COX-1 Inhibitors: Beyond Structure Toward Therapy

Biosynthesis of prostaglandins from arachidonic acid (AA) is catalyzed by cyclooxygenase (COX), which exists as COX-1 and COX-2. AA is in turn released from the cell membrane upon neopathological stimuli. COX inhibitors interfere in this catalytic and disease onset process. The recent prominent discovery involvements of COX-1 are mainly in cancer and inflammation. Five classes of COX-1 inhibitors are known up to now and this classification is based on chemical features of both synthetic compounds and substances from natural sources. Physicochemical interactions identification between such molecules and COX-1 active site was achieved through X-ray, mutagenesis experiments, specific assays and docking investigations, as well as through a pharmacometric predictive model building. All these insights allowed the design of new highly selective COX-1 inhibitors to be tested into those disease models in which COX-1 is involved. Particularly, COX-1 is expressed at high levels in the early to advanced stages of human epithelial ovarian cancer, and it also seems to play a pivotal role in cancer progression. The refinement of COX-1 selective inhibitor structure has progressed to the stage that some of the inhibitors described in this review could be considered as promising active principle ingredients of drugs and hence part of specific therapeutic protocols. This review aims to outline achievements, in the last 5 years, dealing with the identification of highly selective synthetic and from plant extracts COX-1 inhibitors and their theranostic use in neuroinflammation and ovarian cancer. Their gastrotoxic effect is also discussed

The Logic of Probability: A Trip through Uncertainty

In real life we have to deal with uncertainty, imprecision and vagueness. Many ideas were introduced and studied in detail to manage with these problems. Now we briefly expose the main formal concepts which describe non-ideal situations, i.e. Probability, Statistics and Fuzzy Logic. Probability has recent origins with respect to other branches of mathematics which have deep roots in the past, like geometry or algebra.We may say all this started with Antoine Gombaud, Chevalier de Méré (1607–1684), who asked Blaise Pascal (1623–1662) about gambling with dice. The correspondence between Pierre de Fermat and Blaise Pascal, which began in 1654, initially on these questions, led to the introduction of basic concepts, i.e. probability and expectation. Only in 1657, Christian Huygens in "De Ratiociniis in ludo aleae" proposed a first systematic study of the new branch of mathematics. However, the need of an axiomatic construction of the theory of probability arose to analyze more general and complex situations than gambling. A strong formalization was supplied by the monograph "Foundations of the theory of probability" (1933) by Andrey Nikolaevich Kolmogorov.Statistics represent the most popular application of probability theory, providing research tools in several areas, including physical and natural sciences, technology, psychology, economics and medicine. Statistics are the bridge that connects experimental data to the mathematical theory behind itself.Fuzzy logic, sometime confused with probability, wants to express and formalize all the sentences which are not true or false at all; the philosophical idea is that "everything is a matter of degree" (Zadeh). La logica della probabilità: un viaggio attraverso l’incertezzaNella vita reale ci si trova di fronte a molte situazioni caratterizzate da incertezza, imprecisione, vaghezza. Sono state introdotte diverse modellizzazioni per il trattamento di tali concetti e problemi. Ci proponiamo di esporre sinteticamente alcuni lineamenti fondamentali di Probabilità, Statistica e Fuzzy Logic.La probabilità ha origini recenti rispetto alle altre branche della matematica che hanno profonde radici nel passato, come la geometria o l’algebra.Possiamo dire che un passaggio iniziale importante si è avuto con Antoine Gombaud, Chevalier de Méré (1607-1684), che pose a Blaise Pascal (1623-1662) una questione riguardante il gioco dei dadi. La corrispondenza tra Pierre de Fermat e Blaise Pascal, che ha avuto inizio nel 1654, su questioni simili, ha portato all'introduzione di concetti di base, come probabilità e aspettativa. Successivamente Christian Huygens, in "De ludo Ratiociniis in aleae", ha proposto un primo studio sistematico della nuova branca della matematica. Tuttavia, la necessità di una costruzione assiomatica della teoria della probabilità sorse per l’esigenza di analizzare situazioni più generali e complesse rispetto al gioco d'azzardo. Una forte formalizzazione è stata fornita dalla monografia "Fondamenti della teoria della probabilità" (1933) di Andrey Nikolaevich Kolmogorov.La statistica rappresenta l'applicazione più popolare della teoria della probabilità, fornendo strumenti di ricerca in diversi settori, tra cui le scienze fisiche e naturali, la tecnologia, la psicologia, l'economia e la medicina. In un certo senso essa rappresenta il ponte che collega i dati sperimentali con la teoria matematica.La Logica Fuzzy, da non confondere con la probabilità, si occupa del trattamento formale delle proposizioni di cui non si può affermare senza ambiguità che siano vere o false; l'idea filosofica è che "tutto è una questione di gradualità" (Zadeh).Parole Chiave: Incertezza, Probabilità, Statistica, Fuzz

