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Silver drugs have played a vital role in human healthcare for the treatment of infections for many centuries. Currently, due to antibiotic resistance, a potential scenario or the application of silver complexes may arise as substitutes for conventional antibiotics. In this perspective, N-heterocyclic carbene (NHC) ligands have been selected as carrier molecules for silver ions. In this study, we selected two mono NHC-silver halide complexes: bromo[1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene]silver(I) (Ag4MC) and chloro[2-pyridin- N-(2-ethylacetylamido)-2-yl-2H-imidazol-2-ylidene]silver(I) (Ag5MC), and two cationic bis NHC silver complexes: bis[1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene]silver(I) (Ag4BC) and bis[2-pyridin-N-(2-ethylacetylamido)-2-yl-2H-imidazol-2-ylidene]silver(I) (Ag5BC). The inhibitory properties of the four complexes were evaluated for their antimicrobial potential against a set of Gram (+) and Gram (−) bacterial strains and the fungus C. albicans. In addition, further investigations were made using fluorescence and scanning electron microscopy (SEM) in order to gain more insights into the mechanism of action. Some preliminary information on the Ag target was obtained by analyzing the cytosol of E. coli treated with Ag5MC by size-exclusion chromatography (SEC) coupled with inductively coupled plasma mass spectrometry (ICP-MS). [ABSTRACT FROM AUTHOR]

The strict connections/interactions between microbial infections and cancer are nowadays widely accepted. Hence, the dual (or multiple) targeting of microbial infections and cancer is an essential issue to be addressed. In this context, metal complexes have gained considerable importance and effectiveness in medicinal chemistry. Particularly, N-heterocyclic carbene (NHC) complexes with transition metals have emerged as very promising compounds. Among the myriad of NHC–metal complexes, those bearing silver will be the subject of this review. Numerous Ag(I)-NHC complexes have revealed high antibacterial and/or anticancer properties, even higher than those of reference drugs. Herein, we summarize the most recent studies while also discussing the proposed mechanism of action and offering an interesting remark about the research in this field. Literature databases (PubMed/MEDLINE, Scopus, and Google Scholar) were used as sources to search the literature, referring to the last five years. [ABSTRACT FROM AUTHOR]

Heteroleptic coumarin-based silver(I) complexes with improved solubility profiles were synthesised using either triphenylphosphine or an N-heterocyclic carbene as adduct ligands, and were fully characterised using IR and NMR spectroscopy, elemental analysis, and, where possible, X-ray crystallography. The triphenylphosphine adducts formed well-resolved structures, where the oxyacetate ligands asymmetrically chelated the silver(I) ion in a bidentate chelating mode, and the silver(I) ion was also bound to two triphenylphosphine ligands. The solubility profile and photostability of the adducts were considerably improved compared to those of previously isolated simple coumarin silver(I) complexes. Analysis of the coumarin N-heterocyclic carbene(NHC) silver(I) adduct indicated that it likely formed as a complex aggregate species with an overall stoichiometry of 1:1:1 coumarin:Ag(I):NHC. The Kirby Bauer assay and broth microdilution assays were used to assess the silver(I) complexes' and adducts' antimicrobial activity against pathogenic strains of Pseudomonas aeruginosa, Escherichia coli, and MRSA. Interestingly, the formation of more soluble complexes did not increase the activity of the silver(I) complexes and, in effect, made them less effective antimicrobial agents, particularly against Escherichia coli and Pseudomonas aeruginosa, although they retained their activity against MRSA. [ABSTRACT FROM AUTHOR]

Herein, we report the structure-based selection via molecular docking of four N-heterocyclic bis-carbene gold(I) complexes, whose potential as ligands for the hTel23 G-quadruplex structure has been investigated using circular dichroism (CD) spectroscopy, CD melting, and polyacrylamide gel electrophoresis (PAGE). The complex containing a bis(1,2,3,4,6,7,8,9-octahydro-11H-11λ3-pyridazino[1,2-a]indazol-11-yl) scaffold induces a transition from the hybrid (3 + 1) topology to a prevalent parallel G-quadruplex conformation, whereas the complex featuring a bis(2-(2-acetamidoethyl)-3λ3-imidazo[1,5-a]pyridin-3(2H)-yl) moiety disrupted the original G-quadruplex structure. These results deserve particular attention in light of the recent findings on the pathological involvements of G-quadruplexes in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Neonatal diabetes mellitus is a rare disorder of glucose metabolism with onset within the first 6 months of life. The initial treatment is based on insulin infusion. The technologies for diabetes treatment can be very helpful, even if guidelines are still lacking. The current study aimed to provide a comprehensive review of the literature about the safety and efficacy of insulin treatment with technology for diabetes to support clinicians in the management of infants with neonatal diabetes mellitus. A total of 22 papers were included, most of them case reports or case series. The first infants with neonatal diabetes mellitus treated with insulin pumps were described nearly two decades ago. Over the years, continuous glucose monitoring systems were added to treat these individuals, allowing for a better customization of insulin administration. Insulin was diluted in some cases to further minimize the doses. Improvement in technology for diabetes prompted clinicians to use new devices and algorithms for insulin delivery in infants with neonatal diabetes as well. These systems are safe and effective, may shorten hospital stay, and help clinicians weaning insulin during the remission phase in the transient forms or switching from insulin to sulfonylurea when suggested by the molecular diagnosis. New technologies for insulin delivery in infants with neonatal diabetes can be used safely and closed-loop algorithms can work properly in these situations, optimizing blood glucose control. [ABSTRACT FROM AUTHOR]

Purpose: Glycated hemoglobin (HbA1c) as a glycemic index may have limited value in pediatric patients with acute leukemia as they often present with anemia and/ or pancytopenia. To address this issue, we evaluated the usefulness of glycated albumin (GA) as a glycemic monitoring index in pediatric patients with acute leukemia. Methods: Medical records of 25 patients with type 2 diabetes mellitus (T2DM), 63 patients with acute leukemia, and 115 healthy children from Seoul St. Mary's Hospital, The Catholic University of Korea, were retrospectively investigated for serum GA, HbA1c, and fasting blood glucose (FBG) levels, along with demographic data. Results: GA, HbA1c, and FBG levels did not differ between the control and acute leukemia groups. In the T2DM group, positive correlations were observed among GA, HbA1c, and FBG (P<0.01). Although GA level was not associated with the HbA1c level in the control group, GA and HbA1c levels showed a positive correlation in the acute leukemia group (P=0.045). Regression analysis revealed GA and HbA1c levels to be positively correlated in the acute leukemia and T2DM groups even after adjusting for age, sex, and body mass index z-score (P=0.007, P<0.01). Conclusion: GA may be a useful complementary parameter to HbA1c for glycemic monitoring in pediatric patients with acute leukemia, similar to its use in patients with T2DM. [ABSTRACT FROM AUTHOR]

