Search Results (33)

COVID-19 remains a global health challenge, with severe cases often leading to complications and fatalities. The objective of this study was to assess supervised machine learning algorithms for predicting severe COVID-19 based on demographic, clinical, biochemical, and genetic variables, with the aim of identifying the most informative prognostic markers. For Machine Learning (ML) analysis, we utilized a dataset comprising 226 observations with 68 clinical, biochemical, and genetic features collected from 226 patients with confirmed COVID-19 (54—moderate, 142—severe and 30 with mild disease). The target variable was disease severity (mild, moderate, severe). The feature set included demographic variables (age, sex), genetic markers (single-nucleotide polymorphisms (SNPs) in FGB (rs1800790), NOS3 (rs2070744), and TMPRSS2 (rs12329760)), biochemical indicators (IL-6, endothelin-1, D-dimer, fibrinogen, among others), and clinical parameters (blood pressure, body mass index, comorbidities). The target variable was disease severity. To identify the most effective predictive models for COVID-19 severity, we systematically evaluated multiple supervised learning algorithms, including logistic regression, k-nearest neighbors, decision trees, random forest, gradient boosting, bagging, naïve Bayes, and support vector machines. Model performance was assessed using accuracy and the area under the receiver operating characteristic curve (AUC-ROC). Among the predictors, IL-6, presence of depression/pneumonia, LDL cholesterol, AST, platelet count, lymphocyte count, and ALT showed the strongest correlations with severity. The highest predictive accuracy, with negligible error rates, was achieved by ensemble-based models such as ExtraTreesClassifier, HistGradientBoostingClassifier, BaggingClassifier, and GradientBoostingClassifier. Notably, decision tree models demonstrated high classification precision at terminal nodes, many of which yielded a 100% probability for a specific severity class. Full article

Introduction: Antimicrobial resistance has become a global concern, and few new antimicrobials are currently being developed. Fluopsin C has proven broad-spectrum activity, being a promising candidate for new antimicrobial development. To optimize antimicrobial activity, this research aimed at fluopsin C (Flp) encapsulation in liposomes to achieve controlled release and reduce cytotoxicity. Methods: Liposomal formulations were prepared by extruding formulations based on soy phosphatidylcholine (SPC) or poly (ethylene glycol)-distearoylphosphatidylethanolamine (DSPE-PEG) plus cholesterol, and were characterized by their size, polydispersity index, zeta potential, encapsulation efficiency, shelf-life stability, in vitro release profile, cytotoxicity, and antimicrobial activity against Klebsiella pneumoniae in vitro and in vivo. Results: The results indicated that the DSPE-PEG DMSO+Flp formulation presented superior physicochemical stability and unaltered antimicrobial activity. In vitro, CC₅₀ decreased by 54%. No lethal dose was obtained in mice within the concentration range tested. The most effective doses in vivo were 2 × 2 mg/kg for free fluopsin C and 1 × 2 mg/kg for DSPE-PEG DMSO+Flp, resulting in a 40% reduction in mortality from bacteremia. Only discrete inflammatory infiltration was detected in the liver, while kidney necrosis ranged from discrete to moderate. Encapsulation of fluopsin C in liposomes showed promising features supporting to use against infections by MDR K. pneumoniae. Full article

