Notes

Intratumor Heterogeneity involving MIF Appearance Correlates With Extramedullary Involvement of A number of Myeloma.
Adequate pain management, particularly chronic pain, remains a major challenge associated with modern-day medicine. Current pharmacotherapy offers unsatisfactory long-term solutions due to serious side effects related to the chronic administration of analgesic drugs. Morphine and structurally related derivatives (e.g., oxycodone, oxymorphone, buprenorphine) are highly effective opioid analgesics, mediating their effects via the activation of opioid receptors, with the mu-opioid receptor subtype as the primary molecular target. However, they also cause addiction and overdose deaths, which has led to a global opioid crisis in the last decades. Therefore, research efforts are needed to overcome the limitations of present pain therapies with the aim to improve treatment efficacy and to reduce complications. This review presents recent chemical and pharmacological advances on 14-oxygenated-N-methylmorphinan-6-ones, in the search of safer pain therapeutics. We focus on drug design strategies and structure-activity relationships on specific modifications in positions 5, 6, 14 and 17 on the morphinan skeleton, with the goal of aiding the discovery of opioid analgesics with more favorable pharmacological properties, potent analgesia and fewer undesirable effects. Targeted molecular modifications on the morphinan scaffold can afford novel opioids as bi- or multifunctional ligands targeting multiple opioid receptors, as attractive alternatives to mu-opioid receptor selective analgesics.Docking profiles for (+)-strebloside, a cytotoxic cardiac glycoside identified from Streblus asper, and some of its derivatives and Na+/K+-ATPase have been investigated. In addition, binding between (+)-strebloside and its aglycone, strophanthidin, and several of their other molecular targets, including FIH-1, HDAC, KEAP1 and MDM2 (negative regulators of Nrf2 and p53, respectively), NF-κB, and PI3K and Akt1, have been inspected and compared with those for digoxin and its aglycone, digoxigenin. The results showed that (+)-strebloside, digoxin, and their aglycones bind to KEAP1 and MDM2, while (+)-strebloside, strophanthidin, and digoxigenin dock to the active pocket of PI3K, and (+)-strebloside and digoxin interact with FIH-1. Thus, these cardiac glycosides could directly target HIF-1, Nrf2, and p53 protein-protein interactions, Na+/K+-ATPase, and PI3K to mediate their antitumor activity. Overall, (+)-strebloside seems more promising than digoxin for the development of potential anticancer agents.Chagas disease (CD) affects more than 6 million people worldwide. The available treatment is far from ideal, creating a demand for new alternative therapies. Botanical diversity provides a wide range of novel potential therapeutic scaffolds. Presently, our aim was to evaluate the mammalian host toxicity and anti-Trypanosoma cruzi activity of botanic natural products including extracts, fractions and purified compounds obtained from Brazilian flora. In this study, 36 samples of extracts and fractions and eight pure compounds obtained from seven plant species were evaluated. The fraction dichloromethane from Aureliana fasciculata var. fasciculata (AFfPD) and the crude extract of Piper tectoniifolium (PTFrE) showed promising trypanosomicidal activity. AFfPD and PTFrE presented EC50 values 10.7 ± 2.8 μg/mL and 12.85 ± 1.52 μg/mL against intracellular forms (Tulahuen strain), respectively. Additionally, both were active upon bloodstream trypomastigotes (Y strain), exhibiting EC50 2.2 ± 1.0 μg/mL and 38.8 ± 2.1 μg/mL for AFfPD and PTFrE, respectively. Importantly, AFfPD is about five-fold more potent than Benznidazole (Bz), the reference drug for CD, also reaching lower EC90 value (7.92 ± 2.2 μg/mL) as compared to Bz (23.3 ± 0.6 μg/mL). Besides, anti-parasitic effect of eight purified botanic substances was also investigated. Aurelianolide A and B (compounds 1 and 2) from A. fasciculata and compound 8 from P. tuberculatum displayed the best trypanosomicidal effect. Compounds 1, 2 and 8 showed EC50 of 4.6 ± 1.3 μM, 1.6 ± 0.4 μM and 8.1 ± 0.9 μM, respectively against intracellular forms. In addition, in silico analysis of these three biomolecules was performed to predict parameters of absorption, distribution, metabolism and excretion. The studied compounds presented similar ADMET profile as Bz, without presenting mutagenicity and hepatotoxicity aspects as predicted for Bz. Our findings indicate that these natural products have promising anti-T. cruzi effect and may represent new scaffolds for future lead optimization.Potent, cell-permeable, and subtype-selective sialyltransferase inhibitors represent an attractive family of substances that can potentially be used for the clinical treatment of cancer metastasis. These substances operate by specifically inhibiting sialyltransferase-mediated hypersialylation of cell surface glycoproteins or glycolipids, which then blocks the sialic acid recognition pathway and leads to deterioration of cell motility and invasion. A vast amount of evidence for the in vitro and in vivo effects of sialyltransferase inhibition or knockdown on tumor progression and tumor cell metastasis or colonization has been accumulated over the past decades. In this regard, this review comprehensively discusses the results of studies that have led to the recent discovery and development of sialyltransferase inhibitors, their potential biomedical applications in the treatment of cancer metastasis, and their current limitations and future opportunities.We used an LC-MS/MS metabolomics approach to investigate one-carbon metabolism in the plasma of flaxseed-fed White Leghorn laying hens (aged 3.5 years). In our study, dietary flaxseed (via the activity of a vitamin B6 antagonist known as "1-amino d-proline") induced at least 15-fold