Continuous glucose monitoring (CGM) systems, including real-time CGM and intermittently scanned CGM, have revolutionized diabetes management, particularly in children and adolescents with type 1 diabetes (T1D). These systems provide detailed insights into glucose variability and detect asymptomatic and nocturnal hypoglycemia, addressing limitations of traditional self-monitoring blood glucose methods. CGM devices measure interstitial glucose concentrations constantly, enabling proactive therapeutic decisions and optimization of glycemic control through stored data analysis. CGM metrics such as time in range, time below range, and coefficient of variation are crucial for managing T1D, with emerging metrics like time in tight range and glycemia risk index showing potential for enhanced glycemic assessment. Recent advancements suggest the utility of CGM systems in monitoring the early stages of T1D and individuals with obesity complicated by pre-diabetes, highlighting its therapeutic versatility. This review discusses the current CGM systems for T1D during the pediatric age, established and emerging metrics, and future applications, emphasizing the critical role of CGM devices in improving glycemic control and clinical outcomes in children and adolescents with diabetes. [ABSTRACT FROM AUTHOR]

The novel hydrosoluble silver coordination polymer [Ag(NO3)(μ-1κN;2κN′,N″-TPMOH)]n (1) (TPMOH = tris(1H-pyrazol-1-yl)ethanol) was obtained and characterized. While single crystal X-ray diffraction analysis of compound 1 disclosed an infinite 1D helical chain structure in the solid state, NMR analysis in polar solvents confirmed the mononuclear nature of compound 1 in solution. Compound 1 and the analogue [Ag(μ-1κN;2κN′,N″-TPMS)]n (2) (TPMS = tris(1H-pyrazol-1-yl)methane sulfonate) were evaluated with regard to their antimicrobial activities towards the Gram-negative Escherichia coli, Pseudomonas aeruginosa, and Burkholderia contaminans, the Gram-positive Staphylococcus aureus, and the fungal species Candida albicans and Candida glabrata. Compound 1 exhibited minimal inhibitory concentration (MIC) values ranging from 2 to 7.7 µg/mL towards the tested Gram-negative bacteria, 18 µg/mL towards the Gram-positive S. aureus, and 15 and 31 µg/mL towards C. albicans and C. glabrata, respectively. Compound 2 was less effective towards the tested bacteria, with MIC values ranging from 15 to 19.6 µg/mL towards the Gram-negative bacteria and 51 µg/mL towards S. aureus; however, it was more effective against C. albicans and C. glabrata, with MIC values of about 6 µg/mL towards these fungal species. The toxicity of compounds 1 and 2 was assessed by evaluating the survival of the Caenorhabditis elegans model organism to concentrations of up to 100 µg/mL. The value of 50% lethality (LD50) could only be estimated as 73.2 µg/mL for compound 1 at 72 h, otherwise LD50 was >100 µg/mL for both compounds 1 and 2. These results indicate compounds 1 and 2 as novel silver complexes with interesting antimicrobial properties towards bacterial and fungal pathogens. [ABSTRACT FROM AUTHOR]

Purpose: To assess the prevalence of osteosarcopenia (OS) in elderly patients with type 2 diabetes mellitus (T2DM) and explore the related risk factors for developing this condition., Methods: This cross-sectional study enrolled hospitalized T2DM patients aged 60 years and older. Patients underwent assessments of total hip bone mineral density (BMD), grip strength, the Short Physical Performance Battery (SPPB), and body composition. Based on the 2019 Asian Working Group for Sarcopenia (AWGS) criteria, appendicular skeletal muscle mass (ASM), grip strength, and SPPB were measured to diagnose sarcopenia. BMD and T values of the lumbar spine and hip were measured using dual-energy X-ray absorptiometry (DXA). Osteosarcopenia was defined when both sarcopenia and osteoporosis criteria were met. Statistical analysis included binary logistic regression to identify significant risk factors., Results: A total of 254 hospitalized T2DM patients (80 males and 174 females) were included. They were divided into T2DM-OS (n = 58) and T2DM-NOS (n = 196) groups based on the presence of osteosarcopenia. The average ages were 72.724 ± 6.463 and 69.265 ± 6.035 years, respectively. The prevalence of osteosarcopenia in T2DM patients was 22.8%, with 20.7% (12 males) and 79.3% (46 females) in the T2DM-OS group. After adjusting for confounding factors, it was found that male gender (OR: 5.738, 95% CI: 1.602-20.551, P = 0.007), fasting plasma glucose (OR: 0.904, 95% CI: 0.821-0.995, P = 0.038), and ASMI (OR: 0.049, 95% CI: 0.013-0.184, P < 0.001) were major influencing factors for the development of osteosarcopenia in elderly T2DM patients., Conclusions: The prevalence of T2DM-OS is relatively high, with male gender, low fasting plasma glucose, and low ASMI identified as risk factors., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Previous studies have shown that endoplasmic reticulum stress (ERS) -induced apoptosis is involved in the pathogenesis of dilated cardiomyopathy (DCM). However, the molecular mechanism involved has not been fully characterized. Results: In total, eight genes were obtained at the intersection of 1,068 differentially expressed genes (DEGs) from differential expression analysis between DCM and healthy control (HC) samples, 320 module genes from weighted gene co-expression network analysis (WGCNA), and 2,009 endoplasmic reticulum stress (ERGs). These eight genes were found to be associated with immunity and angiogenesis. Four of these genes were related to apoptosis. The upregulation of MX1 may represent an autocompensatory response to DCM caused by a virus that inhibits viral RNA and DNA synthesis, while acting as an autoimmune antigen and inducing apoptosis. The upregulation of TESPA1 would lead to the dysfunction of calcium release from the endoplasmic reticulum. The upregulation of THBS4 would affect macrophage differentiation and apoptosis, consistent with inflammation and fibrosis of cardiomyocytes in DCM. The downregulation of MYH6 would lead to dysfunction of the sarcomere, further explaining cardiac remodeling in DCM. Moreover, the expression of genes affecting the immune micro-environment was significantly altered, including TGF-ß family member. Analysis of the co-expression and competitive endogenous RNA (ceRNA) network identified XIST, which competitively binds seven target microRNAs (miRNAs) and regulates MX1 and THBS4 expression. Finally, bisphenol A and valproic acid were found to target MX1, MYH6, and THBS4. Conclusion: We have identified four ERS-related genes (MX1, MYH6, TESPA1, and THBS4) that are dysregulated in DCM and related to apoptosis. This finding should help deepen understanding of the role of endoplasmic reticulum stress-induced apoptosis in the development of DCM. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) diagnosis and treatment are challenging since symptoms appear late in the disease's progression. Despite clinical risk scores, cardiac event prediction is inadequate, and many at-risk patients are not adequately categorised by conventional risk factors alone. Integrating genomic-based biomarkers (GBBM), specifically those found in plasma and/or serum samples, along with novel non-invasive radiomic-based biomarkers (RBBM) such as plaque area and plaque burden can improve the overall specificity of CVD risk. This review proposes two hypotheses: (i) RBBM and GBBM biomarkers have a strong correlation and can be used to detect the severity of CVD and stroke precisely, and (ii) introduces a proposed artificial intelligence (AI)--based preventive, precision, and personalized (aiP3) CVD/Stroke risk model. The PRISMA search selected 246 studies for the CVD/Stroke risk. It showed that using the RBBM and GBBM biomarkers, deep learning (DL) modelscould be used for CVD/Stroke risk stratification in the aiP3 framework. Furthermore, we present a concise overview of platelet function, complete blood count (CBC), and diagnostic methods. As part of the AI paradigm, we discuss explainability, pruning, bias, and benchmarking against previous studies and their potential impacts. The review proposes the integration of RBBM and GBBM, an innovative solution streamlined in the DL paradigm for predicting CVD/Stroke risk in the aiP3 framework. The combination of RBBM and GBBM introduces a powerful CVD/Stroke risk assessment paradigm. aiP3 model signifies a promising advancement in CVD/Stroke risk assessment. [ABSTRACT FROM AUTHOR]

