MitoRes: a resource of nuclear-encoded mitochondrial genes and their products in Metazoa

BACKGROUND: Mitochondria are sub-cellular organelles that have a central role in energy production and in other metabolic pathways of all eukaryotic respiring cells. In the last few years, with more and more genomes being sequenced, a huge amount of data has been generated providing an unprecedented opportunity to use the comparative analysis approach in studies of evolution and functional genomics with the aim of shedding light on molecular mechanisms regulating mitochondrial biogenesis and metabolism. In this context, the problem of the optimal extraction of representative datasets of genomic and proteomic data assumes a crucial importance. Specialised resources for nuclear-encoded mitochondria-related proteins already exist; however, no mitochondrial database is currently available with the same features of MitoRes, which is an update of the MitoNuc database extensively modified in its structure, data sources and graphical interface. It contains data on nuclear-encoded mitochondria-related products for any metazoan species for which this type of data is available and also provides comprehensive sequence datasets (gene, transcript and protein) as well as useful tools for their extraction and export. DESCRIPTION: MitoRes consolidates information from publicly external sources and automatically annotates them into a relational database. Additionally, it also clusters proteins on the basis of their sequence similarity and interconnects them with genomic data. The search engine and sequence management tools allow the query/retrieval of the database content and the extraction and export of sequences (gene, transcript, protein) and related sub-sequences (intron, exon, UTR, CDS, signal peptide and gene flanking regions) ready to be used for in silico analysis. CONCLUSION: The tool we describe here has been developed to support lab scientists and bioinformaticians alike in the characterization of molecular features and evolution of mitochondrial targeting sequences. The way it provides for the retrieval and extraction of sequences allows the user to overcome the obstacles encountered in the integrative use of different bioinformatic resources and the completeness of the sequence collection allows intra- and interspecies comparison at different biological levels (gene, transcript and protein)

Impact of Cytochrome P450 Enzymes on the Phase I Metabolism of Drugs

The cytochrome P450 (CYP) enzyme family is the major enzyme system catalyzing the phase I metabolism of xenobiotics, including pharmaceuticals and toxic compounds in the environment. A major part of the CYP-dependent xenobiotic metabolism is due to polymorphic and inducible enzymes, which may, quantitatively or qualitatively, alter or enhance drug metabolism and toxicity. Drug–drug interactions are major mechanisms caused by the inhibition and/or induction of CYP enzymes. Particularly, CYP monooxygenases catalyze hydroxylation reactions to form hydroxylated metabolites. The secondary metabolites are sometimes as active as the parent compound, or even more active. The aim of this review is to summarize some of the significative examples of common drugs used for the treatment of diverse diseases and underline the activity and/or toxicity of their metabolites

Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies

Multidrug resistance is a leading concern in public health. It describes a complex phenotype whose predominant feature is resistance to a wide range of structurally unrelated cytotoxic compounds, many of which are anticancer agents. Multidrug resistance may be also related to antimicrobial drugs, and is known to be one of the most serious global public health threats of this century. Indeed, this phenomenon has increased both mortality and morbidity as a consequence of treatment failures and its incidence in healthcare costs. The large amounts of antibiotics used in human therapies, as well as for farm animals and even for fishes in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. It is not negligible that the ongoing COVID-19 pandemic may further contribute to antimicrobial resistance. In this paper, multidrug resistance and antimicrobial resistance are underlined, focusing on the therapeutic options to overcome these obstacles in drug treatments. Lastly, some recent studies on nanodrug delivery systems have been reviewed since they may represent a significant approach for overcoming resistance

NHC-Ag(I) and NHC-Au(I) Complexes with N-Boc-Protected α-Amino Acidate Counterions Powerfully Affect the Growth of MDA-MB-231 Cells

N-Heterocyclic carbene (NHC) metal complexes are attracting scientists' interest as an alluring class of metallodrugs. Indeed, the versatile functionalization of NHC ligands makes them optimal scaffolds to be developed in medicinal chemistry. Besides, amino acids are great biological ligands for metals, such as silver and gold, even though their use is still under-investigated. Aiming to shed light on the anticancer properties of this kind of complex, we investigated a series of silver and gold complexes, stabilized by NHC ligands and bearing carboxylate salts of tert-butyloxy-carbonyl (Boc)-N-protected glycine and l-phenyl-alanine as anionic ligands. The most active complexes, AuM1Gly and AuM1Phe, powerfully affect the growth of MDA-MB-231 breast cancer cells, with IC50 values in the low nanomolar range. Further studies demonstrated the blockade of the human topoisomerase I activity and actin polymerization reaction at 0.001 mu M. These unique features make these complexes very interesting and worthy to be used for future in vivo studies

A case of lung injury resembling diffuse pulmonary hemorrhage after the first administration of alemtuzumab in a patient with multiple sclerosis. Role of the HRCT

