Reverse vaccinology approaches to design a potent multiepitope vaccine against the HIV whole genome: immunoinformatic, bioinformatics, and molecular dynamics approaches.

Substantial advances have been made in the development of promising HIV vaccines to eliminate HIV-1 infection. For the first time, one hundred of the most submitted HIV subtypes and CRFs were retrieved from the LANL database, and the consensus sequences of the eleven HIV proteins were obtained to design vaccines for human and mouse hosts. By using various servers and filters, highly qualified B-cell epitopes, as well as HTL and CD8 + epitopes that were common between mouse and human alleles and were also located in the conserved domains of HIV proteins, were considered in the vaccine constructs. With 90% coverage worldwide, the human vaccine model covers a diverse allelic population, making it widely available. Codon optimization and in silico cloning in prokaryotic and eukaryotic vectors guarantee high expression of the vaccine models in human and E. coli hosts. Molecular dynamics confirmed the stable interaction of the vaccine constructs with TLR3, TLR4, and TLR9, leading to a substantial immunogenic response to the designed vaccine. Vaccine models effectively target the humoral and cellular immune systems in humans and mice; however, experimental validation is needed to confirm these findings in silico.

Pyrano[2,3-b]chromone derivatives as novel dual inhibitors of α-glucosidase and α-amylase: Design, synthesis, biological evaluation, and in silico studies.

Inhibition of α-glucosidase and α-amylase is an important target for treatment of type 2 diabetes. In this work, a novel series of pyrano[2,3-b]chromene derivatives 5a-m was designed based on potent α-glucosidase and α-amylase inhibitors and synthesized by simple chemical reactions. These compounds were evaluated against the latter enzymes. Most of the title compounds exhibited high inhibitory activity against α-glucosidase and α-amylase in comparison to standard inhibitor (acarbose). Representatively, the most potent compound, 4-methoxy derivative 5d, was 30.4 fold more potent than acarbose against α-glucosidase and 6.1 fold more potent than this drug against α-amylase. In silico molecular modeling demonstrated that compound 5d attached to the active sites of α-glucosidase and α-amylase with a favorable binding energies and established interactions with important amino acids. Dynamics of compound 5d also showed that this compound formed a stable complex with the α-glucosidase active site. In silicodrug-likeness as well as ADMET prediction of this compound was also performed and satisfactory results were obtained.

Designing a novel multi-epitope antigen for diagnosing human cytomegalovirus infection: An immunoinformatics approach.

Human cytomegalovirus (HCMV) infection can lead to congenital infections and severe complications, particularly in immunocompromised individuals. Current serological tests for diagnosing HCMV infection often face limitations in sensitivity and specificity. Developing multi-epitope antigens for serological assays offers the potential for enhancing diagnostic accuracy. This study aimed to design a novel multi-epitope antigen for HCMV infection diagnosis using immunoinformatic approaches. Five tegument proteins (universal protein resource [UniProt] ID: Po8318, Po6725, F5HC97, Q6RX10, and F5HC05) were selected based on their antigenic properties and literature review. Six linear B-cell epitopes were predicted within conserved regions of each antigen sequence and linked with appropriate linkers. The designed multi-epitope antigen underwent thorough evaluation for physicochemical properties, solubility, antigenicity, and cross-reactivity. Additionally, the three-dimensional structure of the antigen was predicted, refined, and validated. The nucleotide sequence of the designed antigen was optimized for successful expression in Escherichia coli and inserted into a pET23a (+) vector. Immunoinformatic analysis revealed that the multi-epitope antigen exhibits stability, antigenicity, and lacks cross-reactivity. Our findings suggest that this multi-epitope antigen is a promising candidate for diagnosing HCMV infection. However, further validation through laboratory testing is required to confirm its diagnostic efficacy.

LYZ2-SH3b as a novel and efficient enzybiotic against methicillin-resistant Staphylococcus aureus.

