Search Results (3,467)

Sulfonylureas (SUs) are a class of antidiabetic drugs widely used in the management of diabetes mellitus type 2. They promote insulin secretion by inhibiting the ATP-sensitive potassium channel in pancreatic β-cells. Recently, the exchange protein directly activated by cAMP (Epac) was identified as a new class of target proteins of SUs that might contribute to their antidiabetic effect, through the activation of the Ras-like guanosine triphosphatase Rap1, which has been controversially discussed. We used human embryonic kidney (HEK) 293 cells expressing genetic constructs of various Förster resonance energy transfer (FRET)-based biosensors containing different versions of Epac1 and Epac2 isoforms, alone or fused to different phosphodiesterases (PDEs), to monitor SU-induced conformational changes in Epac or direct PDE inhibition in real time. We show that SUs can both induce conformational changes in the Epac2 protein but not in Epac1, and directly inhibit the PDE3 and PDE4 families, thereby increasing cAMP levels in the direct vicinity of these PDEs. Furthermore, we demonstrate that the binding site of SUs in Epac2 is distinct from that of cAMP and is located between the amino acids E443 and E460. Using biochemical assays, we could also show that tolbutamide can inhibit PDE activity through an allosteric mechanism. Therefore, the cAMP-elevating capacity due to allosteric PDE inhibition in addition to direct Epac activation may contribute to the therapeutic effects of SU drugs. Full article

Knowledge of epidemiology is essential for guiding correct antibiotic prescription, reducing bacteremia-associated mortality, and implementing targeted infection control programs. However, only a few studies have reported on the epidemiology of bloodstream infections (BSIs) in pediatrics. We performed a retrospective analysis of all BSIs (excluding those caused by common skin contaminants) diagnosed from 2006 to 2022 in patients younger than 18 years who were treated at an Italian pediatric tertiary care hospital. Overall, 2395 BSIs were recorded, including 2207 (92.15%) due to bacteria and 188 (7.85%) due to fungi. The incidence rate (BSIs/10,000 hospital discharges, IR) of bacterial BSIs significantly increased during the study period. In particular, BSIs caused by S. aureus (including MRSA), Enterobacterales (including ESBL and AmpC producers), Enterococcus spp., and P. aeruginosa became more common. The frequency of carbapenem-resistant strains was <1% and stable over time. Conversely, there was a significant reduction in the incidence of BSIs due to S. pneumoniae. The BSIs were stratified by patient age, and S. aureus was the most frequent cause of BSIs in all age groups, while E. coli was the most frequent in the Enterobacterales family. S. agalactiae was the third most frequent cause of neonatal early-onset BSIs. The prevalence of Enterococcus spp. increased in the subgroups from 8 days to 5 years of age, while P. aeruginosa became more prevalent in children over 5 years of age. S. aureus was also the most frequent isolate in both community- and hospital-onset BSIs, followed by E. coli. The prevalence of multidrug-resistant (MDR) pathogens was very low. It was <5% for both Gram-positive (i.e., MRSA and VRE) and Gram-negative (ESBL, AmpC, and carbapenem-resistant) pathogens, and MDR pathogens were almost exclusively detected in hospital-onset BSIs. Fungi accounted for just under 8% of BSIs. C. albicans was the most frequently isolated strain, followed by C. parapsilosis. Notably, the IR of fungemia did not change significantly during the study period, in spite of an increase in the absolute number of events. The continuous monitoring of local epidemiology is essential to identify changes in the IRs of pathogens and antibiotic susceptibility and to guide antibiotic treatments, especially in the phase when antibiograms are not yet available. Full article

