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The development of drugs targeting gene products associated with insulin resistance holds the potential to enhance our understanding of type 2 diabetes mellitus (T2DM). The virtual screening, based on a three-dimensional (3D) protein structure, is a potential technique to accelerate the development of molecular target drugs. Among the targets implicated in insulin resistance, the genetic characterization and protein function of Grb14 have been clarified without contradiction. The Grb14 gene displays significant variations in T2DM, and its gene product is known to inhibit the function of the insulin receptor (IR) by directly binding to the tyrosine kinase domain. In the present study, a virtual screening, based on a 3D structure of the IR tyrosine kinase domain (IRβ) in complex with part of Grb14, was conducted to find compounds that can disrupt the complex formation between Grb14 and IRβ. First, ten compounds were selected from 154,118 compounds via hierarchical in silico structure-based drug screening, composed of grid docking-based and genetic algorithm-based programs. The experimental validations suggested that the one compound can affect the blood glucose level. The molecular dynamics simulations and co-immunoprecipitation analysis showed that the compound did not completely suppress the protein-protein interaction between Grb14 and IR, though competitively bound to IR with the tyrosine kinase pseudosubstrate region in Grb14.

Resveratrol is a polyphenolic antioxidant found in grapes, red wine, and peanuts and has been reported to have anti-neoplastic effects on various cancer types. However, the exact mechanism of its anti-cancer effects in oral cancer is not fully understood and remains controversial. Resveratrol exhibits strong hypolipidemic effects; therefore, we examined its effect on lipid metabolism in oral cancer. Resveratrol significantly reduced cell viability and induced autophagic cell death in oral cancer cells but not in normal cells. This selective effect was accompanied by significantly reduced lipogenesis, which is caused by downregulation of the transcription factor sterol regulatory element-binding protein 1 (SREBP1) gene, followed by downregulation of the epidermal fatty acid-binding protein (E-FABP). It was strongly suggested that resveratrol-induced autophagy resulted from the inhibition of SREBP1-mediated cell survival signaling. Luciferase reporter assay further indicated that resveratrol has a potent and specific inhibitory effect on SREBP1-dependent transactivation. Importantly, resveratrol markedly suppressed the growth of oral cancer cells in an animal xenograft model, without exhibiting apparent cytotoxicity. In conclusion, resveratrol induces autophagy in oral cancer cells by suppressing lipid metabolism through the regulation of SREBP1 expression, which highlights a novel mechanism of the anti-cancer effect of resveratrol.

Pain is an essential modality of sensation in the body. Purinergic signaling plays an important role in nociceptive pain transmission, under both physiological and pathophysiological conditions, and is important for communication between both neuronal and non-neuronal cells. Microglia and astrocytes express a variety of purinergic effectors, and a variety of receptors play critical roles in the pathogenesis of neuropathic pain. In this review, we discuss our current knowledge of purinergic signaling and of the compounds that modulate purinergic transmission, with the aim of highlighting the importance of purinergic pathways as targets for the treatment of persistent pain.

Inductively coupled plasma mass spectrometry (ICP-MS) has been used to measure the concentration of trace and rare earth elements (REEs) in soils. Geochemical certified reference materials such as JLk-1, JB-1, and JB-3 were used for the validation of the analytical method. The measured values were in good agreement with the certified values for all the elements and were within 10% analytical error. Beach placer deposits of soils mainly from Odisha, on the east coast of India, have been selected to study selected trace and rare earth elements (REEs), to estimate enrichment factor (EF) and geoaccumulation index (I geo ) in the natural environment. Enrichment factor (EF) and geoaccumulation index (I geo ) results showed that Cr, Mn, Fe, Co, Zn, Y, Zr, Cd and U were significantly enriched, and Th was extremely enriched. The total content of REEs (ƩREEs) ranged from 101.3 to 12,911.3 µg g -1 , with an average 2431.1 µg g -1 which was higher than the average crustal value of ΣREEs. A high concentration of Th and light REEs were strongly correlated, which confirmed soil enrichment with monazite minerals. High ratios of light REEs (LREEs)/heavy REEs (HREEs) with a strong negative Eu anomaly revealed a felsic origin. The comparison of the chondrite normalized REE patterns of soil with hinterland rocks such as granite, charnockite, khondalite and migmatite suggested that enhancement of trace and REEs are of natural origin.