BACKGROUND: Enzybiotics are promising alternatives to conventional antibiotics for drug-resistant infections. Exolysins, as a class of enzybiotics, show antibacterial effects against methicillin-resistant Staphylococcus aureus (MRSA). This study evaluated a novel exolysin containing an SH3b domain for its antibacterial activity against MRSA. METHODS: This study designed a chimeric exolysin by fusing the Cell-binding domain (SH3b) from Lysostaphin with the lytic domain (LYZ2) from the gp61 enzyme. Subsequently, LYZ2-SH3b was cloned and expressed in Escherichia coli (E. coli). Finally, the antibacterial effects of LYZ2-SH3b compared with LYZ2 and vancomycin against reference and clinical isolates of MRSA were measured using the disc diffusion method, the minimal inhibitory concentration (MIC), and the minimal bactericidal concentration (MBC) assays. RESULTS: Analysis of bioinformatics showed that LYZ2-SH3b was stable, soluble, and non-allergenic. Protein purification was performed with a 0.8 mg/ml yield for LYZ2-SH3b. The plate lysis assay results indicated that, at the same concentrations, LYZ2-SH3b has a more inhibitory effect than LYZ2. The MICs of LYZ2 were 4 µg/mL (ATCC 43,300) and 8 µg/mL (clinical isolate ST239), whereas, for LYZ2-SH3b, they were 2 µg/mL (ATCC 43,300) and 4 µg/mL (clinical isolate ST239). This suggests a higher efficiency of LYZ2-SH3b compared to LYZ2. Furthermore, the MBCs of LYZ2 were 4 µg/mL (ATCC 43,300) and 8 µg/mL (clinical isolate ST239), whereas, for LYZ2-SH3b, they were 2 µg/mL (ATCC 43,300) and 4 µg/mL (clinical isolate ST239), thus confirming the superior lytic activity of LYZ2-SH3b over LYZ2. CONCLUSIONS: The study suggests that phage endolysins, such as LYZ2-SH3b, may represent a promising new approach to treating MRSA infections, particularly in cases where antibiotic resistance is a concern. But further studies are needed.

Finding and engineering the newly found bacterial superoxide dismutase enzyme to increase its thermostability and decrease the immunogenicity: a computational and experimental research.

Superoxide dismutase (SOD) is one of the most important antioxidant enzymes that can reduce oxidative stress in the cell environment. Nowadays, bacterial sources of enzyme are commercially applicable in the cosmetics and pharmaceutical industries, but the allergenic effect of proteins from non-human sources has been mentioned as disadvantage of these kinds of enzymes. In this study, to find the suitable bacterial SOD candidate for decreasing immunogenicity, the sequences of five thermophilic bacteria were selected as reference species. Then, linear and conformational B-cell epitopes of the SOD were analyzed by different servers. The stability and immunogenicity of mutant positions were also evaluated. The mutant gene was inserted into the pET-23a expression vector and transformed into E. Coli BL21 (DE3) for expression of the recombinant enzyme. Afterward, the expression of the mutant enzyme was evaluated by SDS-PAGE analysis and the recombinant enzyme activity was assessed. Anoxybacillus gonensis was selected as a reasonable SOD source according to BLAST search, physicochemical properties analysis, and prediction of allergenic features. Regarding our results, five residues including E84, E142, K144, G147, and M148 were predicted as candidates for mutagenesis. Finally, the K144A was chosen as the final modification due to the increase in the stability of the enzyme and decreased immunogenicity of the enzyme as well. The enzyme activity was 240 U/ml at room temperature. Alternation in K144 to alanine caused increased stability of the enzyme. In silico studies confirmed non-antigenic protein after mutation.

Everolimus and temsirolimus are not the same second-line in metastatic renal cell carcinoma: a systematic review and meta-analysis.

