Protosappanin A Protects DOX-Induced Myocardial Injury and Cardiac Dysfunction by Targeting ACSL4/FTH1 Axis-Dependent Ferroptosis.

Doxorubicin (DOX) is an effective anticancer agent, but its clinical utility is constrained by dose-dependent cardiotoxicity, partly due to cardiomyocyte ferroptosis. However, the progress of developing cardioprotective medications to counteract ferroptosis has encountered obstacles. Protosappanin A (PrA), an anti-inflammatory compound derived from hematoxylin, shows potential against DOX-induced cardiomyopathy (DIC). Here, it is reported that PrA alleviates myocardial damage and dysfunction by reducing DOX-induced ferroptosis and maintaining mitochondrial homeostasis. Subsequently, the molecular target of PrA through proteome microarray, molecular docking, and dynamics simulation is identified. Mechanistically, PrA physically binds with ferroptosis-related proteins acyl-CoA synthetase long-chain family member 4 (ACSL4) and ferritin heavy chain 1 (FTH1), ultimately inhibiting ACSL4 phosphorylation and subsequent phospholipid peroxidation, while also preventing FTH1 autophagic degradation and subsequent release of ferrous ions (Fe2+) release. Given the critical role of ferroptosis in the pathogenesis of ischemia-reperfusion (IR) injury, this further investigation posits that PrA can confer a protective effect against IR-induced cardiac damage by inhibiting ferroptosis. Overall, a novel pharmacological inhibitor is unveiled that targets ferroptosis and uncover a dual-regulated mechanism for cardiomyocyte ferroptosis in DIC, highlighting additional therapeutic options for chemodrug-induced cardiotoxicity and ferroptosis-triggered disorders.

The Association between Lead Exposure and Dental Caries: A Systematic Review.

INTRODUCTION: Dental caries has declined over the years, but it remains a major public health issue. This review aimed to investigate the association between lead (Pb) and caries experience in either deciduous or permanent teeth. METHODS: A comprehensive search of PubMed, Embase, and Google Scholar was conducted to identify relevant studies published up until December 2022. Included were human observational studies that investigated the association between Pb exposure and dental caries. The review adhered to the PRISMA guideline. RESULTS: Sixteen studies were included in this review, with nine focusing on deciduous teeth, thirteen on permanent teeth, and six examining both types of teeth. Most of the studies (5 of 6) found a positive association between blood lead (PbB) levels and caries in deciduous teeth, while the findings for permanent teeth were less conclusive, with only 3 of 10 studies finding an association. One of the two studies assessing salivary lead levels found a weak association for permanent teeth. All four studies that measured Pb concentration from teeth found a positive association for both deciduous and permanent teeth. CONCLUSION: Many published studies have indicated a positive association between Pb exposure and caries experience in deciduous dentition. Children with elevated PbB level should be considered having higher caries experience. Due to lack of consensus on measurement and examination technique, there remains insufficient evidence to make any definitive conclusions, especially in permanent dentition, and so more studies are warranted.

Progress in the Application of Microneedles in Eye Disorders and the Proposal of the Upgraded Microneedle with Spinule.

PURPOSE: In the local administration methods for treating eye diseases, the application of microneedles has great potential due to the shortcomings of low efficacy and significant side effects of local administration preparations. This article provides ideas for the research on the application of ophthalmic microneedle in the treatment of eye diseases. RESULTS: This article analyzes the physiological structures of the eyes, ocular diseases and its existing ocular preparations in sequence. Finally, this article reviews the development and trends of ocular microneedles in recent years, and summarizes and discusses the drugs of ocular microneedles as well as the future directions of development. At the same time, according to the inspiration of previous work, the concept of "microneedle with spinule" is proposed for the first time, and its advantages and limitations are discussed in the article. CONCLUSIONS: At present, the application of ocular microneedles still faces multiple challenges. The aspects of auxiliary devices, appearance, the properties of the matrix materials, and preparation technology of ophthalmic microneedle are crucial for their application in the treatment of eye diseases.

