Dual-ROS-scavenging and dual-lingering nanozyme-based eye drops alleviate dry eye disease.

Efficiently removing excess reactive oxygen species (ROS) generated by various factors on the ocular surface is a promising strategy for preventing the development of dry eye disease (DED). The currently available eye drops for DED treatment are palliative, short-lived and frequently administered due to the short precorneal residence time. Here, we developed nanozyme-based eye drops for DED by exploiting borate-mediated dynamic covalent complexation between n-FeZIF-8 nanozymes (n-Z(Fe)) and poly(vinyl alcohol) (PVA) to overcome these problems. The resultant formulation (PBnZ), which has dual-ROS scavenging abilities and prolonged corneal retention can effectively reduce oxidative stress, thereby providing an excellent preventive effect to alleviate DED. In vitro and in vivo experiments revealed that PBnZ could eliminate excess ROS through both its multienzyme-like activity and the ROS-scavenging activity of borate bonds. The positively charged nanozyme-based eye drops displayed a longer precorneal residence time due to physical adhesion and the dynamic borate bonds between phenyboronic acid and PVA or o-diol with mucin. The in vivo results showed that eye drops could effectively alleviate DED. These dual-function PBnZ nanozyme-based eye drops can provide insights into the development of novel treatment strategies for DED and other ROS-mediated inflammatory diseases and a rationale for the application of nanomaterials in clinical settings.

PHOSPHATE1-mediated phosphate translocation from roots to shoots regulates floral transition in plants.

Phosphorus nutrition has been known to influence floral transition in plants for a long time, but the underlying mechanism is unclear. Arabidopsis PHOSPHATE1 (PHO1) plays a critical role in phosphate translocation from roots to shoots, but whether and how it regulates floral transition is unknown. Here, we show that knockout mutation of PHO1 delays flowering under both long-day and short-day conditions. The late flowering of pho1 mutants can be partially rescued by Pi supplementation in rosettes or shoot apices. Grafting assay indicates that the late flowering of pho1 mutants is resulted from impaired phosphate translocation from roots to shoots. Knockout mutation of SPX1 and SPX2, two negative regulators of phosphate starvation response, partially rescues the late flowering of pho1 mutants. PHO1 is epistatic to PHO2, a negative regulator of PHO1, in flowering time regulation. Loss of PHO1 represses the expression of some floral activators, including FT encoding florigen, and induces the expression of some floral repressors in shoots. Genetic analyses indicate that at least jasmonic acid signaling is partially responsible for the late flowering of pho1 mutants. In addition, we find rice PHO1;2, the homology of PHO1, plays a similar role in floral transition. These results suggest that PHO1 integrates phosphorus nutrition and flowering time and could be used as a potential target in modulating phosphorus nutrition-mediated flowering time in plants.

Fermented Gracilaria lemaneiformis polysaccharides alleviate food allergy by regulating Treg cells and gut microbiota.

Food allergy has a significant impact on the health and well-being of individuals, affecting both their physical and mental states. Research on natural bioactive compounds, such as polysaccharides extracted from seaweeds, holds great promise in the treatment of food allergies. In this study, fermented Gracilaria lemaneiformis polysaccharides (F-GLSP) were prepared using probiotic fermentation. Probiotic fermentation of Gracilaria lemaneiformis reduces the particle size of polysaccharides. To compare the anti-allergic activity of F-GLSP with unfermented Gracilaria lemaneiformis polysaccharides (UF-GLSP), an OVA-induced mouse food allergy model was established. F-GLSP exhibited a significant reduction in OVA-specific IgE and mMCP levels in allergic mice. Moreover, it significantly inhibited Th2 differentiation and IL-4 production and significantly promoted Treg differentiation and IL-10 production in allergic mice. In contrast, UF-GLSP only reduced OVA-specific IgE and mMCP in the serum of allergic mice. Furthermore, F-GLSP demonstrated a more pronounced regulation of intestinal flora abundance compared to UF-GLSP, significantly influencing the populations of Firmicutes, Bacteroidetes, Lactobacillus, and Clostridiales in the intestines of mice with food allergy. These findings suggest that F-GLSP may regulate food allergies in mice through multiple pathways. In summary, this study has promoted further development of functional foods with anti-allergic properties based on red algae polysaccharides.