OBJECTIVE: Renal cell carcinoma (RCC) is the most common type of kidney cancer. VEGF inhibitors and mTORs are the most common therapeutic options among the different classes of available treatments. In this study, the effectiveness of Everolimus was compared to Temsirolimus, and Everolimus plusLenvatinib in renal cell carcinoma patients by review of the international clinical evidence. MATERIALS AND METHODS: A systematic review was conducted and all relevant published clinical studies on the efficacy and cost-effectiveness of Everolimus, Temsirolimus, and Lenvatinib plus Everolimus were searched comprehensively in electronic databases including Pubmed, Scopus, Medline, Cochrane Library, and ISI web of science. The Q score and I2 test checked the Heterogeneity and publication bias test, respectively. Egger's test and Begg's test were used to checking publication bias. The hazard ratio (HR) of included studies and subclass analysis were estimated by fixed and random effect models. RESULTS: Out of 1816 found studies, ultimately, were included considering inclusion and exclusion criteria. None of these studies evaluated all three treatment strategies together and each study was about one strategy. Only one study was found for Everolimus plus Lenvatinib, so it was excluded from meta-analysis. Overall, data from 526 patients on Temsirolimus and 648 patients on Everolimus were included in Meta-Analysis. Accordingly, the efficacy of Everolimus and Temsirolimus was not statistically significant in assessed outcomes (PFS, TTSF, and death). However, Everlimus is superior to Temsirolimus in OS (Q = 3.61, p-value: 0.462, I2 = 0%). No heterogeneity or bias was detected. CONCLUSION: According to the results of this study, Everolimus could be related to an increase of OS versus Temsirolimus as a second line treatment of ORCC patients.

Discovery of novel 4,5-diphenyl-imidazol-α-aminophosphonate hybrids as promising anti-diabetic agents: Design, synthesis, in vitro, and in silico enzymatic studies.

Herein, a novel series of 4,5-diphenyl-imidazol-α-aminophosphonate hybrids 4a-m was designed, synthesized, and evaluated as new anti-diabetic agents. These compounds were evaluated against two important target enzymes in the diabetes treatment: α-glucosidase and α-amylase. These new compounds were synthesized in three steps and characterized by different spectroscopic techniques. The in vitro evaluations demonstrated that all the synthesized compounds 4a-m were more potent that standard inhibitor acarbose against studied enzymes. Among these compound, the most potent compound against both studied enzymes was 3-bromo derivative 4l. The latter compound with IC50 = 5.96 nM was 18-times more potent than acarbose (IC50 = 106.63 nM) against α-glucosidase. Moreover, compound 4l with IC50 = 1.62 nM was 27-times more potent than acarbose (IC50 = 44.16 nM) against α-amylase. Molecular docking analysis revealed that this compound well accommodated in the binding site of α-glucosidase and α-amylase enzymes with notably more favorable binding energy as compared to acarbose.

Telmisartan anti-cancer activities mechanism through targeting N-cadherin by mimicking ADH-1 function.

This study aimed to investigate if Telmisartan as a novel N-cadherin antagonist, can overcome cell migration of cancer cells. We investigated the mechanism and influence of Docetaxel and Telmisartan (as an analogous to ADH-1, which is a well-known N-cadherin antagonist) on cancer cells. The effect of ADH-1 and Telmisartan on cell attachment in PC3, DU145, MDA-MB-468 cell lines using recombinant human N-cadherin was studied. Cell viability assay was performed to examine the anti-proliferative effects of Telmisartan, ADH-1 and Docetaxel. Migration was examined via wound healing assay, and apoptosis was determined by flow cytometry. The expression of AKT-1 as a downstream gene of N-cadherin signalling pathway was assayed by real-time PCR. Treatment of PC3, MDA-MB-468 and DU145 cells with Telmisartan (0.1 µM) and ADH-1 (40 µM) resulted in 50%, 58% and approximately 20% reduction in cell attachment to N-cadherin coated plate respectively. It shows reduction of cell attachment in PC3 and MDA-MB-468 cell lines appeared to be more sensitive than that of DU145 cells to the Telmisartan and ADH-1 treatments. Telmisartan (0.1 µM) and Docetaxel (0.01 nM) significantly reduced cell migration in PC3 and MDA-MB-468 cell lines compared with the control group. Using Real-time PCR, we found that Telmisartan, Docetaxel and ADH-1 had significant influence on the AKT-1 mRNA level. The results of the current study for the first time suggest that, Telmisartan, exerts anti-proliferation and anti-migration effects by targeting antagonistically N-cadherin. Also, these data suggest that Telmisartan as a less expensive alternative to ADH-1 could potentiate Docetaxel anticancer effects.