As advanced synthetic technology has enabled drug candidate development with complex structure, resulting in low solubility and membrane permeability, the strategies to improve poorly absorbed drug bioavailability have attracted the attention of pharmaceutical companies. It has been demonstrated that nitric oxide (NO), a vital signaling molecule that plays an important role in various physiological systems, affects intestinal drug absorption. However, NO and its oxidants are directly toxic to the gastrointestinal tract, thereby limiting their potential clinical application as absorption enhancers. In this study, we show that sodium nitroprusside (SNP), an FDA-approved vasodilator, enhances the intestinal absorption of lipophilic drugs in the proximal parts of the small intestine in rats. The SNP pretreatment of the rat gastrointestinal sacs significantly increased griseofulvin and flurbiprofen permeation in the duodenum and jejunum but not in the ileum and colon. These SNP-related enhancement effects were attenuated by the co-pretreatment with dithiothreitol or c-PTIO, an NO scavenger. The permeation-enhancing effects were not observed in the case of antipyrine, theophylline, and propranolol in the duodenum and jejunum. Furthermore, the SNP treatment significantly increased acidic glycoprotein release from the mucosal layers specifically in the duodenum and jejunum but not in the ileum and colon. These results suggest that SNP increases lipophilic drug membrane permeability specifically in the proximal region of the small intestine through disruption of the mucosal layer.

Self-immolative linker is a useful building block of molecular probes, with broad applications in the fields of enzyme activity analysis, stimuli-responsive material science, and drug delivery. This manuscript presents N -methyl dimethyl methyl (i.e., trimethyl) carbamate as a new class of self-immolative linker for the fluorescence detection of enzyme reactions. The trimethyl carbamate was shown to spontaneously undergo intramolecular cyclization upon formation of a carboxylate group, to liberate a fluorophore with the second time rapid reaction kinetics. Interestingly, the auto-cleavage reaction of trimethyl carbamate was also induced by the formation of hydroxyl and amino groups. Fluorescent probes with a trimethyl carbamate could be applicable for fluorescence monitoring of the enzyme reactions catalyzed by esterase, ketoreductase, and aminotransferase, and for fluorescence imaging of intracellular esterase activity in living cells, hence demonstrating the utility of this new class of self-immolative linker.

A new chemical separation has been developed to isolate uranium (U) using two UTEVA columns to minimize iron and thorium interferences from high background area soil samples containing minerals like monazites and ilmenite. The separation method was successfully verified in some certified reference materials (CRMs), for example, JSd-2, JLk-1, JB-1 and JB-3. The same method was applied for purification of U in Fukushima soil samples affected by the Fukushima dai-ichi nuclear power station (FDNPS) accident. Precise and accurate measurement of 234 U/ 238 U and 235 U/ 238 U isotope ratios in chemically separated U were carried out using a multi-collector inductively coupled plasma mass spectrometer (MC-ICP-MS). In this mass spectrometric method, an array of two Faraday cups (10 11 Ω, 10 12 Ω resistor) and a Daly detector were simultaneously employed. The precision of U isotope ratios in an in-house standard was evaluated by replicate measurement. Relative standard deviation (RSD) of 234 U/ 238 U and 235 U/ 238 U were found to be 0.094% (2σ) and 0.590% (2σ), respectively. This method has been validated using a standard reference material SRM 4350B, sediment sample. The replicate measurements of 234 U/ 238 U in SRM shows 0.7% (RSD). This developed method is suitable for separation of U and its isotope ratio measurement in environmental samples.

To investigate the separations of all aldopentoses (ribose, arabinose, xylose and lyxose) and aldohexoses (glucose, galactose, allose, altrose, mannose, gulose, idose and talose) on the D₆ stationary phase prepared by the reaction of chloromethylated styrene-divinylbenzene copolymer and N,N,N',N'-tetramethyl-1,6-diaminohexane, we examined the effect of varying the concentration of the NaOH eluent on the elution orders. Separations of these aldoses were achieved using a 20 mM NaOH eluent. The elution behaviors of the aldoses were probably due to not only the individual pK(a) values, but also the chemical structures of the cyclic aldoses.