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The genome of Helicobacter pylori encodes for carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the ?- and ?-CA classes, which together with urease, have a pivotal role in the acid acclimation of the microorganism within the human stomach. Recently, in the exoproteome of H. pylori, a CA with no indication of the corresponding class was identified. Here, using the protonography and the mass spectrometry, a CA belonging to the ?-class was detected in the outer membrane vesicles (OMVs) generated by planktonic and biofilm phenotypes of four H. pylori strains. The amount of this metalloenzyme was higher in the planktonic OMVs (pOMVs) than in the biofilm OMVs (bOMVs). Furthermore, the content of ?-CA increases over time in the pOMVs. The identification of the ?-CA in pOMVs and bOMVs might shed new light on the role of this enzyme in the colonization, survival, persistence, and pathogenesis of H. pylori.

PubMed: 27100030, Pursuing our recent outcomes regarding the antifungal activity of N-substituted 1,3-thiazolidin-4-ones, we synthesized thirty-six new derivatives introducing aliphatic, cycloaliphatic and heteroaromatic moieties at N1-hydrazine connected with C2 position of the thiazolidinone nucleus and functionalizing the lactam nitrogen with differently substituted (NO2, NH2, Cl and F) benzyl groups. These compounds were tested to evaluate their minimum inhibitory concentration (MIC) against several clinical Candida spp. with respect to topical and systemic reference drugs (clotrimazole, fluconazole, ketoconazole, miconazole, tioconazole, amphotericin B). Moreover, anti-oxidant properties were also evaluated by using different protocols including free radical scavenging (DPPH and ABTS), reducing power (CUPRAC and FRAP), metal chelating and phosphomolybdenum assays. Moreover, for the most active derivatives we assessed the toxicity (CC50) against Hep2 human cells in order to characterize them as multi-target agents for fungal infections. © 2016 Elsevier Masson SAS., This work was supported by local grants from “G. D'Annunzio” University of Chieti to Dr. Simone Carradori (2015).

Accumulating evidence shows a relationship between the human MAO-B (hMAO-B) enzyme and neuropsychiatric/degenerative disorder, personality traits, type II alcoholism, borderline personality disorders, aggressiveness and violence in crime, obsessive-compulsive disorder, depression, suicide, schizophrenia, anorexia nervosa, migraine, dementia, and PD. Thus, MAO-B represents an attractive target for the treatment of a number of human diseases. The discovery, development, and therapeutic use of drugs that inhibit MAO-B are major challenges for future therapy. Various compounds and drugs that selectively target this isoform have been discovered recently. These agents are synthetic compounds or natural products and their analogues, including chalcones, pyrazoles, chromones, coumarins, xanthines, isatin derivatives, thiazolidindiones, (thiazol-2-yl)hydrazones, and analogues of marketed drugs. Despite considerable efforts in understanding the binding interaction with specific substrates or inhibitors, structural information available for the rational design of new hMAO-B inhibitors remains unsatisfactory. Therefore, the quest for novel, potent, and selective hMAO-B inhibitors remains of high interest.

Highly active antiretroviral therapy (HAART) greatly reduces the risk of developing tuberculosis for HIV-infected persons. Nonetheless, HIV-associated tuberculosis continues to occur in countries where HAART is widely used. To identify the characteristics of HIV-infected persons who develop tuberculosis in the context of the availability of HAART, the current authors analysed data taken from 271 patients diagnosed, in Italy, during 1999-2000. These patients represent 0.7% of the 40,413 HIV-infected patients cared for in the clinical units participating in this current study. From the data it was observed that 20 patients (7.4%) had a previous episode of tuberculosis whose treatment was not completed. Eighty-one patients (29.9%) were diagnosed with HIV at tuberculosis diagnosis, 108 (39.8%) were aware of their HIV status but were not on antiretroviral treatment and 82 (30.3%) were on antiretroviral treatment. Patients on antiretroviral treatment were significantly less immunosuppressed than patients with HIV diagnosed concurrently with tuberculosis, or other patients not on antiretrovirals (median CD4 lymphocytes count: 220 cells x mm(-3) versus 100 cells x mm(-3), and 109 cells x mm(-3), respectively). No significant differences in clinical presentation of tuberculosis according to antiretroviral therapy status were recorded. Failure of tuberculosis control interventions (e.g. noncompletion of treatment) and of HIV care (delayed diagnosis of HIV infection and suboptimal uptake of therapy) may contribute to continuing occurrence of HIV-associated tuberculosis in a country where highly active antiretroviral therapy is largely available. However, a significant proportion of cases occur in patients who are on antiretroviral treatment.

