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1.
J Pain Res ; 17: 1441-1451, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38628430

RESUMO

Background: Studies have shown that oral oxycontin tablets can be used for opioid titration. The European Society for Medical Oncology (ESMO) guidelines for adult cancer pain recommend opioid titration through the parenteral route, usually the intravenous or subcutaneous route. Patient-controlled subcutaneous analgesia (PCSA) with hydromorphone needs further evaluation for opioid titration. This prospective multicenter study was designed to compare the efficacy and safety of hydromorphone PCSA with oral oxycontin tablets for opioid titration of cancer pain. Patients and Methods: Eligible patients with cancer pain were randomly assigned in a 1:1 ratio to the PCSA group or the oxycontin group for dose titration. Different titration methods were given in both groups depending on whether the patient had an opioid tolerance. The primary endpoint of this study was time to successful titration (TST). Results: A total of 256 patients completed this study. The PCSA group had a significantly lower TST compared with the oxycontin group (median [95% confidence interval (CI)], 5.5[95% CI:2.5-11.5] hours vs.16.0 [95% CI:11.5-22.5] hours; p<0.001). The frequency (median; interquartile) of breakthrough pain (Btp) over 24 hours was significantly lower in the PCSA group (2.5;2.0-3.5) than in the oxycontin group.(3.0; 2.5-4.5) (p=0.04). The pain was evaluated by numeric rating scale (NRS) score at 12 hours after the start of titration. The pain score (median; interquartile) was significantly lower in the PCSA versus the oxycontin group (2.5;1.5-3.0) vs 4.5;3.0-6.0) (p=0.02). The equivalent dose of oral morphine (EDOM) for a successful titration was similar in both groups (p=0.29), but there was a significant improvement in quality of life (QoL) in both groups (p=0.03). No between-group difference in the incidence of opioid-related adverse effects was observed (p=0.32). Conclusion: Compared with oral oxycontin tablet, the use of PCSA with hydromorphone achieved a shorter titration duration for patients with cancer pain (p<0.001), without significantly increasing adverse events (p=0.32).

2.
Biotechnol J ; 19(2): e2300159, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38403400

RESUMO

Biofilms of the foodborne pathogen Staphylococcus aureus show improved resistance to antibiotics and are difficult to eliminate. To enhance antibacteria and biofilm dispersion via extracellular matrix diffusion, a new lipid nanoparticle was prepared, which employed a mixture of phospholipids and a 0.8% surfactin shell. In the lipid nanoparticle, 31.56 µg mL-1 of erythromycin was encapsulated. The lipid nanoparticle size was approximately 52 nm and the zeta-potential was -67 mV, which was measured using a Marvin laser particle size analyzer. In addition, lipid nanoparticles significantly dispersed the biofilms of S. aureus W1, CICC22942, and CICC 10788 on the surface of stainless steel, reducing the total viable count of bacteria in the biofilms by 103 CFU mL-1 . In addition, the lipid nanoparticle can remove polysaccharides and protein components from the biofilm matrix. The results of laser confocal microscopy showed that the lipid nanoparticles effectively killed residual bacteria in the biofilms. Thus, to thoroughly eliminate biofilms on material surfaces in food factories to avoid repeated contamination, drug-lipid nanoparticles present a suitable method to achieve this.


Assuntos
Nanopartículas , Infecções Estafilocócicas , Humanos , Staphylococcus aureus , Biofilmes , Lipossomos , Antibacterianos/farmacologia , Infecções Estafilocócicas/microbiologia , Bactérias
3.
Inhal Toxicol ; 36(2): 100-105, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38368594