Comparison of carbon and nitrogen accumulation rate between bog and fen phases in a pristine peatland with the fen-bog transition.

Long-term carbon and nitrogen dynamics in peatlands are affected by both vegetation production and decomposition processes. Here, we examined the carbon accumulation rate (CAR), nitrogen accumulation rate (NAR) and δ13 C, δ15 N of plant residuals in a peat core dated back to ~8500 cal year BP in a temperate peatland in Northeast China. Impacted by the tephra during 1160 and 789 cal year BP and climate change, the peatland changed from a fen dominated by vascular plants to a bog dominated by Sphagnum mosses. We used the Clymo model to quantify peat addition rate and decay constant for acrotelm and catotelm layers during both bog and fen phases. Our studied peatland was dominated by Sphagnum fuscum during the bog phase (789 to -59 cal year BP) and lower accumulation rates in the acrotelm layer was found during this phase, suggesting the dominant role of volcanic eruption in the CAR of the peat core. Both mean CAR and NAR were higher during the bog phase than during the fen phase in our study, consistent with the results of the only one similar study in the literature. Because the input rate of organic matter was considered to be lower during the bog phase, the decomposition process must have been much lower during the bog phase than during the fen phase and potentially controlled CAR and NAR. During the fen phase, CAR was also lower under higher temperature and summer insolation, conditions beneficial for decomposition. δ15 N of Sphagnum hinted that nitrogen fixation had a positive effect on nitrogen accumulation, particular in recent decades. Our study suggested that decomposition is more important for carbon and nitrogen sequestration than production in peatlands in most conditions and if future climate changes or human disturbance increase decomposition rate, carbon sequestration in peatlands will be jeopardized.

Interferon lambda modulates proinflammatory cytokines production in PBMCs from patients with chronic kidney disease.

BACKGROUND: CKD is a major cause of morbidity and mortality worldwide. Considerable evidence now indicates that renal inflammation plays a central role in the initiation and progression of CKD. Recent investigations have demonstrated that IFNλ plays an important role in the pathogenesis of autoimmune and inflammatory diseases. However, the association of IFNλ with CKD is still poorly understood. OBJECTIVE: To analyze the correlation between IFNλ levels and pro-inflammatory cytokines, and to investigate the effect of IFNλ on PBMCs in patients with CKD. METHODS: PBMCs were harvested from patients with CKD and healthy controls for measuring the expression level of inflammatory cytokines by RT-qPCR. Spearman correlation test was used to analyze correlation between IFNλ and cytokines as well as eGFR. PBMCs from healthy individuals and CKD patients were subjected to IFNλ protein stimulation. IL6, TNFα, IL10, ISG15 and MX1 mRNA level were measured by RT-PCR, STAT1 and phosphorylated STAT1 protein level were measured by Western blot. RESULTS: Patients with CKD showed higher levels of IFNλ in PBMCs compared to healthy controls. IFNλ mRNA levels were associated with cytokines and eGFR. The transcription of IL6, TNFα, and IL10 was significantly increased in healthy human PBMCs after IFNλ stimulation. In addition, IFNλ acts on PBMCs by p-STAT1 and ISG15 as well as MX1. CONCLUSION: High expression of IFNλ was found in CKD patients and was associated with eGFR and disease-related cytokines. More importantly, IFNλ promoted the expression of pro-inflammatory cytokines in PBMCs, suggesting a potential pro-inflammatory role of IFNλ in CKD.

Vegetation restoration of abandoned cropland improves soil ecosystem multifunctionality through alleviating nitrogen-limitation in the China Danxia.

