Staphylococcus aureus SOS response: Activation, impact, and drug targets.

Staphylococcus aureus is a common cause of diverse infections, ranging from superficial to invasive, affecting both humans and animals. The widespread use of antibiotics in clinical treatments has led to the emergence of antibiotic-resistant strains and small colony variants. This surge presents a significant challenge in eliminating infections and undermines the efficacy of available treatments. The bacterial Save Our Souls (SOS) response, triggered by genotoxic stressors, encompasses host immune defenses and antibiotics, playing a crucial role in bacterial survival, invasiveness, virulence, and drug resistance. Accumulating evidence underscores the pivotal role of the SOS response system in the pathogenicity of S. aureus. Inhibiting this system offers a promising approach for effective bactericidal treatments and curbing the evolution of antimicrobial resistance. Here, we provide a comprehensive review of the activation, impact, and key proteins associated with the SOS response in S. aureus. Additionally, perspectives on therapeutic strategies targeting the SOS response for S. aureus, both individually and in combination with traditional antibiotics are proposed.

Human identification of single hair shaft using a mass spectrometry mRNA typing system.

Hair is one of the most common forms of forensic biological material at various crime scenes. So far, human identification cannot be effectively accomplished with a single telogen hair encountered in forensic casework due to the detection limit. Emerging studies have revealed RNA as a promising biomarker in hair shafts, while the single telogen hair could not be successfully genotyped even after being examined with the recently developed mRNA typing system. MALDI-TOF MS, the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, enables sensitive and accurate measurement of DNA products. To address this problem and further develop the analysis technology of hairs, we established a mass spectrometry system for human identification based on a single hair shaft using 25 polymorphic SNPs located on 18 mRNA molecules (KRT31, RFK, KRT86, KRT35, PABPC1, KMT2D, LEMD2, TBC1D4, CTC1, PPP1R15A, RBM33, LRRC15, KRT33A, KRTAP12-2, KRT81, AHNAK, KRTAP4-8, FLG2). The forensic application of the detection system was evaluated, and all hair samples used were collected from individuals in Shanxi province. Firstly, we demonstrated that the RNA typing results of a single hair shaft were in perfect concordance with DNA typing results and confirmed the consistency between hairs from different body parts. To assess the potential influence of positions along the hair shaft, 6 cm long hair shafts from the distal end were examined by the MALDI-TOF MS system, whose genotype could be successfully detected. The system was capable of detecting aged samples stored for 390 days and could also be employed on various types of hair samples, such as white hair and permed or dyed hair. Finally, 50 unrelated individuals from Shanxi province were genotyped for the population study, and the CDP of the system in the Shanxi population is 0.998928. In this study, we established a mass spectrometry system for human identification based on a single hair shaft. We used a single hair shaft, rather than multiple hair shafts reported in our previous report, to get a full typing profile. The system sensitivity was substantially enhanced, which provided a valuable strategy for forensic practice to perform human identification using hairs.

Fighting Amyotrophic Lateral Sclerosis by Protecting the Liver? A Prospective Cohort Study.

BACKGROUND: Previous studies have observed liver abnormalities in amyotrophic lateral sclerosis (ALS) patients. This study aimed to investigate whether early signs of liver disease, measured by magnetic resonance imaging-derived iron-corrected T1-mapping (cT1), are risk factors for developing ALS. METHODS: cT1 and proton density fat fraction were measured and automatically analyzed using LiverMultiScan® software. The Fibrosis-4 index was calculated using an established formula based on age and blood markers. Cox proportional hazard models were used to examine the relationship between liver disease, liver biomarkers, and incident ALS. RESULTS: In a cohort of 533,707 individuals from UK Biobank, 24 ALS cases were identified among 28,328 participants with liver disease during the follow-up period. Among a total of 33,959 individuals with complete liver imaging data, 15 incident ALS cases were observed during a median follow-up period of 5.6 years. Individuals with liver disease had a higher risk of developing ALS, with an adjusted hazard ratio of 7.35 (95% CI 4.47-12.09; p < 0.001). An increase in cT1 was also associated with a higher risk of ALS. After adjusting for age, sex, Townsend deprivation index, smoking status, alcohol intake frequency, body mass index, proton density fat fraction, Fibrosis-4, and metabolic syndrome, an increase in cT1 remained significantly associated with a higher risk of ALS, with an adjusted hazard ratio of 3.15 (95% CI 1.79-5.55) per 1-SD increase. Sensitivity analyses confirmed these robust results. INTERPRETATION: Liver disease activity, indicated by cT1, increases the risk of developing ALS, independent of metabolic syndrome, liver fat, or fibrosis. ANN NEUROL 2024.

