The cytochrome P4501A1 (CYP1A1) inhibitor bergamottin enhances host tolerance to multidrug-resistant Vibrio vulnificus infection.

PURPOSE: Vibrio vulnificus (V. Vulnificus) infection is characterized by rapid onset, aggressive progression, and challenging treatment. Bacterial resistance poses a significant challenge for clinical anti-infection treatment and is thus the subject of research. Enhancing host infection tolerance represents a novel infection prevention strategy to improve patient survival. Our team initially identified cytochrome P4501A1 (CYP1A1) as an important target owing to its negative modulation of the body's infection tolerance. This study explored the superior effects of the CYP1A1 inhibitor bergamottin compared to antibiotic combination therapy on the survival of mice infected with multidrug-resistant V. Vulnificus and the protection of their vital organs. METHODS: An increasing concentration gradient method was used to induce multidrug-resistant V. Vulnificus development. We established a lethal infection model in C57BL/6J male mice and evaluated the effect of bergamottin on mouse survival. A mild infection model was established in C57BL/6J male mice, and the serum levels of creatinine, urea nitrogen, aspartate aminotransferase, and alanine aminotransferase were determined using enzyme-linked immunosorbent assay to evaluate the effect of bergamottin on liver and kidney function. The morphological changes induced in the presence of bergamottin in mouse organs were evaluated by hematoxylin and eosin staining of liver and kidney tissues. The bacterial growth curve and organ load determination were used to evaluate whether bergamottin has a direct antibacterial effect on multidrug-resistant V. Vulnificus. Quantification of inflammatory factors in serum by enzyme-linked immunosorbent assay and the expression levels of inflammatory factors in liver and kidney tissues by real-time quantitative polymerase chain reaction were performed to evaluate the effect of bergamottin on inflammatory factor levels. Western blot analysis of IκBα, phosphorylated IκBα, p65, and phosphorylated p65 protein expression in liver and kidney tissues and in human hepatocellular carcinomas-2 and human kidney-2 cell lines was used to evaluate the effect of bergamottin on the nuclear factor kappa-B signaling pathway. One-way ANOVA and Kaplan-Meier analysis were used for statistical analysis. RESULTS: In mice infected with multidrug-resistant V. Vulnificus, bergamottin prolonged survival (p = 0.014), reduced the serum creatinine (p = 0.002), urea nitrogen (p = 0.030), aspartate aminotransferase (p = 0.029), and alanine aminotransferase (p = 0.003) levels, and protected the cellular morphology of liver and kidney tissues. Bergamottin inhibited interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α expression in serum (IL-1ß: p = 0.010, IL-6: p = 0.029, TNF-α: p = 0.025) and inhibited the protein expression of the inflammatory factors IL-1ß, IL-6, TNF-α in liver (IL-1ß: p = 0.010, IL-6: p = 0.011, TNF-α: p = 0.037) and kidney (IL-1ß: p = 0.016, IL-6: p = 0.011, TNF-α: p = 0.008) tissues. Bergamottin did not affect the proliferation of multidrug-resistant V. Vulnificus or the bacterial load in the mouse peritoneal lavage fluid (p = 0.225), liver (p = 0.186), or kidney (p = 0.637). CONCLUSION: Bergamottin enhances the tolerance of mice to multidrug-resistant V. Vulnificus infection. This study can serve as a reference and guide the development of novel clinical treatment strategies for V. Vulnificus.

Genetic and epigenetic signatures for improved breeding of cultivated blueberry.