HIV-infected patients may undergo renal damage related to the HIV infection itself, to the presence of co-infections, arterial hypertension, diabetes or to the exposure to nephrotoxic drugs. Tenofovir has been associated with the development of acute renal failure with Fanconi syndrome and acute tubular necrosis and, albeit rarely, with chronic liver disease. Patients with low CD4 cell count, low body weight and with concomitant diseases such as arterial hypertension and diabetes or co-infections with HCV, HBV or Treponema pallidum seem at higher risk of tenofovir-related nephrotoxicity. Other risk factors include previous exposure to nephrotoxic drugs and the association of tenofovir with boosted protease inhibitors or with didanosine. However, from the analysis of published papers the incidence of tenofovir-related renal toxicity seems low, as confirmed also by our personal casuistry (SCOLTA Project). Thus, a careful selection of patients including the evaluation of existent renal disease before starting an antiretroviral regimen including tenofovir is necessary to prevent renal damage. Furthermore, frequent monitoring of renal function in patients at higher risk of renal damage is strongly recommended, as well as a tenofovir dose adjustment if an alteration of renal function is detected.

Purpose: To establish the exact cause and effect relationship between protease inhibitors (PIs) and adverse events. Materials and Method: Prospective, cohort, multicenter study on HIV-positive patients who are beginning treatment with a PI. Causal relationships are evaluated using the RUCAM algorithm. Results: Since the beginning of the study 1207 patients have been enrolled. Average time of observation is 10.7 months. To date, 784 adverse events have been observed, distributed as follows: excluded 3.8%, improbable 18.5%, possible 41.3%, probable 30.1%, and highly probable 6.3%. Saquinavir shows a statistically significant difference in the rate of non-correlated events with respect to other groups. Conclusions: Over 20% of adverse events during PI treatment are shown to be non-correlated to these drugs. Saquinavir shows the highest rate of non-correlated events.

Lignins and lignans as natural polyphenols exhibit a rather broad variety of common physico-chemical features that can be of interest with respect to their use in the pharmaceutical sector. While polyphenol types have antioxidant, antiinflammatory, antibacterial and eventually antiviral activities in common, structural features beyond the polyphenol aspect differ enormously: isolated lignins are oligomers and/or polymers of monolignol C9-building blocks, while lignans are based on dimers thereof. The structural differences caused lignin to be exploited in the pharmaceutical sector mainly as material for the generation of matrices and carrier for drug delivery, while lignans are tested for the suitability as APIs. The chapter gives an overview of this situation, including the biological backgrounds of the two interesting natural polyphenols, isolation and methods for their characterisation.