Blood glucose monitoring constitutes a pivotal element in the clinical management of Type 1 diabetes (T1D), a globally escalating metabolic disorder. Continuous glucose monitoring (CGM) devices have demonstrated efficacy in optimizing glycemic control, mitigating adverse health outcomes, and augmenting the overall quality of life for individuals afflicted with T1D. Recent progress in the field encompasses the refinement of electrochemical sensors, which enhances the effectiveness of blood glucose monitoring. This progress empowers patients to assume greater control over their health, alleviating the burdens associated with their condition, and contributing to the overall alleviation of the healthcare system. The introduction of novel medical devices, whether derived from existing prototypes or originating as innovative creations, necessitates adherence to a rigorous approval process regulated by the Food and Drug Administration (FDA). Diverse device classifications, stratified by their associated risks, dictate distinct approval pathways, each characterized by varying timelines. This review underscores recent advancements in blood glucose monitoring devices primarily based on electrochemical sensors and elucidates their regulatory journey towards FDA approval. The advent of innovative, non-invasive blood glucose monitoring devices holds promise for maintaining stringent glycemic control, thereby preventing T1D-associated comorbidities, and extending the life expectancy of affected individuals. [ABSTRACT FROM AUTHOR]

The primary objectives of the study were (a) to confirm that glucose 6-phosphate dehydrogenase (G6PD) deficiency affects HbA1c values in a sample of children and adolescents with type 1 diabetes (T1D) and (b) to quantify this effect so that a correction can be applied to the HbA1c values found in current clinical practice. The following data were collected: age, sex, G6PD, number of daily capillary blood glucose measurements, 90-day average blood glucose levels prior to the study, HbA1c, and glycated hemoglobin estimated (eA1c) obtained from blood glucose levels. Patients were divided into three groups based on G6PD values: deficient, intermediate, and nondeficient. In each group, a comparison between the average eA1C and HbA1c values was performed. Then, the difference between the eA1c and HbA1c values of each patient and the mean of the differences (MD) of all patients was calculated within the three groups. Finally, a comparison of the MD values between groups was performed. Seventy-four subjects with T1D were studied. Based on the G6PD value, 33 subjects were deficient, 8 were intermediate, and 33 subjects were nondeficient. In deficient patients, the eA1c values were significantly higher than the HbA1c values. In the other two groups, however, there were no differences. The MD values between the three groups were significantly different. In deficient patients, MD values were higher than those in intermediate and in nondeficient patients. No difference was found between intermediate and nondeficient subjects. Our study confirms that G6PD deficiency affects HbA1c values in children and adolescents with T1D, both in deficient subjects and, to a much lesser extent, in intermediate subjects. In deficient subjects, there is an average reduction in HbA1c attributable to enzyme deficiency of 1.3% (14 mmol/mol) and in intermediate subjects of 0.3% (3 mmol/mol). [ABSTRACT FROM AUTHOR]

The main goal of therapeutic management of type 1 Diabetes Mellitus (T1DM) is to maintain optimal glycemic control to prevent acute and long-term diabetes complications and to enable a good quality of life. Postprandial glycemia makes a substantial contribution to overall glycemic control and variability in diabetes and, despite technological advancements in insulin treatments, optimal postprandial glycemia is difficult to achieve. Several factors influence postprandial blood glucose levels in children and adolescents with T1DM, including nutritional habits and adjustment of insulin doses according to meal composition. Additionally, hormone secretion, enteroendocrine axis dysfunction, altered gastrointestinal digestion and absorption, and physical activity play important roles. Meal-time routines, intake of appropriate ratios of macronutrients, and correct adjustment of the insulin dose for the meal composition have positive impacts on postprandial glycemic variability and long-term cardiometabolic health of the individual with T1DM. Further knowledge in the field is necessary for management of all these factors to be part of routine pediatric diabetes education and clinical practice. Thus, the aim of this report is to review the main factors that influence postprandial blood glucose levels and metabolism, focusing on macronutrients and other nutritional and lifestyle factors, to suggest potential targets for improving postprandial glycemia in the management of children and adolescents with T1DM. [ABSTRACT FROM AUTHOR]

The introduction of continuous glucose monitoring (CGM) systems in clinical practice has allowed a more detailed picture of the intra- and interdaily glycemic fluctuations of individuals with type 1 diabetes (T1D). However, CGM-measured glucose control indicators may be occasionally inaccurate. This study aims to assess the discrepancy between the glucose management indicator (GMI) and glycated hemoglobin (HbA1c) (ΔGMI-HbA1c) within a cohort of children and adolescents with T1D, exploring its correlation with other CGM metrics and blood count parameters. In this single-center, cross-sectional study, we gathered demographic and clinical data, including blood count parameters, HbA1c values, and CGM metrics, from 128 pediatric subjects with T1D (43% female; mean age, 13.4 ± 3.6 years). Our findings revealed higher levels of the coefficient of variation (CV) (p < 0.001) and time above range > 250 mg/dL (p = 0.033) among subjects with ΔGMI-HbA1c > 0.3%. No association was observed between blood count parameters and ΔGMI-HbA1c. In conclusion, despite the advancements and the widespread adoption of CGM systems, HbA1c remains an essential parameter for the assessment of glycemic control, especially in individuals with suboptimal metabolic control and extreme glycemic variability. [ABSTRACT FROM AUTHOR]