Background/Objectives: Refractory community-acquired pneumonia (r-CAP) has become a thorny issue in clinical practice, especially after the COVID-19 pandemic, even in immunocompetent patients, as conventionally defined. In this study, we aimed to identify the risk factors for immunocompetent patients with r-CAP. Methods: This was a single-center retrospective study. In total, we collected clinical data from 82 patients with r-CAP in whom the first-line antibiotic therapy failed and 82 patients with general CAP (g-CAP) who recovered with first-line antibiotics, matched at a ratio of 1:1, admitted to Beijing Shijitan Hospital, Capital Medical University, from 1 January 2022, to 31 December 2023. The differences between the two groups (clinical characteristics, peripheral blood cell count, lymphocyte subsets, and regular laboratory indicators) were analyzed using paired t, paired Wilcoxon, Chi-square, or Fisher’s exact tests, and univariate and multivariate logistics regression analyses were conducted to identify the independent risk factors. A model for predicting indicators with statistical significance was established and proved with the receiver operating characteristic (ROC) curve. Results: Warm season, a history of chronic obstructive pulmonary disease, longer time from onset to admission (T_O-A), higher percentages of CD4⁺ T, CD8⁺ T, and double-negative T (DNT) lymphocytes, as well as higher levels of C-reactive protein (CRP), low-density lipoprotein cholesterin (LDL-C), serum sodium ion (Na⁺), and free-calcium ion (FCa²⁺) were regarded as independent risk factors, while T lymphocyte percentage (T%) and total cholesterol (TC) were identified as protective factors. The combined multivariate model using all the above factors proved to be sensitive and specific (AUC = 0.8711, p < 0.0001, R² = 0.4235), and thus better than the respective univariate models. Conclusions: Increased CD4⁺ T%Lym, CD8⁺ T%Lym, and DNT%Lym, warm season, a history of COPD, longer T_O-A, and increased levers of CRP, LDL-C, Na⁺, and FCa²⁺ potentially cause CAP to be refractory, while the T lymphocyte count, namely, the overall cellular immunity, was impaired in r-CAP patients, and increased TC levels could be beneficial to pneumonia recovery. Full article

Background: Acute lung injury (ALI) is a major cause of death in patients with various viral pneumonias. Our team previously identified four volatile compounds from aromatic Chinese medicines. Based on molecular compatibility theory, we defined their combination as aromatic molecular compatibility (AC), though its therapeutic effects and underlying mechanisms remain unclear. Methods: This study used influenza A virus (IAV) A/PR/8/34 to construct cell and mouse models of ALI to explore AC’s protective effects against viral infection. The therapeutic effect of AC was verified by evaluating the antiviral efficacy in the mouse models, including improvements in their lung and colon inflammation, oxidative stress, and the suppression of the NLRP3 inflammasome. In addition, 16S rDNA and lipid metabolomics were used to analyze the potential therapeutic mechanisms of AC. Results: Our in vitro and in vivo studies demonstrated that AC increased the survival of the IAV-infected cells and mice, inhibited influenza virus replication and the expression of proinflammatory factors in the lung tissues, and ameliorated barrier damage in the colonic tissues. In addition, AC inhibited the expression of ROS and the NLRP3 inflammasome and improved the inflammatory cell infiltration into the lung tissues. Finally, AC effectively regulated intestinal flora disorders and lipid metabolism in the model mice, significantly reduced cholesterol and triglyceride expression, and thus reduced the abnormal accumulation of lipid droplets (LDs) after IAV infection. Conclusions: In this study, we demonstrated that AC could treat IAV-induced ALIs through multiple pathways, including antiviral and anti-inflammatory pathways and modulation of the intestinal flora and the accumulation of LDs. Full article

Background: Colistin, a lipopeptide antibiotic usually used as a last resort against multidrug-resistant bacterial strains, has also begun to address the challenge of antimicrobial resistance. Objective: this study evaluates whether hybrid nanoparticles (HNPs) composed of Phospholipon^® 90G, cholesterol, and colistin can enhance its effectiveness against resistant clinical isolates of Klebsiella pneumoniae, a clinically significant Gram-negative bacterium. Methods: HNPs were developed using the ethanol injection method and coated with chitosan through a layer-by-layer technique. HNP characterization included measurements of particle size, polydispersity index (PDI), and zeta potential, along with thermal (DSC) and spectrophotometric (FT-IR) analyses. Ultrafiltration and ATR-FTIR were employed to assess colistin’s association and release efficiencies. The biological evaluation followed CLSI guidelines. Results: uncoated hybrid nanoparticles (U-HNP) and chitosan-coated hybrid nanoparticles (Ch-HNP) described monodisperse populations, with respective PDI values of ~0.124 and ~0.150, Z-averages of ~249 nm and ~250 nm, and zeta potential values of +17 mV and +20 mV. Colistin’s association and release efficiencies were approximately 79% and 10%, respectively. Regarding antimicrobial activity, results showed that colistin as part of HNPs is poorly effective against this microorganism. However, in the most resistant strain, colistin activity increased slightly when the HNP was coated with chitosan. Conclusions: HNPs described high stability against disaggregation, limiting the colistin release and, therefore, affecting antimicrobial performance. Full article