The microbial requirement for nutrient resources can be estimated by soil extracellular enzyme stoichiometry (EES) and their stoichiometries. Implementing the Grain for Green Program has significantly impacted land use and soil nutrient management in the China Danxia. However, drivers of soil microbial nutrient limitation changes in abandoned cropland (AC) remained unclear after vegetation restoration. Here, according to vector analysis, we evaluated microbial nutrient limitation by studying soil EES across vegetation restoration types (naturally restored secondary forests (NF) and artificially planted forests (AF)) with AC as a control. Results showed both NF and AF soils averaged higher C- and P- acquiring enzyme, indicating rapid C and P turnover rates after vegetation restoration. However, vegetation restoration resulted in higher C requirement for microorganisms with higher enzyme C:N and vector length. In addition, microorganisms shifted from N- (< 45°) to P-limited (> 45°) conditions with enzyme N:P less than 1 after vegetation restoration, and NF exacerbated microbial P limitation compared to AF. Decreased N limitation following vegetation restoration could be contributed to improving soil ecosystem multifunctionality. The greater variation of EES was explained by the interaction of pH, soil nutrient, and microbial biomass than by any one of these factors alone, suggesting that both abiotic and biotic factors regulate microbial nutrient limitation and microbial process. Overall, our results revealed vegetation restoration could alleviate N limitation in the China Danxia, and thus enhance soil ecosystem by regulating lower microbial N limitation, which provide insight into nutrient management strategies under ecological restoration of degraded areas.

Isotopic evidence for increased carbon and nitrogen exchanges between peatland plants and their symbiotic microbes with rising atmospheric CO2 concentrations since 15,000 cal. year BP.

Whether nitrogen (N) availability will limit plant growth and removal of atmospheric CO2 by the terrestrial biosphere this century is controversial. Studies have suggested that N could progressively limit plant growth, as trees and soils accumulate N in slowly cycling biomass pools in response to increases in carbon sequestration. However, a question remains over whether longer-term (decadal to century) feedbacks between climate, CO2 and plant N uptake could emerge to reduce ecosystem-level N limitations. The symbioses between plants and microbes can help plants to acquire N from the soil or from the atmosphere via biological N2 fixation-the pathway through which N can be rapidly brought into ecosystems and thereby partially or completely alleviate N limitation on plant productivity. Here we present measurements of plant N isotope composition (δ15 N) in a peat core that dates to 15,000 cal. year BP to ascertain ecosystem-level N cycling responses to rising atmospheric CO2 concentrations. We find that pre-industrial increases in global atmospheric CO2 concentrations corresponded with a decrease in the δ15 N of both Sphagnum moss and Ericaceae when constrained for climatic factors. A modern experiment demonstrates that the δ15 N of Sphagnum decreases with increasing N2 -fixation rates. These findings suggest that plant-microbe symbioses that facilitate N acquisition are, over the long term, enhanced under rising atmospheric CO2 concentrations, highlighting an ecosystem-level feedback mechanism whereby N constraints on terrestrial carbon storage can be overcome.

Histone Lactylation Boosts Reparative Gene Activation Post-Myocardial Infarction.

BACKGROUND: Inflammation resolution and cardiac repair initiation after myocardial infarction (MI) require timely activation of reparative signals. Histone lactylation confers macrophage homeostatic gene expression signatures via transcriptional regulation. However, the role of histone lactylation in the repair response post-MI remains unclear. We aimed to investigate whether histone lactylation induces reparative gene expression in monocytes early and remotely post-MI. METHODS: Single-cell transcriptome data indicated that reparative genes were activated early and remotely in bone marrow and circulating monocytes before cardiac recruitment. Western blotting and immunofluorescence staining revealed increases in histone lactylation levels, including the previously identified histone H3K18 lactylation in monocyte-macrophages early post-MI. Through joint CUT&Tag and RNA-sequencing analyses, we identified Lrg1, Vegf-a, and IL-10 as histone H3K18 lactylation target genes. The increased modification and expression levels of these target genes post-MI were verified by chromatin immunoprecipitation-qPCR and reverse transcription-qPCR. RESULTS: We demonstrated that histone lactylation regulates the anti-inflammatory and pro-angiogenic dual activities of monocyte-macrophages by facilitating reparative gene transcription and confirmed that histone lactylation favors a reparative environment and improves cardiac function post-MI. Furthermore, we explored the potential positive role of monocyte histone lactylation in reperfused MI. Mechanistically, we provided new evidence that monocytes undergo metabolic reprogramming in the early stage of MI and demonstrated that dysregulated glycolysis and MCT1 (monocarboxylate transporter 1)-mediated lactate transport promote histone lactylation. Finally, we revealed the catalytic effect of IL (interleukin)-1ß-dependent GCN5 (general control non-depressible 5) recruitment on histone H3K18 lactylation and elucidated its potential role as an upstream regulatory element in the regulation of monocyte histone lactylation and downstream reparative gene expression post-MI. CONCLUSIONS: Histone lactylation promotes early remote activation of the reparative transcriptional response in monocytes, which is essential for the establishment of immune homeostasis and timely activation of the cardiac repair process post-MI.

