P-phenylenediamine antioxidants and their quinone derivatives: A review of their environmental occurrence, accessibility, potential toxicity, and human exposure.

Substituted p-phenylenediamines (PPDs), a class of antioxidants, have been widely used to extend the lifespan of rubber products, such as tires and pipes. During use, PPDs will generate their quinone derivatives (PPD-Qs). In recent years, PPDs and PPD-Qs have been detected in the global environment. Among them, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q), the oxidation product of N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), has been identified as highly toxic to coho salmon, with the lethal concentration of 50 % (LC50) being 95 ng/L, highlighting it as an emerging pollutant of great concern. This review summarizes the physicochemical properties, global environmental distribution, bioaccessibility, potential toxicity, human exposure risk, and green measures associated with PPDs and PPD-Qs. These chemicals exhibit lipophilicity, bioaccumulation potential, and poor aqueous stability. They have been found in water, air, dust, soil, and sediment worldwide, indicating their significance as emerging pollutants. Notably, current studies have identified electronic waste, such as discarded wires and cables, as a non-negligible source of PPDs and PPD-Qs, in addition to tire wear. PPDs and PPD-Qs exhibit strong bioaccumulation in aquatic organisms and mammals, with a tendency for biomagnification within the food web, posing health threats to humans. Available toxicity data indicate that PPDs and PPD-Qs have negative effects on aquatic organisms, mammals, and invertebrates. Acute exposure leads to death and acute damage, while long-term exposure can cause a series of adverse effects, including growth and development toxicity, reproductive toxicity, neurotoxicity, intestinal toxicity, and multi-organ damage. This paper discusses current research gaps and offers recommendations to understand better the occurrence, behavior, toxicity, and environmental exposure risks of PPDs and PPD-Qs.

Laurocapram, a transdermal enhancer, boosts cephalosporin's antibacterial activity against Methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA), a notorious bacterium with high drug resistance and easy recurrence after surgery, has posed significant clinical treatment challenges. In the current scarcity of new antibiotics, the identification of adjuvants to existing antibiotics is a promising approach to combat infections caused by multidrug-resistant Gram-positive bacteria. The in vitro synergy test, which included a MIC assay, time-kill curve, antimicrobial susceptibility testing, and live/dead bacteria staining assay, revealed that laurocapram, a widely used chemical transdermal enhancer, could potentiate the antibacterial activity of cephalosporins against MRSA. In vitro, laurocapram combined with cefixime showed an excellent synergistic activity against MRSA (FICI = 0.28 ±â€¯0.00). In addition, the combination of laurocapram and cefixime may inhibited the formation of MRSA biofilm and caused cell membrane damage. Following that, we discovered that combining laurocapram with cefixime could alleviate the symptoms of mice in the MRSA skin infection model and the MRSA pneumonia model. In conclusion, laurocapram is a promising and low-cost antibacterial adjuvant, providing a new strategy for further exploring the use of lower doses of cephalosporins to combat MRSA infection.

Repurposing harmaline as a novel approach to reverse tmexCD1-toprJ1-mediated tigecycline resistance against klebsiella pneumoniae infections.

BACKGROUND: A novel plasmid-mediated resistance-nodulation-division (RND) efflux pump gene cluster tmexCD1-toprJ1 in Klebsiella pneumoniae tremendously threatens the use of convenient therapeutic options in the post-antibiotic era, including the "last-resort" antibiotic tigecycline. RESULTS: In this work, the natural alkaloid harmaline was found to potentiate tigecycline efficacy (4- to 32-fold) against tmexCD1-toprJ1-positive K. pneumoniae, which also thwarted the evolution of tigecycline resistance. Galleria mellonella and mouse infection models in vivo further revealed that harmaline is a promising candidate to reverse tigecycline resistance. Inspiringly, harmaline works synergistically with tigecycline by undermining tmexCD1-toprJ1-mediated multidrug resistance efflux pump function via interactions with TMexCD1-TOprJ1 active residues and dissipation of the proton motive force (PMF), and triggers a vicious cycle of disrupting cell membrane integrity and metabolic homeostasis imbalance. CONCLUSION: These results reveal the potential of harmaline as a novel tigecycline adjuvant to combat hypervirulent K. pneumoniae infections.

Enhancing the effectiveness of Polymyxin E with a Fisetin Nanoemulsion against a Colistin-resistant Salmonella typhimurium infection.

