Serum Uric Acid Levels Associated with Outcomes of Neurodegenerative Disorders and Brain Health: Findings from the UK Biobank.

BACKGROUND: The relationship between serum uric acid (SUA) levels and brain-related health remains uncertain. OBJECTIVES: This study aimed to investigate the relationship between SUA levels and some neurodegenerative disorders and brain structure. DESIGN: A longitudinal study. SETTING AND PARTICIPANTS: 384,517 participants who did not have stroke, dementia, and Parkinsonism, with complete urate testes and covariates were included. MEASUREMENTS: Cox proportional hazards models, competing risk models, and restricted cubic spine models were applied. RESULTS: During the median follow-up time of 12.7 years (interquartile range [IQR]:12.0, 13.5), 7821 (2.0%) participants developed stroke, 5103 (1.3%) participants developed dementia, and 2341 (0.6%) participants developed Parkinsonism. Nonlinear relationships were identified between SUA levels and stroke (J-shaped), dementia, and Parkinsonism (U-shaped). SUA levels of 4.2 mg/dl, 6.4 mg/dl, and 6.6 mg/dl yielded the lowest risk of stroke, dementia, and Parkinsonism, respectively. Besides, we found high SUA levels reduced the volumes of total brain, grey matter, white matter, grey matter in the hippocampus, and hippocampus, but increased lateral-ventricle volume. Inflammation accounted for 9.1% and 10.0% in the association of SUA with stroke and lateral-ventricle volume. CONCLUSIONS: Lower SUA levels increased the risk of Parkinsonism, while both lower and higher SUA levels were positively associated with increased risk of stroke and dementia. Moreover, high SUA levels reduced brain structure volumes. Our findings suggest the association between SUA levels and brain-related disorders and highlight the importance of SUA management.

Incidence and Predictors of Postpartum Depression Diagnoses among Active-Duty U.S. Army Soldiers.

Introduction: Understanding the incidence and predictors of postpartum depression (PPD) among active-duty service members is critical given the importance of this population and its unique stressors. Methods: We conducted a retrospective cohort study of all active-duty U.S. Army soldiers with a record of at least one live-birth delivery between January 2012 and December 2013. Multivariate logistic regression models were used to estimate associations between demographic, health-related, and military-specific variables and diagnoses of PPD in the total population (N = 4,178) as well as in a subpopulation without a record of depression before delivery (N = 3,615). Results: The overall incidence of PPD diagnoses was 15.9% (N = 664 cases) among the total population and 10.4% (N = 376 cases) among those without prior depression. Statistically significant predictors of PPD in the adjusted model included lower pay grade, a higher number of prior deployments, a higher number of child dependents, tobacco use, and a history of depression or anxiety before or during pregnancy. For soldiers without a history of depression, lower pay grade, and a history of anxiety before or during pregnancy were significantly associated with PPD. Conclusions: Knowing the predictors of overall and novel onset PPD diagnoses in this population could help establish clearer guidelines on PPD prevention, screening, management, and return to duty.

TaRLK2.4, a transgressive expression receptor like kinase, improves powdery mildew resistance in wheat.

Plants form two immune systems, pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI), to combat Blumeria graminis f. sp. tritici (Bgt) infection during the evolutionary process. In PTI, receptor-like kinases (RLKs) play important roles during pathogen infections. Based on our previous reports, there were 280 TaRLKs identified in early response to powdery mildew infection, which were divided into 34 subfamilies in this study. Differences in gene structures, cis-acting elements, and expression levels implied the function diversity of TaRLKs. TaRLK2.4, a member of LRK10L-RLKs subfamily, contained 665 amino acids, and located on the cell membrane. The main objective of this study was to investigate the role of the receptor-like kinase gene TaRLK2.4 in conferring powdery mildew resistance in wheat. Real-time quantitative PCR results indicated that TaRLK2.4 expressed during Bgt infection process, and exhibited a transgressive expression characteristic in disease resistance NILs (BJ-1). To elucidate the function of TaRLK2.4 during Bgt infection, the comprehensive analysis of virus induced gene silence and over-expression demonstrated that TaRLK2.4 promoted powdery mildew resistance positively. In summary, these results contribute to a deeper understanding of the complex and diverse biological functions of RLKs, and provide new genetic resources for wheat molecular breeding.