Background: Glycemic variability (GV) is a novel parameter used in evaluating the quality of diabetes management. Current guidelines recommend the use of GV indexes alongside the traditional parameter to evaluate glycemic control: hemoglobin A1c (HbA1c). This study aims to evaluate the extent to which HbA1c explains the GV phenomena in patients with Type 1 diabetes (T1DM). Methods: In 147 patients with T1DM, associations between HbA1c and several GV indexes were analyzed. Results: Patients with an HbA1c < 7% had a lower median standard deviation of glycemia (60 vs. 48; p < 0.001), a lower coefficient of variation (34.1 vs. 38.0; p < 0.001), and a significantly increased median time in range (78 vs. 58; p < 0.001). HbA1c was positively correlated with the coefficient of variation (r = 0.349; p < 0.001) and the standard deviation (r = 0.656; p < 0.001) but reversely correlated with a lower time in range (r = −0.637; p < 0.001). Conclusions: HbA1c only partially explains the GV phenomena in patients with T1DM. The HbA1c value is associated more strongly with the time in range and standard deviation than with the coefficient of variation. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is well-recognised as a continuum heralded by the development of islet autoantibodies, progression to islet autoimmunity causing beta cell destruction, culminating in insulin deficiency and clinical disease. Abnormalities of glucose homeostasis are known to exist well before the onset of typical symptoms. Laboratory-based tests such as the oral glucose tolerance test (OGTT) and glycated haemoglobin (HbA1c) have been used to stage T1D and assess the risk of progression to clinical T1D. Continuous glucose monitoring (CGM) can detect early glycaemic abnormalities and can therefore be used to monitor for metabolic deterioration in pre-symptomatic, islet autoantibody positive, at-risk individuals. Early identification of these children can not only reduce the risk of presentation with diabetic ketoacidosis (DKA), but also determine eligibility for prevention trials, which aim to prevent or delay progression to clinical T1D. Here, we describe the current state with regard to the use of the OGTT, HbA1c, fructosamine and glycated albumin in pre-symptomatic T1D. Using illustrative cases, we present our clinical experience with the use of CGM, and advocate for an increased role of this diabetes technology, for monitoring metabolic deterioration and disease progression in children with pre-symptomatic T1D. [ABSTRACT FROM AUTHOR]

In this work, the essential oil of the aerial parts of a not previously investigated accession of Prangos trifida (Mill.) Herrnst. & Heyn (Apiaceae), collected in Northern Italy, was analysed by GC/MS. Twenty-five compounds were identified, accounting for 91.30% of the total oil, which is characterised by a high content of monoterpene hydrocarbons (71.26%). The main constituents of the essential oil were cis-β-ocimene (18.12%), α-phellandrene (12.14%), sylvestrene (11.32%), p-mentha-1,3,8-triene (9.56%) and α-pinene (8.85%). The essential oil of P. trifida showed a good antimicrobial activity directed above all against Gram-positive bacteria, and had an interesting antioxidant activity, thus making it an excellent candidate for future cosmetic and pharmaceutical applications. [ABSTRACT FROM AUTHOR]

The genus Thymus L., belonging to the Lamiaceae family, contains about 220 species with a distribution that mainly extends in Europe, northwest Africa, Ethiopia, Asia, and southern Greenland. Due to their excellent biological properties, fresh and/or dried leaves and aerial parts of several Thymus ssp. have been utilized in the traditional medicine of many countries. To evaluate not only the chemical aspects but also the biological properties, the essential oils (EOs), obtained from the pre-flowering and flowering aerial parts of Thymus richardii subsp. nitidus (Guss.) Jalas, endemic to Marettimo Island (Sicily, Italy), were investigated. The chemical composition of the EOs, obtained by classical hydrodistillation and GC-MS and GC-FID analyses, showed the occurrence of similar amounts of monoterpene hydrocarbons, oxygenated monoterpenes, and sesquiterpene hydrocarbons. The main constituents of the pre-flowering oil were β-bisabolene (28.54%), p-cymene (24.45%), and thymol methyl ether (15.90%). The EO obtained from the flowering aerial parts showed as principal metabolites β-bisabolene (17.91%), thymol (16.26%), and limonene (15.59%). The EO of the flowering aerial parts, and its main pure constituents, β-bisabolene, thymol, limonene, p-cymene, and thymol methyl ether were investigated for their antimicrobial activity against oral pathogens and for their antibiofilm and antioxidant properties. [ABSTRACT FROM AUTHOR]

Silver has a long history of antimicrobial activity and received an increasing interest in last decades owing to the rise in antimicrobial resistance. The major drawback is the limited duration of its antimicrobial activity. The broad-spectrum silver containing antimicrobial agents are well represented by N-heterocyclic carbenes (NHCs) silver complexes. Due to their stability, this class of complexes can release the active Ag+ cations in prolonged time. Moreover, the properties of NHC can be tuned introducing alkyl moieties on N-heterocycle to provide a range of versatile structures with different stability and lipophilicity. This review presents designed Ag complexes and their biological activity against Gram-positive, Gram-negative bacteria and fungal strains. In particular, the structure–activity relationships underlining the major requirements to increase the capability to induce microorganism death are highlighted here. Moreover, some examples of encapsulation of silver–NHC complexes in polymer-based supramolecular aggregates are reported. The targeted delivery of silver complexes to the infected sites will be the most promising goal for the future. [ABSTRACT FROM AUTHOR]

Multidrug-resistant bacteria have raised global concern about the inability to fight deadly infectious diseases. Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa are the most common resistant bacteria that are causing hospital infections. The present study was undertaken to investigate the synergistic antibacterial effect of the ethyl acetate fraction of Vernonia amygdalina Delile leaves (EAFVA) with tetracycline against the clinical isolates MRSA and P. aeruginosa. Microdilution was used to establish the minimum inhibitory concentration (MIC). A checkerboard assay was conducted for the interaction effect. Bacteriolysis, staphyloxanthin, and a swarming motility assay were also investigated. EAFVA exhibited antibacterial activity against MRSA and P. aeruginosa with a MIC value of 125 μg/mL. Tetracycline showed antibacterial activity against MRSA and P. aeruginosa with MIC values of 15.62 and 31.25 μg/mL, respectively. The interaction between EAFVA and tetracycline showed a synergistic effect against MRSA and P. aeruginosa with a Fractional Inhibitory Concentration Index (FICI) of 0.375 and 0.31, respectively. The combination of EAFVA and tetracycline induced the alteration of MRSA and P. aeruginosa, leading to cell death. Moreover, EAFVA also inhibited the quorum sensing system in MRSA and P. aeruginosa. The results revealed that EAFVA enhanced the antibacterial activity of tetracycline against MRSA and P. aeruginosa. This extract also regulated the quorum sensing system in the tested bacteria. [ABSTRACT FROM AUTHOR]