Interfering with tumor metabolism is an emerging strategy for treating cancers that are resistant to standard therapies. Featuring a rapid proliferation rate and exacerbated glycolysis, hepatocellular carcinoma (HCC) creates a highly hypoxic microenvironment with excessive production of lactic and carbonic acids. These metabolic conditions promote disease aggressiveness and cancer-related immunosuppression. The pH regulatory molecules work as a bridge between tumor cells and their surrounding milieu. Herein, we show that the pH regulatory molecules CAIX, CAXII and V-ATPase are overexpressed in the HCC microenvironment and that interfering with their pathways exerts antitumor activity. Importantly, the V-ATPase complex was expressed by M2-like tumor-associated macrophages. Blocking ex vivo V-ATPase activity established a less immune-suppressive tumor microenvironment and reversed the mesenchymal features of HCC. Thus, targeting the unique cross-talk between tumor cells and the tumor microenvironment played by pH regulatory molecules holds promise as a strategy to control HCC progression and to reduce the immunosuppressive pressure mediated by the hypoxic/acidic metabolism, particularly considering the potential combination of this strategy with emerging immune checkpoint-based immunotherapies.

Recently we described some (thiazol-2-yl)hydrazones as antiprotozoal, antifungal and anti-MAO agents as well as Gcn5 HAT inhibitors. Among these last compounds, CPTH2 and CPTH6 showed HAT inhibition in cells and broad anticancer properties. With the aim to identify HAT inhibitors more potent than the two prototypes, we synthesized several new (thiazol-2-yl)hydrazones including some related thiazolidines and pyrimidin-4(3H)-ones, and we tested the whole library existing in our lab against human p300 and PCAF HAT enzymes. Some compounds (1x, 1c', 1d', 1i' and 2m) were more efficient than CPTH2 and CPTH6 in inhibiting the p300 HAT enzyme. When tested in human leukemia U937 and colon carcinoma HCT116 cells (100 mu M, 30 h), 1x, 1i' and 2m gave higher (U937 cells) or similar (HCT116 cells) apoptosis than CPTH6, and were more potent than CPTH6 in inducing cytodifferentiation (U937 cells). (C) 2014 Elsevier Masson SAS. All rights reserved.

Background: It is not known whether antiretroviral therapy (ART) including lopinavir/r has a different effect on the lipid metabolism in HIV patients co-infected with HCV. This study investigated changes in lipid levels, comparing patients with HIV infection alone and those with HCV too, in the lopinavir/r cohort of the SCOLTA project. Methods: We analyzed the data for the lopinavir/r nationwide cohort from 25 Italian infectious disease departments, which comprises 743 HIV-infected patients followed prospectively, comparing subjects with HIV-HCV co-infection and those with single-infection. Results: At enrolment, co-infected patients had significantly lower mean cholesterol than HCV negative cases (162 ± 43 mg/dL vs. 185 ± 52 mg/dL, p = 0.0009). Total and non-HDL cholesterol and triglycerides rose significantly from baseline in HIV single-infection patients, but not in those with co-infection. The patients with dual HIV-HCV infection, treated with an ART regimen including lopinavir/r, have only limited increases in total and non-HDL cholesterol and triglycerides. Conclusions: Changes in serum lipids in co-infected patients differed significantly from those in patients without HCV. It remains to be seen whether this is associated with a lower risk of progression of atherosclerotic disease. © 2007 Elsevier Masson SAS. All rights reserved.

The SCOLTA project (Surveillance Cohort Long-term Toxicity Antiretrovirals) is a system for online surveying of adverse reactions to recently commercialized antiretroviral drugs and a "sentinel" for unexpected and late adverse reactions arising during any antiretroviral treatment (available at: http://www.cisai.info). To date, 25 Italian departments of infectious diseases have participated at the project. The New Drugs Project is a prospective, multicenter, observational pharmacovigilance study involving 1 cohort of patients for each new drug. All patients who were consecutively started on lopinavir (LPV), tenofovir (TDF), peginterferon (IFN), atazanavir (ATZ), enfuvirtide (T-20), and tipranavir (TPV) were enrolled. All grade III or IV adverse events (according to the AIDS Clinical Trials Group definitions) are reported on the web site. The Unexpected Events Project identifies unexpected adverse reactions during treatment and reports them. This paper presents the preliminary findings for the New Drugs Project. Between October 1, 2002, and March 30, 2004, 1184 patients were enrolled. The lopinavir/ritonavir (LPV/r) cohort comprises 703 patients, the TDF cohort 585, IFN 35, ATZ 95, T-20 10, and TPV 8. So far 100 grades III and IV adverse events have been reported, 73 in the LPV/r group. In this cohort the rate of adverse events per 100 person-years was 14.2 on the basis of all patients treated, 9.8 for treatment-naive patients, and 15 for treatment-experienced patients. These findings, though preliminary, show that this data collection method gives timely real-life information from which to assess the impact of short- and long-term toxicity of new antiretroviral drugs. Copyright © 2005 by Lippincott Williams & Wilkins.

