Extracellular Vesicles as a Translational Approach for the Treatment of COVID-19 Disease: An Updated Overview.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic in the years 2020-2022. With a high prevalence, an easy route of transmission, and a long incubation time, SARS-CoV-2 spread quickly and affected public health and socioeconomic conditions. Several points need to be elucidated about its mechanisms of infection, in particular, its capability to evade the immune system and escape from neutralizing antibodies. Extracellular vesicles (EVs) are phospholipid bilayer-delimited particles that are involved in cell-to-cell communication; they contain biological information such as miRNAs, proteins, nucleic acids, and viral components. Abundantly released from biological fluids, their dimensions are highly variable, which are used to divide them into exosomes (40 to 150 nm), microvesicles (40 to 10,000 nm), and apoptotic bodies (100-5000 nm). EVs are involved in many physiological and pathological processes. In this article, we report the latest evidence about EVs' roles in viral infections, focusing on the dual role of exosomes in promoting and inhibiting SARS-CoV-2 infection. The involvement of mesenchymal stromal/stem cells (MSCs) and MSC-derived EVs in COVID-19 treatment, such as the use of translational exosomes as a diagnostical/therapeutic approach, is also investigated. These elucidations could be useful to better direct the discovery of future diagnostical tools and new exosome-derived COVID-19 biomarkers, which can help achieve optimal therapeutic interventions and implement future vaccine strategies.

Antimicrobial Resistance in Pseudomonas aeruginosa before and during the COVID-19 Pandemic.

Pseudomonas aeruginosa (PA) is a major Gram-negative opportunistic pathogen causing several serious acute and chronic infections in the nosocomial and community settings. PA eradication has become increasingly difficult due to its remarkable ability to evade antibiotics. Therefore, epidemiological studies are needed to limit the infection and aim for the correct treatment. The present retrospective study focused on PA presence among samples collected at the San Giovanni di Dio and Ruggi D'Aragona University Hospital in Salerno, Italy; its resistance profile and relative variations over the eight years were analyzed. Bacterial identification and antibiotic susceptibility tests were performed by VITEK® 2. In the 2015-2019 and 2020-2022 timeframes, respectively, 1739 and 1307 isolates of PA were obtained from respiratory samples, wound swabs, urine cultures, cultural swabs, blood, liquor, catheter cultures, vaginal swabs, and others. During 2015-2019, PA strains exhibited low resistance against amikacin (17.2%), gentamicin (25.2%), and cefepime (28.3%); moderate resistance against ceftazidime (34.4%), imipenem (34.6%), and piperacillin/tazobactam (37.7%); and high resistance against ciprofloxacin (42.4%) and levofloxacin (50.6%). Conversely, during the 2020-2022 era, PA showed 11.7, 21.1, 26.9, 32.6, 33.1, 38.7, and 39.8% resistance to amikacin, tobramycin, cefepime, imipenem, ceftazidime, ciprofloxacin, and piperacillin/tazobactam, respectively. An overall resistance-decreasing trend was observed for imipenem and gentamicin during 2015-2019. Instead, a significant increase in resistance was recorded for cefepime, ceftazidime, and imipenem in the second set of years investigated. Monitoring sentinel germs represents a key factor in optimizing empirical therapy to minimize the spread of antimicrobial resistance.

Prevalence and Distribution of High- and Low- Risk HPV Genotypes in Women Living in the Metropolitan Area of Naples: A Recent Update.

