3 T3 fibroblast cells. The wound area in the rats treated with LDH-VAN/IBU/CMC-PEO bionanocomposite fibrous mats was less than other treatment groups. Based on histological analysis, the LDH-VAN/IBU/CMC-PEO bionanocomposite fibrous mats possess a faster wound healing than other nanofibrous mats. Data obtained from the present project indicated that LDH-VAN/IBU/CMC-PEO bionanocomposite fibrous mats could accelerate the wound healing process.

Effect of heat stress on DNA damage: a systematic literature review.

Thermal stress has a direct effect on various types of DNA damage, which depends on the stage of the cell cycle when the cell is exposed to different climate conditions. A literature review was conducted to systematically investigate and assess the overall effect of heat stress and DNA damage following heat exposure. In this study, electronic databases including PubMed, Scopus, and Web of Science were searched to find relevant literature on DNA damage in different ambient temperatures. Outcomes included (1) measurement of DNA damage in heat exposure, (2) three different quantification methods (comet assay, 8-hydroxy-2-deoxyguanosine (8-OHdG), and γ-H2AX), and (3) protocols used for moderate (31) and high temperatures (42). The evidence shows that long exposure and very high temperature can induce an increase in DNA damage through aggregate in natural proteins, ROS generation, cell death, and reproductive damage in hot-humid and hot-dry climate conditions. A substantial increase in DNA damage occurs following acute heat stress exposure, especially in tropical and subtropical climate conditions. The results of this systematic literature review showed a positive association between thermal stress exposure and inhibition of repair of DNA damage.

Thermal stress and TiO2 nanoparticle-induced oxidative DNA damage and apoptosis in mouse hippocampus.

Titanium dioxide (nano-TiO2) is used abundantly in various industrial products and novel medical therapies. In addition, the impact of climate change on the health and safety will undoubtedly increase in the future. However, the effects of exposure to these nanoparticles and heat stress on hippocampal DNA damage and apoptosis remain unclear. This study was conducted to evaluate the DNA damage and apoptosis in the hippocampal tissue and the physiological responses in mice induced by intraperitoneal (i.p.) administration of TiO2 nanoparticles (NPs) and heat stress for 14 consecutive days. The results showed that heat stress and TiO2-NPs were induced in the mouse hippocampus that led to hippocampal reactive oxygen species generation, oxidative damage of DNA, and apoptosis in a partly dose-dependent manner, especially at very hot temperature. High doses of nanosized TiO2 and severe heat stress significantly damaged the function of the hippocampus, as shown in the comet assay and apoptosis tests. The results of this study may provide data for appropriate measures to control and assess the risk of nano-TiO2 and thermal stress hazards to human health, especially workers. Safety guidelines and policies should be considered when handling nanomaterials in a hot environment.

Combined regimens of cisplatin and metformin in cancer therapy: A systematic review and meta-analysis.

INTRODUCTION: Cancer cell resistance to chemotherapy agents is a challenging issue in treating patients with cancer. Findings suggest that a combination of drugs may have synergistic or additive effects. in the present study, we systematically reviewed the combined regimens of metformin with cisplatin in various treating cancers. METHODS: A comprehensive systematic search was performed in PubMed, Scopus, Embase, and other relevant databases with the following keyword "metformin", "cisplatin", "combination", "using all their equivalents and similar terms. Pooled odds ratio (OR) and 95% confidence intervals of cell viability and tumor volume as primary outcomes were calculated using Der-Simonian and Laird method while random effects meta-analysis was used, taking into account clinical and statistical heterogeneity. RESULTS: Overall, 44 studies were retrieved, Findings of the present meta-analysis showed that combined regimens of metformin plus cisplatin was significantly associated with decreased odds of tumor volume and cell viability for all cancers compared with cisplatin alone (pooled OR: 0.40; 95% CI: 0.27, 0.58) and (pooled OR: 0.49; 95% CI: 0.42, 0.58) respectively. The result was same for cell viability in lung cancer (pooled OR: 0.59; 95% CI: 0.49, 0.70). The tumor size reduction and the response rate were evident in the animal xenografts model. CONCLUSION: Findings indicated that combining metformin with cisplatin is a practical therapeutic approach to increase treatment efficacy in the case of cell viability and tumor volume and minimize side effects. A combination of metformin with cisplatin could enhance treatment efficacy through synergistic inhibitory effects on the growth of cancer cells.