Dietary Inflammatory Index and female infertility: findings from NHANES survey.

Background and objectives: Infertility is a pressing public health concern on a national scale and has been linked to inflammatory conditions. However, limited research has been conducted on the impact of the Dietary Inflammatory Index (DII) on female infertility. This study sought to investigate the association between DII and infertility utilizing data from the National Health and Nutrition Examination Survey (NHANES). Methods: This cross-sectional study included a cohort of 3,071 women aged 20-44 years from three NHANES cycles (2013-2018). Dietary information was collected to calculate the Dietary Inflammatory Index (DII), while infertility status was determined through positive responses to specific questions in a questionnaire. The association between DII scores and infertility was assessed using adjusted multivariate logistic regression analyses. Subgroup analysis and restricted cubic spline (RCS) was conducted for further investigation. Results: Among the participants, 354 women (11.53%) were identified as experiencing infertility. Upon adjusting for all covariates, a positive correlation was observed (OR = 1.61, 95% CI: 1.12-2.31). Individuals with DII scores in the highest quartile exhibited significantly greater odds of infertility compared to those in the lowest quartile (OR = 1.71, 95% CI = 1.17-2.51). The relationship between DII and infertility in the RCS models demonstrated an S-shaped curve. When using the median DII as a reference point, a higher DII was associated with an increased prevalence of infertility. Additionally, obesity was found to be a significant factor. Conclusions: Our research indicated that the DII was positively correlated with an increased likelihood of infertility in American women among the ages of 20 and 44. These results contribute to the existing literature and underscore the need for further validation through larger prospective cohort studies.

A novel format of TNF-α binding affibody molecule ameliorate coronary artery endothelial injury in a mouse model of Kawasaki disease.

Kawasaki disease (KD) is a disease characterized by systemic immune vasculitis that often involves coronary arteries and can result in long-term cardiovascular sequelae. Different strategies for treatment of KD-and KD-induced coronary artery lesions are currently under investigation, including passive immunization with anti-TNFα monoclonal antibodies (mAbs). Herein, we examine the potential therapeutic capabilities of a novel type of TNFα-targeting agent based on an affibody molecule possessing fundamentally different properties than mAbs. Using phage display technology, we successfully screened and obtained three TNF-α binding affibody molecules and confirmed their high binding affinity and specificity for recombinant and native TNF-α by surface plasmon resonance (SPR), confocal double immunofluorescence and coimmunoprecipitation assays. Moreover, by binding to TNF-α, the affibody molecules could effectively neutralize TNFα-induced L929 cytotoxicity. To increase the targeting properties and serum half-life, one preferred affibody molecule ZTNF-α263 was redesigned to assemble drugs with bivalent TNFα binding with added specificity for serum albumin (ZTNF-α263-ABD035-ZTNF-α263, hereinafter denoted ZTAT). We further determined its binding ability, TNF-α signal blocking and neutralizing capacity, serum half-life and immunogenicity. Most importantly, our study provides strong evidence that the engineered ZTAT protein was therapeutically effective against KD induced-endothelial injury, as judged by both in vitro and in vivo assessments. These data suggested that because of the flexibility inherent, low-molecular weight anti-TNFα affibody construct ZTAT, can be developed into a potent therapeutic agent that can be produced and purified cost-effectively.

The Formation Criteria of LPSO Phase in Type I LPSO Mg-Y-X Alloy from the Perspective of Liquid-Solid Correlation.