Origanum vulgare subsp. hirtum essential oil prevented biofilm formation and showed antibacterial activity against planktonic and sessile bacterial cells

Essential oils from six different populations of Origanum vulgare subsp. hirtum were compared for their antibiofilm properties. The six essential oils (A to F) were characterized by a combination of gas chromatography with flame ionization detector and gas chromatography with mass spectrometer detector analyses. All oils showed weak activity against the planktonic form of a group of Staphylococcus aureus strains and against a Pseudomonas aeruginosa ATCC 15442 reference strain. The ability to inhibit biofilm formation was investigated at sub-MIC levels of 200, 100, and 50 m g/ml by staining sessile cells with safranin. Sample E showed the highest average effectiveness against all tested strains at 50 m g/ml and had inhibition percentages ranging from 30 to 52%. In the screening that used preformed biofilm from the reference strain P. aeruginosa, essential oils A through E were inactive at 200 m g/ml; F was active with a percentage of inhibition equal to 53.2%. Oregano essential oil can inhibit the formation of biofilms of various food pathogens and food spoilage organisms.Essential oils from six different populations of Origanum vulgare subsp. hirtum were compared for their antibiofilm properties. The six essential oils (A to F) were characterized by a combination of gas chromatography with flame ionization detector and gas chromatography with mass spectrometer detector analyses. All oils showed weak activity against the planktonic form of a group of Staphylococcus aureus strains and against a Pseudomonas aeruginosa ATCC 15442 reference strain. The ability to inhibit biofilm formation was investigated at sub-MIC levels of 200, 100, and 50 m g/ml by staining sessile cells with safranin. Sample E showed the highest average effectiveness against all tested strains at 50 m g/ml and had inhibition percentages ranging from 30 to 52%. In the screening that used preformed biofilm from the reference strain P. aeruginosa, essential oils A through E were inactive at 200 m g/ml; F was active with a percentage of inhibition equal to 53.2%. Oregano essential oil can inhibit the formation of biofilms of various food pathogens and food spoilage organisms

Origanum vulgare subsp. hirtum essential oil prevented biofilm formation and showed antibacterial activity against planktonic and sessile bacterial cells.

Essential oils from six different populations of Origanum vulgare subsp. hirtum were compared for their antibiofilm properties. The six essential oils (A to F) were characterized by a combination of gas chromatography with flame ionization detector and gas chromatography with mass spectrometer detector analyses. All oils showed weak activity against the planktonic form of a group of Staphylococcus aureus strains and against a Pseudomonas aeruginosa ATCC 15442 reference strain. The ability to inhibit biofilm formation was investigated at sub-MIC levels of 200, 100, and 50 m g/ml by staining sessile cells with safranin. Sample E showed the highest average effectiveness against all tested strains at 50 m g/ml and had inhibition percentages ranging from 30 to 52%. In the screening that used preformed biofilm from the reference strain P. aeruginosa, essential oils A through E were inactive at 200 m g/ml; F was active with a percentage of inhibition equal to 53.2%. Oregano essential oil can inhibit the formation of biofilms of various food pathogens and food spoilage organisms.Essential oils from six different populations of Origanum vulgare subsp. hirtum were compared for their antibiofilm properties. The six essential oils (A to F) were characterized by a combination of gas chromatography with flame ionization detector and gas chromatography with mass spectrometer detector analyses. All oils showed weak activity against the planktonic form of a group of Staphylococcus aureus strains and against a Pseudomonas aeruginosa ATCC 15442 reference strain. The ability to inhibit biofilm formation was investigated at sub-MIC levels of 200, 100, and 50 m g/ml by staining sessile cells with safranin. Sample E showed the highest average effectiveness against all tested strains at 50 m g/ml and had inhibition percentages ranging from 30 to 52%. In the screening that used preformed biofilm from the reference strain P. aeruginosa, essential oils A through E were inactive at 200 m g/ml; F was active with a percentage of inhibition equal to 53.2%. Oregano essential oil can inhibit the formation of biofilms of various food pathogens and food spoilage organisms

