MicroRNA replacement therapy in cancer

Despite the recent progress in cancer management approaches, the mortality rate of cancer is still growing and there are lots of challenges in the clinics in terms of novel therapeutics. MicroRNAs (miRNA) are regulatory small noncoding RNAs and are already confirmed to have a great role in regulating gene expression level by targeting multiple molecules that affect cell physiology and disease development. Recently, miRNAs have been introduced as promising therapeutic targets for cancer treatment. Regulatory potential of tumor suppressor miRNAs, which enables regulation of entire signaling networks within the cells, makes them an interesting option for developing cancer therapeutics. In this regard, over recent decades, scientists have aimed at developing powerful and safe targeting approaches to restore these suppressive miRNAs in cancerous cells. The present review summarizes the function of miRNAs in tumor development and presents recent findings on how miRNAs have served as therapeutic agents against cancer, with a special focus on tumor suppressor miRNAs (mimics). Moreover, the latest investigations on the therapeutic strategies of miRNA delivery have been presented.     

Discovery and optimization of aspartate aminotransferase 1 inhibitors to target redox balance in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is extremely refractory to the therapeutic approaches that have been evaluated to date. Recently, it has been demonstrated that PDAC tumors are dependent upon a metabolic pathway involving aspartate aminotransferase 1, also known as glutamate-oxaloacetate transaminase 1 (GOT1), for the maintenance of redox homeostasis and sustained proliferation. As such, small molecule inhibitors targeting this metabolic pathway may provide a novel therapeutic approach for the treatment of this devastating disease. To this end, from a high throughput screen of ～800,000 molecules, 4-(1H-indol-4-yl)-N-phenylpiperazine-1-carboxamide was identified as an inhibitor of GOT1. Mouse pharmacokinetic studies revealed that potency, rather than inherent metabolic instability, would limit immediate cell- and rodent xenograft-based experiments aimed at validating this potential cancer metabolism-related target. Medicinal chemistry-based optimization resulted in the identification of multiple derivatives with >10-fold improvements in potency, as well as the identification of a tryptamine-based series of GOT1 inhibitors.     

Potential roles of YCF54 and ferredoxin‐NADPH reductase for magnesium protoporphyrin monomethylester cyclase

Chlorophyll is synthesized from activated glutamate in the tetrapyrrole biosynthesis pathway through at least 20 different enzymatic reactions. Among these, the MgProto monomethylester (MgProtoME) cyclase catalyzes the formation of a fifth isocyclic ring to tetrapyrroles to form protochlorophyllide. The enzyme consists of two proteins. The CHL27 protein is proposed to be the catalytic component, while LCAA/YCF54 likely acts as a scaffolding factor. In comparison to other reactions of chlorophyll biosynthesis, this enzymatic step lacks clear elucidation and it is hardly understood, how electrons are delivered for the NADPH‐dependent cyclization reaction. The present study intends to elucidate more precisely the role of LCAA/YCF54. Transgenic Arabidopsis lines with inactivated and overexpressed YCF54 reveal the mutual stability of YCF54 and CHL27. Among the YCF54‐interacting proteins, the plastidal ferredoxin‐NADPH reductase (FNR) was identified. We showed in N. tabacum and A. thaliana that a deficit of FNR1 or YCF54 caused MgProtoME accumulation, the substrate of the cyclase, and destabilization of the cyclase subunits. It is proposed that FNR serves as a potential donor for electrons required in the cyclase reaction and connects chlorophyll synthesis with photosynthetic activity.     

