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Diketopiperazines have attracted attention from the point of view of synthesis and biological properties for the treatment of various diseases, including cancer, although 2,6-DKPs have been less studied. In this work is present the inhibitory effects of various 2,6-DKPs derived from α-amino acids over the MDA-MB-231 triple-negative breast cancer cells by the MTT assay. It was found that IC50 values obtained for compounds 1 and (S) enantiomers were between 4.6 x 10− 3 and 4.944 (mM), where 1 and (S)-2a showed the lowest values, for (R) enantiomers were in the range 0.021 and 3.639 mM, where (R)-2b exhibited the lowest value. In addition, the apoptotic induction of the 2,6-DKPs was investigated over MDA-MB-231 cell line by flow cytometry, these results showed that all the compounds studied induced more apoptosis at 48 h than at 24 h in a range of 54.1 to 76.2%, except 12a that exhibited a 3% decrease compared to the 24 h test. According to the biological assays, all the evaluated 2,6-DKPs derivatives could be considered for further studies in vivo, principally those with the lowest IC50 value and (S) stereoisomers as possible antitumoral agents to mama cancer.

Insulin resistance is a feature of pregnancy and is associated with increased levels of angiotensin II (Ang II) and insulin. Therefore, pregnancy may change insulin-induced vasodilation through changes in Ang II receptors. Insulin-induced vasorelaxation was evaluated in phenylephrine-precontracted aortic rings of pregnant and non-pregnant rats, using a conventional isolated organ preparation. Experiments were performed in thoracic or abdominal aorta rings with or without endothelium in the presence and absence of NG-nitro-L-arginine methyl ester (L-NAME) (10−5 M), losartan (10−7 M), or PD123319 (10−7 M). AT1 and AT2 receptor expressions were detected by immunohistochemistry. Insulin-induced vasodilation was endothelium- and nitric oxide–dependent and decreased in the thoracic aorta but increased in the abdominal segment of pregnant rats. The insulin’s vasorelaxant effect was increased by losartan mainly on the thoracic aorta. PD123319 decreased insulin-induced vasorelaxation mainly in the pregnant rat abdominal aorta. AT1 receptor expression was decreased while AT2 receptor expression was increased by pregnancy. In conclusion, pregnancy changes insulin-induced vasorelaxation. Moreover, insulin vasodilation is tonically inhibited by AT1 receptors, while AT2 receptors appear to have an insulin-sensitizing effect. The role of pregnancy and Ang II receptors differ depending on the aorta segment. These results shed light on the role of pregnancy and Ang II receptors on the regulation of insulin-mediated vasodilation.

Objectives The biochemical conditions in which patients arrive before renal transplantation (RT) are rarely evaluated; examples of them are found in the Dialysis Outcomes and Practice Patterns Study (DOPPS). The objective of our study was to ascertain the fulfillment of biochemical goals for patients on renal replacement therapy before RT. Material and Methods Observational, retrospective study of patients who were on a RT protocol between 2012 and 2017 in 2 RT centers in Mexico. The records of 1188 patients with a history of RT and their lab results before transplantation were analyzed. Anthropometric values including hemoglobin, iron levels, calcium, phosphorus, parathyroid hormone, urea, creatinine, uric acid, and left ventricular ejection fraction were studied. All values were categorized as low, optimal, or high levels. Results The fulfillment of pretransplant biochemical objectives for elimination of azotemia (urea and creatinine) was achieved in 60% of the patients. Optimal values for calcium were found in 715 (64%) patients and optimal values for albumin were found in 690 (61.8%) patients. In the case of phosphorus, hemoglobin, uric acid, and parathyroid hormone, the optimal values were below 50%. Conclusions It is essential to improve compliance with biochemical and clinical objectives for patients on renal replacement therapy (dialysis, hemodialysis) before RT. Only half of the variables were within the optimal range before surgical intervention took place.