INTRODUCTION: Human papillomavirus (HPV) can infect both male and female genitals, skin, and mucous membranes, causing benign or malignant lesions. HPV is a common sexually transmitted infection and it is the main cause of cervical cancer. The present retrospective study updated the previously published data on HPV genotypes distribution among women living in Naples. MATERIALS AND METHODS: In this study, 502 cervical scrape specimens were collected from women with abnormal cytological indication and analyzed for HPV DNA identification by Linear Array HPV genotyping test. RESULTS: The HPV infection rate was 24.1%. HPV-16 (14.6%) was the most representative HR-HPV genotypes, followed by HPV-31 (13.8%), -18 (9.2%), and HPV-51 (8.5%). In addition, HPV-42 (16.4%) was the most prevalent genotype among LR-HPV  genotypes (low-risk human papillomavirus). It was also found that women at the age group of 23-29 years (42.5%) were at the highest risk of HPV infection. It was found that the HPV-16 frequency decreased, but HPV-31 and -18 frequency increased a little. The LR HPV-53 frequency decreased, leaving the first place for abundance to the LR HPV-42. HPV-6 frequency did not change. LR HPV -11 was no more present. Merging <23 and 23-29 age classes into one class followed the same result. CONCLUSION: HPV prevalence declined in comparison to the previous data. A frequency variation was recorded for several genotypes in this study.  Data can be useful to implement the preventative strategies and to promote HPV vaccination.

Prevalence and Antibiotic Resistance Profile of Bacterial Pathogens in Aerobic Vaginitis: A Retrospective Study in Italy.

Aerobic vaginitis (AV) is a vaginal infectious condition, characterized by a high inflammatory response and/or signs of epithelial atrophy, a decrease in the amount of Lactobacillus spp. and an increase in enteric origin bacteria. AV, often misdiagnosed, is difficult to treat due to the emerging spread of multi-drug resistant bacterial strains. The present study aimed to define the prevalence of AV, to detect causative bacteria and their antimicrobial resistance pattern. Women 10-95 years old, admitted to San Giovanni di Dio e Ruggi d'Aragona Hospital, Salerno, Italy (in the years 2015-2019) are included in the study. Bacterial identification and antibiotic susceptibility tests were carried out by VITEK® 2. Among 2069 patients, 1176 tested positive for microbial growth. A higher incidence of infection was found in the 55-64 age group. Among the pathogenic strains, 50.4% were Gram-negative, and 49.6% were Gram-positive. Escherichia coli (E. coli) (32.5%) was the most representative strain, followed by Enterococcus faecalis (E. faecalis) (29.4%), Klebsiella pneumoniae (K. pneumoniae) (7.8%) and Enterococcus faecium (E. faecium) (7.7%). E. coli showed high sensitivity to carbapenems and amikacin. K. pneumoniae carbapenems resistance was fluctuating over time. Alarming resistance to vancomycin was not recorded for Enterococci. Both strains were sensitive to teicoplanin, linezolid and tigecycline. Proper diagnosis and an effective therapeutic approach are needed to improve AV management.

Lower Respiratory Tract Pathogens and Their Antimicrobial Susceptibility Pattern: A 5-Year Study.

Lower respiratory tract infections (LRTIs) are the most common infections in humans. It is estimated that 2.74 million deaths worldwide occur each year due to LRTIs. The aim of the study was to determine the frequency and antibiotic susceptibility pattern of microorganisms isolated from respiratory samples of patients with LRTIs. Between January 2015 and December 2019, a total of 7038 sputum and bronchoaspirate samples from suspected LRTI patients were collected. Among them, 2753 samples (39.1%) showed significant microbial growth on culture media. The LRTI rate was higher in patients with male gender (67.1%) and with age between 40-59 years (48.6%). The microorganism identification and antibiotic susceptibility testing were performed with Vitek 2. Out of 4278 isolates species, 3102 (72.5%) were Gram-negative bacteria, 1048 (24.5%) were Gram-positive bacteria, and 128 (3.0%) were Candida spp. Major microorganisms isolated were Acinetobacter baumannii (18.6%), Staphylococcus aureus (15.2%), Pseudomonas aeruginosa (14.2%), and Klebsiella pneumoniae (10.9%). In antimicrobial susceptibility testing, Staphylococcus aureus isolates were mostly resistant to Penicillin G (84.1%) and Oxacillin (48.1%), whereas they demonstrated maximum sensitivity to Tigecycline (100%) and Linezolid (99.5%). Among Gram-negative isolates, Acinetobacter baumannii showed maximum sensitivity to Colistin but was resistant to other antibiotics (95-99%). Klebsiella pneumoniae isolates were mostly resistant to Cefotaxime (72.7%) and sensitive to Gentamicin (54.3%), and Pseudomonas aeruginosa was resistant to Ciprofloxacin (40.3%) and sensitive to Amikacin (85.9%). Gram-negative bacteria represented the species most commonly isolated. A high rate of antimicrobial resistance was observed in this study. In conclusion, the correct identification of causative microorganisms and their susceptibility patterns to antibiotics is crucial for choosing targeted and effective antibiotic therapy in LRTIs, and to prevent the emergence of multidrug-resistant bacteria.

