Naturally occurring compounds acting as potent anti‐metastatic agents and their suppressing effects on Hedgehog and WNT/β‐catenin signalling pathways

Despite numerous remarkable achievements in the field of anti‐cancer therapy, tumour relapse and metastasis still remain major obstacles in improvement of overall cancer survival, which may be at least partially owing to epithelial‐mesenchymal transition (EMT). Multiple signalling pathways have been identified in EMT; however, it appears that the role of the Hedgehog and WNT/β‐catenin pathways are more prominent than others. These are well‐known preserved intracellular regulatory pathways of different cellular functions including proliferation, survival, adhesion and differentiation. Over the last few decades, several naturally occurring compounds have been identified to significantly obstruct several intermediates in Hedgehog and WNT/β‐catenin signalling, eventually resulting in suppression of signal transduction. This article highlights the current state of knowledge associated with Hedgehog and WNT/β‐catenin, their involvement in metastasis through EMT processes and introduction of the most potent naturally occurring agents with capability of suppressing them, eventually overcoming tumour relapse, invasion and metastasis.     

Challenges facing antiangiogenesis therapy: The significant role of hypoxia-inducible factor and MET in development of resistance to anti-vascular endothelial growth factor-targeted therapies

It is now fully recognized that along with multiple physiological functions, angiogenesis is also involved in the fundamental process and pathobiology of several disorders including cancer. Recent studies have fully established the role of angiogenesis in cancer progression as well as invasion and metastasis. Consequently, many therapeutic agents such as monoclonal antibodies targeting angiogenesis pathway have been introduced in clinic with the hope for improving the outcomes of cancer therapy. Bevacizumab (Avastin®) was the first anti-vascular endothelial growth factor (VEGF) targeting monoclonal antibody developed with this purpose and soon received its accelerated US Food and Drug Administration (FDA) approval for treatment of patients with metastatic breast cancer in 2008. However, the failure to meet expecting results in different follow-up studies, forced FDA to remove bevacizumab approval for metastatic breast cancer. Investigations have now revealed that while suppressing VEGF pathway initially decreases tumor progression rate and vasculature density, activation of several interrelated pathways and signaling molecules following VEGF blockade compensate the insufficiency of VEGF and initially blocked angiogenesis, explaining in part the failure observed with bevacizumab single therapy. In present review, we introduce some of the main pathways and signaling molecules involved in angiogenesis and then propose how their interconnection may result in development of resistance to bevacizumab.     

The association between sleep pattern and nutrients intake pattern in healthy overweight and obese adults

Few studies have investigated the association between sleep pattern and nutrient intake pattern. This study was conducted to examine the associations between patterns of nutrient intake and sleep pattern. 108 overweight and obese individuals were recruited to participate in the present cross-sectional study. Participant underwent sleep evaluation through ActiGraph. A 3-day food dietary record was obtained to estimate food intake for each participant. The average of total sleep duration was 7.07 h, average of wake after sleep onset was 0.43 h, average of sleep latency was 0.14 h, and finally, average of sleep efficacy was 93.66%. Moreover, based on principal component analysis, six nutrient intake patterns were identified: the first and second patterns accounting for 53.88% of the total variance and the third and fourth patterns made up 13.6% of the total variance. Totally, the six patterns constitute 74.8% of the total variance. Our results showed that the second nutrient pattern had a negative correlation with total sleep time (P = 0.03); it was positively correlated with sleep latency (P = 0.004). The sixth nutrient pattern was negatively associated with total sleep time (P = 0.007). It was observed that higher intake of the fourth pattern had a negative correlation with total sleep time (P = 0.03). Higher intake of the fifth pattern was positively associated with sleep latency (P = 0.05). In summary, we found that nutrient patterns are correlated with sleep pattern.