General role of the amino and methylsulfamoyl groups in selective cyclooxygenase(COX)-1 inhibition by 1,4-diaryl-1,2,3-triazoles and validation of a predictive pharmacometric PLS model

A novel set of 1,4-diaryl-1,2,3-triazoles were projected as a tool to study the effect of both the heteroaromatic triazole as a core ring and a variety of chemical groups with different electronic features, size and shape on the catalytic activity of the two COX isoenzymes. The new triazoles were synthesized in fair to good yields and then evaluated for their inhibitory activity towards COXs arachidonic acid conversion catalysis. Their COXs selectivity was also measured. A predictive pharmacometric Volsurf plus model, experimentally confirmed by the percentage (%) of COXs inhibition at the concentration of 50 μM and IC50 values of the tested compounds, was built by using a number of isoxazoles of known COXs inhibitory activity as a training set. It was found that two compounds {4-(5-methyl-4-phenyl-1H-1,2,3-triazol-1-yl)benzenamine (18) and 4-[1-(4-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-yl]benzenamine (19)} bearing an amino group (NH2) are potent and selective COX-1 inhibitors (IC50 Combining double low line 15 and 3 μM, respectively) and that the presence of a methylsulfamoyl group (SO2CH3) is not a rule to have a Coxib. In fact, 4-(4-methoxyphenyl)-5-methyl-1-[4-(methylsulfonyl)phenyl]-1H-1,2,3-triazole (23) has COX-1 IC50 Combining double low line 23 μM and was found inactive towards COX-2

Paracentrin 1, a synthetic antimicrobial peptide from the sea-urchin Paracentrotus lividus, interferes with staphylococcal and Pseudomonas aeruginosa biofilm formation

The rise of antibiotic-resistance as well as the reduction of investments by pharmaceutical companies in the development of new antibiotics have stimulated the investigation for alternative strategies to conventional antibiotics. Many antimicrobial peptides show a high specificity for prokaryotes and a low toxicity for eukaryotic cells and, due to their mode of action the development of resistance is considered unlikely. We recently characterised an antimicrobial peptide that was called Paracentrin 1 from the 5-kDa peptide fraction from the coelomocyte cytosol of the Paracentrotus lividus. In this study, the chemically synthesised Paracentrin 1, was tested for its antimicrobial and antibiofilm properties against reference strains of Gram positive and Gram negative. The Paracentrin 1 was active against planktonic form of staphylococcal strains (reference and isolates) and Pseudomonas aeruginosa ATCC 15442 at concentrations ranging from 12.5 to 6.2 mg/ml. The Paracentrin 1 was able to inhibit biofilm formation of staphylococcal and Pseudomonas aeruginosa strains at concentrations ranging from 3.1 to 0.75 mg/ml. We consider the tested peptide as a good starting molecule for novel synthetic derivatives with improved pharmaceutical potentia

Risk assessment in ginecology and obstetrics in Sicily: an approach based on Wolff's Criteria

Objectives To apply Wolff’s Criteria to hospital discharge records (HDR) in order to detect adverse events worthy of further study. Methods Gynecology and Obstetrics Units of three Sicilian hospitals were considered and HDR regarding ordinary and day hospital admissions in 2008 were collected. A matched case-control study was designed, by random selection of 10 controls at maximum for each case. Matching was performed on the variables age and speciality of admission (gynecology or obstetrics). Results Out of a total of 7011 HDR examined, 114 cases were identified with Wolff’s Criteria. Multivariate analysis confirmed a statistically significant association with the origin of admission, diagnosis at the acceptance and length of stay: there was a decreased risk of Wolff’s event in patients having urgent admission compared to elective (OR = 0.47, 95% CI = [0.28-0.78]), an increased risk in patients reporting tumor (OR = 5:41, 95 % CI [1.89-15.47]) and other causes (OR = 2.16, 95% CI [1.10-4.24]) compared to delivery diagnosis at acceptance and in patients whose length of stay was more than 6 days (OR = 23.17, 95% CI = [12.56-42.7]) compared to less or equal than 3 days Conclusion Wolff’s Criteria can be applied for the analysis of clinical risk in hospitals with different structural characteristics, on condition that the HDR database is complete and good quality