The formation criteria of the LPSO phase are important for the design of long-period stacking-ordered (LPSO) Mg alloys. This work focuses on Type I LPSO Mg-Y-X alloys and attempts to explore the formation criteria of the LPSO phase from the perspective of liquid-solid correlation. With the aid of ab-initio molecular dynamics simulation, liquid Mg-Y-X alloys are investigated to obtain the common liquid characteristics from the reported Type I LPSO Mg-Y-X alloys. Following the liquid characteristics, a new Type I LPSO alloy, i.e., Mg-Y-Au, is experimentally confirmed. The discovery of a new Type I LPSO alloy supports liquid-solid correlation, and hence, the formation criteria of the LPSO phase in Type I LPSO alloys can be developed based on the common liquid characteristics of Type I LPSO Mg-Y-X alloys as follows: X should result in the reduction in equilibrium volume and cohesive energy; Y should repulse Y and be attracted by both Mg and X, and X should be repulsed by both Mg and X; X should enhance the threefold and fourfold symmetries and weaken the fivefold and sixfold ones so that the local structural symmetries are distributed close to liquid pure Mg.

What is the impact of acute endocrine and metabolic alterations on long-term ischemic stroke prognosis: a prospective study.

BACKGROUND: Post-stroke stress can trigger instant survival but its influence on long-term ischemic stroke outcomes remains controversial. Thus, we sought to explore the associations of acute post-stroke stress evidenced by endocrine and metabolic changes, with long-term ischemic stroke outcomes. METHODS: Admissions for acute ischemic stroke within seven days of onset were prospectively recruited to determine acute endocrine and metabolic variations measured by thyroid parameters and the stress hyperglycemia ratio (SHR). Long-term ischemic stroke prognoses were followed up for one year, with the primary outcome being a modified Rankin Scale score of 3 to 6. RESULTS: A total of 887 patients were enrolled, of which 535 reached the final one-year followed up at a poor prognosis rate of 29.3%. Patients with poor outcomes were observed to have lower levels of free triiodothyronine (fT3) and higher levels of SHR on admission. Medium values (fT3, 4.4 mmol/L; SHR, 8 nmol/L) were used to divide patients into four gradient stress degrees. Larger acute endocrine and metabolic variations (fT3 < 4.4 mmol/L and SHR ≥ 8 nmol/L) were independently associated with a poor one-year prognosis (adjusted OR = 4.231, P = 0.001). CONCLUSIONS: High degrees of acute post-stroke stress may aggravate long-term ischemic stroke prognosis and timely stress-reduced interventions may help promote post-stroke living quality is equally important as survival.

Deep Learning With Optical Coherence Tomography for Melanoma Identification and Risk Prediction.

Malignant melanoma is the most severe skin cancer with a rising incidence rate. Several noninvasive image techniques and computer-aided diagnosis systems have been developed to help find melanoma in its early stages. However, most previous research utilized dermoscopic images to build a diagnosis model, and only a few used prospective datasets. This study develops and evaluates a convolutional neural network (CNN) for melanoma identification and risk prediction using optical coherence tomography (OCT) imaging of mice skin. Longitudinal tests are performed on four animal models: melanoma mice, dysplastic nevus mice, and their respective controls. The CNN classifies melanoma and healthy tissues with high sensitivity (0.99) and specificity (0.98) and also assigns a risk score to each image based on the probability of melanoma presence, which may facilitate early diagnosis and management of melanoma in clinical settings.

Neuromelanin-MRI identifies locus coeruleus and substantia nigra degeneration as key differentiators in isolated rapid eye movement sleep behavior disorder.

To explore the neuromelanin depigmentation of locus coeruleus (LC) and substantia nigra pars compacta (SNc) in the isolated rapid eye movement sleep behavior disorder (iRBD) using neuromelanin-sensitive MRI (NM-MRI), and to evaluate its utility for iRBD diagnosis. A total of 25 iRBD patients and 25 healthy controls were recruited and underwent NM-MRI. The contrast-to-noise ratio (CNR) of SNc and LC, and the volume of SNc were compared between groups and evaluated visually. The power of NM measures in discriminating iRBD patients from healthy controls were performed with receiver operating characteristic (ROC) curves and the area under curve (AUC) was calculated. The CNR of SNc and LC, the volume of SNc, the SNc/midbrain volume ratio as well as the visual scores of SNc and LC in iRBD patients were significantly decreased than those in controls (all P < 0.05). For quantitative analysis, the LC CNR acquired the highest accuracy in predicting iRBD (AUC 0.95, sensitivity 80%, specificity 100%), followed by SNc volume (AUC 0.93, sensitivity 88%, specificity 96%) and SNc CNR (AUC 0.74, sensitivity 92%, specificity 44%). For visual analysis, the accuracy of the visual score for SNc and LC were 78% (sensitivity 68%, specificity 88%) and 86% (sensitivity 88%, specificity 84%), respectively. The NM in the SNc and LC regions were significantly reduced in iRBD patients. NM measures showed good capability in discriminating iRBD from controls, suggesting that NM-MRI may be a valuable screening tool for iRBD.