     

Functional characterization of two RAB27A missense mutations found in Griscelli syndrome type 2

Human Griscelli syndrome type 2 (GS-2) is characterized by partial albinism and a severe immunologic disorder as a result of RAB27A mutations. In melanocytes, Rab27A forms a tripartite complex with a specific effector Slac2-a/melanophilin and myosin Va, and the complex regulates melanosome transport. Here, we report a novel homozygous missense mutation of Rab27A, i.e. K22R, in a Persian GS-2 patient and the results of analysis of the impact of the K22R mutation and the previously reported I44T mutation on protein function. Both mutations completely abolish Slac2-a/melanophilin binding activity but they affect the biochemical properties of Rab27A differently. The Rab27A(K22R) mutant lacks the GTP binding ability and exhibits cytosolic localization in melanocytes. By contrast, neither intrinsic GTPase activity nor melanosomal localization of Rab27A is affected by the I44T mutation, but the Rab27A(I44T) mutant is unable to recruit Slac2-a/melanophilin. Interestingly, the two mutations differently affect binding to other Rab27A effectors, Slp2-a, Slp4-a/granuphilin-a, and Munc13-4. The Rab27A(K22R) mutant normally binds Munc13-4, but not Slp2-a or Slp4-a, whereas the Rab27A(I44T) mutant shows reduced binding activity to Slp2-a and Munc13-4 but normally binds Slp4-a.     

Hair follicle stem cells: In vitro and in vivo neural differentiation

Hair follicle stem cells (HFSCs) normally give rise to keratinocytes, sebocytes, and transient amplifying progenitor cells. Along with the capacity to proliferate rapidly, HFSCs provide the basis for establishing a putative source of stem cells for cell therapy. HFSCs are multipotent stem cells originating from the bulge area. The importance of these cells arises from two important characteristics, distinguishing them from all other adult stem cells. First, they are accessible and proliferate for long periods. Second, they are multipotent, possessing the ability to differentiate into mesodermal and ectodermal cell types. In addition to a developmental capacity in vitro, HFSCs display an ability to form differentiated cells in vivo. During the last two decades, numerous studies have led to the development of an appropriate culture condition for producing various cell lineages from HFSCs. Therefore, these stem cells are considered as a novel source for cell therapy of a broad spectrum of neurodegenerative disorders. This review presents the current status of human, rat, and mouse HFSCs from both the cellular and molecular biology and cell therapy perspectives. The first section of this review highlights the importance of HFSCs and in vitro differentiation, while the final section emphasizes the significance of cell differentiation in vivo.     

Airborne bacteria and fungi in a wastewater treatment plant: type and characterization of bio-aerosols,emission characterization and mapping

Aerobiologia - Exposure to bioaerosols causes infection, over-sensitivity, respiratory, and lung diseases. This study was conducted at Sanandaj wastewater treatment plant in three seasons of...     

Spectroscopic and molecular docking investigation of polynucleotides and DNA binding affinity to Nile blue dye

We used UV-vis absorption spectroscopy, fluorescence spectrophotometry and molecular docking calculations to investigate intermolecular interaction between the cationic dye, Nile blue (NB), and synthetic polynucleotides, poly(A-T), poly(G-C) and calf thymus DNA (Ct-DNA) at physiological pH. Strong hypsochromic absorbance and fluorescence quenching were observed that showed strong binding of NB to these polynucleotides and DNA. The binding affinity values derived from maximum absorption of the spectra of NB bound to various polynucleotides and Ct-DNA concentrations suggests that NB exhibits greater binding affinity to poly(G-C) than to poly(A-T). The thermodynamic parameters suggested that hydrogen bonds and van der Waals forces might play a major role in the binding of NB to DNA. The molecular docking results suggested that NB was an intercalator of the stacked base pairs of Ct-DNA.     