Background and Purpose: Nutritional status can influence the outcomes and mortality of various diseases. The association between initial nutritional status and ischemic stroke outcomes, however, remains poorly understood. This study investigated whether the Controlling Nutritional Status (CONUT) score at admission could predict functional recovery, complications, and survival following an ischemic stroke. Methods: We enrolled a total of 938 patients experiencing their first acute ischemic stroke and categorized them into three groups based on their CONUT score at admission: CONUT 0–1, CONUT 2–4, and CONUT 5–12. The CONUT score was assessed using the serum albumin, total cholesterol, and lymphocyte count. We evaluated the incidence of complications during their hospital stay. Outcomes, including the Modified Rankin Scale (mRS), Functional Independence Measurement (FIM), Functional Ambulatory Classification (FAC), and mortality, were assessed at baseline, as well as at three and six months post-stroke. Results: CONUT scores were significantly associated with functional outcomes (mRS, FIM, and FAC) and mortality during the six-month follow-up period post-stroke (all p < 0.05). The CONUT 5–12 group exhibited significantly poorer improvements in mRS, FIM, and FAC scores (all p < 0.05) and a lower survival rate (p < 0.01) during the six-month follow-up compared to the CONUT 0–1 and CONUT 2–4 groups. Additionally, the incidence of pneumonia, urinary tract infections, pressure sores, falling injuries, and fractures was significantly higher in the CONUT 5–12 group than in the other groups (all p < 0.01). Conclusions: CONUT scores at admission are associated with functional recovery, mortality, and the incidence of complications following a first-ever ischemic stroke. Consequently, the early identification of patients at risk of malnutrition via CONUT scores can be crucial in enhancing patient assessment after an acute stroke. Full article

Pediococcus pentosaceus, which often occurs in fermented foods, is characterized by numerous positive effects on the human health, such as the presence of possible probiotic abilities, the reduction of cholesterol levels, satisfactory antimicrobial activity, and certain therapeutic functions. This study was conducted with the goal of describing the genomic content of Pediococcus pentosaceus ENM104, a strain known for its inhibitory effects against pathogenic bacteria and its remarkable probiotic potential, including the induction of significant reductions in cholesterol levels and the production of γ-aminobutyric acid (GABA). The P. pentosaceus ENM104 chromosome is circular. The chromosome is 1,734,928 bp with a GC content of 37.2%. P. pentosaceus also harbors a circular plasmid, pENM104, that is 71,811 bp with a GC content of 38.1%. Functional annotations identified numerous genes associated with probiotic traits, including those involved in stress adaptation (e.g., heat stress: htpX, dnaK, and dnaJ), bile tolerance (e.g., ppaC), vitamin biosynthesis (e.g., ribU, ribZ, ribF, and btuD), immunomodulation (e.g., dltA, dltC, and dltD), and bacteriocin production (e.g., pedA). Notably, genes responsible for lowering cholesterol levels (bile salt hydrolase, bsh) and GABA synthesis (glutamate/GABA antiporter, gadC) were also identified. The in vitro assay results using cell-free supernatants of P. pentosaceus ENM104 revealed antibacterial activity against carbapenem-resistant bacteria, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii, and the inhibition zone diameter increased progressively over time. This comprehensive study provides valuable insights into the molecular characteristics of P. pentosaceus ENM104, emphasizing its potential as a probiotic. Its notable cholesterol-lowering, GABA-producing, and antimicrobial capabilities suggest promising applications in the pharmaceutical and food industries. Future research should focus on further exploring these functional properties and assessing the strain’s efficacy in clinical settings. Full article