Phenotypic age mediates effects of Life's Essential 8 on reduced mortality risk in US adults.

Objective: This study aimed to find out whether phenotypic age could mediate the protective effects of a healthy lifestyle on mortality. Methods: We included adult participants with available data for individual phenotypic age (PhenoAge) and Life's Essential 8 (LE8) scores from the National Health and Nutrition Examination Survey 2005-2010 (three cycles) and linked mortality records until 31 December 2019. Adjusted hazard ratios (HR) were estimated to evaluate the associations of PhenoAge and LE8 scores with all-cause and cardiovascular mortality risk. Mediation analyses were performed to estimate the proportional contribution of PhenoAge to the effect of LE8 on mortality risks. Results: A 1-year increment in PhenoAge was associated with a higher risk of all-cause (HR = 1.04 [95% confidence interval, 1.04-1.05]) and cardiovascular (HR = 1.04 [95% confidence interval, 1.04-1.05]) mortality, independent of chronological age, demographic characteristics, and disease history. High level of LE8 (score: 80-100) was associated with a 3.30-year younger PhenoAge. PhenoAge was estimated to mediate 36 and 22% of the effect of LE8 on all-cause and cardiovascular mortality, respectively (all P < 0.001). As for single-metric scores of LE8, PhenoAge mediated 30%, 11%, 9%, and 7% of the effects of the healthy diet, smoking status, blood pressure, and physical activity on all-cause mortality risk, respectively (all P < 0.05). Conclusion: Adherence to LE8 recommendations slows phenotypic aging. PhenoAge could mediate the effect of LE8 on mortality risk.

Exploring the clinical implications of novel SRD5A2 variants in 46,XY disorders of sex development.

This study was conducted retrospectively on a cohort of 68 patients with steroid 5 α-reductase 2 (SRD5A2) deficiency and 46,XY disorders of sex development (DSD). Whole-exon sequencing revealed 28 variants of SRD5A2, and further analysis identified seven novel mutants. The preponderance of variants was observed in exon 1 and exon 4, specifically within the nicotinamide adenine dinucleotide phosphate (NADPH)-binding region. Among the entire cohort, 53 patients underwent initial surgery at Sichuan Provincial People's Hospital (Chengdu, China). The external genitalia scores (EGS) of these participants varied from 2.0 to 11.0, with a mean of 6.8 (standard deviation [s.d.]: 2.5). Thirty patients consented to hormone testing. Their average testosterone-to-dihydrotestosterone (T/DHT) ratio was 49.3 (s.d.: 23.4). Genetic testing identified four patients with EGS scores between 6 and 9 as having this syndrome; and their T/DHT ratios were below the diagnostic threshold. Furthermore, assessments conducted using the crystal structure of human SRD5A2 have provided insights into the potential pathogenic mechanisms of these novel variants. These mechanisms include interference with NADPH binding (c.356G>C, c.365A>G, c.492C>G, and c.662T>G) and destabilization of the protein structure (c.727C>T). The c.446-1G>T and c.380delG variants were verified to result in large alterations in the transcripts. Seven novel variations were identified, and the variant database for the SRD5A2 gene was expanded. These findings contribute to the progress of diagnostic and therapeutic approaches for individuals with SRD5A2 deficiency.

Association of benzodiazepine and Z-hypnotic use with cardiovascular disease risk: insights from a prospective study of 10 million people in China.