In vivo evaluations of Lactobacillus-fermented Eucheuma spinosum polysaccharides on alleviating food allergy activity.

In order to explore the in vivo anti-food allergy activity of Lactobacillus sakei subsp. sakei-fermented Eucheuma spinosum polysaccharides F1-ESP-3, an ovalbumin (OVA)-induced food allergy mouse model was established by ascites immunization and gavage. The weight, temperature, incidence of diarrhea, levels of allergic mediators and inflammatory factors in the serum of mice were analyzed. We analyzed the differentiation of mouse spleen lymphocytes and the proportion of sensitized mast cells by flow cytometry. The intestinal barrier status of mice was analyzed by intestinal pathological tissue sections and microbiota sequencing. The results showed that F1-ESP-3 could alleviate the food allergy symptoms of mice, such as hypothermia and loose stool; levels of OVA-specific immunoglobulin E, mast cell protease and histamine in the serum of sensitized mice and the proportion of dendritic cells and mast cells in mouse spleen were significantly reduced; in addition, F1-ESP-3 may protect the intestinal barrier and further improve the intestinal microenvironment of food-allergic mice by regulating the abundance of Bacteroidetes and Firmicutes. F1-ESP-3 can further improve the intestinal microenvironment of food-allergic mice by upregulating the levels of Lachnospiraceae, and may affect the signal pathways such as NOD-like receptor, MAPK, I kappa B and antigen processing and presentation.

POSTN Regulates Fibroblast Proliferation and Migration in Laryngotracheal Stenosis Through the TGF-ß/RHOA Pathway.

OBJECTIVES: To investigate the role of periostin (POSTN) and the transforming growth factor ß (TGF-ß) pathway in the formation of laryngotracheal stenosis (LTS) scar fibrosis and to explore the specific signaling mechanism of POSTN-regulated TGF-ß pathway in tracheal fibroblasts. METHODS: Bioinformatics analysis was performed on scar data sets from the GEO database to preliminarily analyze the involvement of POSTN and TGF-ß pathways in fibrosis diseases. Expression of POSTN and TGF-ß pathway-related molecules was analyzed in LTS scar tissue at the mRNA and protein levels. The effect of POSTN on the biological behavior of tracheal fibroblasts was studied using plasmid DNA overexpression and siRNA silencing techniques to regulate POSTN expression and observe the activation of TGF-ß1 and the regulation of cell proliferation and migration via the TGF-ß/RHOA pathway. RESULTS: The bioinformatics analysis revealed that POSTN and the TGF-ß pathway are significantly involved in fibrosis diseases. High expression of POSTN and TGF-ß/RHOA pathway-related molecules (TGFß1, RHOA, CTGF, and COL1) was observed in LTS tissue at both mRNA and protein levels. In tracheal fibroblasts, overexpression or silencing of POSTN led to the activation of TGF-ß1 and regulation of cell proliferation and migration through the TGF-ß/RHOA pathway. CONCLUSION: POSTN is a key molecule in scar formation in LTS, and it regulates the TGF-ß/RHOA pathway to mediate the formation of cicatricial LTS by acting on TGF-ß1. This study provides insights into the molecular mechanisms underlying LTS and suggests potential therapeutic targets for the treatment of this condition. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.

Plasma membrane H+-ATPases in mineral nutrition and crop improvement.

Plasma membrane H+-ATPases (PMAs) pump H+ out of the cytoplasm by consuming ATP to generate a membrane potential and proton motive force for the transmembrane transport of nutrients into and out of plant cells. PMAs are involved in nutrient acquisition by regulating root growth, nutrient uptake, and translocation, as well as the establishment of symbiosis with arbuscular mycorrhizas. Under nutrient stresses, PMAs are activated to pump more H+ and promote organic anion excretion, thus improving nutrient availability in the rhizosphere. Herein we review recent progress in the physiological functions and the underlying molecular mechanisms of PMAs in the efficient acquisition and utilization of various nutrients in plants. We also discuss perspectives for the application of PMAs in improving crop production and quality.

