With the rapid rise in the incidence of multidrug resistant infections, there is substantial interest in host defense peptides as templates for production of new antimicrobial therapeutics. Natural peptides are multifunctional mediators of the innate immune response, with some direct antimicrobial activity and diverse immunomodulatory properties. We have previously developed an innate defense regulator (IDR) 1, with protective activity against bacterial infection mediated entirely through its effects on the immunity of the host, as a novel approach to anti-infective therapy. In this study, an immunomodulatory peptide IDR-1002 was selected from a library of bactenecin derivatives based on its substantially more potent ability to induce chemokines in human PBMCs. The enhanced chemokine induction activity of the peptide in vitro correlated with stronger protective activity in vivo in the Staphylococcus aureus-invasive infection model, with a >5-fold reduction in the protective dose in direct comparison with IDR-1. IDR-1002 also afforded protection against the Gram-negative bacterial pathogen Escherichia coli. Chemokine induction by IDR-1002 was found to be mediated through a Gi-coupled receptor and the PI3K, NF-κB, and MAPK signaling pathways. The protective activity of the peptide was associated with in vivo augmentation of chemokine production and recruitment of neutrophils and monocytes to the site of infection. These results highlight the importance of the chemokine induction activity of host defense peptides and demonstrate that the optimization of the ex vivo chemokine-induction properties of peptides is a promising method for the rational development of immunomodulatory IDR peptides with enhanced anti-infective activity.
Case fatality rates for severe malaria remain high even in the best clinical settings because antimalarial drugs act against the parasite without alleviating life-threatening inflammation. We assessed the potential for host-directed therapy of severe malaria of a new class of anti-inflammatory drugs, the innate defense regulator (IDR) peptides, based on host defense peptides. The Plasmodium berghei ANKA model of experimental cerebral malaria was adapted to use as a preclinical screen by combining late-stage intervention in established infections with advanced bioinformatic analysis of early transcriptional changes in co-regulated gene sets. Coadministration of IDR-1018 with standard first-line antimalarials increased survival of infected mice while down-regulating key inflammatory networks associated with fatality. Thus, IDR peptides provided host-directed adjunctive therapy for severe disease in combination with antimalarial treatment.
Innate immunity is triggered by a variety of bacterial molecules, resulting in both protective and potentially harmful pro-inflammatory responses. Further, innate immunity also provides a mechanism for the maintenance of homeostasis between the host immune system and symbiotic or non-pathogenic microorganisms. However, the bacterial factors that mediate these protective effects have been incompletely defined. Here, it was demonstrated that the lantiobiotic nisin Z is able to modulate host immune responses and mediate protective host immunity. Nisin Z induced the secretion of the chemokines MCP-1, IL-8 and Gro-α, and significantly reduced TNF-α induction in response to bacterial LPS in human PBMC. The results correlated with the ability of nisin Z to confer protection against both the Gram-positive organism Staphylococcus aureus, and the Gram-negatives Salmonella enterica sv. Typhimurium and Escherichia coli in murine challenge models. Mechanistic studies revealed that nisin Z modulates host immunity through similar mechanisms as natural host defense peptides, engaging multiple signal transduction pathways and growth factor receptors. The results presented herein demonstrate that, in addition to nisin Z, other bacterial cationic peptides and, in particular, the lantibiotics, could represent a new class of secreted bacterial molecule with immunomodulatory activities.
Background: The aim of this study is to investigate the relationship between16-slice spiral CT perfusion imaging and tumor angiogenesis and VEGF (vascular endothelial growth factor) expression in patients with benign and malignant pulmonary nodules, and differential diagnosis between benign and malignant pulmonary nodules.
Induction of heat shock proteins (HSPs) helps cells to survive severe hyperthermal stress and removes toxic unfolded proteins. At the same time, the cap‐dependent translation of global cellular mRNA is inhibited, due to the loss of function of eukaryotic initiation factor (eIF)4F complex. It has been previously reported that, following heat shock, HSP27 binds to the insoluble granules of eIF4G and impedes its association with cytoplasmic poly(A)‐binding protein (PABP) 1 and eIF4E. In the studies reported here, in addition to heat shock, we have included results of our investigation on the association between eIF4G, PABP1 and HSP27 during recovery from heat shock, when cap‐dependent mRNA translation resumes. We showed here that in the heat‐shocked cells, the PABP1–eIF4G complex dissociated, and both polypeptides translocated with the HSP27 to the nucleus. During recovery after heat shock, PABP1 and eIF4G were redistributed into the cytoplasm and colocalized with each other. In addition, PABP1 expression was upregulated and its translation efficiency was increased during the recovery period, possibly to meet additional demands on the translation machinery. HSP27 remained associated with the eIF4G–PABP1 complex during recovery from heat shock. Therefore, our results raise the possibility that the association of HSP27 with eIF4G may not be sufficient to suppress cap‐dependent translation during heat shock. In addition, we provide evidence that the terminal oligopyrimidine cis‐element of PABP1 mRNA is responsible for the preferential increase of PABP1 mRNA translation in cells undergoing recovery from heat shock.