In Situ Anodic Oxidation Tuning of NiFeV Diselenide to the Core-Shell Heterojunction for Boosting Oxygen Evolution.

Developing non-noble metal-based core-shell heterojunction electrocatalysts with high catalytic activity and long-lasting stability is crucial for the oxygen evolution reaction (OER). Here, we prepared novel core-shell Fe,V-NiSe2@NiFe(OH)x heterostructured nanoparticles on hydrophilic-treated carbon paper with high electronic transport and large surface area for accelerating the oxygen evolution rate via high-temperature selenization and electrochemical anodic oxidation procedures. Performance testing shows that Fe,V-NiSe2@NiFe(OH)x possesses the highest performance for OER compared to as-prepared diselenide core-derived heterojunctions, which only require an overpotential of 243 mV at 10 mA cm-2 and a low Tafel slope of 91.6 mV decade-1 under basic conditions. Furthermore, X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) confirm the morphology and elementary stabilities of Fe,V-NiSe2@NiFe(OH)x after long-term chronopotentiometric testing. These advantages are largely because of the strong synergistic effect between the Fe,V-NiSe2 core with high conductivity and the amorphous NiFe(OH)x shell with enriched defects and vacancies. This study also presents a general approach to designing and synthesizing more active core-shell heterojunction electrocatalysts for OER.

Discrimination and Prediction of Lonicerae japonicae Flos and Lonicerae Flos and Their Related Prescriptions by Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy Combined with Multivariate Statistical Analysis.

LJF and LF are commonly used in Chinese patent drugs. In the Chinese Pharmacopoeia, LJF and LF once belonged to the same source. However, since 2005, the two species have been listed separately. Therefore, they are often misused, and medicinal materials are indiscriminately put in their related prescriptions in China. In this work, firstly, we established a model for discriminating LJF and LF using ATR-FTIR combined with multivariate statistical analysis. The spectra data were further preprocessed and combined with spectral filter transformations and normalization methods. These pretreated data were used to establish pattern recognition models with PLS-DA, RF, and SVM. Results demonstrated that the RF model was the optimal model, and the overall classification accuracy for LJF and LF samples reached 98.86%. Then, the established model was applied in the discrimination of their related prescriptions. Interestingly, the results show good accuracy and applicability. The RF model for discriminating the related prescriptions containing LJF or LF had an accuracy of 100%. Our results suggest that this method is a rapid and effective tool for the successful discrimination of LJF and LF and their related prescriptions.

Mechanism of integrin activation by talin and its cooperation with kindlin.

Talin-induced integrin binding to extracellular matrix ligands (integrin activation) is the key step to trigger many fundamental cellular processes including cell adhesion, cell migration, and spreading. Talin is widely known to use its N-terminal head domain (talin-H) to bind and activate integrin, but how talin-H operates in the context of full-length talin and its surrounding remains unknown. Here we show that while being capable of inducing integrin activation, talin-H alone exhibits unexpectedly low potency versus a constitutively activated full-length talin. We find that the large C-terminal rod domain of talin (talin-R), which otherwise masks the integrin binding site on talin-H in inactive talin, dramatically enhances the talin-H potency by dimerizing activated talin and bridging it to the integrin co-activator kindlin-2 via the adaptor protein paxillin. These data provide crucial insight into the mechanism of talin and its cooperation with kindlin to promote potent integrin activation, cell adhesion, and signaling.