BACKGROUND: Polymyxin E is widely recognized as a last resort for treating multidrug-resistant gram-negative bacteria. Unfortunately, the effectiveness of polymyxin E is significantly reduced when treating life-threatening bacterial infections due to plasmid-mediated polymyxin E resistance. The synergistic effect of applying a polymyxin E adjuvant is a promising strategy for overcoming the growing threat of antibiotic-resistant pathogens. PURPOSE: To evaluate the synergistic effect of fisetin and polymyxin E on S. typhimurium infections in vivo and further elucidate the underlying mechanism of this effect. METHODS: The effect of combining fisetin and polymyxin E to treat mobilized colistin resistance-1-positive (MCR-1-positive) gram-negative bacteria in vitro was examined using various methods, such as checkerboard assays, growth curves and time‒kill curves. To elucidate the mechanism by which fisetin affects MCR-1, we employed ultraviolet (UV) absorption spectroscopy, thin layer chromatography (TLC), and western blot analysis to investigate its effect at the protein level. Subsequently, molecular dynamics simulations (MDS) and metabolomics analysis were utilized to determine the site of interaction between fisetin and MCR-1 as well as the potential pathways and mechanisms involved. A new nanoemulsion of fisetin was produced using high-pressure homogenization, and its stability was tested. Finally, two animal models of S. typhimurium HYM2 infection were established to evaluate the synergistic effect of polymyxin E and fisetin in vivo. RESULTS: Our study revealed that fisetin exhibited a synergistic effect when combined with polymyxin E against MCR-1-positive S. typhimurium. The TLC results demonstrated that fisetin could inhibit the phosphoethanolamine (PEA) transfer of the MCR-1 protein, thereby restoring the activity of polymyxin E in strains against MCR-1. The MDS analysis indicated robust and immediate binding between fisetin and the MCR-1 protein, with both hydrophobic and polar effects playing significant roles in determining the binding energy of the former. Metabolomic studies demonstrated that the addition of fisetin significantly modulated bacterial metabolites. Moreover, it effectively inhibited the activity of ABC transporters in bacteria, thereby mitigating bacterial drug resistance and enhancing the therapeutic efficacy of polymyxin E. Furthermore, in mouse and chick models of infection, intragastric administration of the fisetin nanoemulsion together with polymyxin E resulted in significant therapeutic benefits, including increased survival rates, reduced bacterial colonization, and decreased levels of inflammatory factors. CONCLUSION: Fisetin, an MCR-1 inhibitor and a promising synergistic partner of polymyxin E, has significant potential for clinical application in the treatment of S. typhimurium infections, particularly those resulting extensively from drug-resistant MCR-1-positive strains.

Multi-omics Combined with Machine Learning Facilitating the Diagnosis of Gastric Cancer.

Gastric cancer (GC) is a highly intricate gastrointestinal malignancy. Early detection of gastric cancer forms the cornerstone of precision medicine. Several studies have been conducted to investigate early biomarkers of gastric cancer using genomics, transcriptomics, proteomics, and metabolomics, respectively. However, endogenous substances associated with various omics are concurrently altered during gastric cancer development. Furthermore, environmental exposures and family history can also induce modifications in endogenous substances. Therefore, in this study, we primarily investigated alterations in DNA mutation, DNA methylation, mRNA, lncRNA, miRNA, circRNA, and protein, as well as glucose, amino acid, nucleotide, and lipid metabolism levels in the context of GC development, employing genomics, transcriptomics, proteomics, and metabolomics. Additionally, we elucidate the impact of exposure factors, including HP, EBV, nitrosamines, smoking, alcohol consumption, and family history, on diagnostic biomarkers of gastric cancer. Lastly, we provide a summary of the application of machine learning in integrating multi-omics data. Thus, this review aims to elucidate: i) the biomarkers of gastric cancer related to genomics, transcriptomics, proteomics, and metabolomics; ii) the influence of environmental exposure and family history on multi- -omics data; iii) the integrated analysis of multi-omics data using machine learning techniques.

The synbiotic combination of probiotics and inulin improves NAFLD though modulating gut microbiota.