A structural vaccinology approach for in silico designing of a potential self-assembled nanovaccine against Leishmania infantum.

Visceral leishmaniasis (VL) remains a major public health problem across 98 countries. To date, VL has no effective drug. Vaccines, as the most successful breakthroughs in medicine, can promise an effective strategy to fight various diseases. More recently, self-assembled peptide nanoparticles (SAPNs) have attracted considerable attention in the field of vaccine design due to their multivalency. In this study, a SAPN nanovaccine was designed using various immunoinformatics methods. High-ranked epitopes were chosen from a number of antigens, including Leishmania-specific hypothetical protein (LiHy), Leishmania-specific antigenic protein (LSAP), histone H1, and sterol 24-c-methyltransferase (SMT). To facilitate the oligomerization process, pentameric and trimeric coiled-coil domains were employed. RpfE, a resuscitation-promoting factor of Mycobacterium tuberculosis, was added to induce strong immune responses. Pentameric and trimeric coiled-coil domains as well as eight immunodominant epitopes from antigenic proteins of Leishmania infantum, the causative agent of VL, were joined together using appropriate linkers. High-quality 3D structure of monomeric and oligomeric structures followed by refinement and validation processes demonstrated that the designed nanovaccine could be considered to be a promising medication against the parasite; however, experimental validation is essential to confirm the effectiveness of the nanovaccine.

Predatory and biocontrol potency of Bdellovibrio bacteriovorus toward phytopathogenic strains of Pantoea sp. and Xanthomonas campestris in the presence of exo-biopolymers: in vitro and in vivo assessments.

Bdellovibrios are predatory bacteria that invade other live Gram-negative bacterial cells for growth and reproduction. They have recently been considered as potential living antibiotics and biocontrol agents. In this study, the predatory activity and biocontrol potency of Bdellovibrio bacteriovorus strain SOIR-1 against Pantoea sp. strain BCCS and Xanthomonas campestris, two exo-biopolymer-producing phytopathogens, was evaluated. Plaque formation assays and lysis analysis in the broth co-cultures were used for the in vitro evaluation of bacteriolytic activity of strain SOIR-1. The in vivo biocontrol potential of strain SOIR-1 was evaluated by pathogenicity tests on the onion bulbs and potato tuber slices. The phytopathogens were also recovered from the infected plant tissues and confirmed using biochemical tests and PCR-based 16S rRNA gene sequence analysis. Typical bdellovibrios plaques were developed on the lawn cultures of Pantoea sp. BCCS and X. campestris. The killing rate of strain SOIR-1 toward Pantoea sp. BCCS and X. campestris was 84.3% and 76.3%, respectively. Exo-biopolymers attenuated the predation efficiency of strain SOIR-1 up to 10.2-18.2% (Pantoea sp. BCCS) and 12.2-17.3% (X. campestris). The strain SOIR-1 significantly reduced rotting symptoms in the onion bulbs caused by Pantoea sp. BCCS (69.0%) and potato tuber slices caused by X. campestris (73.1%). Although more field assessments are necessary, strain SOIR-1 has the preliminary potential as a biocontrol agent against phytopathogenic Pantoea sp. BCCS and X. campestris, especially in postharvest storage. Due to the particular physicochemical properties of evaluated exo-biopolymers, they can be used in the designing encapsulation systems for delivery of bdellovibrios.

In Silico Design and Evaluation of PRAME+FliCΔD2D3 as a New Breast Cancer Vaccine Candidate.