Chemical manipulations performed on 2-methyl-3-carbethoxyquinoline (1), a histone acetyltransferase inhibitor previously identified by our research group and active at the sub-millimolar/millimolar level, led to compounds bearing higher alkyl groups at the C2-quinoline or additional side chains at the C6-quinoline positions. Such compounds displayed at least threefold improved inhibitory potency toward p300 protein lysine acetyltransferase activity; some of them decreased histone H3 and H4 acetylation levels in U937 cells and induced high degrees of apoptosis (three compounds >10-fold higher than compound 1) after treatment of U937 cells.

Objective: To evaluate the prevalence and incidence of nephrotoxicity in HIV-infected patients enrolled in the SCOLTA Project tenofovir cohort and to identify possible risk factors. Design: The SCOLTA Project is a prospective, observational, multicenter study involving 25 infectious disease departments in Italy created to assess the incidence of severe adverse events in patients receiving new antiretroviral drugs. Patients: The SCOLTA Project tenofovir cohort includes a total of 754 HIV infected patients. Results: Data including grade II-IV creatinine elevations according to ACTG scale were available in 354 patients, 237 (67%) males with a mean age of 40.1 ± 7.6 years enrolled in the SCOLTA Project tenofovir cohort. During a mean follow up of 19.5 ± 11.5 months creatinine elevations were reported in 9/354 (2.5%) patients, all males. Mean duration of tenofovir therapy at the event was 9.5 ± 5 months. The overall incidence was 1.6 (95% CI 1.5-1.7) per 100 person-years (p-y) and 0.5 (95% CI 0.4-0.6) p-y for grade III. No grade IV creatinine elevations were reported. Patients with nephrotoxicity were older and more frequently male, HCV infected, in CDC stage C and their CD4 cell count was significantly lower than those without nephrotoxicity. No significant difference was found between tenofovir co-administered antiretroviral drugs. Conclusions: Both prevalence and incidence of nephrotoxicity were low in patients receiving tenofovir in a non-selected clinical setting. Renal injury in patients receiving tenofovir seems associated with the presence of co-morbidities and with advanced HIV infection. © 2007 Elsevier Masson SAS. All rights reserved.

Purpose. - This study set out to describe the frequency of lipodystrophy, and identify its risk factors, in HIV-positive patients treated with HAART containing at least one protease inhibitor (PI). We analyzed the data collected in the CISAI study. Method. - The CISAI is a multicenter cohort study that has enrolled 1480 patients. We assessed whether patients had lipodystrophy at a medical visit, with follow-up visits by the same physician at least every 2 months, and also on the basis of patients' own reports. Results. - The lipodystrophy syndrome was detected in about 25% of the patients. Multivariate analysis showed the risk of lipodystrophy was correlated with female sex (RR 1.5; 95% confidence interval, CI, 1.2-2.1), with older age, with homosexuality (RR 1.5; 95% CI 1.0-2.4), with overt disease (RR 1.4; 95% CI 1.1-1.8) and with the duration of treatment before entering this study. The RR for ritonavir was higher than for the other PI (RR 1.4; 95% CI 0.9-1.9). Among patients receiving concomitant antiretroviral therapy the risk of lipodystrophy was greater with stavudine (RR 1.7; 95% CI 1.3-2.3). Conclusions. - The study confirmed the high frequency of the lipodystrophy syndrome among patients treated with PI. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.