Blueberry belongs to the Vaccinium genus and is a highly popular fruit crop with significant economic importance. It was not until the early twentieth century that they began to be domesticated through extensive interspecific hybridization. Here, we collected 220 Vaccinium accessions from various geographical locations, including 154 from the United States, 14 from China, eight from Australia, and 29 from Europe and other countries, comprising 164 Vaccinium corymbosum, 15 Vaccinium ashei, 10 lowbush blueberries, seven half-high blueberries, and others. We present the whole-genome variation map of 220 accessions and reconstructed the hundred-year molecular history of interspecific hybridization of blueberry. We focused on the two major blueberry subgroups, the northern highbush blueberry (NHB) and southern highbush blueberry (SHB) and identified candidate genes that contribute to their distinct traits in climate adaptability and fruit quality. Our analysis unveiled the role of gene introgression from Vaccinium darrowii and V. ashei into SHB in driving the differentiation between SHB and NHB, potentially facilitating SHB's adaptation to subtropical environments. Assisted by genome-wide association studies, our analysis suggested VcTBL44 as a pivotal gene regulator governing fruit firmness in SHB. Additionally, we conducted whole-genome bisulfite sequencing on nine NHB and 12 SHB cultivars, and characterized regions that are differentially methylated between the two subgroups. In particular, we discovered that the ß-alanine metabolic pathway genes were enriched for DNA methylation changes. Our study provides high-quality genetic and epigenetic variation maps for blueberry, which offer valuable insights and resources for future blueberry breeding.

Research perspective in the clinical management of Kawasaki disease.

This study examines research perspective in the clinical diagnosis, treatment, and prevention of cardiovascular complications in Kawasaki Disease (KD). Starting with an overview of the disease, it introduces KD's clinical manifestations, etiology, epidemiological features, and its impact on the cardiovascular system. Subsequently, the study discusses in detail the diagnostic methods, pathological mechanisms, and treatment strategies for KD, including foundational and emerging approaches such as high-dose intravenous immunoglobulin and aspirin therapy, biologic therapy, and corticosteroid pulse therapy. Additionally, it outlines strategies for preventing cardiovascular complications, including early risk assessment and long-term management. The study also explores the intersection of the COVID-19 pandemic with an increase in KD-like symptoms, emphasizing the need for further studies on the association between SARS-CoV-2 and KD. Lastly, it explores future research directions to enhance understanding of KD and improve patient outcomes and quality of life. This study provides valuable insights into the comprehensive treatment and management of KD and highlights avenues for future research.

[Authenticity discrimination for Galli Gigerii Endothelium Corneum based on UPLC-MS/MS and peptidomics].

Peptidomics was employed to systematically analyze the characteristic peptides in Galli Gigerii Endothelium Corneum and its adulterants and establish a method for distinguishing Galli Gigerii Endothelium Corneum from its adulterants, including the gizzard membranes from ducks, geese, and pigeons. UPLC-Q-Exactive Orbitrap-MS was combined with multivariate statistical analysis to analyze the peptides in Galli Gigerii Endothelium Corneum and its adulterants. The structures of peptides were identified by pNovo combined with manual recognition of spectra, and synthetic peptide standards were used for validation. LC-MS/MS was used to optimize the sample pre-processing conditions, including the extraction procedure, extraction time, extraction solvents, and solvent volumes, for the characteristic peptide LESY in Galli Gigerii Endothelium Corneum. Multiple reaction monitoring(MRM) in the ESI~+ mode with m/z 511.24→269.11 and 511.24→243.13 as detection ions was employed for qualitative and quantitative analyses. The established UPLC-MS/MS method demonstrated good specificity, stability, and durability. The content of LESY in 16 batches of Galli Gigerii Endothelium Corneum samples ranged from 55.03 to 113.36 µg·g~(-1). Additionally, a qualitative detection method for the common peptide RDPVLVSR in adulterants was established with m/z 471.28→785.45 and 471.28→670.41 as the detection ions. This study established a convenient, rapid, and accurate detection method for the characteristic peptides in Galli Gigerii Endothelium Corneum and its adulterants. The method possesses good specificity, stability, and durability, providing a valuable reference for the identification and quality control of Galli Gigerii Endothelium Corneum and other traditional Chinese medicines derived from animal sources.

Genome-Wide Identification of the Sulfate Transporters Gene Family in Blueberry (Vaccinium spp.) and Its Response to Ericoid Mycorrhizal Fungi.