Prebiotics can promote the growth of probiotics, cocombine of these is called synbiotics, and synbiotics is powerful regulators of gut microbiota. Intestinal microbiota plays an important role in nonalcoholic fatty liver disease (NAFLD), so synbiotics could be a therapeutic alternative. This study aims to investigate the effect of synbiotics combination of probiotics (Streptococcus Bifidobacterium and Streptococcus thermophilus) and prebiotics (Inulin) in vivo model of early NAFLD using yogurt as carrier. The results demonstrate that the yogurt with synbiotics combination group (HS) improves the biochemical indicators related to total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and insulin resistance (IR) in mice (P< .01). HS improves the development of lipid metabolism and inflammation by activating the AMPK and NFκB signaling pathway. In addition, HS restores the intestinal barrier dysfunction and inflammation caused by a high-fat diet. The 16S rRNA demonstrates that the gut microbiota composition of mice treated with HS is significantly altered specifically, the Firmicutes/Bacteroidetes ratio is significantly lower than in HFD-fed mice (P< .01). Our findings suggest the applicability of HS in preventing obesity-related NAFLD via its antioxidant, anti-inflammatory, and improved lipid metabolism by the gut-liver axis and provide a solid theoretical foundation for developing prebiotics for the prevention of NAFLD.

A new function of thymol nanoemulsion for reversing colistin resistance in Salmonella enterica serovar Typhimurium infection.

BACKGROUND: Adjuvant addition of approved drugs or foodborne additives to colistin might be a cost-effective strategy to overcome the challenge of plasmid-mediated mobile colistin resistance gene emergence, which poses a threat in the clinic and in livestock caused by infections with Gram-negative bacteria, especially carbapenem-resistant Enterobacteriaceae. METHODS: Chequerboard assay was applied to screen the colistin adjuvants from natural compounds. The killing-time curve, combined disc test and membrane permeation assay were conducted to identify the synergy efficacy of thymol and colistin in vitro. Thin-layer chromatography (TLC), LC-MS and fluorescence spectra were used to indicate the interaction of thymol and MCR-1. The potential binding sites were then investigated by molecular simulation dynamics. Finally, a thymol nanoemulsion was prepared with high-pressure homogenization as the clinical dosage form. RESULTS: Thymol presented an excellent synergistic effect in vitro with colistin against Salmonella enterica serovar Typhimurium and Escherichia coli bacteria. Thymol addition, forming a complex with MCR-1, might interfere with the efficacy of MCR-1. Moreover, thymol strengthened colistin activity associated with potentiating membrane damage, destroying the biofilm and enhancing reactive oxygen species-mediated oxidative damage. Thymol nanoemulsion combined with colistin remarkably prevented the intestinal damage caused by S. Typhimurium infection, resulting in a survival rate higher than 60%. CONCLUSIONS: This study achieved a promising thymol oral formulation as colistin adjuvant to combat S. Typhimurium infection, which could be used to extend the lifespan of colistin in clinical veterinary medicine.

Discovery of isatin-ß-methyldithiocarbazate derivatives as New Delhi metallo- ß-lactamase-1 (NDM-1) inhibitors against NDM-1 producing clinical isolates.

New Delhi metallo-ß-lactamase-1 (NDM-1) poses a threat to public health due to its capability to hydrolyze nearly all ß-lactam antibiotics, leaving limited treatment options for NDM-1 positive pathogens. Regrettably, there are presently no effective NDM-1 inhibitors in clinical use. This compels us to seek new compounds to combat multi-drug resistant bacterial infections (MDR). In our study, Zndm19 was identified as a new NDM-1 inhibitor through virtual screening and an NDM-1 enzyme activity inhibition assay. Subsequently, we employed the checkerboard method, time-killing assay, and combined disk test to investigate the synergistic bactericidal efficacy of Zndm19 in combination with meropenem (MEM). Meanwhile, molecular docking and site-directed mutagenesis were conducted to uncover the crucial amino acid residues engaged in Zndm19 binding. Finally, we established a mice peritonitis infection model to assess the synergistic effect of Zndm19 and MEM in vivo. Our findings demonstrated that 16 µg/mL of Zndm19 inhibited NDM-1 activity without affecting NDM-1 expression, restoring the bactericidal activity of MEM against NDM-1-positive Escherichia coli in vitro. Furthermore, MET-67, ASP-124, HIS-189, and HIS-250 amino acid residues constituted the active site of Zndm19 in NDM-1. Importantly, this combination therapy exhibited synergistic anti-infection activity in the mice peritonitis infection model, leading to an approximate 60% increase in survival rates and reduction of tissue bacterial load, effectively combating bacterial infection in vivo. In summary, our research validates that the synthetic novel NDM-1 inhibitor Zndm19 holds promise as a drug to treat drug-resistant bacterial infections, especially those harboring NDM-1.