Phycoremediation Potential of Salt-Tolerant Microalgal Species: Motion, Metabolic Characteristics, and Their Application for Saline-Alkali Soil Improvement in Eco-Farms.

Microalgae have great potential for remediating salt-affected soil. In this study, the microalgae species Coelastrella sp. SDEC-28, Dunaliella salina SDEC-36, and Spirulina subsalsa FACHB-351 were investigated for their potential to rehabilitate salt-affected soils. Nylon screens with optimal aperture sizes and layer numbers were identified to efficiently intercept and harvest biomass, suggesting a correlation between underflow capability and the tough cell walls, strong motility, and intertwining characteristics of the algae. Our investigations proved the feasibility of incorporating monosodium glutamate residue (MSGR) into soil extracts at dilution ratios of 1/200, 1/2000, and 1/500 to serve as the optimal medium for the three microalgae species, respectively. After one growth period of these three species, the electrical conductivities of the media decreased by 0.21, 1.18, and 1.78 mS/cm, respectively, and the pH remained stable at 7.7, 8.6, and 8.4. The hypotheses that microalgae can remediate soil and return profits have been verified through theoretical calculations, demonstrating the potential of employing specific microalgal strains to enhance soil conditions in eco-farms, thereby broadening the range of crops that can be cultivated, including those that are intolerant to saline-alkali environments.

Phosphorus-supplemented seawater-wastewater cyclic system for microalgal cultivation: Production of high-lipid and high-protein algae.

The reuse of wastewater after seawater cultivation is critically important. In this study, a phosphorus-supplemented seawater-wastewater cyclic system (PSSWCS) based on Chlorella pyrenoidosa SDEC-35 was developed. With the addition of phosphorus, the algal biomass and the ability to assimilate nitrogen and carbon were improved. At the nitrogen to phosphorus ratio of 20:1, the biomass productivity per mass of nitrogen reached 3.6 g g-1 (N) day-1 in the second cycle. After the third cycle the protein content reached 35.7% of dry mass, and the major metabolic substances in PSSWCS reached the highest content level of 89.5% (35.7% protein, 38.3% lipid, and 15.5% carbohydrate). After the fourth cycle the lipid content maintained at 40.1%. Furthermore, 100.0% recovery of wastewater in PSSWCS increased the nitrogen and carbon absorption to 15.0 and 396.8 g per tonne of seawater. This study achieved seawater-wastewater recycle and produced high-lipid and high-protein algae by phosphorus addition.

Biophilic Positive Carbon Dot Exerts Antifungal Activity and Augments Corneal Permeation for Fungal Keratitis.

Fungal keratitis (FK) is an infectious eye disease that poses a significant risk of blindness. However, the effectiveness of conventional antifungal drugs is limited due to the intrinsic ocular barrier that impedes drug absorption. There is an urgent need to develop new therapeutic strategies to effectively combat FK. Herein, we synthesized an ultrasmall positively charged carbon dot using a simple stage-melting method. The carbon dot can penetrate the corneal barrier by opening the tight junctions, allowing them to reach the lesion site and effectively kill the fungi. The results both in vitro and in vivo demonstrated that it exhibited good biocompatibility and antifungal activity, significantly improving the therapeutic effect in a mouse model of FK. Therefore, this biophilic ultrasmall size and positive carbon dot, characterized by its ability to penetrate the corneal barrier and its antifungal properties, may offer valuable insights into the design of effective ocular nanomedicines.

Marine-Derived Alternariol Monomethyl Ether Alleviates Ovalbumin-Induced Food Allergy by Suppressing MAPK and NF-κB Signaling Pathways of Mast Cells.

The prevalence of food allergies has grown dramatically over the past decade. Recently, studies have shown the potential of marine substances to alleviate food allergies. We utilized a rat basophilic leukemia (RBL)-2H3 model to evaluate the antiallergic effects of alternariol monomethyl ether (AME) extracted from marine fungi Alternaria sp. Our results showed that AME attenuated food allergy symptoms in mice and reduced histamine release in serum. The population of mast cells in the spleen and mesenteric lymph nodes was considerably reduced. Moreover, in vitro assays also revealed that AME inhibited the release of ß-hexosaminidase and histamine. Transcriptomic analysis uncovered that AME regulated gene expression associated with mast cells. Additionally, Western blotting demonstrated that AME suppressed mast cell activation by modulating MAPK and NF-κB signaling pathways. Taken together, these findings provide a theoretical basis for the potential antiallergic use of marine-derived compounds in the development of functional foods.