RESUMO

OBJECTIVE: The gram-negative bacterial cell wall component endotoxin (lipopolysaccharide, LPS) is a key component of particulate matter (PM). PM exposure is associated with cardiovascular morbidity and mortality. However, the contribution of individual components of PM to acute and chronic cardiovascular measures is not clear. This study examines whether systemic inflammation induced by LPS inhalation causes acute changes in cardiovascular physiology measures. MATERIALS AND METHODS: In this double blinded, placebo-controlled crossover study, fifteen adult volunteers underwent inhalation exposure to 20,000 EU Clinical Center Reference Endotoxin (CCRE). Peripheral blood and induced sputum neutrophils were obtained at baseline and six hours post-exposure. Blood pressure, measures of left ventricular function (ejection fraction (LVEF) and global longitudinal strain (LVGLS)), and indices of endothelial function (flow mediated dilation (FMD) and velocity time integral during hyperemia (VTIhyp)) were measured before and after treatment. Wilcoxon sign-rank tests and linear mixed models were used for statistical analysis. RESULTS: In comparison with normal saline, LPS inhalation resulted in significant increases in peripheral blood and sputum neutrophils but was not associated with significant alterations in blood pressure, LVGLS, LVEF, FMD, or VTIhyp. DISCUSSION AND CONCLUSIONS: In healthy adults, systemic inflammation after LPS inhalation was not associated with acute changes in cardiovascular physiology. Larger studies are needed to investigate the effects of other PM components on inflammation induced cardiovascular dysfunction.


Assuntos
Endotoxinas , Neutrófilos , Adulto , Humanos , Endotoxinas/toxicidade , Lipopolissacarídeos/toxicidade , Estudos Cross-Over , Inflamação , Material Particulado
4.
Int J Mol Sci ; 25(3)2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38339148

RESUMO

Pseudomonas aeruginosa is a clinically challenging pathogen due to its high resistance to antibiotics. Quorum sensing inhibitors (QSIs) have been proposed as a promising strategy to overcome this resistance by interfering with the bacterial communication system. Among the potential targets of QSIs, PqsR is a key regulator of quorum sensing in Pseudomonas aeruginosa. However, the current research on PqsR inhibitors is limited by the lack of diversity in the chemical structures and the screening methods. Therefore, this study aims to develop a multidimensional screening model for PqsR inhibitors based on both ligand- and receptor-based approaches. First, a pharmacophore model was constructed from a training set of PqsR inhibitors to identify the essential features and spatial arrangement for the activity. Then, molecular docking and dynamics simulations were performed to explore the core interactions between PqsR inhibitors and their receptor. The results indicate that an effective PqsR inhibitor should possess two aromatic rings, one hydrogen bond acceptor, and two hydrophobic groups and should form strong interactions with the following four amino acid residues: TYR_258, ILE_236, LEU_208, and GLN_194. Moreover, the docking score and the binding free energy should be lower than -8 kcal/mol and -40 kcal/mol, respectively. Finally, the validity of the multidimensional screening model was confirmed by a test set of PqsR inhibitors, which showed a higher accuracy than the existing screening methods based on single characteristics. This multidimensional screening model would be a useful tool for the discovery and optimization of PqsR inhibitors in the future.


Assuntos
Simulação de Dinâmica Molecular , Farmacóforo , Simulação de Acoplamento Molecular , Percepção de Quorum , Antibacterianos/química
5.
Heliyon ; 10(1): e23702, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38187217

RESUMO

Background: Massive hemoptysis during pregnancy is very rare. Dieulafoy's disease is one of the causes of massive hemoptysis. There are few reports of ECMO use to treat massive hemoptysis during pregnancy. Findings: We report for the first time a patient with Dieulafoy's disease diagnosed at 29 weeks of pregnancy. The patient's hemoptysis occurred rapidly with large volumes. The bleeding amount reached 500 ml within half an hour, with the development of asphyxia and respiratory and cardiac arrest due to a blood clot blocking the airway. After successful cardiopulmonary resuscitation, the ventilator could not maintain effective ventilation. Emergency establishment of VV-ECMO was performed to maintain oxygen, and hemostasis was successfully achieved by performing bronchial artery embolization twice. We successfully cleaned blood clots in the airway four times by freezing and using a foreign body retrieval basket with an electronic bronchoscope. At the same time, small and smooth nodular lesions were found under bronchoscopy, and blood vessels with a diameter of 1.5 mm were found under Doppler mode with an ultrasonic bronchoscope, which was consistent with a diagnosis of Dieulafoy's disease. VV-ECMO was successfully stopped on the 3rd day of the disease course, tracheal intubation was successfully removed on the 5th day of the disease course, and the patient was discharged with no complications on the 16th day of the disease course.