Trend of blood pressure changes among children from 2012 to 2022: findings from student health surveillance in Eastern China.

OBJECTIVES: The primary objective of this study is to examine the secular trends in blood pressure levels from 2012 to 2022 in eastern China. Additionally, to compare two standards [International Blood Pressure Reference for Children and Adolescents (ICBP) and the National Blood Pressure Reference for Chinese Han Children and Adolescents (CCBP)], we calculate the 95th percentile of blood pressure levels for students in developed regions (ECCBP). Secondly, the study aims to investigate potential contributors to elevated blood pressure, including sex, age, behaviors, and mental health. Lastly, the study seeks to estimate the total population aged 7-18 years with elevated blood pressure in Eastern China based on three references. METHODS: The data used in this study were obtained from the Student Health Surveillance program in Jiangsu Province, which has been collecting data since 2012. Trained project members, skilled nurses, and doctors measured anthropometric variables. Additionally, online student questionnaires were administered in 2017, 2019, and 2021 to collect personal information behavior patterns, and mental health. RESULTS: The study examined blood pressure changes in 123 013 children and adolescents in Eastern China from 2012 to 2022. Significant increases were observed in systolic blood pressure (SBP) and pulse pressure difference. Prevalence of elevated blood pressure followed a similar trend with ECCBP and CCBP, ranging from 17.2%/16.3% (2012-2015) to 11.6%/14.6% (2020-2022). Notably, BP with ICBP showed a significant increase in both prevalence and population, from 12.6% [6 713 679, 95% confidence interval (CI): 6 708 931 to 6 718 427] to 14.5% (7 004 208, 95% CI: 6 999 411 to 7 009 004). The study further emphasizes the significant impact of various risk factors on elevated blood pressure among children and adolescents, particularly the detrimental effect of depression on blood pressure, with the odds ratios (OR) in 2021 being 1.310 (95% CI, 1.290-1.330) for ECCBP, 1.239 (95% CI, 1.223-1.255) for CCBP, and 1.189 (95% CI, 1.176-1.202) for ICBP. CONCLUSION: The study revealed significant changes in the population and prevalence of elevated blood pressure in Eastern China from 2012 to 2022. The findings indicate a decline in the prevalence of elevated blood pressure (referred to as CCBP or ECCBP), while highlighting an increasing trend in elevated blood pressure (referred to as ICBP). Untreated high blood pressure can lead to serious cardiovascular diseases in adulthood, underscoring the importance of early prevention and management, particularly through nonpharmacological methods and regular monitoring for students in Eastern China. Raising awareness among educators, parents, and healthcare providers about the association between mental health and elevated blood pressure is essential.

Pattern of lifestyle behaviors and associated risk of being bullied at schools: A latent class analysis of 25,379 adolescents in Jiangsu Province of China.

School bullying is a worldwide problem. Although previous studies examined the association between different lifestyle behaviors and bullying victimization, the complex co-occurrence of these behaviors was not identified, and their association with the risk of being bullied remains unclear. We aimed to identify the behavioral patterns of adolescents and to explore their association with bullying victimization. This cross-sectional study employed data from the "Surveillance for Common Diseases and Health Risk Factors among Students" project implemented in Jiangsu Province of China in 2019, and a total of 25,379 school-enrolled students were included. We used a latent class analysis to identify behavioral patterns and a regression mixture model to explore various demographic characteristics, such as age, sex, and family structure in relation to bullying victimization across different patterns. We considered respondents having targeted behaviors, including smoking, alcohol consumption, illicit drug use, sugar consumption, no fruit consumption, low physical activity, electronic media use, and insufficient sleep. Four behavioral patterns were identified, including the "adolescents without apparent targeted behaviors" (19.65%), "substance and electronic media users" (12.76%), "typical electronic media users" (54.49%), and "typical substance users" (8.10%). The risk of being bullied was the highest in the "substance and electronic media users" (probability: 0.33), tripled that in "adolescents without apparent targeted behaviors" (odds ratio: 3.60, 95% confidence interval: 3.01-4.30). Risk of being bullied was reduced for those "substance and electronic media users" living with a nuclear family. Behavioral patterns and their association with being bullied differ between groups of school-aged adolescents. To better inform decision-making based on the current real-world findings, the implementation of bullying prevention programs could target specific behavioral patterns.

