Design, Synthesis and Biological Evaluation of Novel N-Arylpiperazines Containing a 4,5-Dihydrothiazole Ring.

Arylpiperazines represent one of the most important classes of 5-HT1AR ligands and have attracted considerable interests for their versatile properties in chemistry and pharmacology, leading to the research of new derivatives that has been focused on the modification of one or more portions of such pharmacophore. An efficient protocol for the synthesis of novel thiazolinylphenyl-piperazines (2a-c) and the corresponding acetylated derivatives was used (3a-c). The new compounds were tested for their functional activity and affinity at 5-HT1A receptors, showing an interesting affinity profile with a Ki value of 412 nM for compound 2b. The cytotoxic activity of novel thiazolinylphenyl-piperazines (2a-c) and corresponding N-acetyl derivatives (3a-c) against human prostate and breast cancer cell lines (LNCAP, DU-145 and PC-3, MCF-7, SKBR-3 and MDA-MB231) was investigated according to the procedure described in the literature. The reported data showed a cytotoxic effect for 2a-c and 3a-c compounds (IC50 values ranging from 15 µM to 73 µM) on the investigated cancer cell lines, with no effect on noncancer cells. Future studies will be aimed to investigate the mechanism of action and therapeutic prospects of these new scaffolds.

Beneficial Effects of Two Hydrogen Sulfide (H2S)-Releasing Derivatives of Dexamethasone with Antioxidant Activity on Atopic Dermatitis in Mice.

Hydrogen sulfide (H2S) is particularly produced in the skin, where it participates in the regulation of inflammation, pruritus, cytoprotection, scarring, and angiogenesis. In this study, we compared the effects of dexamethasone (Dex) with two H2S-releasing Dex derivatives in a murine model of atopic dermatitis (AD) induced by topical application of 2,4-dinitrochlorobenzene (DNCB). After sensitization with DNCB, the animals were topically treated for five consecutive days with either the H2S-releasing compounds 4-hydroxy-thiobenzamide (TBZ) and 5-(p-hydroxyphenyl)-1,2-dithione-3-thione (ADT-OH), Dex, or the derivatives Dex-TBZ or Dex-ADT. Topical treatment with equimolar doses of either Dex, Dex-TBZ, or Dex-ADT resulted in similar reductions in dermatitis score, scratching behavior, edema, eosinophilia, splenomegaly, and histological changes. In contrast with Dex, the H2S-releasing derivatives prevented IL-4 elevation and oxidative modification of skin proteins. On an equimolar dose basis, Dex-TBZ, but not Dex-ADT, promoted the elevation of endogenous H2S production and GPx activity. Neither Dex-TBZ nor Dex-ADT decreased GR activity or caused hyperglycemia, as observed with Dex treatment. We conclude that the presence of H2S-releasing moieties in the Dex structure does not interfere with the anti-inflammatory effects of this corticosteroid and adds beneficial therapeutical actions to the parent compound.

The Application of Microwaves, Ultrasounds, and Their Combination in the Synthesis of Nitrogen-Containing Bicyclic Heterocycles.

The use of alternative energy sources, such as microwaves (MW) or ultrasounds (US), and their mutual cross-combination have been widely described in the literature in the development of new synthetic methodologies in organic and medicinal chemistry. In this review, our attention is focused on representative examples, reported in the literature in the year range 2013-2023 of selected N-containing bicyclic heterocycles, with the aim to highlight the advantages of microwave- and ultrasound-assisted organic synthesis.

Design, Synthesis and Evaluation of Novel Molecular Hybrids between Antiglaucoma Drugs and H2S Donors.

Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (H2S) is a gaseous neurotransmitter implicated in various pathophysiological processes. It is involved in the pathological mechanism of glaucomatous neuropathy and exerts promising effects in the treatment of this disease. In this work, we designed and synthetized new molecular hybrids between antiglaucoma drugs and H2S donors to combine the pharmacological effect of both moieties, providing a heightened therapy. Brinzolamide, betaxolol and brimonidine were linked to different H2S donors. The H2S-releasing properties of the new compounds were evaluated in a phosphate buffer solution by the amperometric approach, and evaluated in human primary corneal epithelial cells (HCEs) by spectrofluorometric measurements. Experimental data showed that compounds 1c, 1d and 3d were the hybrids with the best properties, characterized by a significant and long-lasting production of the gasotransmitter both in the aqueous solution (in the presence of L-cysteine) and in the intracellular environment. Because, to date, the donation of H2S by antiglaucoma H2S donor hybrids using non-immortalized corneal cells has never been reported, these results pave the way to further investigation of the potential efficacy of the newly synthesized compounds.