Sulfur metabolism plays a major role in plant growth and development, environmental adaptation, and material synthesis, and the sulfate transporters are the beginning of sulfur metabolism. We identified 37 potential VcSULTR genes in the blueberry genome, encoding peptides with 534 to 766 amino acids. The genes were grouped into four subfamilies in an evolutionary analysis. The 37 putative VcSULTR proteins ranged in size from 60.03 to 83.87 kDa. These proteins were predicted to be hydrophobic and mostly localize to the plasma membrane. The VcSULTR genes were distributed on 30 chromosomes; VcSULTR3;5b and VcSULTR3;5c were the only tandemly repeated genes. The VcSULTR promoters contained cis-acting elements related to the fungal symbiosis and stress responses. The transcript levels of the VcSULTRs differed among blueberry organs and changed in response to ericoid mycorrhizal fungi and sulfate treatments. A subcellular localization analysis showed that VcSULTR2;1c localized to, and functioned in, the plasma membrane and chloroplast. The virus-induced gene knock-down of VcSULTR2;1c resulted in a significantly decreased endogenous sulfate content, and an up-regulation of genes encoding key enzymes in sulfur metabolism (VcATPS2 and VcSiR1). These findings enhance our understanding of mycorrhizal-fungi-mediated sulfate transport in blueberry, and lay the foundation for further research on blueberry-mycorrhizal symbiosis.

Clinical effects of detailed nursing management interventions on medication adherence and disease perception in patients with drug-resistant tuberculosis.

BACKGROUND: Tuberculosis (TB) is a chronic respiratory infectious disease that considerably jeopardizes human health, and there is no effective vaccine suitable for its prevention in the entire population. AIM: To investigate the promotion of medication adherence and disease cognition in patients with drug-resistant (DR-)TB using detailed nursing management. METHODS: In total, 114 patients with DR-TB who were diagnosed and treated at our hospital between January 2019 and January 2023 were included in this study. Patients in the control group (n = 57) were managed with conventional nursing care, while those in the observation group (n = 57) were managed with detailed nursing care. Medication adherence, disease awareness scores, medication safety, and nursing satisfaction were compared between the two groups after the intervention. RESULTS: The post-intervention medication compliance rate was 91.23% in the observation group and 75.44% in the control group, with the former being 15.79% higher than the latter (P < 0.05). There was no statistically significant difference in the disease awareness scores between the two groups before the intervention; the disease awareness scores of the observation group were significantly higher than those of the control group after the intervention (P < 0.05). The incidence of gastrointestinal reactions, joint swelling and pain, hearing loss, electrolyte disorders, and liver and kidney function abnormalities were lower in the observation group than those in the control group. The total nursing satisfaction of the observation group was higher than that of the control group (P < 0.05). CONCLUSION: Implementation of detailed nursing management for patients with DR-TB can effectively improve medication adherence, enhance awareness of the disease, ensure safety of medication, and improve satisfaction with nursing care.

Correlation analysis of human papillomavirus E6/E7 mRNA detection with diagnosis, prognosis and recurrence risk in patients with cervical epithelioma.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) is an important precursor of cervical cancer. Early detection and treatment can reduce the incidence of cervical cancer. AIM: To investigate the detection rate of human papillomavirus (HPV) E6/E7 mRNA in cervical tissue of patients with different types of epithelial cell neoplasia (CIN) and its relationship with CIN progression and diagnosis. METHODS: One hundred women with HPV infection detected by cervical exfoliation cytology between January 2022 and January 2023 were retrospectively selected. These patients were graded CIN based on colposcopy and cervical pathology. The positive expression rates of HPV E6/E7 mRNA and HPV [polymerase chain reaction (PCR)-reverse dot crossing] were compared among all groups. Patients with HPV E6/E7 mRNA expression in the grade 1 CIN group were followed up for 1 yr. The relationship between atypical squamous epithelium and high malignant epithelial neoplasia was investigated by univariate and multivariate analysis. RESULTS: The diagnostic sensitivity, specificity, and sensitivity of PCR-reverse point hybridization technology for secondary CIN were 70.41%, 70.66%, and 0.714, respectively. Sensitivity and specificity for secondary CIN were 752% and 7853%, respectively, the area under the curve value was 0.789. Logistic Multifactorial model analysis revealed that the HPV positive rates and the HPV E6/E7 mRNA positive rates were independent risk factors of CIN grade I (P < 0.05). In CIN grade I patients with positive for HPV E6/E7 mRNA, in its orientation to grade CIN patients, in its orientation to grade CIN patients, at 69.2%, compared with patients negative for HPV E6/E7 mRNA (30.8%), significant difference (P < 0.05). CONCLUSION: HPV E6/E7 mRNA and HPV (PCR-reverse dot hybrid) positive expression have a close relationship with CIN-grade disease progression and is an independent risk factor for high-grade CIN lesions.

