Sakineh Kazemi Noureini

G-rich sequences have the potential to fold into G-quadruplexes (GQs). G-quadruplexes, particularly those positioned in the regulatory regions of proto-oncogenes, have recently garnered attention in anti-cancer drug design. A thermal FRET assay was employed to conduct preliminary screening of various alkaloids, aiming to identify stronger interactions with a specific set of G-rich double-labeled oligonucleotides in both K + and Na + buffers. These oligonucleotides were derived from regions associated with Kit, Myc, Ceb, Bcl2, human telomeres, and potential G-quadruplex forming sequences found in the Nrf2 and Trf2 promoters. Palmatine generally increased the stability of different G-rich sequences into their folded GQ structures, more or less in a concentration dependent manner. The thermal stability and interaction of palmatine was further studied using transition FRET (t-FRET), CD and UV-visible spectroscopy and molecular dynamics simulation methods. Palmatine showed the strongest interaction with T RF2 in both K+ and Na+ buffers even at equimolar concentration ratio. T-FRET studies revealed that palmatine has the potential to disrupt double-strand formation by the T RF2 sequence in the presence of its complementary strand. Palmatine exhibits a stronger interaction with G-rich strand DNA, promoting its folding into G-quadruplex structures. It is noteworthy that palmatine exhibits the strongest interaction with T RF2, which is the shortest sequence among the G-rich oligonucleotides studied, featuring only one nucleotide for two of its loops. Palmatine represents a suitable structure for drug design to develop more specific ligands targeting G-quadruplexes. Whether palmatine can also affect the expression of the T RF2 gene requires further studies.Communicated by Ramaswamy H. Sarma.

Human MRP1 protein plays a vital role in cancer multidrug resistance. Coumarins show promising pharmacological properties. Virtual screening, ADMET, molecular docking and molecular dynamics (MD) simulations were utilized as pharmacoinformatic tools to identify potential MRP1 inhibitors among coumarin derivatives. Using in silico ADMET, 50 hits were further investigated for their selectivity toward the nucleotide-binding domains (NBDs) of MRP1 using molecular docking. Accordingly, coumarin, its symmetrical ketone derivative Lig. No. 4, and Reversan were candidates for focused docking study with the NBDs domains compared with ATP. The result indicates that Lig. No. 4, with the best binding score, interacts with NBDs via hydrogen bonds with residues: GLN713, LYS684, GLY683, CYS682 in NBD1, and GLY1432, GLY771, SER769 and GLN1374 in NBD2, which mostly overlap with ATP binding residues. Moreover, doxorubicin (Doxo) was docked to the transmembrane domains (TMDs) active site of MRP1. Doxo interaction with TMDs was subjected to MD simulation in the NBDs free and occupied with Lig. No. 4 states. The results showed that Doxo interacts more strongly with TMD residues in inward facing feature of TMDs helices. However, when Lig. No. 4 exists in NBDs, Doxo interactions are different, and TMD helices show more outward-facing conformation. This result may suggest a partial competitive inhibition mechanism for the Lig. No. 4 on MRP1 compared with ATP. So, it may inhibit active complex formation by interfering with ATP entrance to NBDs and locking MRP1 conformation in outward-facing mode. This study suggests a valuable coumarin derivative that can be further investigated for potent MRP1 inhibitors.Communicated by Ramaswamy H. Sarma.

Background: Traditional medicine is inspiring in drug development research. Epilobium parviflorum extracts have shown promising therapeutic effects on prostate cancer cells. The similarities between breast and prostate cancers at molecular and metabolic levels prompted us to explore its effects on human breast cancer. Methods: The root, aerial parts and flowers of the plant were, collected and dried separately at ambient temperature and away from direct sunlight. The aquatic and methanolic extracts of each part was prepared. The effect of each extract on the growth of MCF-7 breast carcinoma cells and HEK293 normal cell line was evaluated, using MTT assay. Each experiment was repeated at least three times independently. The IC50 values for each treatment time point were analyzed, using ANOVA at P<0.05. Results: While none of the extracts had considerable toxicity on normal HEK293 cells, some of them showed varying levels of toxicity on the MCF-7 cells. The methanolic extracts were more cytotoxic than the aqueous counterpart. The roots’ methanolic extract showed the strongest cytotoxicity on the MCF-7 cells in a dose and exposure time dependent manner. The IC50 after 48 hours of treatment was determined at 73µg/ml. Conclusion: This study is the first to demonstrate that Epilobium parviflorum had a strong growth inhibiting property on MCF-7 cell line, as a potential model to treat human breast cancer cells. The most cytotoxic effect was noted for the methanolic root extract. Determination of the effective biochemical constituents of the extract against cancer cells is the focus of our future research.

