Drug Repurposing to Inhibit Histamine N-Methyl Transferase.

Lower activity of the histaminergic system is associated with neurological disorders, including Alzheimer's disease (AD). Thus, the enhancement of histaminergic neurotransmission by inhibition of histamine N-methyl transferase (HNMT), which degrades histamine, appears as an important approach. For this purpose, rigid and flexible molecular docking studies of 185 FDA-approved drugs with the HNMT enzyme were carried out to select two compounds to perform molecular dynamics (MD) simulations to evaluate the binding free energies and stability of the enzyme-drug complexes. Finally, an HNMT inhibition assay was performed to corroborate their effect towards HNMT. Molecular docking studies with HNMT allowed the selection of dihydroergotamine and vilazodone since these molecules showed the lowest Gibbs free energy values. Analysis of the binding mode of vilazodone showed interactions with the binding pocket of HNMT with Glu28, Gln143, and Asn283. In contrast, dihydroergotamine binds to the HNMT active site in a different location, apparently because it is overall the more rigid ligand compared to flexible vilazodone. HNMT inhibitory activity for dihydroergotamine and vilazodone was corroborated (IC50 = 72.89 µM and 45.01 µM, respectively) by in vitro assays. Drug repurposing of HNMT was achieved by employing computational studies.

Contribution of hyperglycemia-induced changes in microglia to Alzheimer's disease pathology.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by cognitive and functional impairments. The investigation of AD has focused on the formation of senile plaques, composed mainly by amyloid ß (Aß) peptide, and neurofibrillary tangles (NFTs) in the brain. Senile plaques and NFTs cause the excessive recruitment and activation of microglia, thus generating neuroinflammation and neuronal damage. Among the risk factors for the development of AD, diabetes has increasingly attracted attention. Hyperglycemia, the fundamental characteristic of diabetes, is involved in several mechanisms that give rise to microglial overactivation, resulting in neuronal damage and cognitive impairment. Indeed, various studies have identified the correlation between diabetes and AD. The aim of this review is to describe various mechanisms of the hyperglycemia-induced overactivation of microglia, which leads to neuroinflammation and neuronal damage and consequently contributes to the pathology of AD. The disruption of the regulation of microglial activity by hyperglycemia occurs through many mechanisms, including a greater production of reactive oxygen species (ROS) and glycation end products (AGEs), and a decrease in the elimination of Aß. The future direction of research on the relation between hyperglycemia and AD is addressed, such as the importance of determining whether the hyperglycemia-induced harmful effects on microglial activity can be reversed or attenuated if blood glucose returns to a normal level.

Complications of Renal Transplantation That Influence the Presence of Hyperuricemia in Its First Year of Evolution.

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.

Compliance With Biochemical Objectives in Patients on Renal Replacement Therapy Before Kidney Transplantation in Mexico.

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.

In vitro and computational studies of natural products related to perezone as anti-neoplastic agents.

Many natural phyto-products as perezone (Per) exhibit anti-cancer activities. Using experimental and computational studies, it was described that Poly ADP-ribose polymerase 1(PARP-1) inhibition and the induction of oxidative stress state explain the pro-apoptotic activity of Per. The aim of this study was to evaluate two phyto-products related to Per as anti-cancer agents: hydroxyperezone (OHPer) and its monoangelate (OHPer-MAng). These molecules were structurally characterized employing thermal analysis, IR spectrophotometry and X-ray diffraction techniques. The phyto-compounds evaluated in vitro in six cancer cell lines (K562, MCF-7, MDA-MB-231, HeLa, U373, A549) and non-malignant cells determinate their cytotoxicity, type of induced cell death, ability to avoid cell migration and changes at the redox status of the cell. Using, in vitro and computational studies provided the inhibition of PARP-1 and its potential binding mode. Cell proliferation assays demonstrated that OHPer-MAng treatment significantly induces apoptosis in triple negative breast cancer (TNBC) cell line (MDA-MB-231 IC50 = 3.53 µM), being particularly less cytotoxic to Vero cells (IC50 = 313.92 µM), human lymphocytes (IC50 = 221.46 µM) and rat endothelial cells (IC50=> 400 µM). The treatment of MDA-MB-231 cells with OHPer-MAng showed inhibition of migration by cancer cells. The induction of an oxidative stress state, similar to other quinones and PARP-1 inhibition explains the pro-apoptotic activity of OHPer-MAng. Docking studies showed that OHPer-MAng establishes great non-bonding interactions with the lateral chains of Tyr235, Hys201, Tyr246, Ser203, Asn207, and Gly233 located at the catalytic site of PARP-1, also demonstrating the anti-cancer activity of OHPer-MAng in TNBC cell line.