Portable Photoacoustic Analytical System Combined with Wearable Hydrogel Patch for pH Monitoring in Chronic Wounds.

Timely diagnosis, monitoring, and management of chronic wounds play crucial roles in improving patients' quality of life, but clinical evaluation of chronic wounds is still ambiguous and relies heavily on the experience of clinician, resulting in increased social and financial burden and delay of optimal treatment. During the different stages of the healing process, specific and dynamic changes of pH values in the wound exudate can be used as biomarkers to reflect the wound status. Herein, a pH-responsive agent with well-behaved photoacoustic (PA) properties, nitrazine yellow (NY), was incorporated in poly(vinyl alcohol)/sucrose (PVA/Suc) hydrogel to construct a wearable pH-sensing patch (PVA/Suc/NY hydrogel) for monitoring of pH values during chronic wound healing. According to Rosencwaig-Gersho theory and the combination of 3D printing technology, the PA chamber volume and chopping frequency were systematically optimized to improve the sensitivity of the PA analytical system. The prepared PVA/Suc/NY hydrogel patch had excellent mechanical properties and flexibility and could maintain conformal contact with skin. Moreover, combined with the miniaturized PA analytical device, it had the potential to detect pH values (5.0-9.0) free from the color interference of blood and therapeutic drugs, which provides a valuable strategy for wound pH value monitoring by PA quantitation. This strategy of combining the wearable hydrogel patch with portable PA analysis offers broad new prospects for the treatment and management of chronic wounds due to its features of simple operation, time savings, and anti-interference.

Application of psychological intervention in intensive care unit nursing for patients with severe acute pancreatitis.

BACKGROUND: Severe acute pancreatitis (SAP) is a familiar critical disease in the intensive care unit (ICU) patients. Nursing staff are important spiritual pillars during the treatment of patients, and in addition to routine nursing, more attention needs be paid to the patient's psychological changes. AIM: To investigate the effects of psychological intervention in ICU patients with SAP. METHODS: One hundred ICU patients with SAP were hospitalized in the authors' hospital between 2020 and 2023 were selected, and divided into observation and control groups per the hospitalization order. The control and observation groups received routine nursing and psychological interventions, respectively. Two groups are being compared, using the Self-rating Anxiety Scale (SAS), Self-Determination Scale (SDS), Acute Physiology and Chronic Health Evaluation (APACHE) II, and 36-item Short Form Health Survey (SF-36) scores; nursing satisfaction of patients; ICU care duration; length of stay; hospitalization expenses; and the incidence of complications. RESULTS: After nursing, the SDS, SAS, and APACHE II scores in the experimental group were significantly lower than in the control group (P < 0.05). The SF-36 scores in the observation group were significantly higher than those in the control group (P < 0.05). The nursing satisfaction of patients in the experimental group was 94.5%, considerably higher than that of 75.6% in the control group (P < 0.05). The ICU care duration, length of stay, and hospitalization expenses in the observation group were significantly lower than those in the control group, and the incidence of complications was lower (P < 0.05). CONCLUSION: For patients with SAP, the implementation of standardized psychological intervention measures can effectively alleviate adverse psychological conditions.

Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents.

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.

[Box: see text].

The two-step strategy for enhancing the specific activity and thermostability of alginate lyase AlyG2 with mechanism for improved thermostability.