It is commonly accepted that dietary nucleotides should be considered as essential nutrients originating mainly but not exclusively from meat and fish dishes. Most research in food science related to nutrition nucleotides is focused on raw products, while the effects of thermal processing of ready-to-eat food on nucleotide content are largely overlooked by the scientific community. The aim of this study is to investigate the impact of thermal processing and cold storage on the content of dietary nucleotides in freshly prepared and canned ready-to-eat meat and fish food. The concentrations of ATP, ADP, AMP, IMP, Ino, and Hx were determined using NMR, HPLC, FPMLC, and ATP bioluminescence analytical techniques; freshness indices K and K₁ and adenylate energy charge (AEC) values were estimated to assess the freshness status and confirm a newly unveiled phenomenon of the reappearance of adenylate nucleotides. It was found that in freshly prepared at 65 °C ≤ T ≤ +100 °C and canned food, the concentration of free nucleotides was in the range of 0.001–0.01 µmol/mL and remained unchanged for a long time during cold storage; the correct distribution of mole fractions of adenylates corresponding to 0 < AEC < 0.5 was observed compared to 0.2 < AEC < 1.0 in the original raw samples, with either a high or low content of residual adenylates. It could be assumed that heating at nonenzymatic temperatures T > 65 °C can rupture cell membranes and release residual intracell nucleotides in quite a meaningful concentration. These findings may lead to a conceptual change in the views on food preparation processes, taking into account the phenomenon of the free adenylates renaissance and AEC bioenergetics. Full article

Antibiotic-resistant microorganisms have become a serious threat to public health, resulting in hospital infections, the majority of which are caused by commonly used urinary tract catheters. Strategies for preventing bacterial adhesion to the catheters’ surfaces have been potentially shown as effective methods, such as coating thesurface with antimicrobial biomolecules. Here, novel antimicrobial peptides (AMPs) were designed as potential biomolecules to prevent antibiotic-resistant bacteria from binding to catheter surfaces. Thiolated AMPs were synthesized using solid-phase peptide synthesis (SPPS), and prep-HPLC was used to obtain AMPs with purity greater than 90%. On the other side, the silicone catheter surface was activated by UV/ozone treatment, followed by functionalization with allyl moieties for conjugation to the free thiol group of cystein in AMPs using thiol-ene click chemistry. Peptide-immobilized surfaces were found to become more resistant to bacterial adhesion while remaining biocompatible with mammalian cells. The presence and site of conjugation of peptide molecules were investigated by immobilizing them to catheter surfaces from both ends (C-Pep and Pep-C). It was clearly demonstrated that AMPs conjugated to the surface via theirN terminus have a higher antimicrobial activity. This strategy stands out for its effective conjugation of AMPs to silicone-based implant surfaces for the elimination of bacterial infections. Full article

This study investigated the effects of Lycium chinense Mill (LCM) extract on obesity and diabetes, using both in vitro and high-fat diet (HFD)-induced obesity mouse models. We found that LCM notably enhanced glucagon-like peptide-1 (GLP-1) secretion in NCI-h716 cells from 411.4 ± 10.75 pg/mL to 411.4 ± 10.75 pg/mL compared to NT (78.0 ± 0.67 pg/mL) without causing cytotoxicity, implying the involvement of Protein Kinase A C (PKA C) and AMP-activated protein kinase (AMPK) in its action mechanism. LCM also decreased lipid droplets and lowered the expression of adipogenic and lipogenic indicators, such as Fatty Acid Synthase (FAS), Fatty Acid-Binding Protein 4 (FABP4), and Sterol Regulatory Element-Binding Protein 1c (SREBP1c), indicating the suppression of adipocyte differentiation and lipid accumulation. LCM administration to HFD mice resulted in significant weight loss (41.5 ± 3.3 g) compared to the HFD group (45.1 ± 1.8 g). In addition, improved glucose tolerance and serum lipid profiles demonstrated the ability to counteract obesity-related metabolic issues. Additionally, LCM exhibited hepatoprotective properties by reducing hepatic lipid accumulation and diminishing white adipose tissue mass and adipocyte size, thereby demonstrating its effectiveness against hepatic steatosis and adipocyte hypertrophy. These findings show that LCM can be efficiently used as a natural material to treat obesity and diabetes, providing a new approach for remedial and therapeutic purposes. Full article