A major Streptococcus pneumoniae pathogenic factor is the cholesterol-dependent cytolysin pneumolysin, binding membrane cholesterol and producing permanent lytic or transient pores. During brain infections, vascular damage with variable ischemia occurs. The role of ischemia on pneumolysin’s pore-forming capacity remains unknown. In acute brain slice cultures and primary cultured glia, we studied acute toxin lysis (via propidium iodide staining and LDH release) and transient pore formation (by analyzing increases in the intracellular calcium). We analyzed normal peripheral tissue glucose conditions (80 mg%), normal brain glucose levels (20 mg%), and brain hypoglycemic conditions (3 mg%), in combinations either with normoxia (8% oxygen) or hypoxia (2% oxygen). At 80 mg% glucose, hypoxia enhanced cytolysis via pneumolysin. At 20 mg% glucose, hypoxia did not affect cell lysis, but impaired calcium restoration after non-lytic pore formation. Only at 3 mg% glucose, during normoxia, did pneumolysin produce stronger lysis. In hypoglycemic (3 mg% glucose) conditions, pneumolysin caused a milder calcium increase, but restoration was missing. Microglia bound more pneumolysin than astrocytes and demonstrated generally stronger calcium elevation. Thus, our work demonstrated that the toxin pore-forming capacity in cells continuously diminishes when oxygen is reduced, overlapping with a continuously reduced ability of cells to maintain homeostasis of the calcium influx once oxygen and glucose are reduced. Full article

COVID-19, caused by the SARS-CoV-2 coronavirus, emerged as a global pandemic in late 2019, resulting in significant global public health challenges. The emerging evidence suggests that diminished high-density lipoprotein (HDL) cholesterol levels are associated with the severity of COVID-19, beyond inflammation and oxidative stress. Here, we used nuclear magnetic resonance spectroscopy to compare the lipoprotein and metabolic profiles of COVID-19-infected patients with non-COVID-19 pneumonia. We compared the control group and the COVID-19 group using inflammatory markers to ensure that the differences in lipoprotein levels were due to COVID-19 infection. Our analyses revealed supramolecular phospholipid composite (SPC), phenylalanine, and HDL-related parameters as key discriminators between COVID-19-positive and non-COVID-19 pneumonia patients. More specifically, the levels of HDL parameters, including apolipoprotein A-I (ApoA-I), ApoA-II, HDL cholesterol, and HDL phospholipids, were significantly different. These findings underscore the potential impact of HDL-related factors in patients with COVID-19. Significantly, among the HDL-related metrics, the cholesterol efflux capacity (CEC) displayed the strongest negative association with COVID-19 mortality. CEC is a measure of how well HDL removes cholesterol from cells, which may affect the way SARS-CoV-2 enters cells. In summary, this study validates previously established markers of COVID-19 infection and further highlights the potential significance of HDL functionality in the context of COVID-19 mortality. Full article

SARS-CoV-2 pneumonia in children has a lower incidence and severity compared to adults. Risk factors are adolescence and comorbidities. Our aims were to describe the characteristics of children admitted with SARS-CoV-2 pneumonia, identify risk factors associated with severity and compare the cases according to the variant of SARS-CoV-2. This was a descriptive and retrospective study, including patients aged 0–18 years hospitalized in a tertiary-care hospital between 1 March 2020 and 1 March 2022. Epidemiological, clinical, diagnostic and therapeutic data were analyzed. Forty-four patients were admitted; twenty-six (59%) were male and twenty-seven (61%) were older than 12 years. Thirty-six (82%) had comorbidities, the most frequent of which were obesity and asthma. Seven (15.9%) patients required high-flow oxygen, eleven (25%) non-invasive ventilation and four (9.1%) conventional mechanical ventilation. In critically ill patients, higher levels of anemia, lymphopenia, procalcitonin, lactate dehydrogenase (LDH) and hypoalbuminemia and lower levels of HDL-cholesterol were detected (all p < 0.05). Prematurity (p = 0.022) was associated with intensive care unit admission. Patients were younger during the Omicron wave (p < 0.01); no variant was associated with greater severity. In conclusion, pediatric patients with a history of prematurity or with anemia, lymphopenia, elevated procalcitonin, elevated LDH levels, hypoalbuminemia and low HDL-cholesterol levels may require admission and present more severe forms. Apart from age, no notable differences between SARS-CoV-2 variant periods were found. Full article