Reprogramming of glucose metabolism: The hallmark of malignant transformation and target for advanced diagnostics and treatments.

Reprogramming of cancer metabolism has become increasingly concerned over the last decade, particularly the reprogramming of glucose metabolism, also known as the "Warburg effect". The reprogramming of glucose metabolism is considered a novel hallmark of human cancers. A growing number of studies have shown that reprogramming of glucose metabolism can regulate many biological processes of cancers, including carcinogenesis, progression, metastasis, and drug resistance. In this review, we summarize the major biological functions, clinical significance, potential targets and signaling pathways of glucose metabolic reprogramming in human cancers. Moreover, the applications of natural products and small molecule inhibitors targeting glucose metabolic reprogramming are analyzed, some clinical agents targeting glucose metabolic reprogramming and trial statuses are summarized, as well as the pros and cons of targeting glucose metabolic reprogramming for cancer therapy are analyzed. Overall, the reprogramming of glucose metabolism plays an important role in the prediction, prevention, diagnosis and treatment of human cancers. Glucose metabolic reprogramming-related targets have great potential to serve as biomarkers for improving individual outcomes and prognosis in cancer patients. The clinical innovations related to targeting the reprogramming of glucose metabolism will be a hotspot for cancer therapy research in the future. We suggest that more high-quality clinical trials with more abundant drug formulations and toxicology experiments would be beneficial for the development and clinical application of drugs targeting reprogramming of glucose metabolism.This review will provide the researchers with the broader perspective and comprehensive understanding about the important significance of glucose metabolic reprogramming in human cancers.

Superconductivity under pressure in a chromium-based kagome metal.

Superconductivity in a highly correlated kagome system has been theoretically proposed for years (refs. 1-5), yet the experimental realization is hard to achieve6,7. The recently discovered vanadium-based kagome materials8, which exhibit both superconductivity9-11 and charge-density-wave orders12-14, are nonmagnetic8,9 and weakly correlated15,16. Thus these materials are unlikely to host the exotic superconductivity theoretically proposed. Here we report the discovery of a chromium-based kagome metal, CsCr3Sb5, which is contrastingly featured with strong electron correlations, frustrated magnetism and characteristic flat bands close to the Fermi level. Under ambient pressure, this kagome metal undergoes a concurrent structural and magnetic phase transition at 55 K, with a stripe-like 4a0 structural modulation. At high pressure, the phase transition evolves into two transitions, possibly associated with charge-density-wave and antiferromagnetic spin-density-wave orderings. These density-wave-like orders are gradually suppressed with pressure and, remarkably, a superconducting dome emerges at 3.65-8.0 GPa. The maximum of the superconducting transition temperature, Tcmax = 6.4 K, appears when the density-wave-like orders are completely suppressed at 4.2 GPa, and the normal state exhibits a non-Fermi-liquid behaviour, reminiscent of unconventional superconductivity and quantum criticality in iron-based superconductors17,18. Our work offers an unprecedented platform for investigating superconductivity in correlated kagome systems.

Apoptosis induction and inhibition of invasion and migration in gastric cancer cells by Isoorientin studied using network pharmacology.

BACKGROUND: To investigate the effects of Isoorientin on the apoptosis, proliferation, invasion, and migration of human gastric cancer cells (HGC27 cells). METHODS: We used network pharmacology to predict the targets of drugs and diseases. The CCK-8 assay was used to determine the effects of Isoorientin on the proliferation of HGC27 cells. Flow cytometry was employed to analyze the effects of Isoorientin on cell apoptosis and cell cycle distribution of HGC27 cells. Scratch test and transwell chamber test were conducted to assess the effects of Isoorientin on invasion and migration, respectively. Additionally, qPCR and western blot were performed to examine the impact of Isoorientin on apoptosis-related genes and protein expression, respectively. RESULTS: The Isoorientin significantly inhibited the proliferation, migration, and invasion of HGC27 cells compared to the control group. Furthermore, Isoorientin induced apoptosis in HGC27 cells by upregulating the relative expression of Bax and caspase-3 while downregulating the relative expression of p-PI3K, p-AKT, and Bcl-2 proteins. CONCLUSION: The Isoorientin exhibits inhibitory effects on the proliferation, invasion, and migration of HGC27 cells, and induces apoptosis in gastric cancer cells.

