As a major virulence factor of
(
), listeriolysin O (LLO) can assist in the immune escape of
, 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
infection. Therefore, this study aims to explore the preventive effect of CT against
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
. 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, β-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
infection, which could be further developed into a novel treatment for infections caused by
.
Vitamin A, a fat-soluble essential vitamin, is implicated in a large range of physiological processes. Up to now, the associations between vitamin A and metabolic syndrome (MetS) or other metabolic ...risk factors are controversial in children and adolescents. Thus, we aimed to dig into the relationship of vitamin A with MetS and many other metabolic risk factors. This was a cross-sectional study derived from the China National Nutrition and Health Surveillance of Children and Lactating Mothers. A total of 3025 school-aged (7-17 years) children and adolescents were selected by applying multistage stratified cluster random sampling methods in the Jiangsu Province of eastern China. Through enquiry survey, anthropometric measurement and laboratory examination, relevant information and blood biochemical indexes of the participants were collected in this study. MetS was identified according to the modified criteria of the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III). Multivariate logistic analysis and the generalized additive model (GAM) were used to analyze the relationship between vitamin A and various metabolic risk factors. The overweight, obesity and MetS prevalence of children and adolescents in this study was 14.0%, 11.9% and 5.1%, respectively. The risk of prevalent MetS, general obesity, high low-density lipoprotein (LDL), high total cholesterol (TC) and hyperuricemia increased with vitamin A in a dose-dependent way. Logistic regression analysis showed that serum vitamin A Z scores were positively associated with MetS and central obesity, elevated blood pressure (BP) and elevated triglyceride (TG). Sex stratification analysis showed that both in male and female participants, the risk of prevalent MetS, general obesity, high LDL, high TC and hyperuricemia still increased with vitamin A levels. MetS was at a high prevalence level in children and adolescents in Jiangsu that were 7-17 years old. Vitamin A was positively associated with obesity, MetS, dyslipidemia and hyperuricemia. More public health measures and new visions should focus on the effects of retinol on children and adolescents.
New Delhi metallo-β-lactamase-1 (NDM-1) poses a threat to public health due to its capability to hydrolyze nearly all β-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.
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•Zndm19 could be synthesized simply and had no toxicity on cells at less than 32 μg/mL.•Zndm19 restored the bactericidal ability of meropenem against NDM-1-positive E. coli.•Zndm19 combination with meropenem can treat mice peritonitis infection induced by E.coli ZJ487.
We aimed to identify multiple nutritional health problems and the relevant factors among children and adolescents aged 7-17 years. This study was part of the China Nutrition and Health Surveillance ...of Children and Lactating Mothers in 2016-2017, conducted in Jiangsu Province in eastern China. After sampling, 3025 school-age children and adolescents were enrolled into this study. Demographic information collections and anthropometric measurements were conducted by trained local Center for Disease Control and Prevention (CDC) staff. Venous blood in the amount of 6 mL was drawn from each participant in the morning and used for testing biochemical and nutritional indicators. Multivariate logistic regression analysis and Poisson regression analysis were used for overnutrition- and undernutrition-related disorders to test relevant personal, parental, and household factors. The prevalence of wasting, overweight, and obesity was 5.5%, 14.8%, and 12.7%, respectively. Metabolic syndrome (MetS) was prevalent among 5.1% of participants. Among the study participants, 29.5% had hyperuricemia. The overall prevalence of high low-density lipoprotein (LDL) and high total cholesterol (TC) of all participants was 4.8% and 7.4%, respectively. 0.9% of the participants had vitamin A deficiency (VAD) and 14.6% had marginal vitamin A deficiency; 25.1% had vitamin D deficiency (VDD) and 54.5% had inadequate vitamin D levels. Anemia was present in 4.0% of all participants. The prevalence of zinc deficiency was 4.8%. Demographic characteristics, behavioral characteristics, parents' characteristics, and family characteristics were associated with these multiple malnutrition disorders. The double burdens of malnutrition, which includes overnutrition- and undernutrition-related diseases, were prevalent among the school-age children and adolescents in Jiangsu Province in eastern China. There were various factors related to different nutritional problems. Thus, health education focusing on behavior intervention and nutrition education are necessary in containing nutritional problems among children.
Carbapenem resistance among strains of the nosocomial pathogen
is increasing worldwide, causing serious clinical infections and higher mortality rates. Polymyxins are some of the few "last resort" ...options for treatment of carbapenem-resistant
, including
, however, the emergence of plasmid-mediated colistin resistance gene
has largely rendered polymyxin-class antibiotics ineffective in a clinical setting. We previously identified a natural compound, pterostilbene, which has a synergistic effect in combination with polymyxins. Here, we aimed to determine whether pterostilbene application can restore the bactericidal activity of polymyxins against
positive
. Checkerboard MIC studies confirmed that pterostilbene reduces the MIC of colistin against
positive clinical
isolates, with the bacteria going from resistant to sensitive, and also demonstrated a synergistic effect with colistin (FIC index = 0.11 ± 0.04 or 0.28 ± 0.00). Time-killing assays showed that individually, both pterostilbene and colistin failed to eradicate
strains, while in combination, the two drugs effectively eliminated
ZJ02 and
ZJ05 by 1-3 h post-inoculation. The combined disk test also showed increases in the zones of inhibition only for
positive
and
isolates. A mouse infection model demonstrated that the survival rate of mice at 7 days post-intraperitoneal injection with a lethal dose of
ZJ05 was significantly promoted from 0 to 67% following combination therapy. This is the first time a MCR-1 inhibitor has successfully been used in combination with colistin against human clinical MCR-1 producing
ZJ05 isolate.