6.
Biosens Bioelectron ; 248: 115993, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38183788

RESUMO

Simultaneous, reliable, and ultra-sensitive analysis of promising miRNA biomarkers of colorectal cancer (CRC) in serum is critical for early diagnosis and prognosis of CRC. In this work, we proposed a novel 3D hierarchic assembly clusters-based SERS strategy with dual enrichment and enhancement designed for the ultrasensitive and quantitative analysis of two upregulated CRC-related miRNAs (miR-21 and miR-31). The biosensor contains the following: (1) SERS probe, Au nanocage@Au nanoparticles (AuNC@Au NPs) labeled with Raman reporters (RaRs). (2) magnetic capture unit, Ag-coated Fe3O4 magnetic nanoparticles (AgMNPs) modified with internal standard (IS). (3) signal amplify probes (SA probes) for the formation of hierarchic assembly clusters. Based on this sensing strategy, the intensity ratio IRaRs/IIS with Lg miRNAs presents a wide linear range (10 aM-100 pM) with a limit of detection of 3.46 aM for miR-21, 6.49 aM for miR-31, respectively. Moreover, the biosensor shows good specificity and anti-interference ability, and the reliability and repeatability of the strategy were then verified by practical detection of clinical serum. Finally, the biosensor can distinguish CRC cancer subjects from normal ones and guide the distinct tumor, lymph node, and metastasis (TNM) stages. Overall, benefiting from the face-to-face coupling of hierarchic assembly clusters, rapid magnetic enrichment and IS signal calibration of AgMNPs, the established biosensor achieves ultra-sensitive and simultaneous detection of dual miRNAs and opens potential avenues for prediction and staging of CRC.


Assuntos
Técnicas Biossensoriais , Neoplasias Colorretais , Nanopartículas Metálicas , MicroRNAs , Humanos , MicroRNAs/análise , Ouro , Reprodutibilidade dos Testes , Análise Espectral Raman , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Limite de Detecção
7.
Science ; 383(6681): 413-421, 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38271512

RESUMO

Age-associated B cells (ABCs) accumulate during infection, aging, and autoimmunity, contributing to lupus pathogenesis. In this study, we screened for transcription factors driving ABC formation and found that zinc finger E-box binding homeobox 2 (ZEB2) is required for human and mouse ABC differentiation in vitro. ABCs are reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B cells. In mice with toll-like receptor 7 (TLR7)-driven lupus, ZEB2 is essential for ABC formation and autoimmune pathology. ZEB2 binds to +20-kb myocyte enhancer factor 2b (Mef2b)'s intronic enhancer, repressing MEF2B-mediated germinal center B cell differentiation and promoting ABC formation. ZEB2 also targets genes important for ABC specification and function, including Itgax. ZEB2-driven ABC differentiation requires JAK-STAT (Janus kinase-signal transducer and activator of transcription), and treatment with JAK1/3 inhibitor reduces ABC accumulation in autoimmune mice and patients. Thus, ZEB2 emerges as a driver of B cell autoimmunity.


Assuntos
Autoimunidade , Linfócitos B , Diferenciação Celular , Regulação da Expressão Gênica , Lúpus Eritematoso Sistêmico , Homeobox 2 de Ligação a E-box com Dedos de Zinco , Animais , Humanos , Camundongos , Autoimunidade/genética , Linfócitos B/citologia , Linfócitos B/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Haploinsuficiência , Envelhecimento/imunologia , Modelos Animais de Doenças , Feminino
8.
Int J Biol Sci ; 20(2): 733-750, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38169726

RESUMO

Macrophage pyroptosis and neutrophil extracellular traps (NETs) play a critical role in sepsis pathophysiology; however, the role of macrophage pyroptosis in the regulation of NETs formation during sepsis is unknown. Here, we showed that macrophages transfer mitochondria to neutrophils through microvesicles following pyroptosis; this process induces mitochondrial dysfunction and triggers the induction of NETs formation through mitochondrial reactive oxygen species (mtROS)/Gasdermin D (GSDMD) axis. These pyroptotic macrophage-derived microvesicles can induce tissues damage, coagulation, and NETs formation in vivo. Disulfiram partly inhibits these effects in a mouse model of sepsis. Pyroptotic macrophage-derived microvesicles induce NETs formation through mitochondrial transfer, both in vitro and in vivo. Microvesicles-mediated NETs formation depends on the presence of GSDMD-N-expressing mitochondria in the microvesicles. This study elucidates a microvesicles-based pathway for NETs formation during sepsis and proposes a microvesicles-based intervention measure for sepsis management.