Real-world data for the availability of pediatric medicines in Chinese hospitals: a multi-center survey and analysis.

Aim: No information exists on the availability of pediatric medicines in China. This study aimed to access the availability of different types of pediatric medicine and determine their ratio in medical institution drug catalogs. Methods: Based on drug instructions, an expert meeting method was used to divide pediatric medicines into five categories: child-specific medicine (CSM), co-use medicine for adults and children (CMAC), other pediatric medicines (OCM), off-label medicine use (OMU), and non-child medicine (NM). Results: A total of 60 hospitals nationwide participated in this survey, namely, 20 children's hospitals (C-hosp), 14 maternal and child healthcare hospitals (MCHC-hosp), and 26 general hospitals (G-hosp). The average number of drug catalogs in G-hosp was significantly higher than that in C-hosp and MCHC-hosp. CSM accounted for 9.77% of the C-hosp catalog, 7.12% of the MCHC-hosp catalog, and 1% of the G-hosp catalog. The availability rate of CMAC was 49.63% in C-hosp and 40.87% and 31% in MCHC-hosp and G-hosp, respectively. The proportion of OCM in C-hosp (27.28%) was higher than that in MCHC-hosp (13.4%) and G-hosp (5%). The OMU occupied ratio in C-hosp, MCHC-hosp, and G-hosp is not negligible, which was 12.06%, 8.7%, and 10% respectively. The proportion of NM in C-hosp was almost negligible but was 29.91% and 53% in MCHC-hosp and G-hosp, respectively. Compared to the CSM and CMAC listed in China, the share of CSM in C-hosp was close to 40%, which was much higher than that of G-hosp and MCHC-hosp. In contrast, the share of CMAC in G-hosp was nearly 30%, which was significantly higher than that in C-hosp and MCHC-hosp. Health insurance covers most of these five types of pediatric medicines, with the proportion of insured medicines reaching close to 80% in C-hosp and approximately 85% in MCHC-hosp and G-hosp. Discussion: The availability of specific medicines suitable for use in children is generally low, and even CSM in specialized hospitals such as C-hosp cannot meet the relatively high accessibility level of WHO evaluation standards. Policies and measures should be implemented to boost the research and development of pediatric medicines, as well as supplement safety information lacking in instruction manuals.

Progression of the PI3K/Akt signaling pathway in chronic obstructive pulmonary disease.

Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory disease characterized by a slow progression and caused by the inhalation of harmful particulate matter. Cigarette smoke and air pollutants are the primary contributing factors. Currently, the pathogenesis of COPD remains incompletely understood. The PI3K/Akt signaling pathway has recently emerged as a critical regulator of inflammation and oxidative stress response in COPD, playing a pivotal role in the disease's progression and treatment. This paper reviews the association between the PI3K/Akt pathway and COPD, examines effective PI3K/Akt inhibitors and novel anti-COPD agents, aiming to identify new therapeutic targets for clinical intervention in this disease.

Association between the atherogenic index of plasma and adverse long-term prognosis in patients diagnosed with chronic coronary syndrome.

