Involvement of Free Radicals in the Development and Progression of Alzheimer’s Disease

Alzheimer’s disease (AD) is a major dementia related to an overproduction of free radicals (FRs), which leads to the generation of oxidative stress in brain tissue. Amyloid beta-peptide of 42 amino acid residues (Aβ1–42) is the main source of FRs in patients with AD. βA1–42 results from hydrolysis of the amyloid precursor protein by β-secretase in a process known as the amyloidogenic pathway. During βA1–42 aggregation, the peptide interacts with various transition metals to produce hydrogen peroxide (H2O2) by the Fenton reaction, generating the hydroxyl radical (•OH), which damages lipids, proteins, and nucleic acids, thereby contributing to neurodegeneration. In addition, βA1–42 is recognized by microglial receptors; it activates these cells, causing overproduction of superoxide anion (O2•−) by NADPH oxidase; O2•− is also converted into H2O2 and finally to •OH in the Fenton reaction. Other factors that contribute to oxidative stress during microglial activation are the overproduction of nitric oxide and interleukins and the overexpression of some enzymes, including cyclooxygenase and inducible nitric oxide synthase, all of which contribute to FR production. Currently, various models in vitro and in vivo exist that permit quantification of O2•− and H2O2 and determination of the effects of these reactive oxygen species

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Virtual and In Vitro Screens Reveal a Potential Pharmacophore that Avoids the Fibrillization of Aβ1-42.

Among the multiple factors that induce Alzheimer's disease, aggregation of the amyloid β peptide (Aβ) is considered the most important due to the ability of the 42-amino acid Aβ peptides (Aβ1-42) to form oligomers and fibrils, which constitute Aβ pathological aggregates. For this reason, the development of inhibitors of Aβ1-42 pathological aggregation represents a field of research interest. Several Aβ1-42 fibrillization inhibitors possess tertiary amine and aromatic moieties. In the present study, we selected 26 compounds containing tertiary amine and aromatic moieties with or without substituents and performed theoretical studies that allowed us to select four compounds according to their free energy values for Aβ1-42 in α-helix (Aβ-α), random coil (Aβ-RC) and β-sheet (Aβ-β) conformations. Docking studies revealed that compound 5 had a higher affinity for Aβ-α and Aβ-RC than the other compounds. In vitro, this compound was able to abolish Thioflavin T fluorescence and favored an RC conformation of Aβ1-42 in circular dichroism studies, resulting in the formation of amorphous aggregates as shown by atomic force microscopy. The results obtained from quantum studies allowed us to identify a possible pharmacophore that can be used to design Aβ1-42 aggregation inhibitors. In conclusion, compounds with higher affinity for Aβ-α and Aβ-RC prevented the formation of oligomeric species

LC-MS metabolomic evidence metabolites from Oenothera rosea L´ Hér. ex Ait with antiproliferative properties on DU145 human prostate cancer cell line

Prostate cancer remains one of the leading health issues without a fully effective treatment. Medicinal plants are one of the primary sources of compounds for treating numerous ailments. In this sense, the Oenothera genus contains metabolites with antiproliferative activity on cancer cells. For this, the study aimed to explore the antiproliferative activity of its extracts against prostate cancer and identify its metabolites (under metabolomics analyses) associated with anticancer and/or antiproliferative properties. For this reason, a LC-MS/MS-based metabolomic analysis was performed to demonstrate the possible metabolites present in O. rosea. In addition, the antiproliferative activity of different extracts in the human prostate cancer cell line DU145 was evaluated. All extracts have antiproliferative effects on DU145 cells at 72 h, with moderate activity being the best ethanolic either 48 or 72 h. Finally, by LC-MS/MS-based metabolomics, 307 compounds from aqueous, methanolic, ethanolic, and ethyl acetate extracts from which 40 putative metabolites identified were organized as anti-inflammatory, anticancer, and/or antiproliferative activities according to previously reported. These results provide evidence that O. rosea could be used as an antiproliferative agent due to its chemical contents used as polypharmacy with low concentration levels

Docking results between curcumin, melatonin and ThT with several Aβ_1–42 conformers.

<p>The methodology to obtain the complex is the same as mentioned above for the docking studies with the selected compounds. ΔG values were obtained through docking studies of the ligands with <b>Aβ-α</b> (circles), <b>Aβ-RC</b> (rhombuses) and <b>Aβ-β</b> (squares) (A). The binding modes of curcumin, melatonin and ThT on <b>Aβ-α</b>, <b>Aβ-RC</b>, and <b>Aβ-β</b> (B).</p

Proportions of Aβ_1–42 secondary structures in the absence or presence of 100 μM of the selected compounds.

<p>Proportions of Aβ_1–42 secondary structures in the absence or presence of 100 μM of the selected compounds.</p

AFM analysis after incubating 50 μM Aβ_1–42 alone or in the presence of the selected compounds at 100 μM after 24 h (A to E) or different incubation times (F and G).

<p>Aβ_{<b>1–42</b>} alone (A); Aβ_{<b>1–42</b>} and compound 5 (B); Aβ_{<b>1–42</b>} and compound 8 (C); Aβ_{<b>1–42</b>} and compound 14 (D); Aβ_{<b>1–42</b>} and compound 19 (E). Samples obtained at different incubation times for Aβ_{<b>1–42</b>} alone (F) or with compound 5 (G). Aβ_{<b>1–42</b>} (50 μM in MilliQ water) was incubated at 37°C in a quartz cell in the presence or absence of compounds 5, 8, 14 and 19 (100 μM) and stirred at 250 rpm for 24 h.</p

Comparison of LUMO, HOMO and SOMO (eV) and the electronic energies of the amino acid residues and compounds.

<p><b>(α)</b> After docking studies with <b>Aβ-α</b></p><p><b>(RC)</b> After docking studies with <b>Aβ-RC</b></p><p><b>(β)</b> After docking studies with <b>Aβ-β</b></p><p>Comparison of LUMO, HOMO and SOMO (eV) and the electronic energies of the amino acid residues and compounds.</p

Chemical structures of the inhibitors of Aβ_1–42 fibrillization.

<p>The majority of the compounds shared the presence of amines and/or aromatic rings.</p

Proposed Aβ-α pharmacophore based on the studies with compound 5.

<p>Schematic representation of the polar and nonpolar interactions that favor the interactions with <b>Aβ-α</b> (A); distances between principal chemical groups, the protonated amine (N⁺), the aromatic ring (Ar), and Alkyl substituent (<i>Tert-B</i>) (B). The main interactions involved in the recognition of compound 5 are electrostatic interactions with Glu22 and Asp23, π-π with Phe19 and Phe20 and hydrophobic interactions with Leu17.</p