2,3,7,8-tetrachlorodibenzo-p-dioxin induces lecithin: retinol acyltransferase transcription in the rat kidney

Vitamin A (retinoids) has an essential role in development and throughout life of humans and animals. Consequently, effects of the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on retinoid metabolism may be contributory to its toxicity. This study was performed to clarify the mechanism behind dioxin-induced retinyl ester formation in the rat kidney. In addition we investigated the possible role of CYP1A1 in dioxin-induced all-trans-retinoic acid (atRA) formation. Male Sprague-Dawley rats were exposed to a single oral dose of TCDD in a combined dose-response and time-course study, with doses ranging from 0.1 to 100 microg/kg bw and time points from 1 to 28 days. Levels of atRA and the expression of two potentially retinoic acid (RA)-controlled proteins critically involved in retinoid storage regulation, lecithin: retinol acyltransferase (LRAT) and cellular retinol binding protein I (CRBP I), were analyzed in liver and kidney. The expression and activity of cytochrome P4501A1 (assayed as ethoxyresorufin-O-deethylase activity) was assessed to gain insight into its potential role in RA synthesis. There was a significant increase in LRAT mRNA expression in the kidney, whereas no such increase could be observed in the liver, despite significantly increased atRA levels in both tissues. This suggests a tissue-specific regulation of LRAT by TCDD that may be dependent on other factors than atRA. Neither CRBP I mRNA nor protein levels were altered by TCDD. The time-course relationship between CYP1A1 activity and atRA levels in liver and kidney does not exclude a role of CYP1A1 in TCDD-induced RA synthesis. The observed altered regulation of the retinoid-metabolizing enzyme LRAT, together with the low doses and short time required by TCDD to change tissue RA levels, suggest that enzymes involved in retinoid metabolism are specific and/or direct targets of TCDD.     

Functional analyses of recombinant mouse hepcidin-1 in cell culture and animal model

Hepcidin is a peptide hormone that plays an important role in iron metabolism. We have produced a recombinant mouse hepcidin-1 by using baculovirus expression system. Its expression yield was 25 μg/ml when cell culture media were supplemented with a protease inhibitor cocktail. The recombinant mouse hepcidin-1 and synthetic human hepcidin-25 had similar effects on reducing ferroportin expression in J774A cell line and in peritoneal macrophages. However, synthetic human hepcidin-25 was more efficient than recombinant mouse hepcidin-1 in reducing iron concentration in blood circulation (p < 0.01).     

Native drivers of fish life history traits are lost during the invasion process

Rapid adaptation to global change can counter vulnerability of species to population declines and extinction. Theoretically, under such circumstances both genetic variation and phenotypic plasticity can maintain population fitness, but empirical support for this is currently limited. Here, we aim to characterize the role of environmental and genetic diversity, and their prior evolutionary history (via haplogroup profiles) in shaping patterns of life history traits during biological invasion. Data were derived from both genetic and life history traits including a morphological analysis of 29 native and invasive populations of topmouth gudgeon Pseudorasbora parva coupled with climatic variables from each location. General additive models were constructed to explain distribution of somatic growth rate (SGR) data across native and invasive ranges, with model selection performed using Akaike's information criteria. Genetic and environmental drivers that structured the life history of populations in their native range were less influential in their invasive populations. For some vertebrates at least, fitness‐related trait shifts do not seem to be dependent on the level of genetic diversity or haplogroup makeup of the initial introduced propagule, nor of the availability of local environmental conditions being similar to those experienced in their native range. As long as local conditions are not beyond the species physiological threshold, its local establishment and invasive potential are likely to be determined by local drivers, such as density‐dependent effects linked to resource availability or to local biotic resistance.     

Bottom‐up effect of host plants on life‐history characteristics of Aphidoletes aphidimyza feeding on Aphis gossypii