The potential of repeated mean arterial pressure measurements for predicting early- and late-onset pre-eclampsia in twin pregnancies: Prediction model study.

OBJECTIVE: To investigate the contribution of longitudinal mean arterial pressure (MAP) measurement during the first, second, and third trimesters of twin pregnancies to the prediction of pre-eclampsia. METHODS: A retrospective cohort study was conducted on women with twin pregnancies. Historical data between 2019 and 2021 were analyzed, including maternal characteristics and mean artery pressure measurements were obtained at 11-13, 22-24, and 28-33 weeks of gestation. The outcome measures included pre-eclampsia with delivery <34 and ≥34 weeks of gestation. Models were developed using logistic regression, and predictive performance was evaluated using the area under the curve, detection rate at a given false-positive rate of 10%, and calibration plots. Internal validation was conducted via bootstrapping. RESULTS: A total of 943 twin pregnancies, including 36 (3.82%) women who experienced early-onset pre-eclampsia and 93 (9.86%) who developed late-onset pre-eclampsia, were included in this study. To forecast pre-eclampsia during the third trimester, the most accurate prediction for early-onset pre-eclampsia resulted from a combination of maternal factors and MAP measured during this trimester. The optimal predictive model for late-onset pre-eclampsia includes maternal factors and MAP data collected during the second and third trimesters. The areas under the curve were 0.937 (95% confidence interval [CI] 0.894-0.981) and 0.887 (95% CI 0.852-0.921), respectively. The corresponding detection rates were 83.33% (95% CI 66.53%-93.04%) for early-onset pre-eclampsia and 68.82% (95% CI 58.26%-77.80%) for late-onset pre-eclampsia. CONCLUSION: Repeated measurements of MAP during pregnancy significantly improved the accuracy of late-onset pre-eclampsia prediction in twin pregnancies. The integration of longitudinal data into pre-eclampsia screening may be an effective and valuable strategy.

The association between fat distribution and α1-acid glycoprotein levels among adult females in the United States.

BACKGROUND: Visceral fat accumulation and obesity-induced chronic inflammation have been proposed as early markers for multiple disease states, especially in women. Nevertheless, the potential impact of fat distribution on α1-acid glycoprotein(AGP), a marker of inflammation, remains unclear. This research was conducted to investigate the relationships among obesity, fat distribution, and AGP levels. METHODS: A cross-sectional observational study was performed using blood samples from adult females recruited through the National Health and Nutrition Examination Survey from 2015 to 2018. Serum levels of AGP were measured using the Tina-quant α-1-Acid Glycoprotein Gen.2 assay. Based on the fat distribution data obtained from dual-energy X-ray absorptiometry assessments, body mass index (BMI), total percent fat (TPF), android percent fat (APF), gynoid percent fat (GPF), android fat/gynoid fat ratio (AGR), visceral percent fat (VPF), subcutaneous percent fat (SPF), visceral fat/subcutaneous fat ratio (VSR) were used as dependent variables. To investigate the link between fat distribution and AGP, multivariate linear regression analysis was utilized. Furthermore, a sensitivity analysis was also performed. RESULTS: The present study included 2,295 participants. After adjusting for covariates, BMI, TPF, APF, GPF, VPF, and SPF were found to be positively correlated with AGP levels (BMI: ß = 23.65 95%CI:20.90-26.40; TPF: ß = 25.91 95%CI:23.02-28.80; APF: ß = 25.21 95%CI:22.49-27.93; GPF: ß = 19.65 95%CI:16.96-22.34; VPF: ß = 12.49 95%CI:9.08-15.90; SPF: ß = 5.69, 95%CI:2.89-8.49; AGR: ß = 21.14 95%CI:18.16-24.12; VSR: ß = 9.35 95%CI:6.11-12.59, all P < 0.0001). All the above indicators exhibited a positive dose-response relationship with AGP. In terms of fat distribution, both AGR and VSR showed positive associations with AGP (P for trend < 0.0001). In particular, when compared to individuals in tertile 1 of AGR, participants in tertiles 2 and 3 had 13.42 mg/dL (95% CI 10.66-16.18) and 21.14 mg/dL (95% CI 18.16-24.12) higher AGP levels, respectively. Participants in the highest tertile of VSR were more likely to exhibit a 9.35 mg/dL increase in AGP compared to those in the lowest tertile (95% CI 6.11-12.59). CONCLUSIONS: Overall, this study revealed a positive dose-dependent relationship between fat proportion/distribution and AGP levels in women. These findings suggest that physicians can associate abnormal serum AGP and obesity with allow timely interventions.

