PEGALUS: predictivity of elderly age, arterial gas analysis, and lung ultrasound. A new prognostic score for COVID-19 patients in the emergency department-an observational prospective study.

Background: Periodic surges of COVID-19 patients seeking care in the hospital environment overwhelm systems reduce the availability of resources for treatment of non-COVID-19 cases (Zheng et al. in J Hosp Infect 106:325-329, 2020). Hospital flow and resource management could be greatly enhanced by differentiating patients who are likely at risk of adverse clinical outcomes from those who could safely be discharged after evaluation and managed outside of the hospital setting (Sun et al.

Gas-exchange deficit and systemic hypoperfusion in COVID-19 and non-COVID-19 young adult patients with pneumonia.

Background: Lung damage leading to gas-exchange deficit and sepsis leading to systemic hypoperfusion are well-known features of severe pneumonia. Although frequently described in COVID-19, their prognostic impact in COVID-19-related pneumonia versus COVID-19-unrelated pneumonia has never been compared. This study assesses fundamental gas-exchange and hemodynamic parameters and explores their prognostic impact in COVID-19 pneumonia and non-COVID-19 pneumonia.

Mangostanin, a Xanthone Derived from Fruit, Exerts Protective and Reparative Effects on Oxidative Damage in Human Keratinocytes.

The fruit of (mangosteen) is known in ancient traditional Asian medicine for its antioxidant, anti-inflammatory, immunomodulatory and anticancer activities. These effects are mainly due to the action of polyphenols known as xanthones, which are contained in the pericarp of the fruit. In recent years, there has been a growing interest from pharmaceutical companies in formulating new topicals based on mangosteen full extracts to prevent skin aging.

Keratinocytes Migration Promotion, Proliferation Induction, and Free Radical Injury Prevention by 3-Hydroxytirosol.

3-hydroxytyrosol (HT) is the main phenolic compound found in olive oil with known antioxidant, anti-inflammatory, and antimicrobial properties in several dermatological conditions, both when taken in the form of olive oil or pure in cosmeceutical formulations. To date, its direct effect on the wound healing process and the molecular mechanisms involved have not yet been elucidated. Thus, in the present study, we aimed to explore its effects in vitro in epidermal keratinocyte cultures focusing on the molecular mechanism implied.

Gene Expression Analysis of Mevalonate Kinase Deficiency Affected Children Identifies Molecular Signatures Related to Hematopoiesis.

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory genetic disorder characterized by recurrent fever attacks and systemic inflammation with potentially severe complications. Although it is recognized that the lack of protein prenylation consequent to mevalonate pathway blockade drives IL1β hypersecretion, and hence autoinflammation, MKD pathogenesis and the molecular mechanisms underlaying most of its clinical manifestations are still largely unknown. In this study, we performed a comprehensive bioinformatic analysis of a microarray dataset of MKD patients, using gene ontology and Ingenuity Pathway Analysis (IPA) tools, in order to identify the most significant differentially expressed genes and infer their predicted relationships into biological processes, pathways, and networks.

Psychological Stress and Cancer: New Evidence of An Increasingly Strong Link.

To date stress, a highly complex process that disrupts homeostasis and involves environmental and psychosocial factors, is considered as one of the most crucial factor that affects our daily life, especially urban dweller's life. Clinical and experimental studies widely support the notion that adrenergic stimulation due to chronic stress affects inflammation and metabolism. In this work, supported by several recent scientific evidences, we show how stress plays a positive role in cancer initiation, progression and cancer metastasis, a negative role for anti-tumor immune function and therapy response.

Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of Covid-19.

Background: Understanding how HLA polymorphisms may affect both susceptibility, course and severity of Covid-19 infection could help both at the clinical level to identify individuals at higher risk from the disease and at the epidemiological one to explain the differences in the epidemic trend among countries or even within a specific country. Covid-19 disease in Italy showed a peculiar geographical distribution from the northern most affected regions to the southern ones only slightly touched.

Methods: In this study we analysed the regional frequencies for the most common Italian haplotypes from the Italian Bone Marrow Donor Registry (HLA-A, -B, -C and -DRB1 at four-digit level).

A pilot feasibility study of a questionnaire to determine European Union-wide CAM use.

Background: No questionnaire specifically measuring the core components of complementary and alternative medicine (CAM) use has been validated for use across European Union (EU) countries. We aimed to determine the face validity, acceptability and the participants' comprehension of a pre-existing questionnaire designed to measure 'CAM use', to provide a comparative, standardised questionnaire for use by health care providers, policy makers and purchasers throughout Europe.