Synthesis, Docking Studies and Pharmacological Evaluation of Serotoninergic Ligands Containing a 5-Norbornene-2-Carboxamide Nucleus.

A new series of 5-norbornene-2-carboxamide derivatives was prepared and their affinities to the 5-HT1A, 5-HT2A, and 5-HT2C receptors were evaluated and compared to a previously synthesized series of derivatives characterized by exo-N-hydroxy-5-norbornene-2,3-dicarboximidenucleus, in order to identify selective ligands for the above-mentioned subtype receptors. Arylpiperazines represents one of the most important classes of 5-HT1AR ligands, and recent research concerning new derivatives has been focused on the modification of one or more portions of such pharmacophore. The combination of structural elements (heterocyclic nucleus, propyl chain and 4-substituted piperazine), known to be critical to the affinity to 5-HT1A receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that Norbo-4 and Norbo-18 were the most active and promising derivatives for the serotonin receptor considered in this study.

[Arterial pressure in workers exposed to urban stressors]. / Pressione arteriosa in lavoratori esposti a stressors urbani.

The aim of this study is to evaluate whether occupational exposure to urban stressors could cause alterations of systolic and diastolic blood pressure in "outdoor" workers. The research was conducted on a sample of 101 municipal policemen. The sample was divided in 2 groups according to length of service: group A (length of service between 1 and 15 years) and group B (length of service > 15 years). Group A and Group B were matched for age, overall length of service, cigarette smoking habit and consumption of alcohol and spirits. Group A was then divided into: Al (length of service between 1 and 7 years) and A2 (length of service between 7 and 15 years). The mean values of systolic and diastolic blood pressure at rest showed statistically significant differences with increased values in group B compared to both groups Al (p<0.05) and A2 (p<0.05). The study suggests that occupational exposure to urban stressors affects the blood pressure regulating system enhancing the risk of blood hypertension.

Exposure to formaldehyde in health care: an evaluation of the white blood count differential.

The aim of our study is to estimate if the occupational exposure to formaldehyde can cause alterations of leukocytes plasma values in health care workers employed in a big hospital compared to a control group. We studied employees in operating rooms and laboratories of Pathological Anatomy, Molecular Biology, Molecular Neurobiology, Parasitology and Experimental Oncology (exposed to formaldehyde) and employees of the Department of Internal Medicine (not exposed). The sample studied was composed of 86 workers exposed to formaldehyde and 86 workers not exposed. All subjects underwent a clinical-anamnaestic examination and for all subjects were measured the following values: total white blood cells, lymphocytes, monocytes and granulocytes (eosinophils, basophils, neutrophils). Statistical analysis of data was based on calculation of the mean, standard deviation and the distribution into classes according to the nature of each variable. Differences were considered significant when p was < 0.05. The mean and the distribution of values of the white blood cells, lymphocytes, monocytes and eosinophils were significantly higher in male subjects exposed to formaldehyde compared to not-exposed. Not significant differences were found in female subjects exposed compared to not exposed. The results underline the importance of a careful risk assessment of workers exposed to formaldehyde and the use of appropriate preventive measures. The health care trained and informed about the risks he is exposed to should observe good standards of behavior and, where it is not possible to use alternative materials, the indoor concentrations of formaldehyde should never exceed occupational limit values.

Assessment of liver function in two groups of outdoor workers exposed to arsenic.

PURPOSE: To evaluate whether the exposure to arsenic (As) causes alterations of liver enzymes in two groups of outdoor workers. METHODS: Total urinary As and the levels of AST/GOT, ALT/GPT, and GGT were measured on 80 traffic policemen and 50 police drivers. Personal air samples were obtained for assessing the exposure to As on a subgroup of 20 traffic policemen and 20 police drivers. RESULTS: Mean values of personal exposure to As, urinary As, AST/GOT, and ALT/GPT were significantly higher in traffic policemen than in the police drivers. Multiple linear regression models showed associations between urinary As and airborne As, ALT/GPT and the job variables, and BMI and urinary As. CONCLUSIONS: These findings contribute toward the evaluation of the hepatic effects of exposure to As in the urban workers.

Is urinary 1-hydroxypyrene a valid biomarker for exposure to air pollution in outdoor workers? A meta-analysis.