Germination time and in vitro gastrointestinal digestion impact on the isoflavone bioaccessibility and antioxidant capacities of soybean sprouts.

Soybeans' isoflavone content increases with germination; nevertheless, their bioaccessibility in the gastrointestinal system is limited. This study evaluated the influence of germination time (1, 3, 5, and 7 days) and in vitro gastrointestinal conditions on the isoflavone profile of soybean sprouts. The total isoflavones (4.07 mg/g) and the malonyl genistin (1.37 mg/g) had the highest contents on day 5 in the gastric phase. The highest isoflavone bioaccessibility was observed in daidzein, genistein, and glycitin. An increase in antioxidant capacity was found during germination (day 7 > day 5 > day 3); however, the same trend was not observed during in vitro digestion. In summary, the results indicate that soybean sprouts germinated for 5 days may be more beneficial for consumption since they have the highest and most readily absorbed levels of isoflavones. These data suggest that soybean sprouts may be a functional food that provides bioavailable antioxidants.

CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer.

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

Isolation of aptamers with excellent cross-reactivity and specificity to sulfonamides towards a ratiometric fluorescent aptasensor for the detection of nine sulfonamides in seafood.

Sulfonamides (SAs) is a class of antibiotics that extensively used for treating infectious diseases in livestock industries and aquaculture. Thus, it is urgent need to obtain the bio-receptor, which has excellent cross-reactivity and specificity to SAs, for developing high-throughput methods for the determination of multiple SAs even all commonly-used SAs, to realize the quick screening/detection of total SAs in animal-derived foods. We herein isolated several SAs-specific cross-reactive aptamers by using a library-immobilized SELEX with multi-SAs parallel selection strategy. Two of the isolated aptamers (Sul-01 and Sul-04) can specifically recognize and bind seven SAs respectively with higher binding affinity and no interference of non-sulfonamide antibiotics, and thus can be applied as bio-receptors for developing high-throughput aptasensors for the quick screening/detection of multiple SAs. By using the mixture of Sul-01 and Sul-04 as bio-receptor, a ratiometric fluorescent aptasensor was created for the quick detection of nine SAs including sulfamethoxydiazine (SMD), sulfapyridine (SPD), sulfaquinoxaline (SQ), sulfathiazole (ST), sulfamonomethoxine (SMM), sulfamerazine (SMR), sulfaguanidine (SG), sulfamethazine (SMZ) and sulfadiazine (SD) with a detection limit (LOD) of 0.10-0.50 µM, or total of above nine SAs with a LOD of 0.20 µM. The fluorescent aptasensor was successfully applied to detect each or total of SMD, SPD, SQ, ST, SMM, SMR, SG, SMZ and SD in fish samples with a recovery of 83 %-92 % and a relative standard deviation (RSD, n = 5) < 5 %. This study not only provided several promising bio-receptors for the development of diverse high-throughput aptasensors to achieve the quick screening of multiple SAs residues, but also provided a simple, stable and sensitive method for the quick screening of SMD, SPD, SQ, ST, SMM, SMR, SG, SMZ and SD in seafood.

Genetic Basis Identification of a NLR Gene, TaRGA5-like, That Confers Partial Powdery Mildew Resistance in Wheat SJ106.