Trend of Bacterial Uropathogens and Their Susceptibility Pattern: Study of Single Academic High-Volume Center in Italy (2015-2019).

Urinary tract infections (UTIs) are a very widespread infection that can occur in disparate age range, in both sexes and in pregnancy/menopause state. Treatment of UTIs is difficult due to the emergence of antibiotic-resistant bacterial strains. The present study shows five years of data collected on patients admitted at the University Hospital "San Giovann di Dio e Ruggi d'Aragona" in Salerno, Italy. The investigation exhibits the incidence of the infection, of the gender, and of the age group affected, identifying the most representative bacteria involved, drawing their profile of antimicrobial resistance. Bacterial identification and antibiotic susceptibility testing were performed using the VITEK 2 system. Among the 46382 studied patients, 9896 (21.34%) and 36486 (78.66%) were positive and negative for microorganism growth, respectively. Of 9896 positive patients, 6158 (62.23%) females and 3738 (37.77%) males were identified. The highest incidence of positive subjects (56.66%) was recorded in the elderly (>61 years). 8431 (85.20%) uropathogens were Gram-negative, 1367 (13.81%) were Gram-positive, and 98 (0.99%) were Candida species (Candida spp.). Escherichia coli (E. coli) and Enterococcus faecalis (E. faecalis) were the most representative Gram-negative and Gram-positive strains, respectively. The Gram-negative bacteria most representative were highly resistant to ampicillin, whereas among the Gram-positive bacteria, E. faecalis was highly resistant to gentamicin and streptomycin high level synergy, and Enterococcus faecium (E. faecium) to ampicillin, ampicillin/sulbactam, and imipenem. This retrospective work investigates the local epidemiological trend in our university hospital in order to induce an increasingly targeted empirical therapeutic approach for the treatment of UTIs.

Sepsis-A Retrospective Cohort Study of Bloodstream Infections.

Bloodstream infections (BSIs) are among the leading causes of morbidity and mortality worldwide, among infectious diseases. Local knowledge of the main bacteria involved in BSIs and their associated antibiotic susceptibility patterns is essential to rationalize the empiric antimicrobial therapy. The aim of this study was to define the incidence of infection and evaluate the antimicrobial resistance profile of the main pathogens involved in BSIs. This study enrolled patients of all ages and both sexes admitted to the University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy between January 2015 to December 2019. Bacterial identification and antibiotic susceptibility testing were performed with Vitek 2. A number of 3.949 positive blood cultures were included out of 24,694 total blood cultures from 2015 to 2019. Coagulase-negative staphylococci (CoNS) were identified as the main bacteria that caused BSI (17.4%), followed by Staphylococcus aureus (12.3%), Escherichia coli (10.9%), and Klebsiella pneumoniae (9.4%). Gram-positive bacteria were highly resistant to Penicillin G and Oxacillin, while Gram-negative strains to Ciprofloxacin, Cefotaxime, Ceftazidime, and Amoxicillin-clavulanate. High susceptibility to Vancomycin, Linezolid, and Daptomycin was observed among Gram-positive strains. Fosfomycin showed the best performance to treatment Gram-negative BSIs. Our study found an increase in resistance to the latest generation of antibiotics over the years. This suggests an urgent need to improve antimicrobial management programs to optimize empirical therapy in BSI.

The emerging tick-borne Crimean-Congo haemorrhagic fever virus: A narrative review.