Ruthenium N-heterocyclic carbene (NHC) complexes have unique physico-chemical properties as catalysts and a huge potential in medicinal chemistry and pharmacology, exhibiting a variety of notable biological activities. In this review, the most recent studies on ruthenium NHC complexes are summarized, focusing specifically on antimicrobial and antiproliferative activities. Ruthenium NHC complexes are generally active against Gram-positive bacteria, such as Bacillus subtilis, Staphylococcus aureus, Micrococcus luteus, Listeria monocytogenes and are seldom active against Gram-negative bacteria, including Salmonella typhimurium, Pseudomonas aeruginosa and Escherichia coli and fungal strains of Candida albicans. The antiproliferative activity was tested against cancer cell lines of human colon, breast, cervix, epidermis, liver and rat glioblastoma cell lines. Ruthenium NHC complexes generally demonstrated cytotoxicity higher than standard anticancer drugs. Further studies are needed to explore the mechanism of action of these interesting compounds. [ABSTRACT FROM AUTHOR]

The urgent need to combat antibiotic resistance and develop novel antimicrobial therapies has triggered studies on novel metal-based formulations. N-heterocyclic carbene (NHC) complexes coordinate transition metals to generate a broad range of anticancer and/or antimicrobial agents, with ongoing efforts being made to enhance the lipophilicity and drug stability. The lead silver(I) acetate complex, 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*) (SBC3), has previously demonstrated promising growth and biofilm-inhibiting properties. In this work, the responses of two structurally different bacteria to SBC3 using label-free quantitative proteomics were characterised. Multidrug-resistant Pseudomonas aeruginosa (Gram-negative) and Staphylococcus aureus (Gram-positive) are associated with cystic fibrosis lung colonisation and chronic wound infections, respectively. SBC3 increased the abundance of alginate biosynthesis, the secretion system and drug detoxification proteins in P. aeruginosa, whilst a variety of pathways, including anaerobic respiration, twitching motility and ABC transport, were decreased in abundance. This contrasted the affected pathways in S. aureus, where increased DNA replication/repair and cell redox homeostasis and decreased protein synthesis, lipoylation and glucose metabolism were observed. Increased abundance of cell wall/membrane proteins was indicative of the structural damage induced by SBC3 in both bacteria. These findings show the potential broad applications of SBC3 in treating Gram-positive and Gram-negative bacteria. [ABSTRACT FROM AUTHOR]

Foeniculum vulgare (Apiaceae) is an aromatic fennel with important practices in medicinal and traditional fields, used in the treatment of digestive complications, and gastrointestinal and respiratory disorders. Its leaves and stems, tender and fresh, are used in the production of pasta dressing and main courses, while its seeds, with a strong smell of anise, are excellent flavoring for baked goods, meat dishes, fish, and alcoholic beverages. The aim of this work is concerning the extraction of essential oil (EO) from the leaves of F. vulgare subsp. vulgare var. vulgare, investigating antimicrobial, antibiofilm, and antioxidant efficacy. In particular, GC-MS analysis showed how the chemical composition of EO was influenced by the massive presence of monoterpene hydrocarbons (α-pinene 33.75%) and phenylpropanoids (estragole 25.06%). F. vulgare subsp. vulgare var. vulgare EO shows excellent antimicrobial activity against both Gram-positive and Gram-negative strains. This EO can inhibit biofilm formation at very low concentrations and has a good ability to scavenge oxygen radicals in vitro. F. vulgare subsp. vulgare var. vulgare EO also has an increased activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) enzymes and decreased ROS levels in zymosan opsonized PMNs (OZ). [ABSTRACT FROM AUTHOR]

The morbidity of cardiovascular diseases (CVDs) gradually increases worldwide. Long noncoding RNAs (lncRNAs) are a large class of non-(protein)-coding RNAs with lengths beyond 200 nucleotides. Increasing evidence suggests that lncRNA NEAT1 plays important roles in the pathogenesis of CVDs, such as myocardial infarction, heart failure, myocardial ischemia-reperfusion (I/R) injury, atherosclerosis, hypertension, cardiomyopathy, and others. We summarized the current studies of NEAT1 in CVDs, which shed light on the understanding of the molecular mechanisms of CVDs and understanding the therapeutic potential of NEAT1., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Prangos ferulacea (L.) Lindl, which belongs to the Apiaceae family, is a species that mainly grows in the eastern Mediterranean region and in western Asia. It has been largely used in traditional medicine in several countries and it has been shown to possess several interesting biological properties. With the aim to provide new insights into the phytochemistry and pharmacology of this species, the essential oils of flowers and leaves from a local accession that grows in Sicily (Italy) and has not yet been previously studied were investigated. The chemical composition of both oils, obtained by hydrodistillation from the leaves and flowers, was evaluated by GC-MS. This analysis allowed us to identify a new chemotype, characterized by a large amount of (Z)-β-ocimene. Furthermore, these essential oils have been tested for their possible antimicrobial and antioxidant activity. P. ferulacea essential oils exhibit moderate antimicrobial activity; in particular, the flower essential oil is harmful at low and wide spectrum concentrations. They also exhibit good antioxidant activity in vitro and in particular, it has been shown that the essential oils of the flowers and leaves of P. ferulacea caused a decrease in ROS and an increase in the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST) in OZ-stimulated PMNs. Therefore, these essential oils could be considered as promising candidates for pharmaceutical and nutraceutical preparations. [ABSTRACT FROM AUTHOR]

Big Data, and the derived analysis techniques, such as artificial intelligence and machine learning, have been considered a revolution in the modern practice of medicine. Big Data comes from multiple sources, encompassing electronic health records, clinical studies, imaging data, registries, administrative databases, patient-reported outcomes and OMICS profiles. The main objective of such analyses is to unveil hidden associations and patterns. In cardiac surgery, the main targets for the use of Big Data are the construction of predictive models to recognize patterns or associations better representing the individual risk or prognosis compared to classical surgical risk scores. The results of these studies contributed to kindle the interest for personalized medicine and contributed to recognize the limitations of randomized controlled trials in representing the real world. However, the main sources of evidence for guidelines and recommendations remain RCTs and meta-analysis. The extent of the revolution of Big Data and new analytical models in cardiac surgery is yet to be determined. [ABSTRACT FROM AUTHOR]

Human angiogenin (ANG) is a 14-kDa ribonuclease involved in different pathophysiological processes including tumorigenesis, neuroprotection, inflammation, innate immunity, reproduction, the regeneration of damaged tissues and stress cell response, depending on its intracellular localization. Under physiological conditions, ANG moves to the cell nucleus where it enhances rRNA transcription; conversely, recent reports indicate that under stress conditions, ANG accumulates in the cytoplasmic compartment and modulates the production of tiRNAs, a novel class of small RNAs that contribute to the translational inhibition and recruitment of stress granules (SGs). To date, there is still limited and controversial experimental evidence relating to a hypothetical role of ANG in the epidermis, the outermost layer of human skin, which is continually exposed to external stressors. The present study collects compelling evidence that endogenous ANG is able to modify its subcellular localization on HaCaT cells, depending on different cellular stresses. Furthermore, the use of recombinant ANG allowed to determine as this special enzyme is effectively able to counter at various levels the alterations of cellular homeostasis in HaCaT cells, actually opening a new vision on the possible functions that this special enzyme can support also in the stress response of human skin. [ABSTRACT FROM AUTHOR]