AIM: To assess the association between Benzodiazepines (BZDs) or Z-hypnotic use and cardiovascular diseases (CVD) incidence in residents in Beijing, China. METHODS: We included 2,415,573 individuals with a prescription record for BZDs or Z-hypnotics in the Beijing Medical Claim Data for Employees database during 2010-2017, and 8,794,356 non-users with other prescriptions for the same period. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional risk models for 712,850 exposed and 712,850 unexposed participants who were matched 1:1 by propensity score. RESULTS: BZDs or Z-hypnotics users had a higher risk of CVD than non-users, with an HR of 1.11 (95% CI: 1.10, 1.13). Compared with non-users, those who used them for less than 3 months had the lowest risk of CVD, and those for more than 5 years had the highest risk, with HRs of 0.50 (0.48, 0.51) and 1.78 (1.72, 1.83), respectively. The risk of CVD was relatively low in those who used only one of the long-acting BZDs, short-acting BZDs, or Z-hypnotics compared to unexposed individuals. Individuals exposed to all three types of drugs had the highest risk, 2.33 (2.22, 2.44) times that of non-users. Users below the median dose had a lower risk of CVD compared to non-users, whereas users exceeding the median dose had an increased risk. CONCLUSION: BZD or Z-hypnotic use in general was nominally associated with an elevated risk of CVD. However, for short-term, single-type, and low-to-moderate-dose users, not only did this elevated risk disappear, but drug use also demonstrated a protective effect.

G4LDB 3.0: a database for discovering and studying G-quadruplex and i-motif ligands.

Non-canonical nucleic acid structures, such as G-quadruplex (G4) and i-Motif (iM), have garnered significant research interest because of their unique structural properties and biological activities. Thousands of small molecules targeting G4/iM structures have been developed for various chemical and biological applications. In response to the growing interest in G4-targeting ligands, we launched the first G4 Ligand Database (G4LDB) in 2013. Here, we introduce G4LDB 3.0 (http://www.g4ldb.com), an upgraded version featuring extensive enhancements in content and functionality. The new version includes over 4800 G4/iM ligands and approximately 51 000 activity entries. Key upgrades include advanced search capabilities, dynamic knowledge graphs, enhanced data visualization, along with a new dynamic analysis function that automatically displays ligand structure clustering results and chemical space distribution. With these updates, G4LDB 3.0 further evolves into a comprehensive resource and valuable research tool. The significant improvements address the increasing demand for efficient data handling and user experience, highlighting the critical role of G4LDB in advancing research on G-quadruplexes and i-motifs.

TMCO1 promotes ferroptosis and ECM deposition in glaucomatous trabecular meshwork via ERK1/2 signaling.

Glaucoma, a leading cause of global blindness, is marked by irreversible retinal ganglion cells (RGCs) loss, elevated intraocular pressure (IOP), and extracellular matrix (ECM) deposition in the trabecular meshwork (TM). Transmembrane and coiled-coil domain protein 1 (TMCO1), implicated in calcium regulation, has potential links to primary open-angle glaucoma (POAG). Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, is also observed in glaucoma. This study investigates the role of TMCO1 in POAG, focusing on its involvement in TM ECM deposition via ferroptosis induction and ERK1/2 phosphorylation inhibition. In both in vivo and in vitro models, we demonstrated that dexamethasone (DEX) stimulation upregulates TMCO1, leading to increased ECM deposition and ferroptosis in human trabecular meshwork cells (HTMCs). Furthermore, treatment with ferrostatin-1 (Fer-1), a ferroptosis inhibitor, significantly reduced ECM deposition and ferroptosis in HTMCs. These findings establish TMCO1 as a critical regulator of ferroptosis and ECM deposition through the ERK/MAPK pathway, positioning it as a promising therapeutic target for glaucoma.

Characterization of extreme rainfall changes and response to temperature changes in Guizhou Province, China.