Assuntos
Armadilhas Extracelulares , Sepse , Camundongos , Animais , Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , Mitocôndrias/metabolismo , Macrófagos/metabolismo , Sepse/metabolismo
9.
Biochem Genet ; 62(1): 504-529, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37386336

RESUMO

Although immunotherapy is a valuable treatment for gastric cancer (GC), identifying the patients who would benefit most from this approach presents a challenge. In this study, GC patients were divided into two subtypes by consensus clustering according to T cell-mediated tumor killing related genes (TTKRGs), and there were significant differences in tumor-infiltrating immune cells, signaling pathways, and gene expression of immunomodulators and inhibitory immune checkpoints between the two subtypes. Then, we developed an individualized signature based on TTKRGs, and its clinical and predictive value in GC patients for chemotherapeutic and immunotherapeutic responses was assessed. We confirmed the expression levels of signature genes in GC tumor tissue using quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, to improve the accuracy of GC prognosis predictions, we established a nomogram. We further identified some compounds as sensitive drugs targeting GC risk groups. The signature showed significant predictive ability across RNA-seq, microarray, and qRT-PCR cohorts, which could assist in predicting survival, immunotherapeutic and chemotherapeutic outcomes in GC patients.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Prognóstico , Linfócitos T , Análise por Conglomerados , RNA-Seq
10.
Phytomedicine ; 123: 155251, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38056151

RESUMO

BACKGROUND: Insomnia and depressive disorder are two common symptoms with a reciprocal causal relationship in clinical practice, which are usually manifested in comorbid form. Several medications have been widely used in the treatment of insomnia and depression, but most of these drugs show non-negligible side effects. Currently, many treatments are indicated for insomnia and depressive symptom, including Chinese herbal medicine such as Gastrodia elata Blume (G. elata), which has excellent sedative-hypnotic and antidepressant effects in clinical and animal studies. PURPOSE: To summarize the mechanisms of insomnia and depression and the structure-activity mechanism for G. elata to alleviate these symptoms, particularly by hypothalamic-pituitary-adrenal (HPA) axis and intestinal flora, aiming to discover new approaches for the treatment of insomnia and depression. METHODS: The following electronic databases were searched from the beginning to November 2023: PubMed, Web of Science, Google Scholar, Wanfang Database, and CNKI. The following keywords of G. elata were used truncated with other relevant topic terms, such as depression, insomnia, antidepressant, sedative-hypnotic, neuroprotection, application, safety, and toxicity. RESULTS: Natural compounds derived from G. elata could alleviate insomnia and depressive disorder, which is involved in monoamine neurotransmitters, inflammatory response, oxidative stress, and gut microbes, etc. Several clinical trials showed that G. elata-derived natural compounds that treat depression and insomnia have significant and safe therapeutic effects, but further well-designed clinical and toxicological studies are needed. CONCLUSION: G. elata exerts a critical role in treating depression and insomnia due to its multi-targeting properties and fewer side effects. However, more clinical and toxicological studies should be performed to further explore the sedative-hypnotic and antidepressant mechanisms of G. elata and provide more evidence and recommendations for its clinical application. Our review provides an overview of G. elata treating insomnia with depression for future research direction.


