Integrative metagenomics, volatilomics and chemometrics for deciphering the microbial structure and core metabolic network during Chinese rice wine (Huangjiu) fermentation in different regions.

Huangjiu is a spontaneously fermented alcoholic beverage, that undergoes intricate microbial compositional changes. This study aimed to unravel the flavor and quality formation mechanisms based on the microbial metabolism of Huangjiu. Here, metagenome techniques, chemometrics analysis, and headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) metabolomics combined with microbial metabolic network were employed to investigate the distinctions and relationship between the microbial profiles and the quality characteristics, flavor metabolites, functional metabolic patterns of Huangjiu across three regions. Significant variations (P < 0.05) were observed in metabolic rate of physicochemical parameters and biogenic amine concentration among three regions. 8 aroma compounds (phenethyl acetate, phenylethyl alcohol, isobutyl alcohol, ethyl octanoate, ethyl acetate, ethyl hexanoate, isoamyl alcohol, and diethyl succinate) out of 448 volatile compounds were identified as the regional chemical markers. 25 dominant microbial genera were observed through metagenomic analysis, and 13 species were confirmed as microbial markers in three regions. A metabolic network analysis revealed that Saccharomycetales (Saccharomyces), Lactobacillales (Lactobacillus, Weissella, and Leuconostoc), and Eurotiales (Aspergillus) were the predominant populations responsible for substrate, flavor (mainly esters and phenylethyl alcohol) metabolism, Lactobacillales and Enterobacterales were closely linked with biogenic amine. These findings provide scientific evidence for regional microbial contributions to geographical characteristics of Huangjiu, and perspectives for optimizing microbial function to promote Huangjiu quality.

Comparison of Therapeutic Effects Between Conventional 2D Laparoscopy and 3D Laparoscopy in the Treatment of Colorectal Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: This study aimed to evaluate the effectiveness and safety of 2D laparoscopy vs 3D laparoscopy for the treatment of colorectal cancer. METHODS: A literature search was conducted through PubMed, Web of Science, and Embase from their inception to January 2024. Studies investigating different outcomes of colorectal surgery were included. Results are presented as odds ratios (ORs) or mean differences (MDs) with 95% confidence intervals (CIs). The protocol for this review has been registered on PROSPERO (CRD42024504902). RESULTS: A total of 10 publications were retrieved in this article. The 3D group is associated with a significant improvement in intraoperative blood loss (MD = -8.04, 95% CI = -14.18 to -1.89, P = 0.01, I2 = 55%), operative time (MD = -17.33, 95% CI = -29.15 to -5.51, P = 0.004, I2 = 90%), and postoperative hospital stay (MD = -0.23, 95% CI = -0.43 to -0.04, P = 0.02, I2 = 48%) compared to that of patients treated in the 2D group, particularly for rectal cancer patients above three results (MD = -10.36, 95% CI = -15.00 to -5.73, P < 0.001, I2 = 0%), (MD = -18.85, 95% CI = -34.88 to -2.82, P = 0.02, I2 = 57%), and (MD = -0.93, 95% CI = -1.53 to -0.34, P = 0.002, I2 = 0%), respectively. There was no significant statistical difference in the time of pass flatus (MD = -0.14, 95% CI = -0.49 to 0.21, P = 0.44, I2 = 79%) and the number of dissected lymph nodes (MD = 0.36, 95% CI = -0.49 to 1.21, P = 0.41, I2 = 45%), but the 3D group had an earlier postoperative pass flatus for rectal cancer patients (MD = -0.46, 95% CI = -0.66 to -0.27, P<0.001, I2 = 0%) and the more number of dissected lymph nodes for colon cancer patients (MD = 1.54, 95% CI = 0.05 to 3.03, P = 0.04, I2 = 69%) than the 2D group. There was no significant difference in postoperative overall complication (OR = 0.94, 95% CI = 0.67 to 1.31, P = 0.71, I2 = 0%) and anastomotic leakage (OR = 0.93, 95% CI = 0.48 to 1.80, P = 0.83, I2 = 0%) in the two groups, regardless of rectal cancer and colon surgery patients. CONCLUSION: This meta-analysis demonstrates that 3D laparoscopy could reduce the amount of blood loss, accelerate postoperative pass flatus, and shorten the operation time and postoperative hospital stay over 2D for radical rectal cancer surgery, without obvious advantage for radical colon cancer surgery. Moreover, 3D laparoscopy increases the number of dissected lymph nodes for radical colon cancer surgery but may not be observed in rectal cancer surgery.

A Novel Recombinant Human Filaggrin Segment (rhFLA-10) Alleviated a Skin Lesion of Atopic Dermatitis.