Combination effect of doxorubicin and HIF inhibitor on MCF-7 CD44+/CD24- subpopulation cells in hypoxic condition

Abstract Hypoxia-inducible factors (HIFs) and cancer stem cells (CSCs) are two challenging causes of radiotherapy and chemotherapy resistance, leading to most cases of failure and recurrence in breast cancer therapy. This study was conducted to investigated the inhibitory effect of combination therapy with doxorubicin (an anthracycline) and FM19G11 (an HIF inhibitor) on MCF-7 cells and their CSC-like cells (CSC-LCs). MCF-7 CSC-LCs with a CD44+/CD24- phenotype were sorted and characterized by flow cytometry. A combination of doxorubicin and FM19G11 caused more cytotoxic effects on MCF-7 and CSC-LCs compared to doxorubicin monotherapy. The largest synergistic effect was observed in CSC-LCs under hypoxic conditions; however, MCF-7 cells showed no synergism in normoxic conditions. The administration of doxorubicin and FM19G11 induced late apoptotic and necrotic cell death in MCF-7 and CSC-LCs. Additionally, G2 phase arrest was observed in both cells. Our results demonstrated that co-administration of FM19G11 and doxorubicin had a synergistic effect in hypoxia and improved drug resistance in breast cancer stem cells.

A Preliminary Study of NER and MMR Pathways Involved in Chemotherapy Response in Bladder Transitional Cell Carcinoma: Impact on progression-free survival.

One of the main genotoxic drugs used in bladder cancer chemotherapy is cisplatin. While it is applied in most types of cancers, resistance to cisplatin is wildly common. In order to overcome drug resistance, it is necessary to determine a predictive marker. This study was conducted to provide basic data for selecting and designing a gene profile for further cohort and RCT studies in the future to improve response to treatment in bladder cancer. The expression levels of ERCC1, MLH1, MSH2, and CTR1 mRNA were determined in the tumor tissue using real-time q-PCR. Progression-free survival (PFS) was analyzed in term of the level of genes expression. The results revealed that the level of ERCC1 mRNA expression was higher in the recurrence (R) group compared to the no recurrence (NR) group. Moreover, the PFS time was increased in the patients with an ERCC1 expression level of below 1.57. The level of MLH1 and MSH2 mRNA expression was lower in the R group compared to the NR group; therefore, PFS time was increased in the patients with MLH1 and MSH2 gene expression levels above the cutoff point. While the level of CTR1 mRNA expression was higher in the R group versus the NR group, the PFS time was longer in the patients with CTR1 expression levels of below 1.265 compared to the patients with high levels of CTR1 expression. It can be concluded that the level of ERCC1, MLH1, MSH2, and CTR1 mRNA expression may be associated with PFS time as possible therapeutic targets for decreasing cisplatin resistance.

The Inhibitory Effect of Curcumin on Hypoxia Inducer Factors (Hifs) as a Regulatory Factor in the Growth of Tumor Cells in Breast Cancer Stem-Like Cells.

Hypoxia in the microenvironment is related to chemotherapy resistance, tumor progression, and metastasis. Curcumin, as a phenolic compound extracted from the turmeric, has been used as an anti-cancer agent with low toxicity in recent years. Since curcumin has inhibitory activities against hypoxia-inducible factors (HIFs) in several cancers, this study was conducted to examine the effect of curcumin on MCF-7 cells and cancer stem-like cells (CS-LCs) under hypoxic and normoxic conditions. CS-LCs were isolated from MCF-7 cells using the magnet activated cell sorting (MACS) method based on CD44 +/ CD24 - surface markers. The effects of curcumin on the viability of MCF-7 cells and CS-LCs were examined in hypoxic and normoxic conditions using the MTT test. The effects of curcumin on apoptosis and cell cycle of CS-LCs and MCF-7 cells were analyzed using flow cytometry. Moreover, the inhibitory effects of curcumin on the levels of HIF-1 and HIF-2α protein in CS-LCs were investigated using the western blot method. Early apoptosis occurred in CSC-LCs more than MCF-7 cells under hypoxic conditions. Flow cytometry assay showed that curcumin caused cell cycle arrest of CSC-LCs and MCF-7 at the G2/M phase under hypoxic conditions while under normoxic conditions, arrest occurred at the G0/G1 phase in MCF-7 cells and at S and G2/M phases in CS-LCs. Based on the results, the curcumin inhibited the expression of HIF-1 by degrading ARNT in CS-LCs.In conclusion, curcumin has inhibitory effects on MCF- 7 cells and CS- LCs and thus may be used as an antitumor agent.