(
) type A strains are the main cause of gas gangrene in humans and animals. Treatment of this lethal disease is limited, and the prognosis is not good. Alpha-toxin (CPA) and perfringolysin O (PFO) ...secreted by
play irreplaceable roles in cytotoxicity to host cells, persistence in host tissues, and lethality of gas gangrene pathology. This work determined the influence of amentoflavone, a biflavonoid isolated from
and other plants, on hemolysis and cytotoxicity mediated by CPA and PFO and evaluated the
therapeutic effect on gas gangrene. Our data showed that amentoflavone could block the hemolysis and cytotoxicity induced by CPA and PFO
, thereby mediating significant protection against mortality of infected mice in a mouse gas gangrene model, efficient bacterial clearance in tissues and alleviation of histological damage
. Based on the above results, amentoflavone may be a potential candidate against
infection by reducing CPA and PFO-mediated virulence.
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.
The Prevalence of myopia is increasing in China. This study aimed to explore the distribution of spherical equivalent (SE) and its association with age, body mass index (BMI), gender in a non-myopic ...Chinese children population aged 6 to 12 years.
A total of 6362 students were recruited for ophthalmological investigation. Demographic and myopia related behavioral information was collected. SE value was measured by the Topcon RM-8900 or KR-800autorefractors. Potential independent risk factors were determined with Odds Ratio (OR) and 95% Confidence Interval (CI) by logistic regression analysis. We further constructed the nomogram model to predict future onset of myopia.
Among the study population, 3900 (61.3%) were non-myopic. The prevalence of myopia is 38.0% for boys and 39.5% for girls. The average SE values were 0.50 ± 0.70 D for boys and 0.60 ± 0.80 D for girls. The mean SE values decreased with age, and the value of height and BMI took on a stable trend. Threshold values for myopia varied across age groups and gender. Paternal myopia (OR: 1.22, 95%CI: 1.01-1.48), near-work activities on weekends (2.56, 1.17-5.61), and outdoor activities (0.68, 0.54-0.86) were associated with potential myopic in students.
A series of age-gender based SE threshold values were established to predict myopia in Chinese children aged 6 to 12 years. High risk factors for myopia included paternal myopia, near-work activities on weekends, and outdoor activities. Countermeasures are encouraged to reverse the increasing trend of myopia in children.
Tigecycline is one of the few last-resort antibiotics for the treatment of carbapenem-resistant Enterobacteriaceae infection, the incidence of which has been rapidly increasing. However, the ...emergence and spread of tigecycline resistance genes tet(X) (including tet(X3) and tet(X4)) has largely compromised the efficient usage of tetracyclines in the clinical settings.
The synergistic effect was determined by a checkerboard minimum inhibitory concentration (MIC) assay, a time-killing assay and scanning electron microscopy (SEM) analysis. In-depth mechanisms were defined using an enzyme inhibition assay, western blotting, RT-PCR analysis, molecular dynamics (MD) simulations, biolayer interferometry (BLI) assay and metabolomics analysis.
Herein, our work identified a natural compound, plumbagin, as an effective broad-spectrum inhibitor of Tet(X) (also known as monooxygenase) by simultaneously inhibiting the activity and the production of Tet(X3)/Tet(X4). Plumbagin in combination with tetracyclines showed a synergistic bactericidal effect against Tet(X3)/Tet(X4)-producing bacteria. Mechanistic studies revealed that direct engagement of plumbagin with the catalytic pocket of Tet(X3)/Tet(X4) induced an alternation in its secondary structure to inhibit the activity of these monooxygenases. As a consequence, monotherapy or combination therapy with plumbagin increases the oxidative stress and metabolism in bacteria. Moreover, in a mouse systemic infection model of tet(X4)-positive E. coli, the combination of plumbagin and methacycline exhibited remarkable treatment benefits, as shown by a reduced bacterial load and the alleviation of pathological injury.
Plumbagin, as an inhibitor of Tet(X3)/Tet(X4), represents a promising lead drug, as well as an adjunct with tetracyclines to treat bacterial infections, especially for extensively drug-resistant bacteria harbouring Tet(X3)/Tet(X4).
The National Natural Science Foundation of China.
The emergence of KPC-producing Gram-negative bacteria in clinical practice highlights the need to search for novel antimicrobials and new anti-infection strategies. In this study, we constructed a ...laboratory KPC-2-positive strain,
E. coli
BL21(DE3) (pET28a-KPC-2) and identified the activity of KPC-2 in this strain. Using enzyme inhibition assays, checkerboard MIC assays, growth curves, time-killing assays and combined disk test, we found that the natural compound corosolic acid (CA) significantly inhibited the activity of the class A β-lactamase KPC-2, which is common among clinical isolates. CA treatment increased the antibacterial or bactericidal activity of imipenem and meropenem against
E. coli
BL21(DE3) (pET28a-KPC-2)
in vitro
(FIC index = 0.17 ± 0.03 for both carbapenems). In addition, the mouse intraperitoneal infection model confirmed that the combination therapy significantly reduced the bacterial load in the livers and spleens following subcutaneous administration. Our results showed that CA can be used to extend the life of carbapenems, providing a viable strategy for severe infections caused by KPC-2-positive bacteria.
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