Assuntos
Gastrodia , Distúrbios do Início e da Manutenção do Sono , Animais , Extratos Vegetais/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico
11.
Neural Netw ; 171: 485-496, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38157732

RESUMO

All man-made flying objects in the sky, ships in the ocean can be regarded as small infrared targets, and the method of tracking them has been received widespread attention in recent years. In search of a further efficient method for infrared small target recognition, we propose a hierarchical attention-guided multiscale aggregation network (HAMANet) in this thesis. The proposed HAMANet mainly consists of a compound guide multilayer perceptron (CG-MLP) block embedded in the backbone net, a spatial-interactive attention module (SiAM), a pixel-interactive attention module (PiAM) and a contextual fusion module (CFM). The CG-MLP marked the width-axis, height-axis, and channel-axis, which can result in a better segmentation effect while reducing computational complexity. SiAM improves global semantic information exchange by increasing the connections between different channels, while PiAM changes the extraction of local key information features by enhancing information exchange at the pixel level. CFM fuses low-level positional information and high-level channel information of the target through coding to improve network stability and target feature utilization. Compared with other state-of-the-art methods on public infrared small target datasets, the results show that our proposed HAMANet has high detection accuracy and a low false-alarm rate.


Assuntos
Redes Neurais de Computação , Reconhecimento Psicológico , Humanos , Semântica , Processamento de Imagem Assistida por Computador
12.
Heliyon ; 9(12): e22873, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38125480

RESUMO

Objectives: The spread of SARS-Cov-2 remains a global concern along with the emergence of variants. This study aims to characterize the epidemiological and clinical features of hospitalized patients who were dragonized with five different variants of SARS-CoV-2 during the past 3 years. Methods: This retrospective study recruited 432 COVID-19 patients who were hospitalized in the First Hospital of Changsha from January 2020 to August 2022. Clinical records on clinical symptoms, laboratory profiles, and chest CT images was collected. The epidemiological and clinical features were compared between COVID-19 patients infected with either the wild-type, Omicron variant or pre- Omicron variants (e.g., Alpha, Beta, Delta). Results: A total of 432 laboratory-confirmed COVID-19 inpatients were dialogized during three waves, including 247 cases during the wild-type transmission period, 65 cases during the transmission period of pre-Omicron variants, and 119 cases during the transmission period of Omicron variants. The proportion of moderately or severely ill inpatients showed a gradual decline from the wild-type transmission period to the Omicron transmission period. The common symptoms of inpatients infected with SARS-CoV-2 wildtype strains included fever (67.61 %), cough (57.89 %), fatigue (33.60 %), and shortness of breath (12.15 %). In contrast, patients infected with other variants mostly showed upper respiratory symptoms. Based on chest CT images, a lower degree of acute pulmonary infection was observed among inpatients infected with the Omicron variants than those infected with the wild-type strain (31.09 % vs 93.12 %, p-value<0.01). Conclusions: Compared with the wild-type strain, SARS-CoV-2 variants of concern, especially the Omicron variant, mostly caused a lower degree of acute pulmonary infection, indicating the reduced disease severity and mortality among hospitalized COVID-19 patients.

13.
ACS Chem Biol ; 18(12): 2474-2484, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37992317

RESUMO

Bacterial trans-acyltransferase polyketide synthases (trans-AT PKSs) synthesize natural products with intricate structures and potent biological activities. They generally contain various unusual modules or trans-acting enzymes. Herein, we report the trans-AT PKS-derived biosynthetic pathway of the shuangdaolide with a rare internal 2-hydroxycyclopentenone moiety. The multidomain protein SdlR catalyzes the synthesis of 16,17-epoxide during polyketide chain elongation. The SdlR contains a ketoreductase, an acyl carrier protein, a flavoprotein monooxygenase, and a serine hydrolase domain. This online epoxidation occurs at unusual positions away from the thioester. Then, two tailoring enzymes, SdlB and SdlQ, convert a methylene to a carbonyl group and oxidize a hydroxyl group to a carbonyl group, respectively. The following spontaneous opening of 16,17-epoxide induces the formation of a new C-C bond to generate the 2-hydroxycyclopentenone moiety. The characterization of the shuangdaolide pathway extends the understanding of the trans-AT PKSs, facilitating the mining and identification of this class of natural products.