Methods: Established procedures were employed to translate the questionnaire into 4 EU languages.

Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class.

Here we describe a novel caged form of the highly reactive bioeffector molecule, nitroxyl (HNO). Reacting the labile nitric oxide (NO)- and HNO-generating salt of structure iPrHN-N(O)═NO(-)Na(+) (1, IPA/NO) with BrCH(2)OAc produced a stable derivative of structure iPrHN-N(O)═NO-CH(2)OAc (2, AcOM-IPA/NO), which hydrolyzed an order of magnitude more slowly than 1 at pH 7.4 and 37 °C.

Glycosylated PROLI/NO derivatives as nitric oxide prodrugs.

GlcNAc-PROLI/NO prodrugs that are activated by N-acetylglucosaminidase to release nitric oxide (NO) are described. A classical acid-amine coupling is used to bifunctionalize these PROLI/NO prodrugs, which on activation generate up to 4 mol of NO, a peptide residue, and an N-acetylglucosamine residue. Many of the prodrugs synthesized are efficient sources of intracellular NO.

Synthesis and evaluation of piperazine and homopiperazine analogues of JS-K, an anti-cancer lead compound.

Here we report a number of novel JS-K structural analogues with sub-micromolar anti-proliferative activities against human leukemia cell lines HL-60 and U937; JS-K is the anti-cancer lead compound O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate. The ability of these compounds to generate intracellular nitric oxide correlated well with their observed anti-proliferative effects: analogues that had potent inhibitory activity against leukemia cells formed elevated levels of intracellular nitric oxide.

Rhabdomyolysis: a case study exploring the possible side effect of lipid lowering medication by a HIV positive patient taking a protease inhibitor.

This case study explores the incidence of rhabdomyolysis in a HIV positive patient that was taking a lipid lowering drug and a protease inhibitor concurrently while under chiropractic treatment for generalized muscular soreness. Dyslipidemia is a very common problem both in the general and HIV population, with many patients being prescribed lipid lowering drugs. While extremely rare, adverse effects of lipid lowering drugs have been documented to include myopathy such as rhabdomyolysis.

Aryl bis(diazeniumdiolates): potent inducers of S-glutathionylation of cellular proteins and their in vitro antiproliferative activities.

A number of bis(diazeniumdiolates) that we designed to release up to 4 mol of nitric oxide (NO) and that are structural analogues of the NO prodrug and anticancer lead compound O(2)-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2- diolate (PABA/NO) were synthesized and studied. A majority of these compounds yielded higher levels of NO, were better inhibitors of proliferation of a number of cancer cell lines, and more rapidly induced substantially increased levels of S-glutathionylation of cellular proteins in comparison with PABA/NO. In most cases, the antiproliferative activity and extents of S-glutathionylation correlated well with levels of intracellular NO release.

Cell-permeable esters of diazeniumdiolate-based nitric oxide prodrugs.

Although O(2)-(2,4-dinitrophenyl) derivatives of diazeniumdiolate-based nitric oxide (NO) prodrugs bearing a free carboxylic acid group were activated by glutathione to release NO, these compounds were poor sources of intracellular NO and showed diminished antiproliferative activity against human leukemia HL-60 cells. The carboxylic acid esters of these prodrugs, however, were found to be superior sources of intracellular NO and potent inhibitors of HL-60 cell proliferation.

Synthesis, mechanistic studies, and anti-proliferative activity of glutathione/glutathione S-transferase-activated nitric oxide prodrugs.

Nitric oxide (NO) prodrugs such as O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) are a growing class of promising NO-based therapeutics. Nitric oxide release from the anti-cancer lead compound, JS-K, is proposed to occur through a nucleophilic aromatic substitution by glutathione (GSH) catalyzed by glutathione S-transferase (GST) to form a diazeniumdiolate anion that spontaneously releases NO. In this study, a number of structural analogues of JS-K were synthesized and their chemical and biological properties were compared with those of JS-K.

Hydrolytic reactivity trends among potential prodrugs of the O2-glycosylated diazeniumdiolate family. Targeting nitric oxide to macrophages for antileishmanial activity.