BACKGROUND: The Atherogenic Index of Plasma (AIP) is a newly identified biomarker associated with lipid metabolism, demonstrating significant prognostic capabilities in individuals diagnosed with cardiovascular disease. However, its impact within the context of chronic coronary syndromes (CCS) remains unexplored. Thus, the present investigation sought to examine the potential association between AIP levels and long-term clinical outcomes in patients diagnosed with CCS. METHODS: A total of 404 patients diagnosed with CCS and who underwent coronary angiography were included in this study. The AIP index was calculated as log (triglycerides / high-density lipoprotein-cholesterol). The patients were categorized into four groups based on their AIP values: Q1 (< -0.064), Q2 (-0.064 to 0.130), Q3 (0.130 to 0.328), and Q4 (> 0.328). The occurrence of major adverse cardiovascular events (MACE) was monitored during the follow-up period for all patients. Cox regression analysis and Kaplan-Meier curve analysis were employed to examine the relationship between AIP and MACE. Furthermore, ROC analysis was utilized to determine the optimal cut-off value of AIP for predicting clinical MACE. RESULTS: During the median 35 months of follow-up, a total of 88 patients experienced MACE. Notably, the group of patients with higher AIP values (Q4 group) exhibited a significantly higher incidence of MACE compared to those with lower AIP values (Q1, Q2, and Q3 groups) (31.7% vs. 16.8%, 15.7%, and 23.0% respectively; P = 0.023). The Kaplan-Meier curves illustrated those patients in the Q4 group had the highest risk of MACE relative to patients in the other groups (log-rank P = 0.014). Furthermore, the multivariate Cox regression analysis demonstrated that individuals in the Q4 group had a 7.892-fold increased risk of MACE compared to those in the Q1 group (adjusted HR, 7.892; 95% CI 1.818-34.269; P = 0.006). Additionally, the ROC curve analysis revealed an optimal AIP cut-off value of 0.24 for predicting clinical MACE in patients with CCS. CONCLUSION: Our data indicate, for the first time, that AIP is independently associated with poor long-term prognosis in patients suffering from CCS. The optimal AIP cut-off value for predicting clinical MACE among CCS patients was 0.24.

A nomogram for distinguishing benign and malignant parotid gland tumors using clinical data and preoperative blood markers: development and validation.

PURPOSE: This study aimed to construct and validate a nomogram that incorporated clinical data and preoperative blood markers to differentiate BPGTs from MPGTs more efficiently and at low cost. METHODS: We retrospectively analyzed patients who underwent parotidectomy and histopathological diagnosis at the First Affiliated Hospital of Guangxi Medical University from January 2013 to June 2022. Subjects were randomly divided into training and validation sets with a 7:3 ratio. In the training set, the least absolute shrinkage and selection operator (LASSO) regression analysis was performed to select the most relevant features from 19 variables and built a nomogram using logistic regression. We evaluated the model's performance using receiver-operating characteristic (ROC) curves, calibration curves, clinical decision curve analysis (DCA), and clinical impact curve analysis (CICA). RESULTS: The final sample consisted of 644 patients, of whom 108 (16.77%) had MPGTs. The nomogram included four features: current smoking status, pain/tenderness, peripheral facial paralysis, and lymphocyte-to-monocyte ratio (LMR). The optimal cut-off value for the nomogram was 0.17. The areas under the ROC curves (AUCs) of the nomogram were 0.748 (95% confidence interval [CI] = 0.689-0.807) and 0.754 (95% CI = 0.636-0.872) in the training and validation sets, respectively. The nomogram also showed good calibration, high accuracy, moderate sensitivity, and acceptable specificity in both sets. The DCA and CICA demonstrated that the nomogram had significant net benefits for a wide range of threshold probabilities (0.06-0.88 for the training set; 0.06-0.57 and 0.73-0.95 for the validation set). CONCLUSION: The nomogram based on clinical characteristics and preoperative blood markers was a reliable tool for discriminating BPGTs from MPGTs preoperatively.

Targeting KAT2A inhibits inflammatory macrophage activation and rheumatoid arthritis through epigenetic and metabolic reprogramming.