Motor Neuron Transdifferentiation of Neural Stem Cell from Adipose-Derived Stem Cell Characterized by Differential Gene Expression

Adipose-derived stem cells (ADSC) are adult stem cells which can be induced into motor neuron-like cells (MNLC) with a preinduction-induction protocol. The purpose of this study is to generate MNLC from neural stem cells (NSC) derived from ADSC. The latter were isolated from the perinephric regions of Sprague–Dawley rats, transdifferentiated into neurospheres (NS) using B27, EGF, and bFGF. After generating NSC from the NS, they induced into MNLC by treating them with Shh and RA, then with GDNF, CNTF, BDNF, and NT-3. The ADSC lineage was evaluated by its mesodermal differentiation and was characterized by immunostaining with CD90, CD105, CD49d, CD106, CD31, CD45, and stemness genes (Oct4, Nanog, and Sox2). The NS and the NSC were evaluated by immunostaining with nestin, NF68, and Neurod1, while the MNLC were evaluated by ISLET1, Olig2, and HB9 genes. The efficiency of MNLC generation was more than 95 ± 1.4 % (mean ± SEM). The in vitro generated myotubes were innervated by the MNLC. The induced ADSC adopted multipolar motor neuron morphology, and they expressed ISLET1, Olig2, and HB9. We conclude that ADSC can be induced into motor neuron phenotype with high efficiency, associated with differential expression of the motor neuron gene. The release of MNLC synaptic vesicles was demonstrated by FM1-43, and they were immunostained with synaptophysin. This activity was correlated with the intracellular calcium ion shift and membrane depolarization upon stimulation as was demonstrated by the calcium indicator and the voltage-sensitive dye, respectively.     

Tumor growth of neurofibromin-deficient cells is driven by decreased respiration and hampered by NAD+ and SIRT3

Neurofibromin loss drives neoplastic growth and a rewiring of mitochondrial metabolism. Here we report that neurofibromin ablation dampens expression and activity of NADH dehydrogenase, the respiratory chain complex I, in an ERK-dependent fashion, decreasing both respiration and intracellular NAD⁺. Expression of the alternative NADH dehydrogenase NDI1 raises NAD⁺/NADH ratio, enhances the activity of the NAD⁺-dependent deacetylase SIRT3 and interferes with tumorigenicity in neurofibromin-deficient cells. The antineoplastic effect of NDI1 is mimicked by administration of NAD⁺ precursors or by rising expression of the NAD⁺ deacetylase SIRT3 and is synergistic with ablation of the mitochondrial chaperone TRAP1, which augments succinate dehydrogenase activity further contributing to block pro-neoplastic metabolic changes. These findings shed light on bioenergetic adaptations of tumors lacking neurofibromin, linking complex I inhibition to mitochondrial NAD⁺/NADH unbalance and SIRT3 inhibition, as well as to down-regulation of succinate dehydrogenase. This metabolic rewiring could unveil attractive therapeutic targets for neoplasms related to neurofibromin loss.Subject terms: Cancer metabolism, Cell biology     

The mouse QTL map helps interpret human genome-wide association studies for HDL cholesterol

Genome-wide association (GWA) studies represent a powerful strategy for identifying susceptibility genes for complex diseases in human populations but results must be confirmed and replicated. Because of the close homology between mouse and human genomes, the mouse can be used to add evidence to genes suggested by human studies. We used the mouse quantitative trait loci (QTL) map to interpret results from a GWA study for genes associated with plasma HDL cholesterol levels. We first positioned single nucleotide polymorphisms (SNPs) from a human GWA study on the genomic map for mouse HDL QTL. We then used mouse bioinformatics, sequencing, and expression studies to add evidence for one well-known HDL gene (Abca1) and three newly identified genes (Galnt2, Wwox, and Cdh13), thus supporting the results of the human study. For GWA peaks that occur in human haplotype blocks with multiple genes, we examined the homologous regions in the mouse to prioritize the genes using expression, sequencing, and bioinformatics from the mouse model, showing that some genes were unlikely candidates and adding evidence for candidate genes Mvk and Mmab in one haplotype block and Fads1 and Fads2 in the second haplotype block. Our study highlights the value of mouse genetics for evaluating genes found in human GWA studies.