Hepatocellular carcinoma (HCC) is an aggressive form of liver cancer that arises in a background of chronic hepatic injury. Metabolic syndrome-associated fatty liver disease (MAFLD) and its severe form, nonalcoholic steatohepatitis (NASH), are increasingly common mechanisms for new HCC cases. NASH-HCC patients are frequently obese and medically complex, posing challenges for clinical management. In this review, we discuss NASH-specific challenges and the associated implications, including benefits of minimally invasive operative approaches in obese patients; the value of y90 as a locoregional therapy; and the roles of weight loss and immunotherapy in disease management. The relevant literature was identified through queries of PubMed, Google Scholar, and clinicaltrials.gov. Provider understanding of clinical nuances specific to NASH-HCC can improve treatment strategy and patient outcomes. Full article

Chronic and continuous alcohol consumption increases the risk of cognitive decline and may lead to alcohol-related dementia. We investigated the potential of Heracleum moellendorffii Hance root extract (HME) for treating alcohol-related cognitive impairment. Behavioral tests evaluated the effects of HME on cognitive function and depression. Changes in hippocampus and liver tissues were evaluated by Western blotting and H&E staining. The group treated with HME 200 mg/kg showed a significant increase in spontaneous alternation in Y-maze and a decrease in immobility in a forced swimming test (FST) compared to the vehicle-treated group. These results suggest that HME can restore memory deficits and reverse depressive symptoms caused by chronic alcohol consumption. The HME-treated group also upregulated brain-derived neurotrophic factor (BDNF), phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated cAMP response element-binding protein (CREB) in the hippocampus. Additionally, it reduced lipid vacuolation in the liver and increased the expression of aldehyde dehydrogenase 1 (ADH1). The administration of HME improves cognitive impairment and reverses depressive symptoms due to alcohol consumption, restoring neural plasticity in the hippocampus and alcohol metabolism in the liver. These findings suggest that HME is a promising treatment for alcohol-related brain disorders. Molecular mechanisms underlying the therapeutic effects of HME and its active ingredients should be investigated further. Full article

Cyclic nucleotide phosphodiesterases (PDEs) consist of a family of enzymes expressed in several types of cells, including inflammatory cells, that play a pivotal role in inflammation. Several studies have demonstrated that the inhibition of PDE4 results in a reduced inflammatory response via PKA and CREB signaling. Hence, PDE4 suppression improves the inflammatory feedback typical of several diseases, such as inflammatory bowel disease (IBD). In our previous studies, we have demonstrated that miR-369-3p regulates inflammatory responses, modulating different aspects of the inflammatory process. The aim of this study was to demonstrate an additional anti-inflammatory effect of miR-369-3p targeting PDE4B, one of the widely expressed isoforms in immune cells. We found that miR-369-3p was able to reduce the expression of PDE4B, elevating the intracellular levels of cAMP. This accumulation increased the expression of PKA and pCREB, mitigating the release of pro-inflammatory cytokines and promoting the release of anti-inflammatory cytokines. To prove that PDE4B is a good therapeutic target in IBD, we also demonstrate that the expression of PDE4B was increased in UC patients compared to healthy controls, affecting the immune infiltrate. PDE4B is considered an important player in inflammatory progression; hence, our results show the ability of miR-369-3p to ameliorate inflammation by targeting PDE4B, supporting its future application as a new therapeutic approach in IBD. Full article