Genetic Polymorphism of Mismatch Repair Genes and Susceptibility to Prostate Cancer.

PURPOSE: Mismatch repair (MMR) is one of the DNA repair systems that correct mispaired bases during DNA replication errors. Polymorphisms in genes can increase susceptibility to the development of prostate cancer (PCa). In this study, we investigated mutL homolog 1 (MLH1) -93G>A (rs1800734) and mutS homolog 3 (MSH3) (rs26279) polymorphisms with the risk of PCa. MATERIALS AND METHODS: In this study of Iranian population, 175 histopathologically confirmed (PCa) patients and 230 benign prostate hyperplasia (BPH) as the controls were recruited. The genotypes of MLH1 and MSH3 were determined by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: There was no significant difference of MLH1 (P = 0.4) and MSH3 (P?=?0.5) genotype distributions among PCa cases and controls. And also patients with PCa were not significant differences compared to those without in stage of cancer, grade of tumor, perineural invasion, and vascular invasion. CONCLUSION: Our results did not show adequate evidence for any significant association of MLH1 and MSH3 polymorphisms and PCa .

Hepatoprotective effect of silyamarin in individuals chronically exposed to hydrogen sulfide; modulating influence of TNF-α cytokine genetic polymorphism.

BACKGROUND AND THE PURPOSE OF THE STUDY: Silymarin, a standardized extract of the milk thistle (Silybum marianum), is believed to exert some of its hepatoprotective effects though inhibition of free radicals and inflammation. In this study the effect of some pro- and anti-inflammatory cytokines and also antioxidant genes polymorphisms on the hepatoprotective effects of silymarin in the occupationally exposed individuals to hydrogen sulfide (H2S) in the sour natural gas refinery was investigated. METHODS: We genotyped seven polymorphisms in six genes reported by others as modifiers of oxidative stress (NQO1, mEPXH1, GSTT1 and GSTM1) and inflammation (TNF-α and TGF-ß1) for an association in effect of decreasing in liver function tests (LFTs). The LFTs of 77 sour gas refinery workers were measured before and after administration of silymarin (140 mg, three times per day for 1 month). RESULTS: A significant reduction of blood AST, ALT and ALP was observed after 30 days of consumption (p < 0.001). The decreasing effect of silymarin on ALT in the subjects with high producer genotype (A allele carriers) was less than low producers. There were no significant associations between TGF-ß1 and the studied genes of oxidative stress pathway and the effectiveness of silymarin. CONCLUSION: This is the first report about the effectiveness of silymarin in the subjects exposed chronically to H2S. Meanwhile, the modulatory effect of TNF-α on the effectiveness of silymarin might be used for individualize therapy.

Is there a significant trend in prevalence of consanguineous marriage in Tehran? A review of three generations.

Consanguineous marriage is a common practice in Iran. The present study surveyed the trend in consanguineous marriage across three generations of Iranians. Index cases, consisting of 400 individuals attending the diabetes and osteoporosis clinic in Shariati Hospital, were interviewed. Data on consanguinity status for 1789 marriages within the index cases' families were obtained. Generation 1 consisted of marriages contracted before 1948, Generation 2 consisted of marriages contracted between 1949 and 1978, and Generation 3 consisted of marriages contracted after 1979. Prevalence of consanguineous marriage within these three generations was 8.8%, 16.6% and 19%, respectively, and represented a significant trend (p < 0.001). First cousin marriage was the most common type of consanguinity (69%). Socioeconomic level of families was not significantly related to having a consanguineous marriage. These data suggest that premarital genetic counseling and mass media efforts are needed to increase public awareness about genetic risks associated with consanguineous marriage.