Background: The most prevalent cancer in women over the world is breast cancer. Immunotherapy is a promising method to effectively treat cancer patients. Among various immunotherapy methods, tumor antigens stimulate the immune system to eradicate cancer cells. Preferentially expressed antigen in melanoma (PRAME) is mainly overexpressed in breast cancer cells, and has no expression in normal tissues. FliCΔD2D3, as truncated flagellin (FliC), is an effective toll-like receptor 5 (TLR5) agonist with lower inflammatory responses. The objective of the present study was to utilize bioinformatics methods to design a chimeric protein against breast cancer. Methods: The physicochemical properties, solubility, and secondary structures of PRAME+FliCΔD2D3 were predicted using the tools ProtParam, Protein-sol, and GOR IV, respectively. The 3D structure of the chimeric protein was built using I-TASSER and refined with GalaxyRefine, RAMPAGE, and PROCHECK. ANTIGENpro and VaxiJen were used to evaluate protein antigenicity, and allergenicity was checked using AlgPred and Allergen FP. Major histocompatibility complex )MHC( and cytotoxic T-lymphocytes )CTL( binding peptides were predicted using HLApred and CTLpred. Finally, B-cell continuous and discontinuous epitopes were predicted using ABCpred and ElliPro, respectively. Results: The stability and solubility of PRAME+FliCΔD2D3 were analyzed, and its secondary and tertiary structures were predicted. The results showed that the derived peptides could bind to MHCs and CTLs. The designed chimeric protein possessed both linear and conformational epitopes with a high binding affinity to B-cell epitopes. Conclusion: PRAME+FliCΔD2D3 is a stable and soluble chimeric protein that can stimulate humoral and cellular immunity. The obtained results can be utilized for the development of an experimental vaccine against breast cancer.

Current trends in chemical modifications of magnetic nanoparticles for targeted drug delivery in cancer chemotherapy.

Nowadays, magnetic nanoparticles (MNPs) have been rapidly investigated and attracted worldwide attention due to their great potential as mediators of heat for treating hyperthermia and their possibility to deliver drugs at specific locations, which can thereby limit systematic effects. Cancer therapy via MNPs proposes novel properties rather than normal methods such as almost zero side effects and a high-efficiency rate of effectiveness. The key aim of targeted drug delivery is to reduce side effects of the main cancer treatment that other usual chemotherapies will attend to the body, and thus controlling the effectiveness of the drug on a specific location that tumoral tissue exist. Herein, the high potential of MNPs has been studied, and different examples of their effectiveness on drug delivery and hypothermia therapy have been provided.

Mutational Analysis of Ocriplasmin to Reduce Proteolytic and Autolytic Activity in Pichia pastoris.

BACKGROUND: Ocriplasmin (Jetrea) is using for the treatment of symptomatic vitreomacular adhesion. This enzyme undergoes rapid inactivation and limited activity duration as a result of its autolytic nature after injection within the eye. Moreover, the proteolytic activity can cause photoreceptor damage, which may result in visual impairment in more serious cases. RESULTS: The present research aimed to reduce the disadvantages of ocriplasmin using site-directed mutagenesis. To reduce the autolytic activity of ocriplasmin in the first variant, lysine 156 changed to glutamic acid and, in the second variant for the proteolytic activity reduction, alanine 59 mutated to threonine. The third variant contained both mutations. Expression of wild type and three mutant variants of ocriplasmin constructs were done in the Pichia pastoris expression system. The mutant variants were analyzed in silico and in vitro and compared to the wild type. The kinetic parameters of ocriplasmin variants showed both variants with K156E substitution were more resistant to autolytic degradation than wild-type. These variants also exhibited reduced Kcat and Vmax values. An increase in their Km values, leading to a decreased catalytic efficiency (the Kcat/Km ratio) of autolytic and mixed variants. Moreover, in the variant with A59T mutation, Kcat and Vmax values have reduced compared to wild type. The mix variants showed the most increase in Km value (almost 2-fold) as well as reduced enzymatic affinity to the substrate. Thus, the results indicated that combined mutations at the ocriplasmin sequence were more effective compared with single mutations. CONCLUSIONS: The results indicated such variants represent valuable tools for the investigation of therapeutic strategies aiming at the non-surgical resolution of vitreomacular adhesion.

The interaction of phages and bacteria: the co-evolutionary arms race.

Since the dawn of life, bacteria and phages are locked in a constant battle and both are perpetually changing their tactics to overcome each other. Bacteria use various strategies to overcome the invading phages, including adsorption inhibition, restriction-modification (R/E) systems, CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated proteins) systems, abortive infection (Abi), etc. To counteract, phages employ intelligent tactics for the nullification of bacterial defense systems, such as accessing host receptors, evading R/E systems, and anti-CRISPR proteins. Intense knowledge about the details of these defense pathways is the basis for their broad utilities in various fields of research from microbiology to biotechnology. Hence, in this review, we discuss some strategies used by bacteria to inhibit phage infections as well as phage tactics to circumvent bacterial defense systems. In addition, the application of these strategies will be described as a lesson learned from bacteria and phage combats. The ecological factors that affect the evolution of bacterial immune systems is the other issue represented in this review.