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. The pore-forming cholesterol-dependent cytolysin (CDC) pneumolysin (PLY) and the physiological metabolite hydrogen peroxide (H₂O₂) can greatly increase the virulence of pneumococci. Although most studies have focused on the contribution of both virulence factors to the course of pneumococcal infection, it is unknown whether or how H₂O₂ can affect PLY activity. Of note, S. pneumoniae exploits endogenous H₂O₂ as an intracellular signalling molecule to modulate the activity of several proteins. Here, we demonstrate that H₂O₂ negatively affects the haemolytic activity of PLY in a concentration-dependent manner. Prevention of cysteine-dependent sulfenylation upon substitution of the unique and highly conserved cysteine residue to serine in PLY significantly reduces the toxin’s susceptibility to H₂O₂ treatment and completely abolishes the ability of DTT to activate PLY. We also detect a clear gradual correlation between endogenous H₂O₂ generation and PLY release, with decreased H₂O₂ production causing a decline in the release of PLY. Comparative transcriptome sequencing analysis of the wild-type S. pneumoniae strain and three mutants impaired in H₂O₂ production indicates enhanced expression of several genes involved in peptidoglycan (PG) synthesis and in the production of choline-binding proteins (CPBs). One explanation for the impact of H₂O₂ on PLY release is the observed upregulation of the PG bridge formation alanyltransferases MurM and MurN, which evidentially negatively affect the PLY release. Our findings shed light on the significance of endogenous pneumococcal H₂O₂ in controlling PLY activity and release. Full article

Chenodeoxycholic acid (CA) is a naturally occurring bile acid that is produced in the liver from cholesterol. Three CA complexes using Zn(II), Mg(II), and Ca(II) ions were synthesized to examine the chelation tendencies of CA towards these metal ions. The complexation reaction of CA with the metal ions under investigation was conducted with a 1:1 molar ratio (CA to metal) at 60–70 °C in neutralized media, which consisted of a binary solvent of MeOH and H₂O (1:1). The resulting CA complexes were characterized using elemental data (metal, H, C, and Cl analysis) and spectral data (UV–visible, FT-IR, and ¹H NMR). The results suggested that CA in anion form utilized oxygen atoms of the carboxylate group (-COO⁻) to capture Zn(II), Mg(II), and Ca(II) ions. This produced complexes with the general compositions of [Zn(CA)(H₂O)Cl], [Mg₂(CA)₂(H₂O)₄Cl₂], and [Ca₂(CA)₂(H₂O)₄Cl₂]·2H₂O, respectively. The Kirby–Bauer disc diffusion assay was then used to explore the bioactivity of the CA complexes toward three fungal species (Aspergillus niger, Candida albicans, and Penicillium sp.), three Gram-positive bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and Bacillus subtilis), and two Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli). The Ca(II) and Mg(II) complexes exhibited marked inhibitory effects on the cell growth of the fungal species Aspergillus niger with potency equal to 127 and 116% of the activity of the positive control, respectively. The Zn(II) and Ca(II) complexes strongly inhibited the growth of Penicillium sp., while the Zn(II) and Mg(II) complexes showed strong growth inhibition towards the Gram-negative species Pseudomonas aeruginosa. Full article

