Mechanisms underlying the pathophysiology of type 2 diabetes: From risk factors to oxidative stress, metabolic dysfunction, and hyperglycemia.

Type 2 diabetes (T2D) is a complex multifactorial disease that emerges from the combination of genetic and environmental factors, and obesity, lifestyle, and aging are the most relevant risk factors. Hyperglycemia is the main metabolic feature of T2D as a consequence of insulin resistance and ß-cell dysfunction. Among the cellular alterations induced by hyperglycemia, the overproduction of reactive oxygen species (ROS) and consequently oxidative stress, accompanied by a reduced antioxidant response and impaired DNA repair pathways, represent essential mechanisms underlying the pathophysiology of T2D and the development of late complications. Mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and inflammation are also closely correlated with insulin resistance and ß-cell dysfunction. This review focus on the mechanisms by which oxidative stress, mitochondrial dysfunction, ER stress, and inflammation are involved in the pathophysiology of T2D, highlighting the importance of the antioxidant response and DNA repair mechanisms counteracting the development of the disease. Moreover, we indicate evidence on how nutritional interventions effectively improve diabetes care. Additionally, we address key molecular characteristics and signaling pathways shared between T2D and Alzheimer's disease (AD), which might probably be implicated in the risk of T2D patients to develop AD.

Cytotoxic and genotoxic effects in human gingival fibroblast and ions release of endodontic sealers incorporated with nanostructured silver vanadate.

The cytotoxic and genotoxic effects of commercial endodontic sealers (AH Plus, Sealer 26 and Endomethasone N) incorporated with nanostructured silver vanadate decorated with silver nanoparticles (AgVO3 - at concentrations 2.5, 5, and 10%) on human gingival fibroblast (HGF), and the silver (Ag+ ) and vanadium (V4+ /V5+ ) ions release were evaluated. Cytotoxicity, cell death, and genotoxicity tests were carried out with extract samples of 24-hr and 7-days. The release of Ag+ and V4+ /V5+ was evaluated. Cytotoxicity in HGF was caused by AH Plus (AP) with 5 and 10% of AgVO3 (83.84 and 67.49% cell viability, respectively) with 24-hr extract (p < 0.05), as well as all concentrations of AP with 7-days extract (p < 0.05 -AP 0% = 73.17%; AP 2.5% = 75.07%; AP 5% = 70.62%; AP 10% = 68.46% cell viability). The commercial sealers Sealer 26 (S26) and Endomethasone N (EN) were cytotoxic (p < 0.05 - S26 0% = 34.81%; EN 0% = 20.99% cell viability with 7-days extract). AP 10% with 7-days extract induced 32% apoptotic cells in HGF (p < 0.05). Genotoxic effect was not observed. The AP groups released more Ag+ , while S26 and EN released more V4+ /V5+ in 24 hr. The Ag+ can be cytotoxic. In conclusion, the cytotoxicity caused to HGF can be attributed by the commercial sealers and enhanced by incorporation of AgVO3 , was not observed genotoxic effect, and apoptosis was induced only by AH Plus 10% 7-days extract. Ag+ can influence cell viability.

Acetylcholinesterase inhibitory activity, anti-inflammatory, and neuroprotective potential of Hippeastrum psittacinum (Ker Gawl.) herb (Amaryllidaceae).

Hippeastrum psittacinum, Amaryllidaceae, is used in traditional medicine as a purgative, aphrodisiac, and anticough remedy. The ethanol extract (EE) and alkaloid-rich fractions (ARF) from H. psittacinum bulbs were evaluated for their acetylcholinesterase (AChE) inhibition. The EE cytotoxic and anti-inflammatory effects in RAW 264.7 cells, and the neuroprotective and genotoxic activities in SH-SY5Y cells, were also estimated. Fifteen alkaloids were identified in the EE by gas chromatography-mass spectrometry. ARFs were less active for AChE inhibition than EE. The viability of both cell lines was higher than 70% with EE concentrations below 25 µg/mL. The EE decreased nitrite release in RAW cells stimulated with lipopolysaccharide, showing values of 83, 67, and 53% at 6.25, 12.5, and 25 µg/mL, respectively. Furthermore, the EE partially protected SH-SY5Y cells from hydrogen peroxide-mediated deleterious effects by approximately 50% at the same concentrations. The micronucleus assays showed that the extract caused chromosomal missegregation at concentrations above 12.5 µg/mL. The in silico analyses showed that some alkaloids presented properties of permeation of the blood-brain barrier and the intestine. Our findings present new evidence of the potential of H. psittacinum potential as an AChE inhibitor, as well as an anti-inflammatory and neuroprotective agent.

From dual binding site acetylcholinesterase inhibitors to allosteric modulators: A new avenue for disease-modifying drugs in Alzheimer's disease.

The lack of an effective treatment for Alzheimer' disease (AD), an increasing prevalence and severe neurodegenerative pathology boost medicinal chemists to look for new drugs. Currently, only acethylcholinesterase (AChE) inhibitors and glutamate antagonist have been approved to the palliative treatment of AD. Although they have a short-term symptomatic benefits, their clinical use have revealed important non-cholinergic functions for AChE such its chaperone role in beta-amyloid toxicity. We propose here the design, synthesis and evaluation of non-toxic dual binding site AChEIs by hybridization of indanone and quinoline heterocyclic scaffolds. Unexpectely, we have found a potent allosteric modulator of AChE able to target cholinergic and non-cholinergic functions by fixing a specific AChE conformation, confirmed by STD-NMR and molecular modeling studies. Furthermore the promising biological data obtained on human neuroblastoma SH-SY5Y cell assays for the new allosteric hybrid 14, led us to propose it as a valuable pharmacological tool for the study of non-cholinergic functions of AChE, and as a new important lead for novel disease modifying agents against AD.