Wheat powdery mildew is an important fungal disease that seriously jeopardizes wheat production, which poses a serious threat to food safety. SJ106 is a high-quality, disease-resistant spring wheat variety; this disease resistance is derived from Wheat-wheatgrass 33. In this study, the powdery mildew resistance genes in SJ106 were located at the end of chromosome 6DS, a new disease resistance locus tentatively named PmSJ106 locus. This interval was composed of a nucleotide-binding leucine-rich repeat (NLR) gene cluster containing 19 NLR genes. Five NLRs were tandem duplicated genes, and one of them (a coiled coil domain-nucleotide binding site-leucine-rich repeat (CC-NBS-LRR; CNL) type gene, TaRGA5-like) expressed 69-836-fold in SJ106 compared with the susceptible control. The genome DNA and cDNA sequences of TaRGA5-like were amplified from SJ106, which contain several nucleotide polymorphisms in LRR regions compared with susceptible individuals and Chinese Spring. Overexpression of TaRGA5-like significantly increased resistance to powdery mildew in susceptible receptor wheat Jinqiang5. However, Virus induced gene silence (VIGS) of TaRGA5-like resulted in only a small decrease of SJ106 in disease resistance, presumably compensated by other NLR duplicated genes. The results suggested that TaRGA5-like confers partial powdery mildew resistance in SJ106. As a member of the PmSJ106 locus, TaRGA5-like functioned together with other NLR duplicated genes to improve wheat resistance to powdery mildew. Wheat variety SJ106 would become a novel and potentially valuable germplasm for powdery mildew resistance.

IGF2BP2 Maintains Retinal Pigment Epithelium Homeostasis by Stabilizing PAX6 and OTX2.

Purpose: N6-methyladenosine (m6A) methylation is a chemical modification that occurs on RNA molecules, where the hydrogen atom of adenine (A) nucleotides is replaced by a methyl group, forming N6-methyladenosine. This modification is a dynamic and reversible process that plays a crucial role in regulating various biological processes, including RNA stability, transport, translation, and degradation. Currently, there is a lack of research on the role of m6A modifications in maintaining the characteristics of RPE cells. m6A readers play a crucial role in executing the functions of m6A modifications, which prompted our investigation into their regulatory roles in the RPE. Methods: Phagocytosis assays, immunofluorescence staining, flow cytometry experiments, ß-galactosidase staining, and RNA sequencing (RNA-seq) were conducted to assess the functional and cellular characteristics changes in retinal pigment epithelium (RPE) cells following short-hairpin RNA-mediated knockdown of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). RNA-seq and ultraviolet crosslinking immunoprecipitation with high-throughput sequencing (HITS-CLIP) were employed to identify the target genes regulated by IGF2BP2. adeno-associated virus (AAV) subretinal injection was performed in 6- to 8-week-old C57 mice to reduce IGF2BP2 expression in the RPE, and the impact of IGF2BP2 knockdown on mouse visual function was assessed using immunofluorescence, quantitative real-time PCR, optical coherence tomography, and electroretinography. Results: IGF2BP2 was found to have a pronounced effect on RPE phagocytosis. Subsequent in-depth exploration revealed that IGF2BP2 modulates the mRNA stability of PAX6 and OTX2, and the loss of IGF2BP2 induces inflammatory and aging phenotypes in RPE cells. IGF2BP2 knockdown impaired RPE function, leading to retinal dysfunction in vivo. Conclusions: Our data suggest a crucial role of IGF2BP2 as an m6A reader in maintaining RPE homeostasis by regulating the stability of PAX6 and OTX2, making it a potential target for preventing the occurrence of retinal diseases related to RPE malfunction.

Hydrographic proxies for submarine groundwater discharge in the Jiulong River estuary and global perspectives.