In the present study, the chemical compositions of the essential oils from roots, stems, leaves and fruits of Foeniculum vulgare subsp. piperitum collected in Sicily were evaluated by GC and GC-MS. The main components of the roots were terpinolene (33.15%), γ-terpinene (12.18%) and fenchyl acetate (11.23%). Stems and leaves were very rich in α-phellandrene (36.85% and 41.59%, respectively) and β-phellandrene (19.68% and 25.79%, respectively), whereas the main components of fruits were terpinolene (20.10%) and limonene (17.84%) These results were compared with those of the EOs of the same vegetative parts of Foeniculum vulgare subsp. vulgare, collected in the same station and in the same days. The oils of F. vulgare subsp. vulgare showed completely different compositions, with estragole, (E)-anethole and α-pinene as main compounds, clearly indicating the differentiation of the two subspecies. Our results were also compared with those reported in literature for other accessions of Foeniculum vulgare subsp. piperitum [ABSTRACT FROM AUTHOR]

Synthetic chemicals are used to protect crops and agricultural products, thereby producing high yields. However, intensive use of these synthetic chemicals significantly affects the environment and sustainable agriculture production. Moreover, direct or indirect exposure to these synthetic chemicals may cause acute or chronic toxicity in humans and animals. Due to their biodegradability, low toxicity, and being environmentally friendly, secondary metabolites derived from plant sources are being studied as a sustainable approach. Apiaceae family crops are a good source of bioactive phytochemicals. Many studies have found that Apiaceae extracts and essential oils possess various biocidal activities: antibacterial, antifungal, herbicidal, insecticidal or repellent, and larvicidal activities, among others. These various potent bioactivities make the Apiaceae an excellent alternative source for synthetic chemicals. In this context, the present review highlights the biocidal activities of some Apiaceae species and their potential applications in agriculture to protect the plant and agricultural products against pests, weeds, phytopathogens, and foodborne and food spoilage microorganisms. [ABSTRACT FROM AUTHOR]

Drug resistance threatening humans may be linked with antimicrobial and anthelmintic resistance in other species, especially among farm animals and, more in general, in the entire environment. From this perspective, Green Veterinary Pharmacology was proven successful for the control of parasites in small ruminants and for the control of other pests such as varroa in bee farming. As in anthelmintic resistance, antimicrobial resistance (AMR) represents one of the major challenges against the successful treatment of infectious diseases, and antimicrobials use in agriculture contributes to the spread of more AMR bacterial phenotypes, genes, and proteins. With this systematic review, we list Italian plants with documented antimicrobial activity against possible pathogenic microbes. Methods: The literature search included all the manuscripts published since 1990 in PubMed, Web of Science, and Scopus using the keywords (i) "antimicrobial, plants, Italy"; (ii) "antibacterial, plant, Italy"; (iii) "essential oil, antibacterial, Italy"; (iv) "essential oil, antimicrobial, Italy"; (v) "methanol extract, antibacterial, Italy"; (vi) "methanol extract, antimicrobial, Italy". Results: In total, 105 manuscripts that documented the inhibitory effect of plants growing in Italy against bacteria were included. One hundred thirty-five plants were recorded as effective against Gram+ bacteria, and 88 against Gram−. This will provide a ready-to-use comprehensive tool to be further tested against the indicated list of pathogens and will suggest new alternative strategies against bacterial pathogens to be employed in Green Veterinary Pharmacology applications. [ABSTRACT FROM AUTHOR]

In recent decades, insights into metal ion homeostasis have grown exponentially, and a more systemic understanding of metal ion intoxication and homeostasis has been acquired [[2]]. The use of metal complexes for health and healing has been in use for over the last several millennia and perhaps longer. Moreover, in metal medicine, drugs themselves do not contain a metal but act on native biometals or metal-containing biomolecules or influence metal-trafficking pathways in ways that affect cellular processes. [Extracted from the article]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no modifying treatments available. The molecular mechanisms underpinning disease pathogenesis are not fully understood. Recent studies have employed co-expression networks to identify key genes, known as "switch genes", responsible for dramatic transcriptional changes in the blood of ALS patients. In this study, we directly investigate the root cause of ALS by examining the changes in gene expression in motor neurons that degenerate in patients. Co-expression networks identified in ALS patients' spinal cord motor neurons revealed 610 switch genes in seven independent microarrays. Switch genes were enriched in several pathways, including viral carcinogenesis, PI3K-Akt, focal adhesion, proteoglycans in cancer, colorectal cancer, and thyroid hormone signaling. Transcription factors ELK1 and GATA2 were identified as key master regulators of the switch genes. Protein-chemical network analysis identified valproic acid, cyclosporine, estradiol, acetaminophen, quercetin, and carbamazepine as potential therapeutics for ALS. Furthermore, the chemical analysis identified metals and organic compounds including, arsenic, copper, nickel, and benzo(a)pyrene as possible mediators of neurodegeneration. The identification of switch genes provides insights into previously unknown biological pathways associated with ALS. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled trials of time restricted eating (TRE) in adults have demonstrated improvements in glucose variability as captured by continuous glucose monitors (CGM). However, little is known about the feasibility of CGM use in TRE interventions in adolescents, or the expected changes in glycemic profiles in response to changes in meal-timing. As part of a pilot trial of TRE in adolescents with obesity, this study aimed to 1) assess the feasibility of CGM use, 2) describe baseline glycemic profiles in adolescents with obesity, without diabetes, and 3) compare the difference between glycemic profiles in groups practicing TRE versus control. Methods: This study leverages data from a 12-week pilot trial (ClinicalTrials.gov Identifier: NCT03954223) of late TRE in adolescents with obesity compared to a prolonged eating window. Feasibility of CGM use was assessed by monitoring 1) the percent wear time of the CGM and 2) responses to satisfaction questionnaires. A computation of summary measures of all glycemic data prior to randomization was done using EasyGV and R. Repeat measures analysis was conducted to assess the change in glycemic variability over time between groups. Review of CGM tracings during periods of 24-hour dietary recall was utilized to describe glycemic excursions. Results: Fifty participants were enrolled in the study and 43 had CGM and dietary recall data available (16.4 + 1.3 years, 64% female, 64% Hispanic, 74% public insurance). There was high adherence to daily CGM wear (96.4%) without negative impacts on daily functioning. There was no significant change in the glycemic variability as measured by standard deviation, mean amplitude glycemic excursion, and glucose area under the curve over the study period between groups. Conclusions: CGM use appears to be a feasible and acceptable tool to monitor glycemic profiles in adolescents with obesity and may be a helpful strategy to confirm TRE dosage by capturing glycemic excursions compared to self-reported meal timing. There was no effect of TRE on glucose profiles in this study. Further research is needed to investigate how TRE impacts glycemic variability in this age group and to explore if timing of eating window effects these findings. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is well-recognised as a continuum heralded by the development of islet autoantibodies, progression to islet autoimmunity causing beta cell destruction, culminating in insulin deficiency and clinical disease. Abnormalities of glucose homeostasis are known to exist well before the onset of typical symptoms. Laboratory-based tests such as the oral glucose tolerance test (OGTT) and glycated haemoglobin (HbA 1c ) have been used to stage T1D and assess the risk of progression to clinical T1D. Continuous glucose monitoring (CGM) can detect early glycaemic abnormalities and can therefore be used to monitor for metabolic deterioration in pre-symptomatic, islet autoantibody positive, at-risk individuals. Early identification of these children can not only reduce the risk of presentation with diabetic ketoacidosis (DKA), but also determine eligibility for prevention trials, which aim to prevent or delay progression to clinical T1D. Here, we describe the current state with regard to the use of the OGTT, HbA 1c , fructosamine and glycated albumin in pre-symptomatic T1D. Using illustrative cases, we present our clinical experience with the use of CGM, and advocate for an increased role of this diabetes technology, for monitoring metabolic deterioration and disease progression in children with pre-symptomatic T1D., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Anthemis secundiramea is a perennial herb native widespread throughout the Mediterranean basin. The oil obtained from the flowers of this plant has antimicrobial properties against gram-positive and -negative bacteria, and inhibits the biofilm formation. The extract of A. secundiramea also has antioxidant activity—increasing the activity of different enzymes (SOD, CAT, and GPx). Surprisingly, in the oil extracted from the flowers, there is a single molecule, called (+)-(E)-chrysanthenyl acetate: This makes the A. secundiramea flowers extract extremely interesting for future topical, cosmetic, and nutraceutical applications. [ABSTRACT FROM AUTHOR]