High-protein compound yogurt with quinoa improved clinical features and metabolism of high-fat diet-induced nonalcoholic fatty liver disease in mice.

Gut microbiota dysbiosis plays a crucial role in the occurrence and progression of nonalcoholic fatty liver disease (NAFLD), which may be influenced by nutritional supplementation. Quinoa, a type of pseudocereal, has gained prominence due to its high nutritional value and diverse applications. This study aimed to determine whether yogurt containing quinoa can ameliorate NAFLD and alleviate metabolic disorders by protecting against the divergence of gut microbiota. Our findings suggested that quinoa yogurt could significantly reduce the body weight gain and fat tissue weight of high-fat diet (HFD)-fed obese mice. In addition, quinoa yogurt significantly reduced liver steatosis and enhanced glucose homeostasis and insulin sensitivity. Additional research indicates that quinoa yogurt can reduce the levels of proinflammatory cytokines (i.e., tumor necrosis factor α, IL-1ß, and IL-6) and inhibit endotoxemia and systemic inflammation. The characteristics of the gut microbiota were then determined by analyzing 16S rRNA. In addition, we discovered that the gut microbiota was disturbed by HFD consumption. Particularly, intestinal probiotics and beneficial intestinal secretions were increased, leading to the expression of glucagon-like peptide-1 in the colon, contributing to NAFLD. Furthermore, endotoxemia and systemic inflammation in HFD-fed mice were restored to the level of control mice when they were fed yogurt and quinoa. Therefore, yogurt containing quinoa can effectively alleviate NAFLD symptoms and may exert its effects via microbiome-gut-liver axis mechanisms. According to some research, the role of the enteric-liver axis may also influence metabolic disorders to reduce the development of NAFLD.

Urinary antibiotic concentrations in preschool children from eastern China and health risk assessment.

Despite limited biomonitoring studies suggesting extensive antibiotic exposure in general population, the body burden of antibiotics in young children and their potential health risks remain unclear. To assess the antibiotic exposure levels in young children, 508 preschoolers aged 3-6 years were recruited from eastern China in 2022, and a total of 50 representative antibiotics from 8 categories, including 17 human antibiotics (HAs), 4 antibiotics preferred as HAs (PHAs), 16 veterinary antibiotics (VAs), and 13 antibiotics preferred as VAs (PVAs), were analyzed by UPLC-MS/MS. Hazard quotient (HQ) and hazard index (HI) were calculated to evaluate the health risks, and multivariate logistic regression was applied to examine diet with antibiotic exposure. Our results showed that there were 41 antibiotics detected in children's urine, and the overall detection frequency was as high as 100%. Sulfonamides, macrolides, ß-lactams, quinolones, and azoles were the predominant categories of antibiotic detected. Among the studied children, 6.5% had a sum of estimated daily intake (EDI) of all VAs and PVAs larger than 1 µg/kg/day. Notably, 10.0% of the children had a microbiological HI value exceeding 1, primarily contributed by ciprofloxacin. Children with higher consumption of seafood had a relatively increased exposure to multiple categories of antibiotics, including HAs, VAs, quinolones, azoles, and others. Principal component analysis suggested that "Aquatic products and viscera preferred dietary pattern" scores were positively correlated with the exposure levels of ciprofloxacin (OR: 1.23; 95% CI: 1.02-1.47) and carbadox (OR: 1.32; 95% CI: 1.10-1.59), and a relatively increased exposure of PHAs was realized in children with higher "Meat-egg preferred dietary pattern" scores (OR: 1.24; 95% CI: 1.03-1.50). In conclusion, there was a widespread exposure to antibiotics among preschool children from eastern China, and children who consumed more animal-derived foods may had an increased exposure to antibiotics.

Design, methodology, and baseline of eastern China student health and wellbeing cohort study.