Introduction:Benign pneumoperitoneum (BPPT) is defined as asymptomatic free intraabdominal air or as pneumoperitoneum without peritonitis. Symptomatic free air requires surgical anagement, but management of asymptomatic pneumoperitoneum is controversial. In this study, we investigate the diagnosis and treatment of BPPT in children.Clinical Findings:The clinical data of 9 pediatric patients with BPPT who were admitted to our hospital from January 2000 to January 2015 were retrospectively analyzed to summarize the diagnosis and treatment. Overall, 9 cases were included with 8 males and 1 female, aged from 4 days to 4 years. Among them there were 6 newborns (including 1 premature infant). Patients were all admitted to hospital with the major clinical symptom of abdominal distension, including 2 cases accompanied by tachypnea, 2 cases with vomiting, 1 case with diarrhea, and 2 cases with fever. No previous constipation or obstructive defecation existed. Six newborns had meconium defecation within 24 hours after birth. Physical examination revealed all patients with relaxed abdominal wall except 1 patient with abdominal distension had slight muscle stiffness and hyperactive bowel sounds. Abdominal X-ray suggested free air under the diaphragm in all cases.Interventions/Outcomes:All patients except for one case of laparotomy were conservatively treated and cured with fasting, infection prevention, rehydration, abdominocentesis, and close observation. Nine cases of patients were all discharged with no death occurrence. After discharge follow-up of 7 months to 6 years was conducted. There was no recurrence of similar symptoms, and children were in good growth and development.Conclusion:The diagnosis of BPPT mainly relies on clinical symptoms in patient, careful abdominal examination, abdominal X-ray combined with abdominocentesis, and the exclusion of gastrointestinal perforation for confirmation. Conservative treatment can cure the disease. Attention should be paid to distinguish with surgical pneumoperitoneum to avoid unnecessary surgical exploration.
BackgroundSmall cell carcinoma of the cervix (SCCC) is a very rare tumor. Due to its rarity and the long time period, there is a paucity of information pertaining to prognostic factors associated with survival. The objective of this study was to determine whether clinicopathologic finings or immunohistochemical presence of molecular markers predictive of clinical outcome in patients with SCCC.Methodology and FindingsWe retrospectively reviewed a total of 293 patients with SCCC (47 patients from Cancer Center of Sun Yat-sen University in china, 71 patients from case report of china journal, 175 patients from case report in PubMed database). Of those 293 patients with SCCC, the median survival time is 23 months. The 3-year overall survival rates (OS) and 3-year disease-free survival rates (DFS) for all patients were 34.5% and 31.1%, respectively. Univariate and multivariate analysis showed that FIGO stage (IIb–IV VS I–IIa, Hazard Ratio (HR) = 3.08, 95% confidence interval (CI) of ratio = [2.05, 4.63], P<0.001), tumor mass size (≥4 cm VS <4 cm, HR = 2.37, 95% CI = [1.28, 4.36], P = 0.006) and chromogranin A (CgA) (Positive VS Negative, HR = 1.81, 95% CI = [1.12, 2.91], P = 0.015) were predictive of poor prognosis. CgA stained positive was found to be highly predictive of death in early-stage (FIGO I–IIa) patient specifically.ConclusionsPatients with SCCC have poor prognosis. FIGO stage, tumor mass size and CgA stained positive may act as a surrogate for factors prognostic of survival. CgA may serve as a useful marker in prognostic evaluation for early-stage patients with SCCC.
Diabetes-related brain damage of primary onset middle-age T2DM patients with right DLPFC-posterior parietal lobe and parahippocampal gyrus default network causes impairment of spatial working memory and mild cognitive dysfunction.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.