Boron compounds importance have been raising due to the development of its synthesis and remarkable biological activities, so in this manner the study here presented is focused on the synthesis of novel isoindolinylphenylboronic anhydrides (2a, 2c and 2e) and bis-isoindolinylphenylboronic anhydrides (2b and 2d), as well as a comparative study of the antiproliferative activity of these and their precursors (a-e), 1(a-e) over glioblastoma cells U373 and the cytotoxic activity over normal microglial cells. All compounds were characterized by spectroscopic methods; 1H, 13C, 11B NMR, IR and HRMS. 1H and 11B NMR data at variable temperature of 2b and 2d showed equilibrium between species that contain a tetrahedral and a trigonal boron atom due to an intramolecular N→B coordination and decoordination bond. The study of frontier molecular orbitals of B-derivatives showed that 2b′and 2d′ are harder molecules than 2a, 2c and 2e, therefore can react with a second isoindoline to obtain 2b and 2d. Whereas, HOMO site of potassium derived 1bK and 1dK are over NCHCO2K moiety, consequently, to react with 2b′ and 2d′ to obtain 2b and 2d. These results clarify the obtainment of 2a-2d independently of the equimolecular ratio of reagents. On another hand, the biological assay showed that compound 2d possessed the most pronounced effect over U373 cells with no effect over normal microglial cells, providing a new set of boron compounds with important antitumoral activity.

Introduction Renal transplantation (RT) has evolved to improve its functionality. Some factors have been little studied, one of which is hyperuricemia and its impact on renal graft function. The objective of this study is to determine the prevalence of complications of renal transplantation and its influence on hyperuricemia values in the first year of evolution. Material and Methods The authors completed a retrospective, observational study of 2 RT units in Mexico from January 2013 to December 2017. In total, 1009 files met the inclusion criteria; the levels of uric acid (UA) and creatinine (Cr) were determined before transplantation and in months 1, 3, 6, 9, and 12 after transplantation. Descriptive analysis was performed with measures of central tendency, measures of dispersion, difference of means with Student t test, and SPSS version 25 (IBM, Armonk, NY, United States). Results The mean pretransplant UA was 6.24 mg/dL (standard deviation [SD] 1.97); per month was 4.73 mg/dL (SD 1.49). There is a difference in means between categorized groups of UA in the 5 post-RT moments (1, 3, 6, 9, and 12 months). A positive correlation of 0.41 to 0.47 was found with Spearman’s test. The delayed function of the graft influenced in the first month after transplant in presenting hyperuricemia and acute dysfunction in month 6 showed that the rejection had no significance at any time. Conclusions The relationship between the values of UA and Cr in the RT represents a moderate positive correlation; delayed graft function in the first month impacts the presence of hyperuricemia, as well as acute dysfunction at month 6 after transplantation.

Alzheimer’s disease (AD) represents the principal cause of dementia among the elderly. Great efforts have been established to understand the physiopathology of AD. Changes in neurotransmitter systems in patients with AD, including cholinergic, GABAergic, serotoninergic, noradrenergic, and histaminergic changes have been reported. Interestingly, changes in the histaminergic system have been related to cognitive impairment in AD patients. The principal pathological changes in the brains of AD patients, related to the histaminergic system, are neurofibrillary degeneration of the tuberomammillary nucleus, the main source of histamine in the brain, low histamine levels, and altered signaling of its receptors. The increase of histamine levels can be achieved by inhibiting its degrading enzyme, histamine N-methyltransferase (HNMT), a cytoplasmatic enzyme located in astrocytes. Thus, increasing histamine levels could be employed in AD patients as co-therapy due to their effects on cognitive functions, neuroplasticity, neuronal survival, neurogenesis, and the degradation of amyloid beta (Aβ) peptides. In this sense, the evaluation of the impact of HNMT inhibitors on animal models of AD would be interesting, consequently highlighting its relevance.

Cancer is one of the leading causes of morbidity and mortality worldwide. This disease is characterized by uncontrolled growth and proliferation of abnormal cells with a high probability to develop metastasis. Recently, it was demonstrated that perezone, a sesquiterpene quinone, is capable to induce cell death in leukemia (K562), prostate (PC-3), colorectal (HCT-15) and lung (SKLU-1) cancer cell lines; however, its mechanism of action is unknown. Therefore, in this study, in vitro and computational studies were performed to determine the mechanism of action of perezone. Firstly, changes in K562 cell viability, as well as changes in the redox status of the cell in response to treatment with several concentrations of perezone were analyzed. The type of cell death induced, and the modification of the cell cycle were determined. In addition, MD simulations and docking studies were performed to investigate the interaction of perezone with seven regulators of the apoptotic process. Finally, the ability of perezone to inhibit PARP-1 was evaluated by in vitro studies. K562 cells treated with perezone exhibited decreased viability and more oxidized status, being this effect concentration-dependent. In addition, the increase of G0/G1 phase of cell cycle and apoptosis were observed. According to the performed computational studies conducted, perezone showed the highest affinity to PARP-1 enzyme being this complex the most stable due to the presence of a small and deep cavity in the active site, which allows perezone to fit deeply by forming hydrogen bonds and hydrophobic interactions, which drive this interaction. The activity of perezone as PARP-1 inhibitor was corroborated with an IC50 = 181.5 μM. The pro-apoptotic action of perezone may be related to PARP-1 inhibition and changes in the redox state of the cell. The obtained results allowed to understand the biological effect of perezone and, consequently, these could be employed to develop novel PARP-1 inhibitors.