Serum IL-6 and TNF-α Levels Are Correlated with Disease Severity in Patients with Ankylosing Spondylitis.

OBJECTIVE: Previous studies have shown that a number of cytokines participate in the regulation of ankylosing spondylitis (AS). To investigate the potential role of interleukin (IL)-6 and tumor necrosis factor- α (TNF-α) in AS pathogenesis, this study examined the serum levels of IL-6 and TNF-α in patients with AS and its clinical association with disease activity. MATERIALS AND METHODS: The serum concentrations of IL-6 and TNF-α from 80 patients with AS and 46 healthy control patients (HCs) were examined by electrochemiluminescence immunoassay. The correlations between the serum IL-6 and TNF-α levels and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), computed tomography (CT) imaging-based classification, and laboratory indicators were analyzed using the Spearman correlation test. RESULTS: Compared to HCs, patients with AS showed higher levels of IL-6 and TNF-α. There was also a positive correlation between the serum IL-6 and TNF-α levels and the BASDAI, the progression of AS, and the CT imaging-based classification. The serum levels of IL-6 correlated closely with C-reactive protein and the erythrocyte sedimentation rate. More important, patients with AS with hip joint involvement exhibited a significant elevation of serum levels of TNF-α, and higher IL-6 was detected in patients with the involvement of joints other than the hip and sacroiliac joints. CONCLUSION: The serum levels of IL-6 and TNF-α can function as important indicators for auxiliary diagnosis and disease activity evaluation of AS.

Obesity Promotes Tumor Immune Evasion in Ovarian Cancer Through Increased Production of Myeloid-Derived Suppressor Cells via IL-6.

BACKGROUND: Obesity is defined as a chronic, low-grade inflammatory disease that can cause obesity-associated disorders, such as cancer. Obesity has traditionally been thought to be a risk factor for ovarian cancer. Few reports have focused on the specific pathogenesis of obesity-related ovarian cancer. When considering the correlation between obesity and the relative risk of death from ovarian cancer, we investigated whether obesity promotes tumor immune escape in ovarian cancer. RESULTS: In the present study, obese mice were found to have higher rates of tumor growth and tumor infiltration than mice of normal weight. Obesity increased the proportion of myeloid-derived suppressor cells (MDSCs) in peripheral blood compared with mice of normal weight. In addition, the levels of CCL25, CD40L, GM-CSF, IL-5, IGFBP2, IL-6, MMP3, and MMP9 in the peripheral blood, bone marrow, and ovarian tissue of obese mice were higher than in mice of normal weight. Moreover, IL-5 and IL-6 significantly enhanced the expression levels of S100A8 and S100A9 in MDSCs. When compared with the levels in mice of normal weight, the expression levels of S100A8 and S100A9 in the MDSCs of OB/OB mice were also higher within the tumor microenvironment. The infiltration of MDSCs in ovarian cancer was found to be positively correlated with the expression levels of IL-6. The IL-6 expression levels in ovarian cancer tissue are positively correlated with the expression levels of S100A8 and S100A9, which is consistent with the results of previous animal experiments. Finally, we found that LMT28 can suppress the tumor growth by inhibiting IL-6. CONCLUSION: Obesity promotes the expression of the MDSC-related immunosuppressive genes S100A8 and S100A9 by upregulating IL-6, thus promoting tumor immune evasion and metastasis in ovarian cancer.

TTK, CDC25A, and ESPL1 as Prognostic Biomarkers for Endometrial Cancer.