The aim of this study was to evaluate the usefulness and specificity of urinary 1-hydroxypyrene (1-OHPu) as a biomarker of the exposure from urban pollution to polycyclic aromatic hydrocarbons (PAHs) among outdoor workers in a meta-analysis. Our meta-analysis was performed according to standard methods, and the results show that the concentrations of 1-OHPu tend to be higher in exposed workers than in unexposed workers (if we exclude two highly heterogeneous articles), in exposed non-smokers than in unexposed non-smokers and in exposed than in unexposed workers who were carriers of the CYP1A1 genotype and in those with the glutathione-S-transferase M1 (-)genotype. These genotypes enhance the effect of exposure, particularly in non-smokers. Smoking reduces the differences between exposed and unexposed subjects. In conclusion, our results suggest that the use of the 1-OHPu biomarker appears to be reliable for studying occupational exposure to PAHs from urban pollution, as long as environmental and behavioural factors are considered.

Cadmium and hypertension in exposed workers: A meta-analysis.

OBJECTIVES: In the general population, cadmium seems to be responsible for hypertension, atherosclerosis and an increase in acute coronary events. Therefore, the purpose of this meta-analysis was to analyze controlled studies conducted on cadmium and arterial pressure in occupationally-exposed workers. MATERIALS AND METHODS: After analyzing all the relevant articles found in the literature, 6 publications were selected. RESULTS: A higher prevalence of hypertension and higher values of systolic and diastolic blood pressure were recorded in the exposed subjects. CONCLUSIONS: Cadmium in occupationally-exposed individuals appears to induce an increase in systolic and diastolic blood pressure and an increase in the prevalence of hypertension.

Correlation between total blood lead values and peripheral blood counts in workers occupationally exposed to urban stressors.

The aim of the study was to assess the relationship between occupational exposure to airborne lead (Pb) and alterations in peripheral blood counts in workers of the Municipal Police assigned to different types of outdoor tasks. Then, 337 both male and female subjects were enrolled and divided on the basis of sex, cigarette smoking habit and kind of task. Exposure to airborne Pb, dosage of total blood Pb and peripheral blood count were carried out. A significant positive correlation was detected between the values of total blood Pb and values of plasma reticulocytes (%RET) both in the total sample and for all the classes of the subdivision except for police drivers. Some statistically significant correlations were present but discontinuous for other variables of peripheral blood counts. Results suggest that occupational exposure to low doses of airborne Pb is able to influence lines of the hematopoietic system in exposed workers, with special reference to %RET.

Prevalence of systemic arterial hypertension, electrocardiogram abnormalities, and noise-induced hearing loss in agricultural workers.

ABSTRACT The literature suggests that farmers nowadays are more likely to contract cardiovascular diseases than in the past. This study involved 79 farmers and 64 controls. The workers completed a questionnaire to identify exclusion factors for audiological and cardiovascular risk factors. The participants underwent medical examination, measurement of blood pressure, electrocardiogram, blood tests, audiometry, and measurement of noise exposure. The farmers were found to have a higher prevalence of systolic and diastolic arterial hypertension as well as electrocardiogram (ECG) abnormalities compared with the controls. A significant prevalence of arterial hypertension was detected in the farmers exposed to noise, when compared with those who were not exposed. These results suggest that farmers are at risk of cardiovascular effects and that noise is a cardiovascular risk factor for farmers.

Urban pollution.

Air pollution represents a health risk for people living in urban environment. Urban air consists in a complex mixture of chemicals and carcinogens and its effects on health can be summarized in acute respiratory effects, neoplastic nonneoplastic (e.g. chronic bronchitis) chronic respiratory effects, and effects on other organs and systems. Air pollution may be defined according to origin of the phenomena that determine it: natural causes (natural fumes, decomposition, volcanic ash) or anthropogenic causes which are the result of human activities (industrial and civil emissions). Transport is the sector that more than others contributes to the deterioration of air quality in cities. In this context, in recent years, governments of the territory were asked to advance policies aimed at solving problems related to pollution. In consideration of the many effects on health caused by pollution it becomes necessary to know the risks from exposure to various environmental pollutants and to limit and control their effects. Many are the categories of "outdoor" workers, who daily serve the in urban environment: police, drivers, newsagents, etc.

Assessment of occupational exposure to benzene, toluene and xylenes in urban and rural female workers.