To overcome the trade-off challenge encountered in the engineering of alginate lyase AlyG2 from Seonamhaeicola algicola Gy8T and to expand its potential industrial applications, we devised a two-step strategy encompassing activity enhancement followed by thermal stability engineering. To enhance the specific activity of efficient AlyG2, we strategically substituted residues with bulky steric hindrance proximal to the active pocket with glycine or alanine. This led to the generation of three promising positive mutants, with particular emphasis on the T91S mutant, exhibiting a 1.91-fold specific activity compared to the wild type. To mitigate the poor thermal stability of T91S, mutants with negative ΔΔG values in the thermal flexibility region were screened out. Notably, the S72Ya mutant not only displayed 17.96 % further increase in specific activity but also exhibited improved stability compared to T91S, manifesting as a remarkable 30.97 % increase in relative activity following a 1-hour incubation at 42 °C. Furthermore, enhanced kinetic stability was observed. To gain deeper insights into the mechanism underlying the enhanced thermostability of the S72Ya mutant, we conducted molecular dynamics simulations, principal component analysis (PCA), dynamic cross-correlation map (DCCM), and free energy landscape (FEL) analysis. The results unveiled a reduction in the flexibility of the surface loop, a stronger correlation dynamic and a narrower motion subspace in S72Ya system, along with the formation of more stable hydrogen bonds. Collectively, our findings suggest amino acids substitutions resulting in smaller side chains proximate to the active site can positively impact enzyme activity, while reducing the flexibility of surface loops emerges as a pivotal factor in conferring thermal stability. These insights offer valuable guidance and a framework for the engineering of other enzyme types.

Secondary metabolites from the fungus Cladosporium xylophilum.

A new cladosporol derivative xylophilum A (1), together with 10 known compounds (2-11), were isolated from the rice fermentation of the fungus Cladosporium xylophilum. Their structures were established by extensive spectroscopic methods and comparison of their NMR data with literatures. The antimicrobial activity of compound 1 against 11 kinds of pathogenic microbial was evaluated, but no significant activity was found (MIC >100 µg/ml).

Three new flavonoids from the roots of Sophora tonkinensis.

Three new flavonoids including two isoflavanones sophortones A and B (1 and 2), and one chalcone sophortone C (3) were isolated from the roots of Sophora tonkinensis. Their structures were established by UV, IR, HRESIMS, and NMR data. The absolute configurations of 1 and 2 were determined by electronic circular dichroism (ECD) calculations.

Real-time predictive model of extrauterine growth retardation in preterm infants with gestational age less than 32 weeks.

The aim of this study was to develop a real-time risk prediction model for extrauterine growth retardation (EUGR). A total of 2514 very preterm infants were allocated into a training set and an external validation set. The most appropriate independent variables were screened using univariate analysis and Lasso regression with tenfold cross-validation, while the prediction model was designed using binary multivariate logistic regression. A visualization of the risk variables was created using a nomogram, while the calibration plot and receiver operating characteristic (ROC) curves were used to calibrate the prediction model. Clinical efficacy was assessed using the decision curve analysis (DCA) curves. Eight optimal predictors that namely birth weight, small for gestation age (SGA), hypertensive disease complicating pregnancy (HDCP), gestational diabetes mellitus (GDM), multiple births, cumulative duration of fasting, growth velocity and postnatal corticosteroids were introduced into the logistic regression equation to construct the EUGR prediction model. The area under the ROC curve of the training set and the external verification set was 83.1% and 84.6%, respectively. The calibration curve indicate that the model fits well. The DCA curve shows that the risk threshold for clinical application is 0-95% in both set. Introducing Birth weight, SGA, HDCP, GDM, Multiple births, Cumulative duration of fasting, Growth velocity and Postnatal corticosteroids into the nomogram increased its usefulness for predicting EUGR risk in very preterm infants.

Ten-year observation of corneal densitometry and associated factors following small incision lenticule extraction.

AIM: To investigate the long-term changes of corneal densitometry (CD) and its contributing elements after small incision lenticule extraction (SMILE). METHODS: Totally 31 eyes of 31 patients with mean spherical equivalent of -6.46±1.50 D and mean age 28.23±7.38y were enrolled. Full-scale examinations were conducted on all patients preoperatively and during follow-up. Visual acuity, manifest refraction, axial length, corneal thickness, corneal higher-order aberrations, and CD were evaluated. RESULTS: All surgeries were completed successfully without complications or adverse events. Ten-year safety index was 1.17±0.20 and efficacy 1.04±0.28. CD value of 0-6 mm zones in central layer was statistically significantly lower 10y postoperatively, compared with preoperative values (0-2 mmΔ=-1.62, 2-6 mmΔ=-1.24, P<0.01). There were no correlations between CD values and factors evaluated. CONCLUSION: SMILE is a safe and efficient procedure for myopia on a long-term basis. CD values get lower 10y postoperatively, whose mechanism is to be further discussed.