Glycosylated diazeniumdiolates of structure R 2NN(O)NO-R' (R' = a saccharide residue) are potential prodrugs of the nitric oxide (NO)-releasing but acid-sensitive R 2NN(O)NO (-) ion. Moreover, cleaving the acid-stable glycosides under alkaline conditions provides a convenient protecting group strategy for diazeniumdiolate ions. Here, we report comparative hydrolysis rate data for five representative glycosylated diazeniumdiolates at pH 14, 7.

Second-generation aspirin and indomethacin prodrugs possessing an O(2)-(acetoxymethyl)-1-(2-carboxypyrrolidin-1-yl)diazenium-1,2-diolate nitric oxide donor moiety: design, synthesis, biological evaluation, and nitric oxide release studies.

The carboxylic acid group of the anti-inflammatory (AI) drugs aspirin and indomethacin was covalently linked to the 1-(2-carboxypyrrolidin-1-yl)diazen-1-ium-1,2-diolate ion via a one-carbon methylene spacer to obtain two new hybrid prodrugs. The aspirin prodrug ( 23) was a 2.2-fold more potent AI agent than aspirin, whereas the indomethacin prodrug ( 26) was about 1.

Synthesis, nitric oxide release, and anti-leukemic activity of glutathione-activated nitric oxide prodrugs: Structural analogues of PABA/NO, an anti-cancer lead compound.

Diazeniumdiolate anions and their prodrug forms are reliable sources of nitric oxide (NO) that have generated interest as promising therapeutic agents. A number of structural analogues of O(2)-(2,4-dinitro-5-(4-(N-methylamino)benzoyloxy)phenyl) 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO), an anti-cancer lead compound that is designed to release NO upon activation by glutathione, were prepared. The nitric oxide release patterns of these O(2)-(2,4-dinitrophenyl) diazeniumdiolates in the presence of glutathione were tested and it was found that in the absence of competing pathways, these compounds release nearly quantitative amounts of NO.

Nitric oxide prodrugs: diazeniumdiolate anions of hindered secondary amines.

Nitric oxide prodrugs derived from hindered secondary amines were prepared. The decomposition patterns of these prodrugs indicate that alpha-methyl groups around the nitrogen bearing the diazeniumdiolate group prolong their half-life in aqueous buffer.

O2-acetoxymethyl-protected diazeniumdiolate-based NSAIDs (NONO-NSAIDs): synthesis, nitric oxide release, and biological evaluation studies.

A novel group of O2-acetoxymethyl-protected diazeniumdiolate-based non-steroidal anti-inflammatory prodrugs (NONO-NSAIDs) were synthesized by esterifying the carboxylate group of aspirin, ibuprofen, or indomethacin with O2-acetoxymethyl 1-[N-(2-hydroxyethyl)-N-methylamino]diazeniumdiolate. The resulting nitric oxide (*NO)-releasing prodrugs (7-9) did not exhibit in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC50s>100 microM). In contrast, prodrugs 7 and 8 significantly decreased carrageenan-induced rat paw edema showing enhanced in vivo anti-inflammatory activities (ID50's=552 and 174 micromol/kg, respectively) relative to those of the parent NSAIDs aspirin (ID50=714 micromol/kg) and ibuprofen (ID50=326 micromol/kg).

Metabolism of a liver-selective nitric oxide-releasing agent, V-PYRRO/NO, by human microsomal cytochromes P450.

Endogenously generated nitric oxide (NO) mediates a host of important physiological functions, playing roles in the vascular, immunological, and neurological systems. As a result, exogenous agents that release NO have become important therapeutic interventions and research tools. O(2)-Vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO) is a prodrug designed with the hypothesis that it might release nitric oxide via epoxidation of the vinyl group by cytochrome P450, followed by enzymatic and/or spontaneous epoxide hydration to release the ultimate NO-donating moiety, 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (PYRRO/NO) ion.

Nitric oxide releasing polyurethanes with covalently linked diazeniumdiolated secondary amines.

Two novel strategies for synthesizing stable polyurethanes (PUs) capable of generating bioactive nitric oxide (NO) are described. The methods rely on covalently attaching diazeniumdiolate (N(2)O(2)(-)) groups onto secondary amine nitrogens at various positions within the polymer chain such that, when in contact with water or physiological fluids, only the two molecules of NO available from each diazeniumdiolate moiety are released into the surrounding medium, with potential byproducts remaining covalently bound to the matrix. Extensive analysis of the NO(x)() products released from the polymers was employed to develop appropriate strategies to better stabilize the diazeniumdiolate-based polymer structures.