OBJECTIVE: Endometrial cancer (EC) is one of the most common malignant gynaecological tumours worldwide. This study was aimed at identifying EC prognostic genes and investigating the molecular mechanisms of these genes in EC. METHODS: Two mRNA datasets of EC were downloaded from the Gene Expression Omnibus (GEO). The GEO2R tool and Draw Venn Diagram were used to identify differentially expressed genes (DEGs) between normal endometrial tissues and EC tissues. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Next, the protein-protein interactions (PPIs) of these DEGs were determined by the Search Tool for the Retrieval of Interacting Genes (STRING) tool and Cytoscape with Molecular Complex Detection (MCODE). Furthermore, Kaplan-Meier survival analysis was performed by UALCAN to verify genes associated with significantly poor prognosis. Next, Gene Expression Profiling Interactive Analysis (GEPIA) was used to verify the expression levels of these selected genes. Additionally, a reanalysis of the KEGG pathways was performed to understand the potential biological functions of selected genes. Finally, the associations between these genes and clinical features were analysed based on TCGA cancer genomic datasets for EC. RESULTS: In EC tissues, compared with normal endometrial tissues, 147 of 249 DEGs were upregulated and 102 were downregulated. A total of 64 upregulated genes were assembled into a PPI network. Next, 14 genes were found to be both associated with significantly poor prognosis and highly expressed in EC tissues. Reanalysis of the KEGG pathways found that three of these genes were enriched in the cell cycle pathway. TTK, CDC25A, and ESPL1 showed higher expression in cancers with late stage and higher tumour grade. CONCLUSION: In summary, through integrated bioinformatics approaches, we found three significant prognostic genes of EC, which might be potential therapeutic targets for EC patients.

Synergetic Functional Nanocomposites Enhance Immunotherapy in Solid Tumors by Remodeling the Immunoenvironment.

Checkpoint blockade immunotherapy has demonstrated significant clinical success in various malignant tumors. However, the therapeutic response is limited due to the immunosuppressive tumor microenvironment (ITM). In this study, a functional nanomaterial, layered double hydroxides (LDHs), carrying specific functional miR155 is developed to modulate ITM by synergistically repolarizing tumor associated macrophages (TAMs) to M1 subtype. LDH nanoparticles loaded with miR155 (LDH@155) exhibit superior ability in cellular uptake by murine macrophages, miR escape into the cytoplasm and TAMs specific delivery when introtumoral administration. Meanwhile, upon exposure to LDH@155, TAMs are significantly skewed to M1 subtype, which markedly inhibits myeloid-derived suppressor cells (MDSCs) formation and stimulates T-lymphocytes to secrete more interferon-γ (IFN-γ) cytokines in vitro. Introtumoral administration of LDH@155 reduces the percentage of TAMs and MDSCs in the tumor and elevates CD4+ and CD8+ T cell infiltration and activation, which can promote therapeutic efficiency of α-PD-1 antibody immunotherapy. Furthermore, it is found that LDH@155 significantly decreases the expression level of phosphorylated STAT3 and ERK1/2 and activates NF-κB expression in TAMs, indicating that the STAT3, ERK1/2, and NF-κB signaling pathways may involve in LDH@155-induced macrophage polarization. Overall, the results suggest that LDH@155 nanoparticles may, in the future, function as a promising agent for cancer combinational immunotherapy.

Mercury and arsenic in the surface peat soils of the Changbai Mountains, northeastern China: distribution, environmental controls, sources, and ecological risk assessment.

The potential toxic risk of mercury (Hg) and arsenic (As) in the soils of mining regions and other artificially disturbed lands receives considerable research attention. However, limited investigation has been conducted into the surface soils of natural globally distributed ecosystems, for example peatlands. In this study, we examine the distribution, controlling factors, sources, and potential ecological risks of Hg and As in 96 samples from 42 peatlands in the Changbai Mountains of northeastern China. The results showed that average concentrations (dry weight) of Hg and As at the samples sites were 169.1 ± 0.1 µg kg-1 and 13.0 ± 7.7 mg kg-1, respectively. The distribution of Hg is largely determined by latitude and altitude, while As is controlled more by pH, total organic carbon (TOC), and ratio of TOC and nitrogen (C/N) at the regional scale. Variations in TOC, C/N ratio, and redox conditions contribute to determining the distribution of Hg, while TOC and redox conditions mainly affected the distribution of Arsenic at the local scale. Mercury mostly comes from regional atmospheric wet deposition, whereas elevated concentrations of As are related to local anthropogenic activities. Overall, Hg and As in the peatlands of the Changbai Mountains pose a moderate level of potential risk to ecological health.