In Silico Analysis: Anti-Inflammatory and α-Glucosidase Inhibitory Activity of New α-Methylene-γ-Lactams.

The research about α-methylene-γ-lactams is scarce; however, their synthesis has emerged in recent years mainly because they are isosters of α-methylene-γ-lactones. This last kind of compound is structurally most common in some natural products' nuclei, like sesquiterpene lactones that show biological activity such as anti-inflammatory, anticancer, antibacterial, etc., effects. In this work, seven α-methylene-γ-lactams were evaluated by their inflammation and α-glucosidase inhibition. Thus, compounds 3-methylene-4-phenylpyrrolidin-2-one (1), 3-methylene-4-(p-tolyl)pyrrolidin-2-one (2), 4-(4-chlorophenyl)-3-methylenepyrrolidin-2-one (3), 4-(2-chlorophenyl)-3-methylenepyrrolidin-2-one (4), 5-ethyl-3-methylene-4-phenylpyrrolidin-2-one (5), 5-ethyl-3-methylene-4-(p-tolyl)pyrrolidin-2-one (6) and 4-(4-chlorophenyl)-5-ethyl-3-methylenepyrrolidin-2-one (7) were evaluated via in vitro α-glucosidase assay at 1 mM concentration. From this analysis, 7 exerts the best inhibitory effect on α-glucosidase compared with the vehicle, but it shows a low potency compared with the reference drug at the same dose. On the other side, inflammation edema was induced using TPA (12-O-tetradecanoylphorbol 13-acetate) on mouse ears; compounds 1-7 were tested at 10 µg/ear dose. As a result, 1, 3, and 5 show a better inhibition than indomethacin, at the same doses. This is a preliminary report about the biological activity of these new α-methylene-γ-lactams.

Chemical Constituents from Agave applanata and Its Antihyperglycemic, Anti-inflammatory, and Antimicrobial Activities Associated with Its Tissue Repair Capability.

Agave applanata is a Mexican agave whose fresh leaves are employed to prepare an ethanol tonic used to relieve diabetes. It is also applied to skin to relieve varicose and diabetic foot ulcers, including wounds, inflammation, and infections. In this study, the chemical composition of this ethanol tonic is established and its association with antihyperglycemic, anti-inflammatory, antimicrobial, and wound healing activities is discussed. The fresh leaves of A. applanata were extracted with ethanol : H2O (85 : 15). A fraction of this extract was lyophilized, and the remainder was partitioned into CH2Cl2, n-BuOH, and water. CH2Cl2 and n-BuOH fractions were subjected to a successive open column chromatography process. The structure of the isolated compounds was established using nuclear magnetic resonance and mass spectrometry spectra. The antihyperglycemic activity was evaluated through in vivo sucrose and glucose tolerance experiments, as well as ex vivo intestinal absorption and hepatic production of glucose. Wound healing and edema inhibition were assayed in mice. The minimum inhibitory concentrations (MICs) of the hydroalcoholic extract, its fractions, and pure compounds were determined through agar microdilution against the most isolated pathogens from diabetic foot ulcers. Fatty acids, ß-sitosterol, stigmasterol, hecogenin (1: ), N-oleyl-D-glucosamine, ß-daucosterol, sucrose, myo-inositol, and hecogenin-3-O-α-L-rhamnopyranosyl-(1 → 3)-ß-D-xylopyranosyl-(1 → 2)-[ß-D-xylopyranosyl-(1 → 3)-ß-D-glucopyranosyl-(1 → 3)]-ß-D-glucopyranosyl-(1 → 4)-ß-D-galactopyranoside (2: ) were characterized. This research provides evidence for the pharmacological importance of A. applanata in maintaining normoglycemia, showing anti-inflammatory activity and antimicrobial effects against the microorganisms frequently found in diabetic foot ulcers. This plant plays an important role in wound healing and accelerated tissue reparation.

Phytochemical analysis and antihyperglycemic activity of Castilleja arvensis.

