Search

Background: In the last decades, growing evidence demonstrates interest in phytoestrogen intake to modulate targets in different types of cancer. Plant lignans have proven efficacious in blocking estrogen receptors of breast cancer cells. Among them, four phytoestrogen lignans: pinoresinol, matairesinol, lariciresinol, and secoisolariciresinol have been most studied. However, available studies have mostly dealt with the anti-cancer effects of groups of lignans in certain foods or plants and the effects of specific lignans, especially from a molecular interaction viewpoint, have been rarely addressed in the literature. Objective: We aimed to in silico predict pharmacological properties, binding ability and binding strength of pinoresinol, matairesinol, lariciresinol and secoisolariciresinol as possible inhibitors of estrogen receptor alpha which is the most important biomarker in breast cancer. Methods: Firstly, we evaluated the pharmacological properties of four lignans using SwissADME. Then we investigated the ligand-receptor interactions of these molecules as positively appraised ligands for ER-positive breast cancer targeted therapy using docking method. We finally compared the inhibitory effect possibility of the lignans against endoxifen which is the active metabolite of tamoxifen. Results: The best binding affinity of endoxifen, matairesinol, pinoresinol, lariciresinol and secoisolariciresinol were respectively -9.2, -7.5, -6.7, -6.7, -5.8 kcal/mol. In the meantime, matairesinol showed a minimum binding energy than other studied lignans in addition to the most similar interactions to endoxifen with conserved domain residues of the active site pocket in Leu:391, Ala:350, Met:421, and Phe:404. Conclusion: Among the studied lignans, matairesinol showed favorable pharmacokinetics and drug-likeliness properties, the least binding energy as well as the most common interactions in conserved residues of the active site pocket with estrogens. This makes it a molecule with low number of nonspecific interactions, better target selectivity, and hence fewer side effects. Thus, our results introduce matairesinol as a possibly effective anti-estrogen receptor inhibitor candidate.

Background: Aging is an organized biological process that is regulated by highly interconnected pathways between different cells and tissues in the living organism. Identification of similar genes between tissues in different ages may also help to discover the general mechanism of aging or to discover more effective therapeutic decisions. Objective: Objective: According to the wide application of model-based clustering techniques, the aim is to evaluate the performance of the Mixture of Multivariate Normal Distributions (MMNDs) as a valid method for clustering time series gene expression data with the Mixture of Matrix-Variate Normal Distributions (MMVNDs). Methods: In this study, the expression of aging data from NCBI’s Gene Expression Omnibus was elaborated to utilize proper data. A set of common genes which were differentially expressed between different tissues were selected and then clustered together through two methods. Finally, the biological significance of clusters was evaluated, using their ability to find genes in the cell using Enricher. Results: The MMVNDs is more efficient to find co-express genes. Six clusters of genes were observed using the MMVNDs. According to the functional analysis, most genes in clusters 1-6 are related to the B-cell receptors and IgG immunoglobulin complex, proliferating cell nuclear antigen complex, the metabolic pathways of iron, fat, and body mass control, the defense against bacteria, the cancer development incidence, and the chronic kidney failure, respectively. Conclusion: Results showed that most biological changes of aging between tissues are related to the specific components of immune cells. Also, the application of MMVNDs can increase the ability to find similar genes.

Heart diseases are known as the most primary causes of mortality worldwide. Although many therapeutic approaches and medications are proposed for these diseases, the identification of novel therapeutics in fatal heart conditions is promptly demanded. Besides, the interplay between gene expression data and molecular docking provides several novel insights to discover more effective and specific drugs for the treatment of the diseases. This study aimed to discover potent therapeutic drugs in the heart diseases based on the expression profile of heart-specific genes exclusively. Initially, the heart-specific and highly expressed genes were identified by comparing the gene expression profile of different body tissues. Subsequently, the druggable-genes were identified using in silico techniques. The interaction between these druggable genes with more than 1600 FDA approved drugs was then investigated using the molecular docking simulation. By comprehensively analyzing RNA-sequencing data obtained from 949 normal tissue samples, 48 heart-specific genes were identified in both the heart development and function. Notably, of these, 24 heart-specific genes were capable to be considered as druggable genes, among which only MYBPC3, MYLK3, and SCN5A genes entered the molecular docking process due to their functions. Afterward, the pharmacokinetics properties of top 10 ligands with the highest binding affinity for these proteins were studied. Accordingly, methylergonovine, fosaprepitant, pralatrexate, daunorubicin, glecaprevir, digoxin, and venetoclax drugs were competent, in order to interact with the target proteins perfectly. It was shown that these medications can be used as specific drugs for the treatment of heart diseases after fulfilling further experiments in this regard.

