Paulo F. Santos

Effects of Sitagliptin Treatment on Dysmetabolism, Inflammation, and Oxidative Stress in an Animal Model of Type 2 Diabetes (ZDF Rat)

The purpose of this paper is to evaluate the chronic effect of sitagliptin on metabolic profile, inflammation, and redox status in the Zucker Diabetic Fatty (ZDF) rat, an animal model of obese type 2 diabetes. Diabetic and obese ZDF (fa/fa) rats and their controls (ZDF +/+) were treated during 6 weeks with vehicle (control) and sitagliptin (10 mg/kg/bw). Glucose, HbA1c, insulin, Total-c, TGs, IL-1β, TNF-α, CRPhs, and adiponectin were assessed in serum and MDA and TAS in serum, pancreas, and heart. Pancreatic histology was also evaluated. Sitagliptin in diabetic rats promoted a decrease in glucose, HbA1c, Total-c, and TGs accompanied by a partial prevention of insulinopenia, together, with a decrease in CRPhs and IL-1β. Sitagliptin also showed a positive impact on lipid peroxidation and hypertension prevention. In conclusion, chronic sitagliptin treatment corrected the glycaemic dysmetabolism, hypertriglyceridaemia, inflammation, and hypertension, reduced the severity of the histopathological lesions of pancreatic endocrine and exocrine tissues, together with a favourable redox status, which might be a further advantage in the management of diabetes and its proatherogenic comorbidities.

Synthesis and Spectroscopic Characterisation of N-Alkyl Quaternary Ammonium Salts Typical Precursors of Cyanines

The synthesis and spectroscopic characterisation of some representative N-alkyl-substituted quaternary ammonium salts derived from benzothiazole, benzoxazole, benzo-selenazole, indole and quinoline are described. These heterocyclic salts, bearing an activated methyl group in the 2-position in relation to the nitrogen atom and N-methyl, -pentyl, -hexyl and -decyl chains, are typical precursors of cyanine dyes.

Contribution of microglia-mediated neuroinflammation to retinal degenerative diseases.

Retinal degenerative diseases are major causes of vision loss and blindness worldwide and are characterized by chronic and progressive neuronal loss. One common feature of retinal degenerative diseases and brain neurodegenerative diseases is chronic neuroinflammation. There is growing evidence that retinal microglia, as in the brain, become activated in the course of retinal degenerative diseases, having a pivotal role in the initiation and propagation of the neurodegenerative process. A better understanding of the events elicited and mediated by retinal microglia will contribute to the clarification of disease etiology and might open new avenues for potential therapeutic interventions. This review aims at giving an overview of the roles of microglia-mediated neuroinflammation in major retinal degenerative diseases like glaucoma, age-related macular degeneration, and diabetic retinopathy.

Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons

Proteolytic cleavage of the Na+/Ca2+ exchanger (NCX) by calpains impairs calcium homeostasis, leading to a delayed calcium overload and excitotoxic cell death. However, it is not known whether reversal of the exchanger contributes to activate calpains and trigger neuronal death. We investigated the role of the reversal of the NCX in Ca2+ dynamics, calpain activation and cell viability, in α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-stimulated hippocampal neurons. Selective overactivation of AMPA receptors caused the reversal of the NCX, which accounted for approximately 30% of the rise in intracellular free calcium concentration ([Ca2+]i). The NCX reverse-mode inhibitor, 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R7943), partially inhibited the initial increase in [Ca2+]i, and prevented a delayed increase in [Ca2+]i. In parallel, overactivation of AMPA receptors strongly activated calpains and led to the proteolysis of NCX3. KB-R7943 prevented calpain activation, cleavage of NCX3 and was neuroprotective. Silencing of NCX3 reduced Ca2+ uptake, calpain activation and was neuroprotective. Our data show for the first time that NCX reversal is an early event following AMPA receptor stimulation and is linked to the activation of calpains. Since calpain activation subsequently inactivates NCX, causing a secondary Ca2+ entry, NCX may be viewed as a new suicide substrate operating in a Ca2+-dependent loop that triggers cell death and as a target for neuroprotection.

Role of Microglia Adenosine A 2A Receptors in Retinal and Brain Neurodegenerative Diseases

Neuroinflammation mediated by microglial cells in the brain has been commonly associated with neurodegenerative diseases. Whether this microglia-mediated neuroinflammation is cause or consequence of neurodegeneration is still a matter of controversy. However, it is unequivocal that chronic neuroinflammation plays a role in disease progression and halting that process represents a potential therapeutic strategy. The neuromodulator adenosine emerges as a promising targeting candidate based on its ability to regulate microglial proliferation, chemotaxis, and reactivity through the activation of its G protein coupled A2A receptor (A2AR). This is in striking agreement with the ability of A2AR blockade to control several brain diseases. Retinal degenerative diseases have been also associated with microglia-mediated neuroinflammation, but the role of A2AR has been scarcely explored. This review aims to compare inflammatory features of Parkinsons and Alzheimers diseases with glaucoma and diabetic retinopathy, discussing the therapeutic potential of A2AR in these degenerative conditions.