This work describes the effect of two series of isoindolines 1(a–g) and 2(a–g) on histone deacetylase 8 (HDAC8) activity by theoretical study (docking method) and experimental assays using a commercial kit, as well as the effect of isoindolines on HDAC8 expression on HeLa cells. The theoretical study show interactions of the isoindolines with two HDAC8 deep pockets; these binding sites were compared to those of HDAC8 inhibitor, Trichostatin A. It was demonstrated experimentally that tested compounds can act as HDAC8 inhibitors. The expression of HDAC8 by Western blot analysis, remain unchanged in HeLa cells treated with the isoindolines with the exception of compound 2b which seems to increase HDAC8 expression. In conclusion, isoindolines act as HDAC8 inhibitors because they do not decrease the protein expression.

In this study, the partition coefficients (Log P) of two series of isoindolines-2-substituted were calculated from the equation obtained for the multilinear correlation between the electronic properties: the highest occupied molecular orbital and the lowest unoccupied molecular orbital energies, and the steric property volume, and the experimental Log P values were determined for some representative isoindolines. Log P values calculated under quantum chemistry were compared with Log P values obtained by the Log P calculation software ALOGPS 2.1 server; the Log P values calculated showed a better correlation with experimental Log P values than those obtained by means of the software. Log P values calculated were also correlated with the antiproliferative activity of some isoindolines-2-substituted determined on HeLa cells, and the correlation obtained shows a quadratic relationship between Log P values calculated and the antiproliferative activity of isoindolines-2-substituted, suggesting a significant effect of Log P values on biological activity of isoindolines.

Oxidative stress is related to the pathogenesis and progress of several human diseases. NADPH oxidase (NOX), and mainly the NOX2 isoform, produces superoxide anions (O2•- ). To date, it is known that NOX2 can be inhibited by preventing the assembly of its subunits, p47phox and p22phox. In this work, we analyzed the binding to NOX2 of the apocynin dimer, diapocynin (C1), a known NOX2 inhibitor, and of 18 designed compounds (C2-C19) which have chemical relationships to C1, by in silico methods employing a p47phox structure from the Protein Data Bank (PDB code: 1WLP). C1 and six of the designed compounds were recognized in the region where p22phox binds to p47phox and makes π-π interactions principally with W193, W263, and Y279, which form an aromatic-rich region. C8 was chosen as the best compound according to the in silico studies and was synthesized and evaluated in vitro. C8 was able to prevent the production of reactive oxygen species (ROS) similar to C1. In conclusion, targeting the aromatic region of p47phox through π-interactions is important for inhibiting NOX activity.

It is know that compounds with phenol and thiol moieties have antioxidant activity. Therefore, the aim of this study was to synthetized three compounds containing phenol and thiol groups ((cysteine...

The present study was designed to determine whether or not subrenal aortic coarctation (SAC) is able to modify aorta reactivity in pregnant rats.Wistar female rats were subjected to SAC, and the responses to phenylephrine and acetylcholine of aortic segments above (thoracic) and below (abdominal) the coarctation from pregnant and non-pregnant rats were explored.Contractile responses to phenylephrine and relaxant responses to acetylcholine were similar in the thoracic segment from pregnant and non-pregnant SAC rats, whereas both kinds of response were higher in the abdominal segment from pregnant rats (p0.05). L-NAME (a nitric oxide synthase inhibitor) increased the effect of phenylephrine only in the aortic rings from pregnant animals (p0.05) and in general abolished the response to acetylcholine, with the exception of the abdominal segment from pregnant rats, in which only a partial inhibition was observed (p0.05). Indomethacin inhibited the contractile response to phenylephrine and increased the relaxant activity to acetylcholine in both aortic segments from the two groups of animals (p0.05).The lower contractile response to adrenergic agonists and higher relaxant response to acetylcholine that are associated with normal pregnancy are lost as a consequence of the coarctation procedure. Changes in the production of endothelial nitric oxide and contractile prostanoids appear to be associated with the vascular disturbances observed in SAC rats.