Purpose: To describe the study design, methodology, and cohort profile of the Eastern China Student Health and Wellbeing Cohort Study. The cohort baseline includes (1) targeted disease (myopia, obesity, elevated blood pressure, and mental health) and (2) exposures (individual behaviors, environment, metabolomics, and gene and epigenetics). Participants: Annual physical examination, questionnaire-based survey, and bio-sampling have been carried out in the study population. In the first stage (2019-2021), a total of 6,506 students in primary schools are enrolled in the cohort study. Findings to date: Of all the cohort participants, the ratio of male to female is 1.16 among a total of 6,506 student participants, of which 2,728 (41.9%) students are from developed regions and 3,778 (58.1%) students are from developing regions. The initial age of observation is 6-10 years, and they will be observed until they graduate from high school (>18 years of age). (1) Targeted diseases: The growth rates of myopia, obesity, and high blood pressure vary by regions, and for developed regions, the prevalence of myopia, obesity, and elevated blood pressure is 29.2%, 17.4%, and 12.6% in the first year, respectively. For developing regions, the prevalence of myopia, obesity, and elevated blood pressure is 22.3%, 20.7%, and 17.1% in the first year, respectively. The average score of CES-D is 12.9 ± 9.8 in developing regions/11.6 ± 9.0 in developed regions. (2) Exposures: ① The first aspect of individual behaviors: the questionnaire topics include diet, physical exercise, bullying, and family. ② The second aspect of environment and metabolomics: the average desk illumination is 430.78 (355.84-611.56) LX, and the average blackboard illumination is 365.33 (286.83-516.84) LX. Metabolomics like bisphenol A in the urine is 0.734 ng/ml. ③ The third aspect of gene and epigenetics: SNPs (rs524952, rs524952, rs2969180, rs2908972, rs10880855, rs1939008, rs9928731, rs72621438, rs9939609, rs8050136 and so on) are detected. Future plans: Eastern China Student Health and Wellbeing Cohort Study is aiming to focus on the development of student-targeted diseases. For children with student common diseases, this study will focus on targeted disease-related indicators. For children without targeted disease, this study aims to explore the longitudinal relationship between exposure factors and outcomes, excluding baseline confounding factors. Exposure factors include three aspects: (1) individual behaviors, (2) environment and metabolomics, and (3) gene and epigenetics. The cohort study will continue until 2035.

Association between dietary approaches to stop hypertension (DASH) diet and hyperuricemia among Chinese adults: findings from a nationwide representative study.

BACKGROUND: Certain foods and food groups could positively or negatively impact serum uric acid (SUA) levels. However, evidence on the holistic dietary strategy to prevent and control hyperuricemia (HUA) development remains limited. OBJECTIVE: The aim of this research work was to explore the association of dietary approaches to stop hypertension (DASH) diet with SUA levels and odds of HUA among Chinese adults. METHODS: This research premise included 66,427 Chinese adults aged 18 and above who were part of the China Adult Chronic Disease and Nutrition Surveillance in 2015. Dietary consumptions were assessed via the household condiment weighing approach and a three-day, 24-hour dietary recall. Total fat, saturated fat, calcium, protein, potassium, cholesterol, magnesium, fiber, and sodium were all adopted to calculate the DASH score (score range, 0-9). The associations of DASH score with SUA levels and odds of HUA were evaluated using multiple linear and logistic regression models, respectively. RESULTS: We established that a higher DASH score was linked with a lower SUA levels (ß = - 0.11; 95% CI: - 0.12, - 0.1; p < 0.001) and odds of HUA (OR = 0.85; 95% CI: 0.83, 0.87; p < 0.001) after adjustment for age, sex, ethnicity, education status, marital status, health behaviours and health factors. The association of the DASH diet with odds of HUA was stronger among men (p-interaction = 0.009), non-Han Chinese (p-interaction< 0.001) as well as rural residents (p-interaction< 0.001). CONCLUSIONS: Our results illustrate that the DASH diet was remarkably negatively with SUA levels and odds of HUA in the Chinese adult population.

The Application of Cinnamon Twig Extract as an Inhibitor of Listeriolysin O against Listeria monocytogenes Infection.