There is a growing interest in the pharmaceutical industry to design novel tailored drugs for RNA targeting. The vertebrate-specific RNase A superfamily is nowadays one of the best characterized family of enzymes and comprises proteins involved in host defense with specific cytotoxic and immune-modulatory properties. We observe within the family a structural variability at the substrate-binding site associated to a diversification of biological properties. In this work, we have analyzed the enzyme specificity at the secondary base binding site. Towards this end, we have performed a kinetic characterization of the canonical RNase types together with a molecular dynamic simulation of selected representative family members. The RNases' catalytic activity and binding interactions have been compared using UpA, UpG and UpI dinucleotides. Our results highlight an evolutionary trend from lower to higher order vertebrates towards an enhanced discrimination power of selectivity for adenine respect to guanine at the secondary base binding site (B2). Interestingly, the shift from guanine to adenine preference is achieved in all the studied family members by equivalent residues through distinct interaction modes. We can identify specific polar and charged side chains that selectively interact with donor or acceptor purine groups. Overall, we observe selective bidentate polar and electrostatic interactions: Asn to N1/N6 and N6/N7 adenine groups in mammals versus Glu/Asp and Arg to N1/N2, N1/O6 and O6/N7 guanine groups in non-mammals. In addition, kinetic and molecular dynamics comparative results on UpG versus UpI emphasize the main contribution of Glu/Asp interactions to N1/N2 group for guanine selectivity in lower order vertebrates. A close inspection at the B2 binding pocket also highlights the principal contribution of the protein ß6 and L4 loop regions. Significant differences in the orientation and extension of the L4 loop could explain how the same residues can participate in alternative binding modes. The analysis suggests that within the RNase A superfamily an evolution pressure has taken place at the B2 secondary binding site to provide novel substrate-recognition patterns. We are confident that a better knowledge of the enzymes' nucleotide recognition pattern would contribute to identify their physiological substrate and eventually design applied therapies to modulate their biological functions. [ABSTRACT FROM AUTHOR]

Purpose: To identify the specific diagnostic biomarkers related to pituitary adenomas (PAs), we performed serological antibody profiles for three types of PAs, namely Acromegaly, Cushing's and Nonfunctional Pituitary Adenomas (NFPAs), using the human proteome (HuProt) microarray. This is the first study describing the serum autoantibody profile of PAs., Experimental Design: We performed serological autoantibody profiling of four healthy controls, four Acromegaly, three Cushing's and three NFPAs patient samples to obtain their autoantibody profiles, which were used for studying expression, interaction and altered biological pathways. Further, significant autoantibodies of PAs were compared with data available for glioma, meningioma and AAgAtlas for their specificity., Results: Autoantibody profile of PAs led to the identification of differentially expressed significant proteins such as AKNAD1 (AT-Hook Transcription Factor [AKNA] Domain Containing 1), NINJ1 (Nerve injury-induced protein 1), L3HYPDH (Trans-3-hydroxy-L-proline dehydratase), RHOG (Rho-related GTP-binding protein) and PTP4A1 (Protein Tyrosine Phosphatase Type IVA 1) in Acromegaly. Protein ABR (Active breakpoint cluster region-related protein), ST6GALNAC6 (ST6 N-acetylgalactosaminide alpha-2, 6-sialyltransferase 6), NOL3 (Nucleolar protein 3), ANXA8 (Annexin A8) and POLR2H (RNA polymerase II, I and III subunit H) showed an antigenic response in Cushing's patient's serum samples. Protein dipeptidyl peptidase 3 (DPP3) and reticulon-4 (RTN4) exhibited a very high antigenic response in NFPA patients. These proteins hold promise as potential autoantibody biomarkers in PAs., (© 2022 Wiley-VCH GmbH.)

The ribonuclease A superfamily is a vertebrate-specific family of proteins that encompasses eight functional members in humans. The proteins are secreted by diverse innate immune cells, from blood cells to epithelial cells and their levels in our body fluids correlate with infection and inflammation processes. Recent studies ascribe a prominent role to secretory RNases in the extracellular space. Extracellular RNases endowed with immuno-modulatory and antimicrobial properties can participate in a wide variety of host defense tasks, from performing cellular housekeeping to maintaining body fluid sterility. Their expression and secretion are induced in response to a variety of injury stimuli. The secreted proteins can target damaged cells and facilitate their removal from the focus of infection or inflammation. Following tissue damage, RNases can participate in clearing RNA from cellular debris or work as signaling molecules to regulate the host response and contribute to tissue remodeling and repair. We provide here an overall perspective on the current knowledge of human RNases' biological properties and their role in health and disease. The review also includes a brief description of other vertebrate family members and unrelated extracellular RNases that share common mechanisms of action. A better knowledge of RNase mechanism of actions and an understanding of their physiological roles should facilitate the development of novel therapeutics. [ABSTRACT FROM AUTHOR]