Hormone replacement therapy and cardioprotection. A new dawn? A statement of the \u27Gruppo di studio sulle malattie cardiovascolari nella donna\u27 of the societ? italiana di cardiologia on hormone replacement therapy in postmenopausal women

Cardiovascular disease is the leading cause of death in women in western countries. Despite preventive strategies, in the past decades, the incidence of cardiovascular events has shown a decline in men but a rise in women, matching the growth of the population of postmenopausal women. Several epidemiological findings suggest the causative pathophysiological role of ovarian hormone deficiency in the development of cardiovascular disease in women. Observational and randomized studies have suggested that hormone replacement therapy in early postmenopause could be beneficial from a cardiovascular point of view. Conversely, aging, time since menopause and presence of cardiovascular risk factors or cardiovascular disease may decrease its efficacy and increase the risk of cardiovascular events. It is plausible that the unfavorable effects of the estrogen/progestin combination used in the randomized studies are not related to the hormone preparation per se but rather to the use of hormones in the less receptive group of women, older and with cardiovascular risk factors. Clinical judgment, choice of the right dose and estrogen/ progestin combination are of pivotal importance to maximize the beneficial effect of estrogen replacement therapy/hormone replacement therapy, especially if given within a reasonable time after the menopause to the women who need the therapy for the relief of menopausal symptoms

Pyrrolomycins as potential anti-staphylococcal biofilms agents

With the goal of discovering new anti-infective agents active against microbial biofilms, we focused on some natural pyrrolomycins, a family of halogenated pyrrole antibiotics. In this study we investigated the anti-staphylococcal biofilm activity of pyrrolomycins C, D, F1, F2a, F2b, F3 and of the synthesized related compounds I, II, III. The susceptibility of six staphylococcal biofilms was determined by methyltiazotetrazolium (MTT) staining. Most of the compounds were active at concentrations of 1.5 μg/mL with significant inhibition percentages. A few of the compounds were active at the lowest screening concentration of 0.045μg/mL. We also report the population log reduction of activity against the two best biofilm forming S. aureus strains as determined by viable plate counts. In order to adequately assess the utility of these compounds, their toxicity against human cells was evaluated. In conclusion, pyrrolomycins and synthetic derivatives are promising compounds for developing novel effective chemical countermeasures against staphylococcal biofilm

Association between feline immunodeficiency virus and Leishmania infantum infections in cats : a retrospective matched case-control study

Feline leishmaniosis caused by Leishmania infantum is often associated with feline immunodeficiency virus (FIV) infection; however, the role and clinical significance of this coinfection remain unknown. This study aimed to assess whether FIV is associated with L. infantum infection in cats from canine leishmaniosis endemic areas and to report the clinical signs and hematological alterations associated with coinfection. A retrospective matched case-control study (ratio 1:2) was conducted. Data of clinical examination and complete blood count (CBC) were selected from a cohort of 705 cats examined for epidemiological studies on feline leishmaniosis conducted between 2012 and 2019. Ninety-one FIV seropositive cases and 182 FIV seronegative control cats were selected. Matching was done according to age, sex, lifestyle and geographic provenience of case cats. Rapid ELISA devices were mainly used to detect anti-FIV antibodies. Anti- Leishmania IgG antibodies were detected by indirect-immunofluorescence test (IFAT). Leishmania DNA was searched in blood, oral and conjunctival swabs by quantitative real-time PCR. Feline immunodeficiency virus seropositive cats had no hematological abnormalities suggestive of an advanced stage of FIV infection and were statistically more frequently IFAT positive, and their risk of being L. infantum antibody positive was 2.8 greater than in the FIV seronegatives. The association of FIV seropositivity with L. infantum antibody positivity was confirmed in the univariable model of logistic regression. A multivariate model found FIV infection and L. infantum PCR positivity as predictors of a positive L. infantum IFAT result. Male outdoor cats from rural or suburban areas were at risk for FIV and L. infantum antibody positivity. Clinical signs more frequently associated with the coinfection were oral lesions, pale mucous membranes and low body condition score (BCS). This study documents that FIV seropositive cats with no hematological abnormalities suggestive of an advanced stage of FIV infection are more prone to be L. infantum seroreactive by IFAT in endemic areas. Therefore, FIV seropositive cats should be tested for L. infantum antibodies and treated for preventing sand fly bites. Pale mucous membranes, low BCS and oral lesions but no CBC abnormalities were significantly associated with the coinfection. The online version contains supplementary material available at 10.1186/s13071-022-05230-w