Assuntos
Produtos Biológicos , Policetídeos , Policetídeo Sintases/metabolismo , Policetídeos/química , Aciltransferases/metabolismo , Compostos de Epóxi
14.
Nat Prod Rep ; 2023 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-37873660

RESUMO

Covering: 2005 to August, 2023Polyamine-containing natural products (NPs) have been isolated from a wide range of terrestrial and marine organisms and most of them exhibit remarkable and diverse activities, including antimicrobial, antiprotozoal, antiangiogenic, antitumor, antiviral, iron-chelating, anti-depressive, anti-inflammatory, insecticidal, antiobesity, and antioxidant properties. Their extraordinary activities and potential applications in human health and agriculture attract increasing numbers of studies on polyamine-containing NPs. In this review, we summarized the source, structure, classification, bioactivities and biosynthesis of polyamine-containing NPs, focusing on the biosynthetic mechanism of polyamine itself and representative polyamine alkaloids, polyamine-containing siderophores with catechol/hydroxamate/hydroxycarboxylate groups, nonribosomal peptide-(polyketide)-polyamine (NRP-(PK)-PA), and NRP-PK-long chain poly-fatty amine (lcPFAN) hybrid molecules.

15.
J Allergy Clin Immunol Glob ; 2(4): 100177, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37876758

RESUMO

Background: Air pollutants, including particulates from wood smoke, are a significant cause of exacerbation of lung disease. γ-Tocopherol is an anti-inflammatory isoform of vitamin E that has been shown to reduce allergen-, ozone-, and endotoxin-induced inflammation. Objective: The objective of this study was to determine whether γ-tocopherol would prevent experimental wood smoke-induced airway inflammation in humans. Methods: This was a randomized, placebo-controlled clinical trial testing the effect of a short course of γ-tocopherol-enriched supplementation on airway inflammation following a controlled exposure to wood smoke particulates. Results: Short-course γ-tocopherol intervention did not reduce wood smoke-induced neutrophilic airway inflammation, but it did prevent wood smoke-induced eosinophilic airway inflammation. Conclusion: γ-Tocopherol is a potential intervention for exacerbation of allergic airway inflammation, but further study examining longer dosing periods is required.

16.
J Med Chem ; 66(21): 14735-14754, 2023 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-37874867

RESUMO

Pseudomonas aeruginosa (P. aeruginosa) is well-known to cause biofilm-associated drug resistance and infections that often lead to treatment failure. Herein, we reported a dual-acting antibiofilm strategy by inhibiting both the bacterial quorum sensing system and the iron uptake system. A series of coumarin derivatives were synthesized and evaluated, and compound 4t was identified as the most effective biofilm inhibitor (IC50 = 3.6 µM). Further mechanistic studies have confirmed that 4t not only inhibits the QS systems but also competes strongly with pyoverdine as an iron chelator, causing an iron deficiency in P. aeruginosa. Additionally, 4t significantly improved the synergistic antibacterial effects of ciprofloxacin and tobramycin by more than 200-1000-fold compared to the single-dose antibiotic treatments. Therefore, our study has shown that 4t is a potentially novel antibacterial synergist candidate to treat bacterial infections.


Assuntos
Pseudomonas aeruginosa , Percepção de Quorum , Cumarínicos/farmacologia , Antibacterianos/farmacologia , Biofilmes , Ferro/farmacologia , Homeostase , Fatores de Virulência , Proteínas de Bactérias
17.
Nat Commun ; 14(1): 6619, 2023 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-37857663

RESUMO

The broad bioactivities of nonribosomal peptides rely on increasing structural diversity. Genome mining of the Burkholderiales strain Schlegelella brevitalea DSM 7029 leads to the identification of a class of dodecapeptides, glidonins, that feature diverse N-terminal modifications and a uniform putrescine moiety at the C-terminus. The N-terminal diversity originates from the wide substrate selectivity of the initiation module. The C-terminal putrescine moiety is introduced by the unusual termination module 13, the condensation domain directly catalyzes the assembly of putrescine into the peptidyl backbone, and other domains are essential for stabilizing the protein structure. Swapping of this module to another two nonribosomal peptide synthetases leads to the addition of a putrescine to the C-terminus of related nonribosomal peptides, improving their hydrophilicity and bioactivity. This study elucidates the mechanism for putrescine addition and provides further insights to generate diverse and improved nonribosomal peptides by introducing a C-terminal putrescine.