Epigenetic regulation of inflammatory macrophages governs inflammation initiation and resolution in the pathogenesis of rheumatoid arthritis (RA). Nevertheless, the mechanisms underlying macrophage-mediated arthritis injuries remain largely obscure. Here, we found that increased expression of lysine acetyltransferase 2A (KAT2A) in synovial tissues was closely correlated with inflammatory joint immunopathology in both RA patients and experimental arthritis mice. Administration of MB-3, the KAT2A-specific chemical inhibitor, significantly ameliorated the synovitis and bone destruction in collagen-induced arthritis model. Both pharmacological inhibition and siRNA silencing of KAT2A, not only suppressed innate stimuli-triggered proinflammatory gene (such as Il1b and Nlrp3) transcription but also impaired NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in vivo and in vitro. Mechanistically, KAT2A facilitated macrophage glycolysis reprogramming through suppressing nuclear factor-erythroid 2-related factor 2 (NRF2) activity as well as downstream antioxidant molecules, which supported histone 3 lysine 9 acetylation (H3K9ac) and limited NRF2-mediated transcriptional repression of proinflammatory genes. Our study proves that acetyltransferase KAT2A licenses metabolic and epigenetic reprogramming for NLRP3 inflammasome activation in inflammatory macrophages, thereby targeting KAT2A represents a potential therapeutic approach for patients suffering from RA and relevant inflammatory diseases.

Household Polluting Fuel Use and Frailty among Older Adults in Rural China: The Moderating Role of Healthy Lifestyle Behaviors.

This study worked to investigate the effect of household polluting fuel use (HPFU), as an indicator of household air pollution exposure, on frailty among older adults in rural China. Additionally, this study aimed to examine the moderating effect of healthy lifestyle behaviors on the aforementioned association. This study employed cross-sectional data from the 2018 Chinese Longitudinal Healthy Longevity Survey, which conducted nationally representative sampling of older adults from 23 provinces in mainland China. The frailty index was calculated using 38 baseline variables that assessed health deficits through questionnaire surveys and health examinations. A total of 4535 older adults aged 65 years and above were included in our study, among whom, 1780 reported using polluting fuels as their primary household cooking fuel. The results of regression analyses and multiple robustness checks indicated a significant increase in the frailty index due to HPFU. This environmental health threat was more profound among women, illiterate individuals, and low-economic-status groups. Moreover, healthy dietary and social activities had significant moderating effects on the association between HPFU and frailty. HPFU can be regarded as a risk factor for frailty among older adults in rural China, with its effects exhibiting socio-economic disparities. The adoption of healthy lifestyle behaviors can alleviate the frailty associated with HPFU. Our findings underscore the significance of using clean fuels and improving household air quality for healthy aging in rural China.

Association between the triglyceride-glucose index and the presence and prognosis of coronary microvascular dysfunction in patients with chronic coronary syndrome.

BACKGROUND: Coronary microvascular dysfunction (CMD) is a strong determinant of prognosis in patients with chronic coronary syndrome (CCS). The triglyceride-glucose index (TyG index), an alternative method to evaluate insulin resistance, is positively correlated with the incidence and adverse outcomes of cardiovascular diseases. However, the relationship between the TyG index and the presence and prognosis of CMD in CCS patients has not been investigated. Therefore, we aimed to evaluate the association between the TyG index and the presence and clinical outcomes of CMD among CCS patients. METHODS: CCS patients who underwent coronary angiography between June 2015 to June 2019 were included. The TyG index was calculated as Ln[fasting triglycerides (mg/dL) × fasting blood glucose (mg/dL)/2]. Coronary angiography­derived index of microvascular resistance (caIMR) was used to measure microvascular function, and CMD was defined as caIMR ≥ 25U. Patients with CMD were divided into three groups (T1, T2, and T3 groups) according to TyG tertiles. The primary endpoint was major adverse cardiac event (MACE). RESULTS: Of 430 CCS patients, 221 patients had CMD. CMD patients had significantly higher TyG index than those without CMD. Sixty-three MACE was recorded during the follow-up duration among CMD patients, and the incidence rate of MACE was higher in the T3 group compared to T1/T2 groups (39.2% vs. 20.5% vs. 25.7%; P = 0.035). Multivariable logistic regression analysis showed that the TyG index was an independent predictor of CMD (OR, 1.436; 95% CI, 1.014-2.034; P = 0.042). Compared to the T1 group, the T3 group strongly correlated with the risk of MACE in CMD patients even after adjusting for additional confounding risk factors (HR, 2.132; 95%CI, 1.066-4.261; P = 0.032). CONCLUSION: TyG index is significantly associated with the risk of CMD, and it is an independent predictor of MACE among CMD patients with CCS. This study suggests that the TyG index has important clinical significance for the early prevention and risk stratification of CMD.