Glioblastoma is a very invasive and prevalent brain tumor that affects 15 in 100,000 persons over the age of 70 years. Studies have shown that the expression of the WD repeat domain 81 (WDR81) gene, which is effective in vesicular transport and inhibition of autophagy, is increased in glioblastoma. The decreased autophagy was found to be related to the increased production of exosomes, which is a major factor in the pathogenesis of glioblastoma. The PI-3kinase complex is a pre-autophagic complex that is highly active in the absence of WDR81. The WDR81 gene, as a negative regulator of PI3K activity, prevents autophagy and increases exosome secretion by preventing the formation of the class III PI3K complex. Therefore, targeted reduction of exosomes can be considered an effective strategy for reducing the pathogenesis of glioblastoma. This study aimed to assess the effect of WDR81 gene silencing with siRNA on exosome levels in a U87-MG cell line. Culturing of U87-MG cells was carried out in Dulbecco’s modified Eagle medium (DMEM) containing 5% FBS and 1% penicillin/streptomycin. Thereafter, silencing of WDR81 was performed using WDR81 siRNA, whose gene expression level was determined via real-time qRT-PCR. Cell viability was evaluated using the MTT assay. The exosomes were extracted from a cell culture using the Exocib kit. The size accuracy of the exosomes was confirmed by dynamic light scattering (DLS). Finally, the protein content and RNA of the exosomes were assessed. WDR81 gene expression of siRNA-transfected cells was decreased to 82% after 24 h compared to the non-transfected control cells. The analysis of the exosomes showed that the concentration of exosomes and their RNA and protein content in the siRNA-transfected cells decreased significantly compared to the non-transfected control cells. No considerable difference was observed in cell viability after transfection with either WDR81-specific siRNAs or scrambled control siRNAs. Our findings showed that silencing the WDR81 gene could reduce the level of exosomes in human U87-MG glioblastoma cells. Therefore, the reduced exosome content may be suggested as a new gene therapy strategy for targeted therapy of glioblastoma by increasing autophagy via activation of PI3KIII. However, more studies are needed in this regard.

In recent years, induced pluripotent stem cells (iPSCs) have been considered as a promising approach in the field of regenerative medicine. iPSCs can be generated from patients' somatic cells and possess the potential to differentiate, under proper conditions, into any cell type. However, the clinical application of iPS cells is restricted because of their tumorigenic potential. Recent studies have indicated that stem cells exert their therapeutic benefit via a paracrine mechanism, and extracellular vesicles have been demonstrated that play a critical role in this paracrine mechanism. Due to lower immunogenicity, easier management, and presenting no risk of tumor formation, in recent years, researchers turned attention to exosomes as potential alternatives to whole-cell therapy. Application of exosomes derived from iPSCs and their derived precursor provides a promising approach for personalized regenerative medicine. This study reviews the physiological functions of extracellular vesicles and discusses their potential therapeutic benefit in regenerative medicine.

Rn7SK-mediated global transcriptional regulation, key function of this small nuclear RNA (snRNA), is mediated by inhibition of the positive transcription elongation factor b (P-TEFb). Recently, we have identified a potential anti-proliferative and tumor-suppressive function of Rn7SK. However, its possible regulatory role in development and cell programming has not been investigated so far. Here, we examined transcriptional levels of Rn7SK in different mouse organs. Interestingly, an increased expression level of the RNA was observed in the brain. Furthermore, we could demonstrate that Rn7SK has a dynamic expression pattern during brain development from embryo to adult: 7SK snRNA expression was particularly high at embryonic day (E) 18.5 and adult stages, while a low level of this non-coding RNA was detected at E11.5. Moreover, a decreased transcription level was identified in proliferating progenitors whereas a strong upregulation of Rn7SK was observed during neural differentiation in vivo. Similar to the in vivo situation, in vitro neuronal differentiation experiments employing embryonic stem cells (ESCs) demonstrated the same expression pattern of 7SK with high expression levels in differentiating neurons. Neuronal differentiation of ESCs was compromised when we knocked down Rn7SK, indicating an important role of 7SK in the acquisition of a neural fate.