Although studies have shown the efficacy of laquinimod (LAQ) on disease progression in patients with multiple sclerosis (MS), there is some controversy about whether it improves the types of outcomes and side effects. The main purpose of the present study was to systematically review and meta-analyze the efficacies and side effects of LAQ in patients with relapsing-remitting MS (RRMS).

This report focuses on the application of zinc oxide nanoparticles (ZnO NPs) carrying phycomolecule ligands as a novel plant growth promoter aimed at increasing the crop productivity of purslane (Portulaca oleracea L.). Experiments were performed under controlled greenhouse conditions using a completely randomized design with nine replications. Purslane seeds were treated with four concentrations of ZnO NPs (0, 10, 100, and 500 mg L−1) and four concentrations of bulk ZnO (0, 10, 100, and 500 mg L−1). The ultrastructural characteristics of the leaves of the plants treated with of 500 mg L−1 ZnO NPs were determined using transmission electron microscopy (TEM). The results indicated that the treatment with ZnO NPs increased the content of chlorophyll a and chlorophyll b, carotenoids, and total phenolic and flavonoid compounds significantly more than the treatment with bulk ZnO. Our findings also showed that the application of high concentrations of ZnO NPs is the most effective strategy to considerably induce the antioxidant capacity and enzymes of purslane plants. Furthermore, the seed germination percentage and sprout growth rates were significantly higher in the plants treated with 500 mg L−1 of ZnO NPs (100% ±0.00), compared to the control plants (93.33% ±1.66). The TEM images revealed the concentration of ZnO NPs and cell membrane rupture, as well as a deformation in the shape of chloroplasts and a decrease in their number in the plants treated with 500 mg L−1 ZnO NPs, compared to the control plants. Owing to their toxicity, high concentrations of ZnO NPs lead to oxidative stress in plants. Thus, our findings provide a new alternative strategy for increasing crop productivity, i.e., the application of ZnO NPs as a novel plant growth booster, in comparison with the bulk ZnO treatment.

Sepsis is a clinical illness with a high rate of mortality all over the world. Oxidative stress is considered the main phenomenon that occurs in sepsis. Rosa damascena Mill. is an ancient herbal plant with high pharmacological activities. Cecal ligation and puncture (CLP) as a standard model was used to induce sepsis in rats. Male adult rats were randomly divided into 5 groups. Different doses of R. damascena essential oil (50 and 100 mg/kg.bw) were gavaged orally for 14 days and on day 15 CLP was performed. After 24 h, blood samples and liver tissues were removed in order to measure oxidative stress [myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH), glutathione-S-transferase, and ferric reducing ability of plasma (FRAP)] and biochemical parameters [alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT), and bilirubin] together with plasma prostaglandin E2 (PGE2) and COX-2 expression. The essential oil was capable of modulating all of the oxidative stress, antioxidant, and anti-inflammatory parameters induced by CLP as characterized by elevations in MPO and MDA levels as well as increases in AST and ALT concentrations concomitant with PGE2 and COX-2 increments. The antioxidant defense system such as GSH and FRAP was also increased in the essential oil treated groups. Our results showed that the essential oil has antioxidative and hepatoprotective activities through reducing the oxidative injury in sepsis caused by CLP.

Telomeres, the specialized dynamic structures at chromosome ends, regularly shrink with every replication. Thus, they function as an internal molecular clock counting down the number of cell divisions. However, most cancer cells escape this limitation by activating telomerase, which can maintain telomere length. Previous studies showed that the benzylisoquinoline alkaloid chelidonine stimulates multiple modes of cell death and strongly down-regulates telomerase. It is still unknown if down-regulation of telomerase by chelidonine boosts substantial telomere shortening. The breast cancer cell line MCF7 was sequentially treated with very low concentrations of chelidonine over several cell passages. Telomere length and telomerase activity were measured by a monochrome multiplex quantitative PCR and a q-TRAP assay, respectively. Changes in population size and doubling time correlated well with telomerase inhibition and telomere shortening. MCF7 cell growth was arrested completely after three sequential treatments with 0.1 μM chelidonine, each ending after 48 h, while telomere length was reduced to almost 10% of the untreated control. However, treatment with 0.01 μM chelidonine did not have any apparent consequence. In addition to dose and time dependent telomerase inhibition, chelidonine changed the splicing pattern of hTERT towards non-enzyme coding isoforms of the transcript. In conclusion, telomere length and telomere stability are strongly affected by chelidonine in addition to microtubule formation.