[Research progress on curcumin improving chronic low-grade inflammation and related diseases].

Chronic low-grade inflammation(CLGI), a relatively new concept without a clear definition, refers to a nonspecific, chronic, continuous, and low-grade inflammation state, and it is closely associated with various chronic diseases, including obesity, inflammatory bowel disease, neurodegenerative diseases, and tumors. Improvement of CLGI can slow down disease progression. Anti-inflammatory treatment is an important strategy for prevention and treatment of CLGI. However, there is currently no definitive drug treatment method. Curcumin is a polyphenolic compound extracted from the rhizome of zingiberaceae, with significant anti-inflammatory activity. Research has shown that curcumin can play an anti-inflammatory role by regulating NF-κB, JAK/STAT, PI3K/Akt, MAPK, NLRP3 inflammasome, Nrf2/ARE, and other inflammation-related pathways. This paper summarized the anti-inflammatory mechanisms, pharmacological effect, and clinical application of curcumin in improving CLGI and other diseases, so as to provide a reference for in-depth research and clinical application of curcumin in improving CLGI.

Environmental Factors Associated with Risk of Crohn's Disease Development in the Crohn's and Colitis Canada - Genetic, Environmental, Microbial Project.

BACKGROUND & AIMS: To date, it is unclear how environmental factors influence Crohn's disease (CD) risk and how they interact with biological processes. This study investigates the association between environmental exposures and CD risk and evaluates their association with pre-disease biomarkers. METHODS: We studied 4289 healthy first-degree relatives (FDRs) of patients with CD from the Crohn's and Colitis Canada - Genetic, Environmental, Microbial (CCC-GEM) project. Regression models identified environmental factors associated with future CD onset and their association with pre-disease biological factors, including altered intestinal permeability measured by urinary fractional excretion of lactulose to mannitol ratio (LMR); gut inflammation via fecal calprotectin (FCP) levels; and fecal microbiome composition through 16S rRNA sequencing. RESULTS: Over a 5.62-year median follow-up, 86 FDRs developed CD. Living with a dog between ages 5 and 15 (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.40-0.96; P = .034), and living with a large family size in the first year of life (HR, 0.43; 95% CI, 0.21-0.85; P = .016) were associated with decreased CD risk, whereas having a bird at the time of recruitment (HR, 2.78; 95% CI, 1.36-5.68; P = .005) was associated with an increased CD risk. Furthermore, living with a dog was associated with reduced LMR, altered relative abundance of multiple bacterial genera, and increased Chao1 diversity, whereas bird owners had higher FCP levels. Large family during participants' first year of life was associated with altered microbiota composition without affecting FCP or LMR. CONCLUSION: This study identifies environmental variables associated with CD risk. These variables were also associated with altered barrier function, subclinical inflammation, and gut microbiome composition shifts, suggesting potential roles in CD pathogenesis.

Secofumitremorgins C and D, a pair of atropisomers from saltern-derived fungus Aspergillus fumigatus GXIMD00544.

A pair of atropisomers secofumitremorgins C (1a) and D (1b), together with fifteen known alkaloids (2-16), were isolated from a saltern-derived fungus Aspergillus fumigatus GXIMD00544. The structures of atropisomers 1a and 1b were elucidated by the detailed spectroscopic data, chemical reaction and quantum chemical calculations. Compounds 1 and 8 displayed antifungal spore germination effects against plant pathogenic fungus associated with sugarcane Fusarium sp. with inhibitory rates of 53% and 77% at the concentration of 100 µM, repectively. Atropisomers 1 also exhibited antifouling potential against Balanus amphitrite larval settlement with an inhibitory rate of 96% at the concentration of 100 µM.