The small nuclear noncoding RNA (snRNA) 7SK is a highly conserved noncoding RNA of 331 nucleotides in animals, which is present in a nuclear ribonucleoprotein complex with proteins such as methylphosphate capping enzyme (MePCE), hexamethylene bisacetamide-inducible proteins 1 and 2 (HEXIM1 and HEXIM2) and La-related protein 7 (Larp7). Regulating the activity of the positive transcription elongation factor b (P-TEFb) is the key function of 7SK noncoding RNA. Recently, we have shown that 7SK snRNA over-expression reduces human embryonic kidney 293T cell line viability. Here, we attempt to monitor the expression level of 7SK snRNA in different human cell lines and cancer tissues. Examination of 7SK transcription either in cell lines or in different malignant tissues including blood (CML), breast and colon showed that 7SK expression significantly down-regulated in cancer. Similar to human cancer tissues and cell lines, 7SK transcriptional level decreased in stem cells in comparison with differentiated cell types. In this regard, over-expression of 7SK snRNA might be a powerful tool for blocking cancer progression by controlling the activity of P-TEFb.

Obesity is a major health problem across the world, but there are few ways to effectively treat or manage it in the long term. Researchers are searching for more convenient, cost-effective and noninvasive therapies for overweight and obese people. Recent studies have illustrated that the microbiome of the body's different organs can be used as a vehicle for in-situ gene therapy. We suggest that the recombinant form of "Pichia pastoris" yeast expressing the hybrid protein of "irisin-furin-transferrin" under the control of the enolase 1 promoter is a new nutraceutical strategy to absorb fewer calories from intestinal nutrients, and induce a higher metabolic rate to expend more calories, similar to that from engaging in physical activity. By comparison, this method can be a long-term, noninvasive treatment and can be used for obese patients who have movement limitations.

Regarding to the high prevalence and comorbidities of chronic high blood glucose in diabetic patients and the limited efficacy and current painful treatments. It is necessary to improve new treatments that are non-invasive and long-term for controlling blood glucose. Recent studies have shown that the healthy microflora in different body organs can perform as the gene vectors for expressing different types of gene therapies in situ. We have proposed that by constructing a recombinant Escherichia coli Nissle 1917 that expresses CTB–IGF-1 hybrid gene under control of ompC glucose sensitive promoter, the intestinal glucose level can be regulated. This method in comparison with other methods is a non-invasive way to control the blood glucose orally and it can be used for all types of diabetes.

The increasing prevalence of diabetes and its complications heralds an alarming situation worldwide. Obesity-associated changes in circulating adiponectin concentrations have the capacity to predict insulin sensitivity and are a link between obesity and a number of vascular diseases. One obvious consequence of obesity is a decrease in circulating levels of adiponectin, which are associated with cardiovascular disorders and associated vascular comorbidities. Human and animal studies have demonstrated decreased adiponectin to be an independent risk factor for cardiovascular disease. However, in animal studies, increased circulating adiponectin alleviates obesity-induced endothelial dysfunction and hypertension, and also prevents atherosclerosis, myocardial infarction, and diabetic cardiac tissue disorders. Further, metabolism of a number of foods and medications are affected by induction of adiponectin. Adiponectin has beneficial effects on cardiovascular cells via its antidiabetic, anti-inflammatory, antioxidant, antiapoptotic, antiatherogenic, vasodilatory, and antithrombotic activity, and consequently has a favorable effect on cardiac and vascular health. Understanding the molecular mechanisms underlying the regulation of adiponectin secretion and signaling is critical for designing new therapeutic strategies. This review summarizes the recent evidence for the physiological role and clinical significance of adiponectin in vascular health, identification of the receptor and post-receptor signaling events related to the protective effects of the adiponectin system on vascular compartments, and its potential use as a target for therapeutic intervention in vascular disease.