This study evaluates the R3THA™ assessment protocol (R3THA-AP™), a technology-supported testing module for personalized rehabilitation in children with cerebral palsy (CP). It focuses on the reliability and validity of the R3THA-AP in assessing hand and arm function, by comparing kinematic assessments with standard clinical assessments. Conducted during a 4-week summer camp, the study assessed the functional and impairment levels of children with CP aged 3–18. The findings suggest that R3THA is more reliable for children aged 8 and older, indicating that age significantly influences the protocol’s effectiveness. The results also showed that the R3THA-AP’s kinematic measurements of hand and wrist movements are positively correlated with the Box and Blocks Test Index (BBTI), reflecting hand function and dexterity. Additionally, the R3THA-AP’s accuracy metrics for hand and wrist activities align with the Melbourne Assessment 2’s Range of Motion (MA2-ROM) scores, suggesting a meaningful relationship between R3THA-AP data and clinical assessments of motor skills. However, no significant correlations were observed between the R3THA-AP and MA2’s accuracy and dexterity measurements, indicating areas for further research. These findings validate the R3THA-AP’s utility in assessing motor abilities in CP patients, supporting its integration into clinical practice. Full article

Cyclic-nucleotide phosphodiesterases (PDEs) represent a superfamily of enzymes playing a pivotal role in cell signaling by controlling cAMP and cGMP levels in response to receptor activation. PDE activity and expression are linked to many diseases including inflammatory diseases. In light of their specific biochemical properties, PDE inhibition has attracted the interest of several researrs In this context, PDE4 inhibition induces anti-inflammatory effects. Piclamilast and rolipram, well-known PDE4 inhibitors, are endowed with common side effects. The selective phosphodiesterase 4B (PDE4B) inhibitors could be a promising approach to overcome these side effects. In the present study, six potential PDE4B inhibitors have been investigated. Through this study, we identified three PDE4B inhibitors in human macrophages activated by lipopolysaccharide. Interestingly, two of them reduced reactive oxygen species production in pro-inflammatory macrophages. Full article

The innate immune system is the body’s natural defense system, which recognizes a wide range of microbial molecules (such as bacterial DNA and RNA) and abnormal molecules within cells (such as misplaced DNA, self-antigens) to play its role. DNA released into the cytoplasm activates the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway to initiate an immune response. Ischemia–reperfusion injury (IRI) after acute myocardial infarction refers to the phenomenon where myocardial tissue suffers further damage upon the restoration of blood flow. This issue is a significant clinical problem in the treatment of myocardial infarction, as it can diminish the effectiveness of reperfusion therapy and lead to further deterioration of cardiac function. Studies have found that the cGAS-STING signaling pathway is closely related to this phenomenon. Therefore, this review aims to describe the role of the cGAS-STING signaling pathway in ischemia–reperfusion injury after myocardial infarction and summarize the current development status of cGAS-STING pathway inhibitors and the application of nanomaterials to further elucidate the potential of this pathway as a therapeutic target. Full article

We have previously demonstrated that the vasopressin type 2 receptor (AVPR2) antagonist tolvaptan reduces cell proliferation and invasion and triggers apoptosis in different human cancer cell lines. To study this effect in vivo, a xenograft model of small cell lung cancer was developed in Fox1^nu/nu nude mice through the subcutaneous inoculation of H69 cells, which express AVPR2. One group of mice (n = 5) was treated with tolvaptan for 60 days, whereas one group (n = 5) served as the control. A reduced growth was observed in the tolvaptan group in which the mean tumor volume was significantly smaller on day 60 compared to the control group. In the latter group, a significantly lower survival was observed. The analysis of excised tumors revealed that tolvaptan effectively inhibited the cAMP/PKA and PI3K/AKT signaling pathways. The expression of the proliferative marker proliferating cell nuclear antigen (PCNA) was significantly lower in tumors excised from tolvaptan-treated mice, whereas the expression levels of the apoptotic marker caspase-3 were higher than those in control animals. Furthermore, tumor vascularization was significantly lower in the tolvaptan group. Overall, these findings suggest that tolvaptan counteracts tumor progression in vivo and, if confirmed, might indicate a possible role of this molecule as an adjuvant in anticancer strategies. Full article