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Ribonucleases (Rnases)2 and Rnase3 belong to the ribonuclease A (RnaseA) superfamily. Apart from their role in molecular evolutionary and functional biological studies, these genes have also been studied in the context of defense against pathogen infection in mammals. However, expression patterns, structures and response to bacterial infection of the two genes in blunt snout bream (Megalobrama amblycephala) remain unknown. In this study, we identified multiple copies of Rnase2 (six) and Rnase3 (three) in the M. amblycephala genome. The nine genes all possess characteristics typical of the RnaseA superfamily. No expression was detected in the early developmental stages, while a weak expression was observed at 120 and 140 h post-fertilization (hpf) for Rnase2b, Rnase2c, Rnase2e and Rnase3a, suggesting that only three copies of Rnase2 and one of Rnase3 are expressed. Interestingly, only Rnase2e was up-regulated in the kidney of M. amblycephala after Aeromonas hydrophila infection, while Rnase3a was significantly up-regulated in liver, gut and blood after the infection. We conclude that the paralogs of Rnase3 are more susceptible to A. hydrophila infection than Rnase2. These results indicate that different Rnase2 and Rnase3 paralogs suggest a role in the innate immune response of M. amblycephala to bacterial infection. [ABSTRACT FROM AUTHOR]

Pancreatic-type ribonucleases (ptRNases) comprise a class of highly conserved secretory endoribonucleases in vertebrates. The prototype of this enzyme family is ribonuclease 1 (RNase 1). Understanding the physiological roles of RNase 1 is becoming increasingly important, as engineered forms of the enzyme progress through clinical trials as chemotherapeutic agents for cancer. Here, we present an in-depth biochemical characterization of RNase 1 homologs from a broad range of mammals (human, bat, squirrel, horse, cat, mouse, and cow) and nonmammalian species (chicken, lizard, and frog). We discover that the human homolog of RNase 1 has a pH optimum for catalysis, ability to degrade double-stranded RNA, and affinity for cell-surface glycans that are distinctly higher than those of its homologs. These attributes have relevance for human health. Moreover, the functional diversification of the 10 RNase 1 homologs illuminates the regulation of extracellular RNA and other aspects of vertebrate evolution. [ABSTRACT FROM AUTHOR]

Cationic antimicrobial peptides ( AMPs) possess fast and broad-spectrum activity against both Gram-negative and Gram-positive bacteria, as well as fungi. It has become increasingly evident that many AMPs, including those that derive from fragments of host proteins, are multifunctional and able to mediate various immunomodulatory functions and angiogenesis. Among these, synthetic apolipoprotein-derived peptides are safe and well tolerated in humans and have emerged as promising candidates in the treatment of various inflammatory conditions. Here, we report the characterization of a new AMP corresponding to residues 133-150 of human apolipoprotein E. Our results show that this peptide, produced either by chemical synthesis or by recombinant techniques in Escherichia coli, possesses a broad-spectrum antibacterial activity. As shown for several other AMPs, ApoE (133-150) is structured in the presence of TFE and of membrane-mimicking agents, like SDS, or bacterial surface lipopolysaccharide ( LPS), and an anionic polysaccharide, alginate, which mimics anionic capsular exo-polysaccharides of several pathogenic microorganisms. Noteworthy, ApoE (133-150) is not toxic toward several human cell lines and triggers a significant innate immune response, assessed either as decreased expression levels of proinflammatory cytokines in differentiated THP-1 monocytic cells or by the induction of chemokines released from PBMCs. This novel bioactive AMP also showed a significant anti-inflammatory effect on human keratinocytes, suggesting its potential use as a model for designing new immunomodulatory therapeutics. [ABSTRACT FROM AUTHOR]

Human Ribonuclease 6 is a secreted protein belonging to the ribonuclease A (RNaseA) superfamily, a vertebrate specific family suggested to arise with an ancestral host defense role. Tissue distribution analysis revealed its expression in innate cell types, showing abundance in monocytes and neutrophils. Recent evidence of induction of the protein expression by bacterial infection suggested an antipathogen function in vivo. In our laboratory, the antimicrobial properties of the protein have been evaluated against Gram-negative and Gram-positive species and its mechanism of action was characterized using a membrane model. Interestingly, our results indicate that RNase6, as previously reported for RNase3, is able to specifically agglutinate Gram-negative bacteria as a main trait of its antimicrobial activity. Moreover, a side by side comparative analysis with the RN6(1-45) derived peptide highlights that the antimicrobial activity is mostly retained at the protein N-terminus. Further work by site directed mutagenesis and structural analysis has identified two residues involved in the protein antimicrobial action (Trp1 and Ile13) that are essential for the cell agglutination properties. This is the first structure-functional characterization of RNase6 antimicrobial properties, supporting its contribution to the infection focus clearance. [ABSTRACT FROM AUTHOR]

Comparative studies on homologous proteins can provide knowledge on how limited changes in the primary structure find their expression in large effects on catalytic activity, stability or the folding behavior. For more than half a century, members of the ribonuclease A superfamily have been the subject of a myriad of studies on protein folding and stability. Both the unfolding and refolding kinetics as well as the structure of several folding intermediates of ribonuclease A have been characterized in detail. Moreover, the RNA-degrading activity of these enzymes provides a basis for their cytotoxicity, which renders them potential tumor therapeutics. Because amphibian ribonuclease A homologues evade the human ribonuclease inhibitor, they emerged as particularly promising candidates. Interestingly, the amphibian ribonuclease A homologues investigated to date are more stable than the mammalian homologues. Nevertheless, despite the generation of numerous genetically engineered variants, knowledge of the folding of amphibian ribonuclease A homologues remains rather limited. An exception is onconase, a ribonuclease A homologue from Rana pipiens, which has been characterized in detail. This review summarizes the data on the unfolding and refolding kinetics and pathways, as well on the stability of amphibian ribonuclease A homologues compared with those of ribonuclease A, the best known member of this superfamily. [ABSTRACT FROM AUTHOR]

Background: Chondroitin sulphate is a complex polysaccharide having important structural and protective functions in animal tissues. Extracted from animals, this compound is used as a human anti-inflammatory drug. Among bacteria, Escherichia coli K4 produces a capsule containing a non-sulphate chondroitin and its development may provide an efficient and cheap fermentative production of the polysaccharide. Results: A random N-methyl-N'-nitro-N-nitrosoguanidine mutagenesis was performed on E. coli K4 to isolate mutants showing an increased production of chondroitin. Several mutants were isolated, one of which, here named VZ15, produced about 80% more chondroitin than the wild type E. coli. We found that the mutant has a missense mutation in the codon 313 of kfoC, the gene encoding chondroitin polymerase (K4CP), with a change from arginine to glutamine. A docking analysis to explain the increased productivity of the K4CP enzyme is presented. Conclusion: The enhanced chondroitin production by the E. coli K4 mutant reported here shows the validity of the strain improvement strategy for more cost-friendly fermentative processes in the production of this pharmaceutically important but so-far expensive polysaccharide. [ABSTRACT FROM AUTHOR]