Submarine groundwater discharge (SGD) significantly impacts most coastal waters. However, its quantification, depending on chemical tracers/proxies, limits its parameterization in numerical models. This study explored the hydrographic proxies of SGD in the Jiulong River estuary (JRE) using 226Ra and 228Ra as SGD tracers. Our results showed significant monthly fluctuations in the flux of SGD, with a peak in June and a minimum in April. On average, the flux of SGD was equivalent to 10 ± 1.67 % of the concurrent river discharge, with the area-normalized rate of 0.007 ± 0.017 to 0.13 ± 0.04 m/day. Positive SGD response to river discharge implies a connection with the surface runoff of the shallow aquifers. Furthermore, the flux of SGD presented a significant negative correlation with the return flow factor and flushing time of the estuary. The radium activities in the estuary were positively correlated with water depth, indicating that SGD was not driven by tidal pumping. Instead, physical mixing in low to middle salinity regions predominated such behavior of radium. Our results indicate that river discharge, flushing time and return flow factor may serve as hydrographic proxies of SGD in the JRE and potentially be applicable in parameterization of SGD in numerical models in similar coastal ecosystems. Globally, a positive correlation between SGD flux and river discharge emphasizes the latter as a general proxy in estuaries.

Novel erythrocyte-shaped electrosprayed nanoparticles for co-delivery of paclitaxel and osimertinib: Preparation, characterization, and evaluation.

In this work, novel erythrocyte-shaped electrosprayed nanoparticles (EENPs) were designed and constructed by tri-axial electrospraying technique with PEG as the outer layer, PLGA as the middle drugs (paclitaxel [PTX] and osimertinib [OSI]) carrier layer and air as the inner layer. The prepared EENP were characterized and evaluated based on their spectral and morphological attributes. After the PTX/OSI ratio and process optimization, the EENP has inspiring features, including nanoscale size, erythrocyte morphology with a concave disk shape, and satisfactory drug loading (DL) and encapsulation efficiency (EE). In vitro drug release showed that PTX and OSI in the formulation were released in the same ratio, and the cumulative release percentage at 24 h was close to 80 %. Furthermore, the TGIR in the EENP formulation group exceeded 90 %, approximately 3.8-fold higher than that in the free drug group. In summary, we developed an erythrocyte three-core-shell nanoparticle for the co-delivery of PTX and OSI, providing a potential chemotherapeutic delivery system for the treatment of breast cancer.

Pulmonary succinate receptor 1 elevation in high-fat diet mice exacerbates lipopolysaccharides-induced acute lung injury via sensing succinate.

BACKGROUND: Individuals with obesity have higher level of circulating succinate, which acts as a signaling factor that initiates inflammation. It is obscure whether succinate and succinate receptor 1 (SUCNR1) are involved in the process of obesity aggravating acute lung injury (ALI). METHODS: The lung tissue and blood samples from patients with obesity who underwent lung wedgectomy or segmental resection were collected. Six-week-old male C57BL/6J mice were fed a high-fat diet for 12 weeks to induce obesity and lipopolysaccharides (LPS) were injected intratracheally (100 µg, 1 mg/ml) for 24 h to establish an ALI model. The pulmonary SUCNR1 expression and succinate level were measured. Exogenous succinate was supplemented to assess whether succinate exacerbated the LPS-induced lung injury. We next examined the cellular localization of pulmonary SUCNR1. Furthermore, the role of the succinate-SUCNR1 pathway in LPS-induced inflammatory responses in MH-s macrophages and obese mice was investigated. RESULT: The pulmonary SUCNR1 expression and serum succinate level were significantly increased in patients with obesity and in HFD mice. Exogenous succinate supplementation significantly increased the severity of ALI and inflammatory response. SUCNR1 was mainly expressed on lung macrophages. In LPS-stimulated MH-s cells, knockdown of SUCNR1 expression significantly inhibited pro-inflammatory cytokines' expression, the increase of hypoxia-inducible factor-1α (HIF-1α) expression, inhibitory κB-α (IκB-α) phosphorylation, p65 phosphorylation and p65 translocation to nucleus. In obese mice, SUCNR1 inhibition significantly alleviated LPS-induced lung injury and decreased the HIF-1α expression and IκB-α phosphorylation. CONCLUSION: The high expression of pulmonary SUCNR1 and serum succinate accumulation at least partly participate in the process of obesity aggravating LPS-induced lung injury.

Screening and evaluation of antioxidants for retinal pigment epithelial cell protection: L-ergothioneine as a novel therapeutic candidate through NRF2 activation.