The morphology, internal architecture, and emplacement mechanisms of the Central Atlantic Magmatic Province (CAMP) lava flows of the Hartford and Deerfield basins (USA) are presented. The Talcott, Holyoke, and Hampden formations within the Hartford basin constitute distinct basaltic units, each exhibiting chemical, mineralogical, and structural differences corresponding to flow fields. Each flow field was the result of several sustained eruptions that produced both inflated pahoehoe flows and subaquatic extrusions: 1–5 eruptions in the Talcott formation and 1–2 in Holyoke and Hampden basalts, where simple flows are dominant. The Deerfield basin displays the Deerfield basalt unit, characterized by pillow lavas and sheet lobes, aligning chemically and mineralogically with the Holyoke basalt unit. Overall, the studied flow fields are composed of thick, simple pahoehoe flows that display the entire range of pahoehoe morphology, including inflated lobes. The three-partite structure of sheet lobes, vertical distribution of vesicles, and segregation structures are typical. The characteristics of the volcanic pile suggest slow emplacement during sustained eruptive episodes and are compatible with a continental basaltic succession facies model. The studied CAMP basalts of the eastern United States are correlated with the well-exposed examples on both sides of the Atlantic Ocean (Canada, Portugal, and Morocco). Full article

Violent social and political conflicts have caused several challenges to internally displaced persons (IDPs), especially girls and young women, among which is sexual violence (SV). Despite extensive records on SV in humanitarian contexts, studies to assess the level, examine the disclosure pattern (DP) and evaluate the availability of abortion care in these settings have received inadequate attention. This scoping review sought to synthesise the current African-based research on SV, DP, and abortion and post-abortion care (APAC) in humanitarian contexts. We conducted a systematic search of five databases: MEDLINE, PubMed, Scopus, Embase and Google Scholar, where the articles retrieved met the criteria for inclusion. The review adhered to PRISMA guidelines and the Critical Appraisal Skills Programme (CASP), containing ten questions to help confirm the validity of the research design and the originality of the results in comparison with similar studies. A series of inclusion and exclusion criteria were applied after the search, and 35 eligible articles from ten African countries with evidence of sexual violence, disclosure patterns, and APAC in camp settings were included in the study. Results described situations of SV in humanitarian settings in Africa as “terrible”, “bad”, “an epidemic”, and “severe” as girls were used as sex objects, for profile enhancement and as a weapon of war. We also found that the illegality of APAC in Africa is causing a high occurrence of clandestine abortions in conflict contexts. Disclosing SV among IDPs in Africa did not follow a clear-cut pattern but was generally determined by socio-demographic characteristics. Sexual health is a fundamental right of all, as enshrined in SDG 3, which makes this topic a major public health issue. We therefore conclude that although disclosure may aggravate stigmatisation in some instances due to adverse reactions, it is still crucial to the healing processes. Full article

The melanocortin 4 receptor (MC4R) gene plays a central role in regulating energy homeostasis and food intake in livestock, thereby affecting their economic worth and growth. In a previous study, the p.T117M mutation in the sheep MC4R gene, which leads to the transition of threonine to methionine, was found to affect the body weight at six months and the average daily gain in Hu sheep. However, there are still limited studies on the frequency of the sheep p.T117M missense mutation globally, and the underlying cellular mechanism remains elusive. Therefore, this study first used WGS to investigate the distribution of the MC4R gene p.T117M mutation in 652 individuals across 22 breeds worldwide. The results showed that the mutation frequency was higher in European breeds compared with Chinese sheep breeds, particularly in Poll Dorset sheep (mutation frequency > 0.5). The p.T117M mutation occurs in the first extracellular loop of MC4R. Mechanistically, the basal activity of the mutated receptor is significantly increased. Specifically, upon treatment with α-MSH and ACTH ligands, the cAMP and MAPK/ERK signaling activation of M117 MC4R is enhanced. These results indicate that the T117M mutation may change the function of the gene by increasing the constitutive activity and signaling activation of cAMP and MAPK/ERK, and, thus, may regulate the growth traits of sheep. In conclusion, this study delved into the global distribution and underlying cellular mechanisms of the T117M mutation of the MC4R gene, establishing a scientific foundation for breeding sheep with superior growth, thereby contributing to the advancement of the sheep industry. Full article