elevated plasma cystathionine. Surprisingly, plasma homocysteine (Hcy) was stable in flaxseed-fed hens despite such highly elevated cystathionine. To explain stable Hcy, our data suggest accelerated Hcy remethylation via BHMT and MS-B12. Also supporting accelerated Hcy remethylation, we observed elevated S-adenosylmethionine (SAM), an elevated SAMSAH ratio, and elevated methylthioadenosine (MTA), in flaxseed-fed hens. These results suggest that flaxseed increases SAM biosynthesis and possibly increases polyamine biosynthesis. The following endpoint phenotypes were observed in hens consuming flaxseed decreased physiological aging, increased empirical lifespan, 9-14% reduced body mass, and improved liver function. Overall, we suggest that flaxseed can protect women from ovarian tumor metastasis by decreasing omental adiposity. We also propose that flaxseed protects cancer patients from cancer-associated cachexia by enhancing liver function.A series of N-pyridyl ureas bearing 1,2,4- (1a, 2a, and 3a) and 1,3,4-oxadiazole moiety (1b, 2b, 3b) was prepared and characterized by HRMS, 1H and 13C NMR spectroscopy, as well as X-ray diffraction. The inspection of the crystal structures of (1-3)a,b and the Hirshfeld surface analysis made possible the recognition of the (oxadiazole)···(pyridine) and (oxadiazole)···(oxadiazole) interactions. The presence of these interactions was confirmed theoretically by DFT calculations, including NCI analysis for experimentally determined crystal structures as well as QTAIM analysis for optimized equilibrium structures. The preformed database survey allowed the verification of additional examples of relevant (oxadiazole)···π interactions both in Cambridge Structural Database and in Protein Data Bank, including the cocrystal of commercial anti-HIV drug Raltegravir.We assessed the residual distribution and temporal trend of picarbutrazox sprayed by agricultural multicopters on Chinese cabbage and considered fortification levels and flying speeds. In plot 2, 14 days after the last spraying, the residues decreased by ~91.3% compared with those in the samples on day 0. The residues in the crops decreased by ~40.8% of the initial concentration owing to growth (dilution effect) and by ~50.6% after excluding the dilution effect. As the flight speed increased, picarbutrazox residues decreased (p less then 0.05, least significant deviation [LSD]). At 2 m s-1 flight speed, the residual distribution differed from the dilution rate of the spraying solution. Panobinostat The average range of picarbutrazox residues at all sampling points was 0.007 to 0.486, below the limit of quantitation -0.395, 0.005-0.316, and 0.005-0.289 mg kg-1 in plots 1, 2, 3, and 4, respectively, showing significant differences (p less then 0.05, LSD). These results indicated that the residual distribution of picarbutrazox sprayed by using a multicopter on the Chinese cabbages was not uniform. However, the residues were less than the maximum residue limit in all plots. Accordingly, picarbutrazox was considered to have a low risk to human health if it was sprayed on cabbage according to the recommended spraying conditions.This communication reports a novel synthesis route for the preparation of monofunctionalized β-cyclodextrin in a single stage. The approach involves only the in-situ protection of secondary hydroxyl groups as an excellent alternative to the classical procedure involving a series of five steps of protection and deprotection of hydroxyl groups (both primary and secondary ones) belonging to β-cyclodextrin.Neurological and neurodegenerative diseases are debilitating conditions, and frequently lack an effective treatment. Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of 2-AG (2-arachidonoylglycerol), a neuroprotective endocannabinoid intimately linked to the generation of pro- and anti-inflammatory molecules. Consequently, synthesizing selective MAGL inhibitors has become a focus point in drug design and development. The purpose of this review was to summarize the diverse synthetic scaffolds of MAGL inhibitors concerning their potency, mechanisms of action and potential therapeutic applications, focusing on the results of studies published in the past five years. The main irreversible inhibitors identified were derivatives of hexafluoroisopropyl alcohol carbamates, glycol carbamates, azetidone triazole ureas and benzisothiazolinone, whereas the most promising reversible inhibitors were derivatives of salicylketoxime, piperidine, pyrrolidone and azetidinyl amides. We reviewed the results of in-depth chemical, mechanistic and computational studies on MAGL inhibitors, in addition to the results of in vitro findings concerning selectivity and potency of inhibitors, using the half maximal inhibitory concentration (IC50) as an indicator of their effect on MAGL. Further, for highlighting the potential usefulness of highly selective and effective inhibitors, we examined the preclinical in vivo reports regarding the promising therapeutic applications of MAGL pharmacological inhibition.Green Chemistry has become in the last two decades an increasing part of research interest. Nonconventional «green» sources for chemical reactions include micro-wave, mechanical mixing, visible light and ultrasound. 1,2,3-triazoles have important applications in pharmaceutical chemistry while their 1,2,4 counterparts are developed to a lesser extent. In the review presented here we will focus on synthesis of 1,2,3 and 1,2,4-triazole systems by means of classical and « green chemistry » conditions involving ultrasound chemistry and mechanochemistry. The focus will be on compounds/scaffolds that possess biological/pharmacophoric properties. Finally, we will also present the formal cycloreversion of 1,2,3-triazole compounds under mechanical forces and its potential use in biological systems.
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