Diffuse pulmonary hemorrhage (DPH) is an uncommon, acute condition characterized by a variable combination of hemoptysis, dyspnoea, anemia, hypoxernia, and an initial nonspecific imaging features such as diffuse and bilateral ground glass pulmonary opacities that can be induced by different causes. DPH is a rare manifestation of adverse drug reactions. We report here the case of a 25-year-old woman that has been admitted to our pulmonary clinic for the onset of chest pain, cough and haemoptysis, started one week after her first treatment with alemtuzumab for multiple sclerosis. Computed tomography (CT) scan of the chest at the admission showed diffuse and bilateral ground glass pulmonary opacities. Her symptoms resolved completely without any treatment, after the interruption of alemtuzumab, and a CT scan of the chest performed one month later showed total disappearance of the pulmonary opacities

Gene expression signature induced by grape intake in healthy subjects reveals wide-spread beneficial effects on peripheral blood mononuclear cells

Abstract Using a transcriptomic approach, we performed a pilot study in healthy subjects to evaluate the changes in gene expression induced by grape consumption. Blood from twenty subjects was collected at baseline (T0), after 21 days of grape-rich diet (T1) and after one-month washout (T2). Gene expression profiling of peripheral blood mononuclear cells from six subjects identified 930 differentially expressed transcripts. Gene functional analysis revealed changes (at T1 and/or T2) suggestive of antithrombotic and anti-inflammatory effects, confirming and extending previous finding on the same subjects. Moreover, we observed several other favourable changes in the transcription of genes involved in crucial processes such as immune response, DNA and protein repair, autophagy and mitochondrial biogenesis. Finally, we detected significant changes in many long non-coding RNAs genes, whose regulatory functions are being increasingly appreciated. Altogether, our data suggest that a grape diet may exert its beneficial effects by targeting different strategic pathways

Beta-Blocker Use in Older Hospitalized Patients Affected by Heart Failure and Chronic Obstructive Pulmonary Disease: An Italian Survey From the REPOSI Register

Beta (β)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to β2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective β1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge (admission, 36.9% vs. 51.3%; discharge, 38.0% vs. 51.7%). In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD (adj. OR, 95% CI: 0.50, 0.37-0.67), while the diagnosis of COPD was not associated with the choice of selective β1-BB (adj. OR, 95% CI: 1.33, 0.76-2.34). Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a β1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

The “Diabetes Comorbidome”: A Different Way for Health Professionals to Approach the Comorbidity Burden of Diabetes

(1) Background: The disease burden related to diabetes is increasing greatly, particularly in older subjects. A more comprehensive approach towards the assessment and management of diabetes’ comorbidities is necessary. The aim of this study was to implement our previous data identifying and representing the prevalence of the comorbidities, their association with mortality, and the strength of their relationship in hospitalized elderly patients with diabetes, developing, at the same time, a new graphic representation model of the comorbidome called “Diabetes Comorbidome”. (2) Methods: Data were collected from the RePoSi register. Comorbidities, socio-demographic data, severity and comorbidity indexes (Cumulative Illness rating Scale CIRS-SI and CIRS-CI), and functional status (Barthel Index), were recorded. Mortality rates were assessed in hospital and 3 and 12 months after discharge. (3) Results: Of the 4714 hospitalized elderly patients, 1378 had diabetes. The comorbidities distribution showed that arterial hypertension (57.1%), ischemic heart disease (31.4%), chronic renal failure (28.8%), atrial fibrillation (25.6%), and COPD (22.7%), were the more frequent in subjects with diabetes. The graphic comorbidome showed that the strongest predictors of death at in hospital and at the 3-month follow-up were dementia and cancer. At the 1-year follow-up, cancer was the first comorbidity independently associated with mortality. (4) Conclusions: The “Diabetes Comorbidome” represents the perfect instrument for determining the prevalence of comorbidities and the strength of their relationship with risk of death, as well as the need for an effective treatment for improving clinical outcomes

Antidiabetic Drug Prescription Pattern in Hospitalized Older Patients with Diabetes

Objective: To describe the prescription pattern of antidiabetic and cardiovascular drugs in a cohort of hospitalized older patients with diabetes. Methods: Patients with diabetes aged 65 years or older hospitalized in internal medicine and/or geriatric wards throughout Italy and enrolled in the REPOSI (REgistro POliterapuie SIMI—Società Italiana di Medicina Interna) registry from 2010 to 2019 and discharged alive were included. Results: Among 1703 patients with diabetes, 1433 (84.2%) were on treatment with at least one antidiabetic drug at hospital admission, mainly prescribed as monotherapy with insulin (28.3%) or metformin (19.2%). The proportion of treated patients decreased at discharge (N = 1309, 76.9%), with a significant reduction over time. Among those prescribed, the proportion of those with insulin alone increased over time (p = 0.0066), while the proportion of those prescribed sulfonylureas decreased (p < 0.0001). Among patients receiving antidiabetic therapy at discharge, 1063 (81.2%) were also prescribed cardiovascular drugs, mainly with an antihypertensive drug alone or in combination (N = 777, 73.1%). Conclusion: The management of older patients with diabetes in a hospital setting is often sub-optimal, as shown by the increasing trend in insulin at discharge, even if an overall improvement has been highlighted by the prevalent decrease in sulfonylureas prescription