Assuntos
Peptídeos , Putrescina , Peptídeos/genética , Peptídeos/química , Peptídeo Sintases/metabolismo
19.
ACS Nano ; 17(20): 20073-20086, 2023 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-37792448

RESUMO

Despite the potential indicating role of tyrosinase (TYR) in cutaneous melanoma, how to capture the real changes of TYR in suspicious skin remains a major challenge. Unlike the traditional human serum test, this study reports a sensing platform that incorporates a wearable microneedle (MN) patch and trimetallic Au@Ag-Pt nanoparticles (NPs) for surface-enhanced Raman scattering (SERS) and colorimetric dual-mode detecting TYR in human skin in situ toward potential melanoma screening. In the presence of TYR, catechol immobilized on MN is preferentially oxidized to benzoquinone, which competitively impedes the interaction of MN and Au@Ag-Pt NPs, triggering the SERS-colorimetric signal reciprocal switch. Using a B16F10 mouse melanoma model, our platform is capable of noninvasively piercing the skin surface and detecting TYR levels before and during anti-PD-1 antibody treatment, which would be highly informative for prognostic judgment and illness monitoring of melanoma. Through in situ sensing for capturing the metabolic changes of TYR in advance, this platform was successfully applied to discriminate the melanoma subjects from skin moles and normal ones (p < 0.001), as well as screen potential melanoma from lactate dehydrogenase (LDH)-negative patients. Melanoma growth and prognosis can still be monitored through recording the continuous change of TYR levels. More importantly, the well-defined flexible and stretchable characteristics of the MN patch allow robustly adhering to the skin without inducing chemical or physical irritation. We believe this platform integrating MN-based in situ sensing, TYR responsiveness, and SERS/colorimetric dual-readout strategy will have high clinical importance in early diagnosis and monitoring of cutaneous melanoma.


Assuntos
Melanoma , Nanopartículas Metálicas , Neoplasias Cutâneas , Dispositivos Eletrônicos Vestíveis , Animais , Camundongos , Humanos , Melanoma/diagnóstico , Melanoma/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Neoplasias Cutâneas/diagnóstico , Análise Espectral Raman , Ouro
20.
Int J Womens Health ; 15: 1501-1514, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37840555

RESUMO

Objective: This study aimed to investigate the association of reproductive hormones with primary dysmenorrhea in Chinese women. Methods: A case-control study was conducted and patients with primary dysmenorrhea and non-dysmenorrhea participants were recruited. Oxytocin, PGF2α, vasopressin, estriol and estradiol were respectively measured in plasma collected three to five days after menstruation. Restricted cubic spline and multiple logistic regression models were adopted to analyze the association between hormones and primary dysmenorrhea. Results: There were 604 participants enrolled in our study including 300 patients with primary dysmenorrhea. After adjustment for the potential confounders, oxytocin levels (Q3: OR (95% CI) = 0.50 (0.27~0.95) (p=0.035); Q4: 0.34 (0.17~0.66) (p=0.001)) and PGF2α levels (Q3: 0.45 (0.24~0.87) (p=0.017); Q4: 0.43 (0.22~0.84) (p=0.013)) were respectively associated with an decreased risk of primary dysmenorrhea, but estradiol (Q2: 2.18 (1.13~4.19) (p=0.020); Q3: 2.17 (1.12~4.19) (p=0.022)) and vasopressin (Q3: 2.88 (1.48~5.63) (p=0.002); Q4: 3.20 (1.65~6.22) (p<0.001)) with an increased risk of primary dysmenorrhea, respectively. Among patients with primary dysmenorrhea, the higher estriol level was associated with higher frequent dysmenorrhea (Q2: 3.12 (1.32~7.34) (p=0.009); Q3: 4.97 (2.08~11.85) (p<0.001)) and always dysmenorrhea (Q2: 2.51 (1.03~6.11) (p=0.041); Q3: 3.10 (1.25~7.73) (p=0.015)). Similarly, high estriol levels were associated with the higher degree of pain significantly only when hormone levels were at a high level (Q3: 2.06 (1.03~4.18) (p=0.043)). Conclusion: Higher serum vasopressin and estradiol concentrations as well as lower oxytocin and PGF2α levels were associated with higher risk of primary dysmenorrhea. Estrogen showed a reverse U-shape association on the frequency and degree of pain among patients with primary dysmenorrhea.

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