As a major virulence factor of Listeria monocytogenes (L. monocytogenes), listeriolysin O (LLO) can assist in the immune escape of L. monocytogenes, which is critical for the pathogen to evade host immune recognition, leading to various infectious diseases. Cinnamon twig (CT), as a traditional medicine, has been widely used in clinics for multiple functions and it has exhibited excellent safety, efficacy and stability. There are few reports on the effects of the extracts of traditional medicine on bacterial virulence factors. CT has not been reported to be effective in the treatment of L. monocytogenes infection. Therefore, this study aims to explore the preventive effect of CT against L. monocytogenes infection in vivo and in vitro by targeting LLO. Firstly, a hemolysis assay and a cell viability determination are used to detect the effect of CT extract on the inhibition of the cytolytic activity of LLO. The potential mechanism through which CT extract inhibits LLO activity is predicted through network pharmacology, molecular docking assay, real-time polymerase chain reaction (RT-PCR), Western blotting and circular dichroism (CD) analysis. The experimental therapeutic effect of CT extract is examined in a mouse model infected with L. monocytogenes. Then, the ingredients are identified through a high-performance liquid chromatography (HPLC) and thin layer chromatography (TLC) analysis. Here we find that CT extract, containing mainly cinnamic acid, cinnamaldehyde, ß-sitosterol, taxifolin, catechin and epicatechin, shows a potential inhibition of LLO-mediated hemolysis without any antimicrobial activity. The results of the mechanism research show that CT extract treatment can simultaneously inhibit LLO expression and oligomerization. Furthermore, the addition of CT extract led to a remarkable alleviation of LLO-induced cytotoxicity. After treatment with CT extract, the mortality, bacterial load, pathological damage and inflammatory responses of infected mice are significantly reduced when compared with the untreated group. This study suggests that CT extract can be a novel and multicomponent inhibitor of LLO with multiple strategies against L. monocytogenes infection, which could be further developed into a novel treatment for infections caused by L. monocytogenes.

Isoflavone glucoside genistin, an inhibitor targeting Sortase A and Listeriolysin O, attenuates the virulence of Listeria monocytogenes in vivo and in vitro.

As a common intracellular facultative anaerobic Gram-positive bacterium, Listeria monocytogenes (L. monocytogenes) exhibits strong resistance to extreme environments, such as low temperature and a wide range of pH values, causing contamination in food production and processing. Sortase A (SrtA) and listeriolysin O (LLO), two crucial virulence factors of L. monocytogenes, are widely recognized as potential targets for the development of anti-L. monocytogenes infection drugs. In this study, we found that genistin simultaneously inhibits the peptidase activity of SrtA and the hemolytic activity of LLO without affecting the growth of L. monocytogenes, alleviating concerns about developing resistance. Furthermore, we demonstrated that genistin reduces L. monocytogenes biofilm formation and invasion of human colorectal cancer (Caco-2) cells. Subsequent mechanistic studies revealed that genistin inhibited LLO-mediated Caco-2 cell damage by blocking LLO oligomerization. Fluorescence quenching assay revealed the potential binding mode of SrtA and LLO to genistin. Genistin might bind to the active pocket of SrtA through residues Leu33, Asn29, and Met40, interacting with D1 domain of LLO involved in oligomerization and pore formation through residues Asn259. Studies in infection models revealed that genistin reduces mortality and pathological damage in mice infected with L. monocytogenes. These results indicate that genistin is a promising anti-virulence agent that could be considered an alternative candidate for the treatment of L. monocytogenes infection.

Naringenin Microsphere as a Novel Adjuvant Reverses Colistin Resistance via Various Strategies against Multidrug-Resistant Klebsiella pneumoniae Infection.

The efficacy of colistin, the last option against multidrug-resistant (MDR) Gram-negative bacteria, is severely threatened by the prevalence of plasmid- or chromosome-mediated colistin resistance genes. Herein, naringenin has dramatically restored colistin sensitivity against colistin-resistant Klebsiella pneumoniae infection without affecting bacterial viability, inducing resistance and causing obvious cell toxicity. Mechanism analysis reveals that naringenin potentiates colistin activity by multiple strategies including inhibition of mobilized colistin resistance gene activity, repression of two-component system regulation, and acceleration of reactive oxygen species-mediated oxidative damage. A lung-targeted delivery system of naringenin microspheres has been designed to facilitate naringenin bioavailability, accompanied by an effective potentiation of colistin for Klebsiella pneumoniae infection. Consequently, a new recognition of naringenin microspheres has been elucidated to restore colistin efficacy against colistin-resistant Gram-negative pathogens, which may be an effective strategy of developing potential candidates for MDR Gram-negative bacteria infection.

Anti-inflammatory, antioxidant and anti-virulence roles of atractylodin in attenuating Listeria monocytogenes infection.