Different geographical zones have regional heterogeneity in underlying earth surface structure and microclimate which result in different evolution trends and their response to climate change varies in extreme rainfalls in these zones. In the Guizhou province of China, there are complex landforms, which lead to spatial redistribution of rainfall, frequent extreme rainfall, and disasters high risk of geologic disasters. Research on extreme climate in Guizhou mostly paid attention to its spatio-temporal characteristics and modeling, but lack of analysis on its characteristics of extreme rainfall variability and response to temperature changes under different subsurface conditions. This study investigated the characteristics of the extreme rainfall spatiotemporal and recurrence periods in Guizhou province and discussed the relationship between the response of extreme rainfall to temperature change. Daily rainfall data from 1990 to 2020 and 2021-2100 at 31 meteorological observation stations throughout the province were collected to calculate extreme precipitation. This research had the following results. (1) Both historical and future periods show an upward trend in extreme rainfall in Guizhou province, with a spatial distribution pattern of "high in the south and low in the north, high in the east and low in the west" and "high in the southeast and low in the northwest", respectively; the spatial distribution of extreme rainfall under each recurrence period is consistent with the non-recurrence period. (2) Both historical and future periods show an upward trend in temperature in Guizhou province, with a spatial distribution consistent with that of the extreme rainfall in the corresponding period. (3) The change in extreme rainfall intensity with increasing temperature is almost always greater than the C-C rate for different periods and underlying earth surface structure; Extreme rainfall has a Hook response structure to temperature change, and the climate response structure shifts to the right with climate warming. The results of the study can provide a basis for decision-making on regional disaster prevention and mitigation in the context of temperature change.

Engineered Cell Elongation Promotes Extracellular Electron Transfer of Shewanella Oneidensis.

To investigate how cell elongation impacts extracellular electron transfer (EET) of electroactive microorganisms (EAMs), the division of model EAM Shewanella oneidensis (S. oneidensis) MR-1 is engineered by reducing the formation of cell divisome. Specially, by blocking the translation of division proteins via anti-sense RNAs or expressing division inhibitors, the cellular length and output power density are all increased. Electrophysiological and transcriptomic results synergistically reveal that the programmed cell elongation reinforces EET by enhancing NADH oxidation, inner-membrane quinone pool, and abundance of c-type cytochromes. Moreover, cell elongation enhances hydrophobicity due to decreased cell-surface polysaccharide, thus facilitates the initial surface adhesion stage during biofilm formation. The output current and power density all increase in positive correction with cellular length. However, inhibition of cell division reduces cell growth, which is then restored by quorum sensing-based dynamic regulation of cell growth and elongation phases. The QS-regulated elongated strain thus enables a cell length of 143.6 ± 40.3 µm (72.6-fold of that of S. oneidensis MR-1), which results in an output power density of 248.0 ± 10.6 mW m-2 (3.41-fold of that of S. oneidensis MR-1) and exhibits superior potential for pollutant treatment. Engineering cellular length paves an innovate avenue for enhancing the EET of EAMs.

Expressional respones of hsp70 genes against abiotic and entomopathgenic stresses in four different noctuid larval species (Lepidoptera: Noctidae).

Heat shock proteins (Hsps) are stress response proteins. In a previous study, host larval Hsp70s were identified as the structural proteins of virions of Heliothis virescens ascovirus 3h (HvAV-3h), an insect virus that mainly infects noctuid larvae. To investigate the response of hsp70s of healthy Mythimna separata, Spodoptera exigua, Spodoptera frugiperda, and Spodoptera litura larvae to various abiotic or entomopathogenic stresses, quantitative PCR was used to detect larval hsp70s expression patterns. Results showed distinct expression patterns of hsp70s in response to different abiotic stresses. Notably, Mshsp70 expression pattern resembled Slhsp70 under most treatments. In healthy larvae, no tissue tropism was observed concerning the relative expression of Mshsp70, Sfhsp70, and Slhsp70. After infection with HvAV-3h, the expression of hsp70s in all dissected tissues of all tested larval species increased. Significant differences were found in the fat bodies of M. separata, S. exigua, and S. litura as well as in the hemolymph of S. exigua and S. litura. Subsequent silencing of Slhsp70, resulted in a significant decrease in DNA replication levels of HvAV-3h in S. litura larvae at 24 and 72 h post RNA interference, indicating that Slhsp70 is necessary for DNA replication in HvAV-3h. These data can provide references for the studying on the stress response of noctuid larvae to different environmental factors.