Some new symmetric rigidified triheterocyclic heptamethinecyanine dyes absorbing in the near infrared

Abstract Several new rigidified heptamethinecyanine dyes bearing different N -alkyl chains were readily prepared by a novel semi-catalyzed method, envisioning their potential usefulness for photodynamic therapy. All dyes displayed absorption within the so-called “phototherapeutic window”. In order to improve the structural versatility of the dyes, it was incorporated in the exocyclic conjugated bridge present in the polimethine chain a chlorine atom. In some cases the later underwent an unexpected in situ substitution by a third oxygenated heterocyclic group, depending on the solubility of the chloro dye in the reaction solvent. Two possible mechanisms for the formation of these triheterocyclic dyes are proposed. The full spectroscopic characterisation of all the cyanines synthesised is described.

Crystal structures of a benzoselenazole-derived squarylium cyanine dye and three derivatives substituted at the central squaric ring

The crystal structures of 4-[(3-hexylbenzoselenazol-3-ium-2-yl)methylidene]-2-[(3-hexyl-3H-benzoselenazol-2-ylidene)methyl]-3-oxocyclobut-1-en-1-olate and its analogues substituted at the squaric ring with O-methyl, NH-methyl and N,N-diethylamino groups have been determined using single crystal X-ray crystallography techniques. The unsubstituted squaraine dye is symmetrical and packs as a stepped ribbon array (via a C–H⋯O close interaction), which is in contrast to the slip-stacked arrangements observed in similar squaraine analogues. Each of the substituted analogues is asymmetric and pack in slightly differing slip-stacked charge-transfer columns. The NH-methyl analogue packs with a single water molecule per squaraine unit.

Bone mineral density after simultaneous kidney-pancreas transplantation: four years follow-up of 57 recipients.

Bone disease and an high risk of fractures are major problems in transplantation. Among diabetic patients undergoing simultaneous kidney-pancreas (SKP) transplantation, there are few studies assessing long-term effects on bone mass. The aim of this study was to evaluate bone mineral density (BMD) over 4 years follow-up after SKP transplantation. Fifty-seven patients had 22.8 +/- 5.3 years of prior diabetes, 65% were female, and the overall mean age was 24.3 +/- 5.93 years. At the time of transplantation, the lumbar spine and femoral neck T-scores were -1.75 +/- 1.05 and -1.95 +/- 0.73, respectively; 28% of subjects had evidence of osteoporosis. One year after transplantation, 77.6% of patients displayed improved lumbar T-scores to -1.33 +/- 0.94 (P = .044) with stable femoral neck T-scores. Bone densitometry enhanced gradually through the 4 years follow-up: lumbar T-score to -1.04 +/- 0.67 (P = .004) and femoral neck T-score to -1.69 +/- 0.49 (P = .12). At year 4, no osteoporosis cases were detected but 86.7% of patients did not receive steroids in the immunosuppressive regimen. The graft function remained stable (serum creatinine, 1.2 mg/dL; fasting glucose, 87.7 mg/dL). During the follow-up, BMD improved more significantly at cortical sites. Our study reports a reduced prevalence of fractures (8.7%) compared with the literature, which could be related to a steroid-sparing protocol and/or aggressively treatment of osteoporosis.

Recombinant human erythropoietin treatment protects the cardio-renal axis in a model of moderate chronic renal failure

Chronic kidney disease (CKD) patients develop anemia because of the low kidney erythropoietin (EPO) production, thus promoting cardiovascular complications. The degree of renal insufficiency might determine the moment to start recombinant human erythropoietin (rhEPO) therapy, but the molecular basis for these options deserves better elucidation. This study aimed to clarify the cardio-renal effects of earlier rhEPO therapy in rats with moderate chronic renal failure (CRF). Four groups of rats were evaluated for 15 weeks (control; rhEPO − 50 IU/kg/week; CRF − 3/4 nephrectomy; CRF + rhEPO) to assess renal and hematology data, EPO levels, blood pressure, heart rate, peripheral catecholamines contents, serum-transforming growth factor-β1 (TGF-β1), kidney gene expression of EPO, Caspase 9 (Casp9), and vascular endothelial growth factor (Vegf). This model of moderate CRF showed moderate and corrected anemia, hypertension, tachycardia, sympathetic overactivity, and increased serum TGF-β1 content. The remnant kidney showed a proliferative profile, with hypertrophy, downregulated gene expression of EPO, and upregulated gene expression of Vegf and Casp9. rhEPO treatment promoted erythrocytosis and prevented tachycardia and catecholamines increment, with a rise of serum TGF-β1. Furthermore, the decreased kidney gene expression of EPO and the overexpression of Casp9 were prevented, demonstrating a renoprotective action on the remnant kidney. In conclusion, rhEPO therapy promotes a protective effect on the cardio-renal axis, which might be mainly attributed to its pro-proliferative and anti-apoptotic properties. These findings might recommend its use in earlier stages of CRF, acting as an erythropoiesis stimulating agent, to efficiently correct not only the anemia, one of the major complications in these patients, but also the succeeding adverse cardio-renal effects.

A Novel Approach to the Hexahydropyrrolo[2,3-b]indole Nucleus: A Synthesis of (±)-Desoxyeseroline

Abstract A new synthesis of (±)-dcsoxyeseroline from the bis -enamine, methyl β- N -(3-melhyl-1-indolyl)-β- N -melhylamino acrylate, via a 3,3-sigmatropic rearrangement is described.