The predatory midge Aphidoletes aphidimyza (Rondani) (Diptera: Cecidomyiidae) is widely used for the control of Aphis spp. in many agricultural systems. We aimed to determine the most suitable host plant for rearing the predatory midges on the prey Aphis gossypii Glover (Hemiptera: Aphididae). Six host plants were selected: cucumber (Cucumis sativus L. cv. Beith Alpha), tomato (Solanum lycopersicum L. cv. Falat111), eggplant (Solanum melongena L. cv. Yummy), pepper (Capsicum annuum L. cv. Bertene) (all Solanaceae), okra [Abelmoschus esculentus (L.) Moensch cv. Clemson Spineless] (Malvaceae), and squash (Cucurbita pepo L. cv. Hybrid rajai) (Cucurbitaceae). Some physical traits (length and density of trichomes) and chemical attributes (nitrogen content) of prey host plants were investigated. The results showed that prey host plants differed significantly in their effect on fitness of the predator. The shortest immature development time (18.07 ± 0.257 days), the longest female adult longevity (7.5 ± 0.18 days), and the highest fecundity (89 eggs/female) of A. aphidimyza were found with squash as prey food. The highest intrinsic rate of increase (0.171 ± 0.009 day^?1) and also the shortest mean generation time (22.4 ± 0.32 days) were also obtained when A. aphidimyza fed on A. gossypii reared on squash. Canonical correlation analysis (CCA) approved the correlation between life‐history traits of A. aphidimyza and characteristics of prey host plants. The suitability of squash for rearing A. aphidimyza can be attributed to the higher nitrogen content, longer trichomes, and relatively high density of trichomes, which provided a better environment for A. gossypii and indirectly favored A. aphidimyza. This study showed that squash is the most suitable host plant for rearing A. aphidimyza feeding on A. gossypii.     

Utilizing the Metallic Nano-Rods in Hexagonal Configuration to Enhance Sensitivity of the Plasmonic Racetrack Resonator in Sensing Application

A high sensitive plasmonic refractive index sensor based on metal-insulator-metal (MIM) waveguides with embedding metallic nano-rods in racetrack resonator has been proposed. The refractive index changes of the dielectric material inside the resonator together with temperature changes can be acquired from the detection of the resonance wavelength, based on their linear relationship. With optimum design and considering a tradeoff among detected power, structure size, and sensitivity, the finite difference time domain simulations show that the refractive index and temperature sensitivity values can be obtained as high as 2610 nm per refractive index unit (RIU) and 1.03 nm/°C, respectively. In addition, resonance wavelengths of resonator are obtained experimentally by using the resonant conditions. The effects of nano-rods radius and refractive index of racetrack resonator are studied on the sensing spectra, as well. The proposed structure with such high sensitivity will be useful in optical communications that can provide a new possibility for designing compact and high-performance plasmonic devices.     

Radiation dose and cancer risks from radiation exposure during abdominopelvic computed tomography (CT) scans: comparison of diagnostic and radiotherapy treatment planning CT scans

In the present study, radiation doses and cancer risks resulting from abdominopelvic radiotherapy planning computed tomography (RP-CT) and abdominopelvic diagnostic CT (DG-CT) examinations are compared. Two groups of patients who underwent abdominopelvic CT scans with RP-CT (n = 50) and DG-CT (n = 50) voluntarily participated in this study. The two groups of patients had approximately similar demographic features including mass, height, body mass index, sex, and age. Radiation dose parameters included CTDI_vol, dose–length product, scan length, effective tube current, and pitch factor, all taken from the CT scanner console. The ImPACT software was used to calculate the patient-specific radiation doses. The risks of cancer incidence and mortality were estimated based on the BEIR VII report of the US National Research Council. In the RP-CT group, the mean ± standard deviation of cancer incidence risk for all cancers, leukemia, and all solid cancers was 621.58 ± 214.76, 101.59 ± 27.15, and 516.60 ± 189.01 cancers per 100,000 individuals, respectively, for male patients. For female patients, the corresponding risks were 742.71 ± 292.35, 74.26 ± 20.26, and 667.03 ± 275.67 cancers per 100,000 individuals, respectively. In contrast, for DG-CT cancer incidence risks were 470.22 ± 170.07, 78.23 ± 18.22, and 390.25 ± 152.82 cancers per 100,000 individuals for male patients, while they were 638.65 ± 232.93, 62.14 ± 13.74, and 575.73 ± 221.21 cancers per 100,000 individuals for female patients. Cancer incidence and mortality risks were greater for RP-CT than for DG-CT scans. It is concluded that the various protocols of abdominopelvic CT scans, especially the RP-CT scans, should be optimized with respect to the radiation doses associated with these scans.