Castilleja genus comprises approximately 211 species, some of them exhibiting potential in treating various diseases. Remarkably, despite its abundance, there is a significant lack of scientific studies that explore the chemical composition and/or therapeutic activity of this genus. In this work, the chemical composition of Castilleja arvensis was determined, and its antihyperglycemic activity was evaluated in vivo, in vitro, and ex vivo. Hydroalcoholic extract of C. arvensis (HECa) was obtained from the maceration of aerial parts. HECa was fractionated by liquid-liquid extractions to obtain the CH2Cl2 fraction (DF), EtOAc fraction (EF), n-BuOH fraction (BF) and aqueous residue (AR). The antihyperglycemic activity was determined in vivo through oral glucose and sucrose tolerance tests in normoglycemic CD-1 mice. Ex vivo assays were performed to determine intestinal glucose absorption, muscular glucose uptake and hepatic glucose production. α-glucosidase inhibitory activity was evaluated in vitro. Phytochemical screening was carried out through conventional chromatography techniques. Structure elucidation of the isolated compounds was performed by GC-MS and NMR experiments. HECa, its fractions and AR showed significant antihyperglycemic activity in vivo. According to the in vitro and ex vivo assays, this effect can be attributed to different mechanisms of action, including a delay in intestinal glucose absorption, an improvement in insulin sensitivity, and the regulation of hepatic glucose production. These effects may be due to different metabolites identified in fractions from the HECa, including genkwanin, acacetin, verbascoside and ipolamiide. Thus, current research shows that C. arvensis is an important source of bioactive compounds for the management of glycemia.

Obstructive sleep apnea and Alzheimer's disease-related cerebrospinal fluid biomarkers in mild cognitive impairment.

Previous studies have demonstrated that sleep-breathing disorders, and especially obstructive sleep apnea (OSA), can be observed in patients with a higher risk of progression to Alzheimer's disease (AD). Recent evidence indicates that cerebrospinal fluid (CSF) AD-biomarkers are associated with OSA. In this study, we investigated these associations in a sample of patients with mild cognitive impairment (MCI), a condition that is considered the first clinical phase of AD, when patients showed biomarkers consistent with AD pathology. A total of 57 patients (mean age = 66.19; SD = 7.13) with MCI were included in the study. An overnight polysomnography recording was used to assess objective sleep parameters (i.e. apnea/hypopnea index [AHI], total sleep time, sleep efficiency, sleep latency, arousal index, awakening, stage 1, 2, and slow-wave sleep and rapid eye movement sleep, periodic limb movement index, O2 saturation during sleep, and percentage of time O2 saturation <90%). Phosphorylated-tau (P-tau), total-tau (T-tau), and amyloid-beta 42 (Aß42) were measured in CSF. Unadjusted correlation analyses showed that a higher AHI (reflecting higher OSA severity) was related to higher P-tau and T-tau (both results remained significant after Bonferroni correction, p = 0.001). Importantly, these associations were observed even after adjusting for potential confounders (i.e. age, sex, body mass index, sleep medication, smoking, hypertension, and heart disease). Although more research is needed to establish a causal link, our findings provide evidence that OSA could be related to the pathophysiological mechanisms involved in neurodegeneration in MCI patients.

Electro-clinical analysis of epilepsy patients with generalized seizures on adjunctive perampanel treatment.

Quantifying epileptiform discharges before and after the initiation of treatment can be useful for evaluating the efficacy of antiepileptic drugs in generalized epilepsy. The aim of this study was to determine if the selective α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist perampanel alters the electroencephalographic signals in patients with drug resistant generalized seizures (primary or secondary). We also assessed the clinical efficacy, safety and tolerability of perampanel as an adjunctive treatment for patients with refractory generalized seizures after 3, 6 and 12 months of treatment to determine if there is an electro-clinical correlation. We carried out a 1-year retrospective, unicentric, observational, descriptive and non-interventional study to analyze changes in epileptiform discharges, seizure frequency and adverse effects in patients with generalized seizures taking perampanel as an add-on treatment. Perampanel significantly reduced the total number, total duration, maximal duration and average duration of epileptiform discharges in patients with primary generalized epilepsy (n = 44). In patients with focal onset epilepsy and secondary generalized seizures (n = 8) significant decreases in the maximal duration and average duration of epileptiform discharges were found. These findings correlate with the significant decrease in seizure frequency and clinical improvement observed after taking perampanel as an adjunctive therapy for 3, 6 and 12 months. To our knowledge, this is the first study to show that perampanel reduces epileptiform activity, and that this effect correlates with patients' clinical improvement. Analysing patients' electroencephalographic activity in response to perampanel could be useful for assessing the drug's efficacy and optimising adjunctive treatments.