Crimean-Congo Haemorrhagic Fever (CCHF) is an increasingly relevant viral zoonosis caused by the negative-sense single-stranded (ss) RNA Crimean-Congo Haemorrhagic Fever Orthonairovirus (CCHFV) (Nairoviridae family, Bunyavirales order). The viral genome is divided into three segments (L-M-S) of distinct size and functions. The infection is generally mediated by a tick vector, in particular belonging to the Hyalomma genus, and the transmission follows a tick-vertebrate-tick ecologic cycle, with asymptomatic infected animals functioning as reservoirs and amplifiers for CCHFV. Human hosts could be infected primarily through infected ticks or by contact with infected hosts or their body fluids and tissues, also in a nosocomial way and in occupational contexts. Infected symptomatic patients generally manifest a nonspecific illness, which progresses across four stages, with possibly lethal outcomes. Disease outbreaks show a widespread geographic diffusion and a highly variable mortality rate, dramatically peaking in untreated patients. The lack of an adequate animal model and the elevated virus biological risk (only manageable under biosafety level 4 conditions) represent strongly limiting factors for a better characterization of the disease and for the development of specific therapies and vaccines. The present review discusses updated information on CCHFV-related disease, including details about the virus (taxonomy, structure, life cycle, transmission modalities) and considering CCHF pathogenesis, epidemiology and current strategies (diagnostic, therapeutic and preventive).

Curcumin (Diferulolylmethane) Reduces Transglutaminase 2 Overexpression Induced by Retinoic Acid in Human Nervous Cell Lines.

OBJECTIVES: Curcumin, a naturally occurring compound derived from turmeric (Curcuma longa) has long been suggested to have strong therapeutic or preventive potential against human diseases because of its antioxidative, anticancerous, and anti-inflammatory effects. Curcumin is known to exert anti-inflammatory effects by interrupting NF-κB signaling at multiple levels. Many observations indicate that curcumin shows its valuable potential by inhibiting the activity of I-κB kinase. Transglutaminase 2 (TG2) expression is increased in inflammatory diseases. Data in the literature suggest that this enzyme activates the proinflammatory transcriptional factor NF-κB by inducing the polymerization of its inhibitory subunit I-κBα, which in turn results in the dissociation of NF-κB and its translocation to the nucleus, where it is capable of upregulating host inflammatory genes. Interestingly, NF-κB regulatory response elements are also present in the TG2 promoter, suggesting a possible role for this pathway in the mechanism responsible for chronic inflammation. On the basis of these literature data, our objective was to analyze the effects of curcumin on TG2 expression in human nervous cell lines. METHODS: Human nervous cell lines were treated with curcumin alone or in association with retinoic acid in order to induce TG2 overexpression. TG2 levels were analyzed by Western blot and real-time PCR analyses. RESULTS: Curcumin was able to downregulate the expression of TG2 in human nervous cell lines, which was also the case after treatment with retinoic acid. CONCLUSIONS: These results suggest a possible use of curcumin in reducing TG2 overexpression in human nervous cells.

Sirtuin functions and modulation: from chemistry to the clinic.

Sirtuins are NAD(+)-dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, senescence, proliferation, apoptosis, DNA repair, cell metabolism, and caloric restriction. The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer. Furthermore, recent interest focusing on sirtuin modulators as epigenetic players in the regulation of fundamental biological pathways has prompted increased efforts to discover new small molecules able to modify sirtuin activity. Here, we review the role, mechanism of action, and biological function of the seven sirtuins, as well as their inhibitors and activators.

Possible physiopathological effects of the transglutaminase activity on the molecular mechanisms responsible for human neurodegenerative diseases.

Transglutaminases are a class of ubiquitous enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for both physiological or pathological processes. Recently, transglutaminase activity has been shown to be responsible for a widespread human autoimmune disease, the Celiac Disease. Interestingly, neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, supranuclear palsy, Huntington's disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible molecular mechanisms responsible for such diseases and on the possible therapeutic effects of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity.

Transglutaminase activity as a possible therapeutical target in neurodegenerative diseases.

Transglutaminases are ubiquitous enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for both physiological or pathological processes. For example, neurodegenerative diseases, such as Alzheimer's Disease, Parkinson's Disease, supranuclear palsy, Huntington's Disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible molecular mechanisms responsible for such diseases and on the possible therapeutic effects of selective transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity. The article presents some promising patents on the transglutaminase activity.