Effect of chemical modification with carboxymethyl dextran on kinetic and structural properties of L-asparaginase.

l-asparaginase is a chemotherapy agent in the treatment of childhood leukemia. l-asparaginase has several side effects and a short blood half-life in patients. Chemical modification of l-asparaginase can decrease its side effects and improve its pharmacokinetic properties. The aim of this project was twofold: to chemically modify l-asparaginase with carboxymethyl dextran via carbodiimide cross linker, and to evaluate and compare the biochemical and structural properties of the native and modified enzymes. Chemical modification was done at 25 °C, in 0.1 M phosphate buffer, pH 7.2, and in the presence of N-hydroxysuccinimide and carbodiimide. Electrophoresis and free amino groups determination confirmed the chemical modification. Biochemical studies showed that the chemical modification could result in higher specific activity and stability of the modified enzyme. Structural studies further confirmed the chemical modification and revealed conformational changes in the modified enzyme. Taken together, the results showed that chemical modification with carboxymethyl dextran brings about improvement of biochemical properties through several changes in the structural attributes of l-asparaginase and might enhance its applicability in the treatment of childhood leukemia.

TGF-ß and WNT signaling pathways in cardiac fibrosis: non-coding RNAs come into focus.

Cardiac fibrosis describes the inappropriate proliferation of cardiac fibroblasts (CFs), leading to accumulation of extracellular matrix (ECM) proteins in the cardiac muscle, which is found in many pathophysiological heart conditions. A range of molecular components and cellular pathways, have been implicated in its pathogenesis. In this review, we focus on the TGF-ß and WNT signaling pathways, and their mutual interaction, which have emerged as important factors involved in cardiac pathophysiology. The molecular and cellular processes involved in the initiation and progression of cardiac fibrosis are summarized. We focus on TGF-ß and WNT signaling in cardiac fibrosis, ECM production, and myofibroblast transformation. Non-coding RNAs (ncRNAs) are one of the main players in the regulation of multiple pathways and cellular processes. MicroRNAs, long non-coding RNAs, and circular long non-coding RNAs can all interact with the TGF-ß/WNT signaling axis to affect cardiac fibrosis. A better understanding of these processes may lead to new approaches for diagnosis and treatment of many cardiac conditions. Video Abstract.

A new multi-epitope peptide vaccine induces immune responses and protection against Leishmania infantum in BALB/c mice.

Visceral leishmaniasis (VL) is a tropical and subtropical disease which is endemic in more than eighty countries around the world. Leishmania infantum is one of the main causative agents of VL disease. Currently, there is no approved-to-market vaccine for VL therapy. In this study, we evaluated cellular and humoral immune responses induced by our newly designed multi-epitope vaccine in BALB/c mice. Four antigenic proteins, including histone H1, sterol 24-c-methyltransferase (SMT), Leishmania-specific hypothetical protein (LiHy), and Leishmania-specific antigenic protein (LSAP) were chosen for the prediction of potential immunodominant epitopes. Moreover, to enhance vaccine immunogenicity, two toll-like receptors 4 (TLR4) agonists, resuscitation-promoting factors of Mycobacterium tuberculosis (RpfE and RpfB), were employed as the built-in adjuvants. Immunization with the designed multi-epitope vaccine elicited a robust Th1-type immune response, compared to other groups, as shown by increased levels of IL-2, IFN-γ, TNF-α, and IgG2a. Furthermore, a significant decrease was observed in Th-2-type-related cytokines such as IL-4 in immunized mice. The designed construct also induced a significant reduction in parasite load (p < 0.0001), conferring protection against L. infantum challenge. This study could be promising in gaining insight towards the potential of peptide epitope-based vaccines as effective protective approaches against Leishmania species.