OBJECTIVES: This is the first research study to compare among female, non-smoker workers: (a) the exposure to benzene, toluene and xylenes (BTXs) in urban air during work in the street (traffic policewomen, TP) vs. work in vehicles (police drivers, PD); (b) the exposure to BTXs in urban environments (in street and in car) vs. rural environments (roadwomen, RW); (c) the values of blood benzene, urinary trans, trans muconic acid (t,t-MA) and urinary S-phenylmercapturic acid (S-PMA) in urban areas (in street and in car) vs. rural areas. METHODS: Passive personal samplings and data acquired using fixed monitoring stations located in different areas of the city were used to measure environmental and occupational exposure to BTXs during the work shift in 48 TP, 21 PD and 22 RW. In the same study subjects, blood benzene, t,t-MA and S-PMA were measured at the end of each work shift. RESULTS: Personal exposure of urban workers to benzene seemed to be higher than the exposure measured by the fixed monitoring stations. Personal exposure to benzene and toluene was (a) similar among TP and PD and (b) higher among urban workers compared to rural workers. Personal exposure to xylenes was (a) higher in TP than in PD and (b) higher among urban workers compared to rural workers. Blood benzene, t,t-MA and S-PMA levels were similar among TP and PD, although the blood benzene level was significantly higher in urban workers compared to rural workers. In urban workers, airborne benzene and blood benzene levels were significantly correlated. CONCLUSIONS: Benzene is a human carcinogen, and BTXs are potential reproductive toxins at low dose exposures. Biological and environmental monitoring to assess exposure to BTXs represents a preliminary and necessary tool for the implementation of preventive measures for female subjects working in outdoor environments.

Plasma cortisol concentrations and lifestyle in a population of outdoor workers.

The aim of this study was to assess whether exposure to urban pollution in outdoor workers, may alter plasma cortisol concentrations also in relation to the effect of smoking and drinking habits. The research was carried out on 498 outdoor police workers, divided into three groups; Group A: traffic policemen (TP), Group B: drivers (D), Group C: Other duties (OD). To evaluate separately the effect of using alcohol and smoking, each group was divided into three subgroups: (1) non-smokers and non-drinkers, (2) smokers and non-drinkers, (3) non-smokers and drinkers. Our results show cortisol mean values were significantly higher in the TP group compared to the D and OD groups without significant differences between the last two groups. The results suggest that exposure to pollutants associated with urban psychosocial stress may play a more important role on plasma cortisol levels than smoking and alcohol.

The importance of a taste. A comparative study on wild food plant consumption in twenty-one local communities in Italy.

A comparative food ethnobotanical study was carried out in twenty-one local communities in Italy, fourteen of which were located in Northern Italy, one in Central Italy, one in Sardinia, and four in Southern Italy. 549 informants were asked to name and describe food uses of wild botanicals they currently gather and consume. Data showed that gathering, processing and consuming wild food plants are still important activities in all the selected areas. A few botanicals were quoted and cited in multiple areas, demonstrating that there are ethnobotanical contact points among the various Italian regions (Asparagus acutifolius, Reichardia picroides, Cichorium intybus, Foeniculum vulgare, Sambucus nigra, Silene vulgaris, Taraxacum officinale, Urtica dioica, Sonchus and Valerianella spp.). One taxon (Borago officinalis) in particular was found to be among the most quoted taxa in both the Southern and the Northern Italian sites. However, when we took into account data regarding the fifteen most quoted taxa in each site and compared and statistically analysed these, we observed that there were a few differences in the gathering and consumption of wild food plants between Northern and Southern Italy. In the North, Rosaceae species prevailed, whereas in the South, taxa belonging to the Asteraceae, Brassicaceae, and Liliaceae s.l. families were most frequently cited. We proposed the hypothesis that these differences may be due to the likelihood that in Southern Italy the erosion of TK on wild vegetables is taking place more slowly, and also to the likelihood that Southern Italians' have a higher appreciation of wild vegetables that have a strong and bitter taste. A correspondence analysis confirmed that the differences in the frequencies of quotation of wild plants within the Northern and the Southern Italian sites could be ascribed only partially to ethnic/cultural issues. An additional factor could be recent socio-economic shifts, which may be having a continued effort on people's knowledge of wild food plants and the way they use them. Finally, after having compared the collected data with the most important international and national food ethnobotanical databases that focus on wild edible plants, we pointed out a few uncommon plant food uses (e.g. Celtis aetnensis fruits, Cicerbita alpine shoots, Helichrysum italicum leaves, Lonicera caprifolium fruits, Symphytum officinale leaves), which are new, or have thus far been recorded only rarely.