Transglutaminase inhibition as a possible therapeutical approach to protect cells from death in neurodegenerative diseases.

Transglutaminases are ubiquitous enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Recently, "tissue" transglutaminase (transglutaminase 2), a member of the transglutaminase family of enzymes, has been shown to be involved in the molecular mechanisms responsible for some human pathologies, including celiac disease, a very widespread human pathology. Transglutaminase activity has also been hypothesized to be involved in the pathogenetic mechanisms responsible for other several human diseases, including neurodegenerative diseases, often associated to celiac disease. Neurodegenerative diseases, such as Alzheimer's Disease, Parkinson's Disease, supranuclear palsy, Huntington's Disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible therapeutic effects of selective transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity and on the strategies to design such transglutaminase inhibitors. In addition, the review also examines available patents that relates to cysteamine and derivatives.

Possible involvement of transglutaminase-catalyzed reactions in the physiopathology of neurodegenerative diseases.

Transglutaminases are ubiquitous enzymes, which catalyze post-translational modifications of proteins. Recently, transglutaminases and tranglutaminase-catalyzed post-translational modification of proteins have been shown to be involved in the molecular mechanisms responsible for several human diseases. Transglutaminase activity has been hypothesized to be involved also in the pathogenetic mechanisms responsible for human neurodegenerative diseases. Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, supranuclear palsy, Huntington's disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. In this review, we focus on the possible molecular mechanisms by which transglutaminase activity could be involved in the pathogenesis of neurodegenerative diseases, and on the possible therapeutic effects of selective transglutaminase inhibitors for the cure of patients with diseases characterized by aberrant transglutaminase activity.

Transglutaminase inhibition: A therapy to protect cells from death in neurodegeneration?

Transglutaminases (TGs; E.C. 2.3.2.13) are ubiquitous enzymes which catalyze post-translational modifications of proteins. TGs and TG-catalyzed post-translational modifications of proteins have been shown to be involved in the molecular mechanisms responsible for several human diseases. In particular, TG activity has been hypothesized to also be involved also in the molecular mechanisms responsible for human neurodegenerative diseases. In support of this hypothesis, Basso et al recently demonstrated that the TG inhibition protects against oxidative stress-induced neuronal death, suggesting that multiple TG isoforms participate in oxidative stress-induced cell death and that nonselective TG isoform inhibitors will be most effective in fighting oxidative death in neurological disorders. In this commentary, we discuss the possible molecular mechanisms by which TG activity could be involved in the pathogenesis of neurological diseases, with particular reference to neurodegenerative diseases, and the possible involvement of multiple TG isoforms expressed simultaneously in the nervous system in these diseases. Moreover, therapeutic strategies based on the use of selective or nonselective TG inhibitors for the amelioration of the symptoms of patients with neurological diseases, characterized by aberrant TG activity, are also discussed.

Pathophysiological roles of transglutaminase - catalyzed reactions in the pathogenesis of human diseases.

Transglutaminases (TGs, E.C. 2.3.2.13) are related and ubiquitous enzymes which catalyze the cross linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate. These enzymes are also capable of catalyzing other reactions which are important for cell life. To date, at least eight different human TGs have been identified. The distribution and the physiological roles of human TGs have been widely studied in numerous cell types and tissues and recently their roles in several diseases have begun to be identified. It has been hypothesized that transglutaminase activity is directly involved in the patho-genetic mechanisms responsible for several human diseases. In particular, TG2, a member of the TG enzyme family, has been shown to be involved in the molecular mechanisms responsible for a very widespread human pathology, Celiac Disease (CD), one of the most common food intolerances described in the western population. The main food agent that provokes the strong and diffuse clinical symptoms has been known for several years to be gliadin, a protein present in a very large number of human foods derived from vegetables. The aim of this review is to summarize the most recent findings concerning the relationships between the biochemical properties of the transglutaminase activity and the basic molecular mechanisms responsible for CD. In addition, we present some clinical associations of CD with other human diseases, with particular reference to neuropsychiatric disorders. Possible molecular links between biochemical activities of transglutaminase enzymes, CD and neuropsychiatric disorders are discussed.