Investigations of antiproliferative and antioxidant activity of ß-lactam morpholino-1,3,5-triazine hybrids.

This article reports for the first time the synthesis of some novel ß-lactam morpholino-1,3,5-triazine hybrids by a [2+2]-cycloaddition reaction of imines 7a-c, 9a-c and 11 with ketenes derived from substituted acetic acids. The reaction was totally diastereoselective, leading exclusively to the formation of cis-ß-lactams 8a-l, 10a-f and 12a-c. The synthesized compounds were tested for activity towards SW1116, MCF-7 and HepG2 cancer cell lines and non-cancerous HEK-293 cell line by MTT assay. None of the compounds exert an observable effect on HepG2, MCF-7 and HEK-293 cells, but compounds 7b, 8f, 8g, 8l, 10c, and 10e exhibited excellent growth inhibitory activity (IC50 < 5 µM) against SW 1116 cells, comparable to that of doxorubicin (IC50 = 6.9 µM). An evaluation of the antioxidant potential of each of the compounds, performed by diphenylpicrylhydrazyl (DPPH) assay, indicated that 7b, 9a, 9b and 9c have strong free radical scavenging activity. UV absorption titration studies reveal that 7b, 8l, 8g and 8f interact strongly with calf-thymus DNA (CT-DNA) in the order of 8l > 7b > 8f > 8g. Collectively, the in vitro capabilities of some of these morpholino-triazine imines and ß-lactams suggest possible applications to development of new antioxidants and DNA binding therapeutics.

Circulating microRNAs as potential diagnostic biomarkers and therapeutic targets in prostate cancer: Current status and future perspectives.

Prostate cancer (PCa) is one of the most common malignancies among men. Despite advancement in technology and medicine over past decades, late diagnosis remains a critical milestone in effective treatment. Therefore, it is necessary to identify novel and reliable biomarkers which are specifically sensitive and specific for prognosis and prediction of clinical outcomes. MicroRNAs (miRNAs) play important roles in posttranslational regulations of genes. Circulating and exosomal miRNAs can be applied as useful diagnostic markers for a different type of malignancies, including PCa. Herein, we summarized various roles of miRNAs (diagnostic, therapeutic, and prognostic) in PCa. Moreover, we highlighted exosomal miRNAs as a new candidate in diagnosis and monitoring response to therapy in patients with PCa.

MiR-26a and miR-26b downregulate the expression of sucrase-isomaltase enzyme: A new chapter in diabetes treatment.

Type II diabetes is a metabolic disease that has affected 460 million people around the globe and become a heavy burden on health care system. Diabetic patients suffer from hyperglycemia and hyperinsulinemia which can damage vital organs in body like heart, kidneys, eyes and nervous system. Different strategies have been introduced to control or lessen these diabetic complications in which one of the most promising approaches is the inhibition of intestinal sucrase-isomaltase (SI). Inhibition of this enzyme will block the release of glucose into bloodstream and lead to reduced postprandial hyperglycemia. MicroRNAs are small regulatory molecules that play critical roles in different cellular pathways and molecular mechanisms. It is proved that microRNAs have significant effects on cellular mechanisms involved in diabetes and can be used as biomarkers for diagnosis of this metabolic disease. Based on bioinformatics analysis miR-26a and miR-26b can interact with a conserved 3'-UTR region of SI mRNA which lead to a hypothesis that these miRs may have negative regulatory effect on this enzyme. In this study, we investigated the impact of high glucose conditions on expression of sucrase-isomaltase, miR-26a and miR-26b in caco-2 cell line. It is proved that in a simulated diabetic condition there is a reverse correlation between the expression pattern of these miRs and SI. QRT-PCR method was used to evaluate the expression of our target molecules. Interestingly, transfection of miR-26a and miR-26b in caco-2 cell line reduced the transcription of SI mRNA and decreased the sucrase and maltase activity of its active sites. To sum up, our results demonstrate the first evidence of the significant effect of miR-26a and miR-26b on SI expression and activity. We proved that these microRNAs may directly inhibit this enzyme and can be used as a new scaffold in search of finding novel treatments for type II diabetes.