Nobiletin, an activator of the pyruvate kinase isozyme M1/M2 protein, upregulated the glycolytic signalling pathway and alleviated depressive-like behaviour caused by artificial light exposure at night in zebrafish.

We established a zebrafish model of depression-like behaviour induced by exposure to artificial light at night (ALAN) and found that nobiletin (NOB) alleviated depression-like behaviour. Subsequently, based on the results of a 24-h free movement assay, clock gene expression and brain tissue transcriptome sequencing, the glycolysis signalling pathway was identified as a potential target through which NOB exerted antidepressant effects. Using the ALAN zebrafish model, we found that supplementation with exogenous L-lactic acid alleviated depressive-like behaviour. Molecular docking and molecular dynamics simulations revealed an inter-molecular interaction between NOB and the pyruvate kinase isozyme M1/M2 (PKM2) protein. We then used compound 3 k to construct a zebrafish model in which PKM2 was inhibited. Our analysis of this model suggested that NOB alleviated depression-like behaviour via inhibition of PKM2. In summary, NOB alleviated depressive-like behaviour induced by ALAN in zebrafish via targeting of PKM2 and activation of the glycolytic signalling pathway.

Screening of herbal extracts binding with vascular endothelial growth factor by applying HerboChip platform.

BACKGROUND: Traditional Chinese medicine (TCM) has been hailed as a rich source of medicine, but many types of herbs and their functions still need to be rapidly discovered and elucidated. HerboChip, a target-based drug screening platform, is an array of different fractions deriving from herbal extracts. This study was designed to identify effective components from TCM that interact with vascular endothelial growth factor (VEGF) as a target using HerboChip. METHODS: Selected TCMs that are traditionally used as remedies for cancer prevention and wound healing were determined and extracted with 50% ethanol. Biotinylated-VEGF was hybridized with over 500 chips coated with different HPLC-separated fractions from TCM extracts and straptavidin-Cy5 was applied to identify plant extracts containing VEGF-binding fractions. Cytotoxicity of selected herbal extracts and their activities on VEGF-mediated angiogenic functions were evaluated. RESULTS: Over 500 chips were screened within a week, and ten positive hits were identified. The interaction of the identified herbal extracts with VEGF was confirmed in cultured endothelial cells. The identified herbs promoted or inhibited VEGF-mediated cell proliferation, migration and tube formation. Results from western blotting analysis demonstrated the identified herbal extracts significantly affected VEGF-triggered phosphorylations of eNOS, Akt and Erk. Five TCMs demonstrated potentiating activities on the VEGF response and five TCMs revealed suppressive activities. CONCLUSIONS: The current results demonstrated the applicability of the HerboChip platform and systematically elucidated the activity of selected TCMs on angiogenesis and its related signal transduction mechanisms.

Controlling factors of iron plaque formation and its adsorption of cadmium and arsenic throughout the entire life cycle of rice plants.

Iron (Fe) plaque, which forms on the surface of rice roots, plays a crucial role in immobilizing heavy metal(loids), thus reducing their accumulation in rice plants. However, the principal factors influencing Fe plaque formation and its adsorption capacity for heavy metal(loid)s throughout the rice plant's lifecycle remain poorly understood. Thus, this study investigated the dynamics of Fe plaque formation and its ability to adsorb cadmium (Cd) and arsenic (As) across different growth stages, aiming to identify the key drivers behind these processes. The findings reveal that the rate of radial oxygen loss (ROL) and the abundance of plaque-associated microbes are the primary drivers of Fe plaque formation, with their relative importance ranging from 1.4% to 81%. Similarly, the adsorption of As by Fe plaque is principally determined by the rate of ROL and the quantity of Fe plaque, with subsequent effects from the total Fe in rhizospheric soil, arsenate-reducing bacteria, and organic matter-degrading bacteria. The relative importance of these factors ranges from 6.0% to 11.7%. By contrast, the adsorption of Cd onto Fe plaque is primarily affected by competition for adsorption sites with ammonium in soils and the presence of organic matter-degrading bacteria, contributing 25.5% and 23.5% to the adsorption process, respectively. These findings provide significant insights into the development of Fe plaque and its absorption of heavy metal(loid)s throughout the lifecycle of rice plants.