The introduction of protease inhibitors has proven a watershed in human immunodeficiency virus infection therapy and has initiated an era of highly active antiretroviral therapy. However, the numerous data on the effectiveness of these therapeutic regimens have been cited with an ever-growing number of communications concerning adverse reactions. In particular, the widescale use of protease inhibitors has underlined a series of events not evidenced in the controlled clinical studies that permitted the registration of these drugs. We are conducting a cohort multicenter study to evaluate the incidence of adverse events during treatment with protease inhibitors. To date, A cases of bilateral osteonecrosis of the femoral head have been reported out of 1073 person-years. While the pathogenesis of this event is unclear, it may be a long-term complication of protease inhibitor treatment.

Objective: To assess the probability that protease inhibitor (PI) therapy might be discontinued because of adverse events (AE) and to evaluate the incidence rate of adverse reactions during PI treatment. Design: A prospective cohort, multicenter study on HIV-positive patients starting treatment with at least one PI. Setting: Ten departments of infectious diseases in Northern Italy. Patients: A total of 1207 patients who started PI therapy in September 1997 and were consecutively observed up to April 1999. Main Outcome Measures: Adverse reactions following initiation of PI therapy, and time to therapy discontinuation due to AE. Results: During the study period, 35.9% patients presented adverse reactions of any grade, whereas 9.7% presented at least one serious AE. After 12 months of treatment, the percentage of patients who had interrupted treatment was 36% of ritonavir-treated patients, 14.2% of those treated with indinavir, 13.6% of ritonavir-saquinavir hard gel capsules (HGC)-treated patients, and 8.5% and 2.1%, respectively, for those treated with nelfinavir and saquinavir HGC. Women and patients with hepatitis experienced a significantly greater number of adverse events compared with other categories. Gastrointestinal events were more frequently observed in patients treated with either ritonavir alone or in combination with saquinavir HGC, as well as in patients receiving nelfinavir, although in this group serious events were rare. Here again, neurologic, metabolic, and hepatic toxicity occurred more frequently in ritonavir and ritonavirsaquinavir HGC treated patients. Allergic reactions were more often observed in patients receiving nelfinavir. Indinavir-treated patients presented the highest incidence of renal toxicity. Conclusion: Ritonavir is the drug associated with the largest number of reactions, which appear during the first few months of treatment. Saquinavir HGC and nelfinavir are the best tolerated drugs in a clinical setting.

The aim of our study is to compare the tolerability of zidovudine/lamivudine/indinavir when used in post-exposure prophylaxis (PEP) subjects and in HIV-infected patients. HIV-negative patients were enrolled as part of the surveillance protocol for professional exposure at the Luigi Sacco Hospital in Milan. HIV-positive patients were selected among all subjects undergoing treatment with zidovudine/lamivudine/indinavir from the CISAI cohort, an Italian cohort for the evaluation of adverse reactions to HAART. In both studies patients were followed prospectively and the severity of the reactions was evaluated using the AIDS Clinical Trial Group adverse experience grading scales. Up to September 1999, 37 HIV-seronegative subjects had undergone treatment with zidovudine/lamivudine/indinavir. From a total of 1207 patients belonging to the CISAI cohort, 199 were identified as being treated with the same regimen. The frequency of adverse events in the PEP subjects was 70.3% compared to 11.1% for HIV-infected patients. In the first group, adverse events caused treatment interruption in 21 subjects (56.7%) versus 14 patients (7%) among the HIV-infected group. Only one case of a severe event (grade 3–4) was observed in the prophylaxis group against 12 in the treatment group. Our study shows that treatment interruption is eight times higher in HIV-negative subjects compared to HIV-seropositive patients, and that the incidence of adverse events is approximately six times higher, though such events, are for the most part, not severe.