Background: Listeria monocytogenes (L. monocytogenes), as a pandemic foodborne pathogen, severely threatens food security and public health care worldwide, which evolves multiple bacterial virulence factors (such as listeriolysin O, LLO) for manipulating the immune response of L. monocytogenes-host interactions. Methods: Hemolysis assay was employed to screen a potential LLO inhibitor and the underlying mechanisms were investigated using molecular dynamics (MD) simulation and oligomerization assay. The effects of candidates on immune response were examined by qRT-PCR and immunoblotting analysis. Histological analysis, ELISA assay and biochemistry detection were conducted to assess in vivo efficacy of candidates. Results: In the present study, natural terpenoid atractylodin was characterized as an alternative drug candidate for the treatment of L. monocytogenes by the regulation of LLO function and host Nrf2/NLRP3 signaling pathway. Notably, in vivo infection model by L. monocytogenes also highlighted that atractylodin treatment provided effective therapeutic benefits, as evidenced by decreased bacterial burden and diminished inflammation. Congruently, the survival rate of L. monocytogenes-infection mice increased significantly from 10.0% to 40.0% by atractylodin treatment. Conclusion: Collectively, our study showed for the first time that atractylodin has tremendous potential to attenuate L. monocytogenes pathogenicity by blocking LLO pore formation and mediating the suppression of inflammation and oxidative stress, providing a promising therapeutic strategy and broadening the applications of atractylodin against L. monocytogenes infection.

Dietary Quality and Relationships with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) among United States Adults, Results from NHANES 2017-2018.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new definition for the evidence of hepatic steatosis and metabolic dysfunctions. The specific role of the dietary factors in the development and progress of the disease are not well illuminated. Thus, we conducted this study on the associations between dietary quality assessed by five dietary quality indexes (Dietary Inflammatory Index, DII; Mediterranean diet, MED; Dietary Approach to Stop Hypertension, DASH; Alternate Healthy Eating Index diet, AHEI; Healthy Eating Indices, HEI) and MAFLD phenotypes. This study was extracted from the latest NHANES 2017-2018 wave. Demographic information, health status, lifestyles, and dietary habits were reported in the questionnaire. Multivariate logistic regression and multivariate ordinal logistic regression methods were applied to explore the associations between dietary quality indexes and MAFLD or MAFLD with liver fibrosis. The weighted prevalence of Non-MAFLD, MAFLD without fibrosis, and MAFLD with fibrosis were 47.05%, 36.67%, and 16.28%, respectively, at the cutoff value of a median Controlled Attenuation Parameter (CAP) 248 dB/m and a median Liver Stiffness Measurement (LSM) 6.3 kPa. When the diagnostic cutoff values of CAP changed to 285 dB/m, the weighted prevalence of Non-MAFLD, MAFLD without liver fibrosis, and MAFLD with fibrosis turned to 64.62%, 22.08%, and 13.30%, respectively. All five dietary quality indexes, including DII, HEI-2015, AHEI, DASH, and MED, were all significantly associated with MAFLD phenotypes. DII was positively associated with MAFLD phenotypes, while other four dietary quality indexes, including HEI-2015, AHEI, DASH, and MED, were significantly associated with lower risk of MAFLD phenotypes. MAFLD is becoming a threatening public health concern among adult Americans and dietary quality is markedly associated with MAFLD phenotypes.

Commercialized artemisinin derivatives combined with colistin protect against critical Gram-negative bacterial infection.

The emergence and spread of the mcr-1 gene and its mutants has immensely compromised the efficient usage of colistin for the treatment of drug-resistant Gram-negative bacterial infection in clinical settings. However, there are currently no clinically available colistin synergis. Here we identify artemisinin derivatives, such as dihydroartemisinin (DHA), that produces a synergistic antibacterial effect with colistin against the majority of Gram-negative bacteria (FIC < 0.5) without induced resistance, particularly those carrying the mcr-1 gene. Mechanism analysis reveals the direct engagement of DHA with the active center of MCR-1 to inhibit the activity of MCR-1. Meanwhile, the results from transcriptome and electron microscope analysis show that DHA could also simultaneously affect the flagellar assembly and the energy metabolism of bacteria. Moreover, in the mouse infection models of Gram-negative bacteria, combination therapy shows remarkable treatment benefits, as shown by an improved survival rate, reduced morbidity, alleviated pathological injury and decreased bacterial loading. Due to the generally safe profile of specialized malaria medication administration in humans, artemisinin derivatives are a promising class of multi-target inhibitors on bacterial resistance and virulence that can be used to extend the usage life of colistin and to tackle the inevitability of serious bacterial infection with colistin.