Alveolar macrophages (AM) are long-lived tissue-resident innate immune cells of the airways. AM are key effectors of recognition, initiation, and resolution of the host defense against microbes and play an essential role in mediating host responses to Streptococcus pneumoniae infection. Lipid metabolism in AM can significantly impact cellular function and biology. Dysregulated metabolism contributes to an accumulation of lipids, unfolded protein response induction, and inflammatory cytokine production. Our study was designed to investigate the impact of Ch25h on mediating innate immune responses by macrophages during S. pneumoniae infection. Using wild-type and Ch25^−/− mice, we examined the role of cholesterol metabolism on inflammatory cytokine production and bacterial clearance. Our results demonstrate that Ch25h plays an important role in the initiation and intensity of cytokine and chemokine production in the lung during S. pneumoniae infection. In the absence of Ch25h, there was enhanced phagocytosis and bacterial clearance. Taken together, our findings demonstrate the important role of Ch25h in modulating host responsiveness to S. pneumoniae infection. Full article

COVID-19 infection triggered a global public health crisis during the 2020–2022 period, and it is still evolving. This highly transmissible respiratory disease can cause mild symptoms up to severe pneumonia with potentially fatal respiratory failure. In this cross-sectional study, 41 PCR-positive patients for SARS-CoV-2 and 42 healthy controls were recruited during the first wave of the pandemic in Mexico. The plasmatic expression of five circulating miRNAs involved in inflammatory and pathological host immune responses was assessed using RT-qPCR (Reverse Transcription quantitative Polymerase Chain Reaction). Compared with controls, a significant upregulation of miR-146a, miR-155, and miR-221 was observed; miR-146a had a positive correlation with absolute neutrophil count and levels of brain natriuretic propeptide (proBNP), and miR-221 had a positive correlation with ferritin and a negative correlation with total cholesterol. We found here that CDKN1B gen is a shared target of miR-146a, miR-221-3p, and miR-155-5p, paving the way for therapeutic interventions in severe COVID-19 patients. The ROC curve built with adjusted variables (miR-146a, miR-221-3p, miR-155-5p, age, and male sex) to differentiate individuals with severe COVID-19 showed an AUC of 0.95. The dysregulation of circulating miRNAs provides new insights into the underlying immunological mechanisms, and their possible use as biomarkers to discriminate against patients with severe COVID-19. Functional analysis showed that most enriched pathways were significantly associated with processes related to cell proliferation and immune responses (innate and adaptive). Twelve of the predicted gene targets have been validated in plasma/serum, reflecting their potential use as predictive prognosis biomarkers. Full article

Plasma membrane cholesterol is required for proper trafficking and localization of receptors that facilitate severe acute respiratory syndrome coronavirus 2 infection. High-density lipoproteins (HDL) mobilize plasma membrane cholesterol, and HDL-cholesterol levels are associated with the severity of COVID-19 disease and mortality. However, HDL-cholesterol levels poorly reflect the function of this complex family of particles, and a detailed assessment of COVID-19-associated changes in HDL functionality and its prognostic value is lacking. In the present study, we assessed HDL cholesterol efflux capacity, HDL anti-inflammatory and antioxidant properties, and changes in HDL composition and metabolism in COVID-19 (n = 48) and non-COVID pneumonia patients (n = 32). COVID-19 infection markedly reduced the activity of lecithin-cholesteryl-acyltransferase and functional parameters of HDL, such as the cholesterol efflux capacity, arylesterase activity of paraoxonase 1, and anti-oxidative capacity of apoB-depleted serum when compared to non-COVID pneumonia at baseline, paralleled by markedly reduced levels of HDL-cholesterol. Of particular interest, low HDL cholesterol efflux capacity was associated with increased mortality risk in COVID-19 patients, independent of HDL-C levels. Our results highlight profound effects of COVID-19 infection on HDL function, metabolism, and composition. Low HDL cholesterol efflux capacity indicates a fatal course of COVID-19, independent of HDL-cholesterol levels. Full article