The continual exposure of retinal tissues to oxidative stress leads to discernible anatomical and physiological alterations. Specifically, the onslaught of oxidative damage escalates the irreversible death of retinal pigmented epithelium (RPE) cells, pinpointed as the fundamental pathological event in dry age-related macular degeneration (AMD). There is a conspicuous lack of effective therapeutic strategies to counteract this degenerative process. This study screened a library of antioxidants for their ability to protect RPE cells against oxidative stress and identified L-ergothioneine (EGT) as a potent cytoprotective agent. L-ergothioneine provided efficient protection against oxidative stress-damaged RPE and maintained cell redox homeostasis and normal physiological functions. It maintained the normal structure of the retina in mice under oxidative stress conditions. Transcriptomic analysis revealed that EGT counteracted major gene expression changes induced by oxidative stress. It upregulated antioxidant gene expression and inhibited NRF2 translocation. The inhibition of NRF2 abolished EGT's protective effects, suggesting that NRF2 activation contributes to its mechanism of action. In conclusion, we identified EGT as a safe and effective small-molecule compound that is expected to be a novel antioxidative agent for treating AMD.

Identification of a shared gene signature and biological mechanism between diabetic foot ulcers and cutaneous lupus erythemnatosus by transcriptomic analysis.

Diabetic foot ulcers (DFU) and cutaneous lupus erythematosus (CLE) are both diseases that can seriously affect a patient's quality of life and generate economic pressure in society. Symptomatically, both DLU and CLE exhibit delayed healing and excessive inflammation; however, there is little evidence to support a molecular and cellular connection between these two diseases. In this study, we investigated potential common characteristics between DFU and CLE at the molecular level to provide new insights into skin diseases and regeneration, and identify potential targets for the development of new therapies. The gene expression profiles of DFU and CLE were obtained from the Gene Expression Omnibus (GEO) database and used for analysis. A total of 41 common differentially expressed genes (DEGs), 16 upregulated genes and 25 downregulated genes, were identified between DFU and CLE. GO and KEGG analysis showed that abnormalities in epidermal cells and the activation of inflammatory factors were both involved in the occurrence and development of DFU and CLE. Protein-protein interaction network (PPI) and sub-module analysis identified enrichment in seven common key genes which is KRT16, S100A7, KRT77, OASL, S100A9, EPGN and SAMD9. Based on these seven key genes, we further identified five miRNAs(has-mir-532-5p, has-mir-324-3p,has-mir-106a-5p,has-mir-20a-5p,has-mir-93-5p) and7 transcription factors including CEBPA, CEBPB, GLI1, EP30D, JUN,SP1, NFE2L2 as potential upstream molecules. Functional immune infiltration assays showed that these genes were related to immune cells. The CIBERSORT algorithm and Pearson method were used to determine the correlations between key genes and immune cells, and reverse key gene-immune cell correlations were found between DFU and CLE. Finally, the DGIbd database demonstrated that Paquinimod and Tasquinimod could be used to target S100A9 and Ribavirin could be used to target OASL. Our findings highlight common gene expression characteristics and signaling pathways between DFU and CLE, indicating a close association between these two diseases. This provides guidance for the development of targeted therapies and mutual interactions.

Superconductivity and Charge-Density-Wave-Like Transition in Th2Cu4As5.

We report the synthesis, crystal structure, and physical properties of a novel ternary compound, Th2Cu4As5. The material crystallizes in a tetragonal structure with lattice parameters a = 4.0639(3) Å and c = 24.8221(17) Å. Its structure can be described as an alternating stacking of fluorite-type Th2As2 layers with antifluorite-type double-layered Cu4As3 slabs. The measurement of electrical resistivity, magnetic susceptibility, and specific heat reveals that Th2Cu4As5 undergoes bulk superconducting transition at 4.2 K. Additionally, all these physical quantities exhibit anomalies at 48 K, accompanied by a sign change in the Hall coefficient, suggesting a charge-density-wave-like (CDW) phase transition. Drawing from both experimental data and band calculations, we propose that the superconducting and CDW-like phase transitions are, respectively, associated with the Cu4As3 slabs and the As plane in the Th2As2 layers.