Atopic dermatitis (AD), a prevalent chronic inflammatory skin disorder, is marked by impaired skin barrier function and persistent pruritus. It significantly deteriorates patients' quality of life, making it one of the most burdensome non-lethal skin disorders. Filaggrin plays a crucial role in the pathophysiology of barrier disruption in AD, interacting with inflammatory mediators. It is an integral part of the extracellular matrix architecture, serving to protect the skin barrier and attenuate the inflammatory cascade. In this study, we engineered a novel recombinant human filaggrin (rhFLA-10) expression vector, which was subsequently synthesized and purified. In vitro and ex vivo efficacy experiments were conducted for AD. rhFLA-10, at low concentrations (5 to 20 µg/mL), was non-toxic to HACaT cells, significantly inhibited the degranulation of P815 mast cells, and was readily absorbed by cells, thereby exerting a soothing therapeutic effect. Furthermore, rhFLA-10 demonstrated anti-inflammatory properties (p < 0.05). In vivo, efficacy experiments further substantiated that rhFLA-10 could effectively ameliorate AD in mice and facilitate the repair of damaged skin (p < 0.001). These findings underscore the considerable potential of rhFLA-10 in the treatment of AD.

Evaluation of mavacamten in patients with hypertrophic cardiomyopathy.

AIMS: We aimed to comprehensively assess the safety and efficacy of mavacamten in hypertrophic cardiomyopathy (HCM) patients. METHODS: A systematic review and meta-analysis was conducted, and efficacy [changes in postexercise left ventricular outflow tract (LVOT) gradient, left ventricular ejection fraction (LVEF), peak oxygen consumption (pVO 2 ), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS), and the proportion of patients exhibiting an improvement of at least one New York Heart Association (NYHA) functional class from baseline)], safety (total count of treatment-emergent adverse events and SAEs, as well as the proportion of patients experiencing at least one adverse event or SAE), and cardiac biomarkers (NT-proBNP and cTnI) outcomes were evaluated. RESULTS: We incorporated data from four randomized controlled trials, namely EXPLORER-HCM, VALOR-HCM, MAVERICK-HCM, and EXPLORER-CN. Mavacamten demonstrated significant efficacy in reducing the postexercise LVOT gradient by 49.44 mmHg ( P  = 0.0001) and LVEF by 3.84 ( P  < 0.0001) and improving pVO 2 by 0.69 ml/kg/min ( P  = 0.4547), KCCQ CSS by 8.11 points ( P  < 0.0001), and patients with at least one NYHA functional class improvement from baseline by 2.20 times ( P  < 0.0001). Importantly, mavacamten increased 1.11-fold adverse events ( P  = 0.0184) 4.24-fold reduced LVEF to less than 50% ( P  = 0.0233) and 1.06-fold SAEs ( P  = 0.8631). Additionally, mavacamten decreased NT-proBNP by 528.62 ng/l ( P  < 0.0001) and cTnI by 8.28 ng/l ( P  < 0.0001). CONCLUSION: Mavacamten demonstrates both safety and efficacy in patients with HCM, suggesting its potential as a promising therapeutic strategy for this condition. Further research is warranted to confirm these results and explore its long-term effects.

Identification of Potential Crucial Biomarkers in STEMI Through Integrated Bioinformatic Analysis. / Identificação de Potenciais Biomarcadores Cruciais em IAMCSST por Meio de Análise Bioinformática Integrada.

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) is one of the leading causes of fatal cardiovascular diseases, which have been the prime cause of mortality worldwide. Diagnosis in the early phase would benefit clinical intervention and prognosis, but the exploration of the biomarkers of STEMI is still lacking. OBJECTIVES: In this study, we conducted a bioinformatics analysis to identify potential crucial biomarkers in the progress of STEMI. METHODS: We obtained GSE59867 for STEMI and stable coronary artery disease (SCAD) patients. Differentially expressed genes (DEGs) were screened with the threshold of |log2fold change| > 0.5 and p <0.05. Based on these genes, we conducted enrichment analysis to explore the potential relevance between genes and to screen hub genes. Subsequently, hub genes were analyzed to detect related miRNAs and DAVID to detect transcription factors for further analysis. Finally, GSE62646 was utilized to assess DEGs specificity, with genes demonstrating AUC results exceeding 75%, indicating their potential as candidate biomarkers. RESULTS: 133 DEGs between SCAD and STEMI were obtained. Then, the PPI network of DEGs was constructed using String and Cytoscape, and further analysis determined hub genes and 6 molecular complexes. Functional enrichment analysis of the DEGs suggests that pathways related to inflammation, metabolism, and immunity play a pivotal role in the progression from SCAD to STEMI. Besides, related-miRNAs were predicted, has-miR-124, has-miR-130a/b, and has-miR-301a/b regulated the expression of the largest number of genes. Meanwhile, Transcription factors analysis indicate that EVI1, AML1, GATA1, and PPARG are the most enriched gene. Finally, ROC curves demonstrate that MS4A3, KLRC4, KLRD1, AQP9, and CD14 exhibit both high sensitivity and specificity in predicting STEMI. CONCLUSIONS: This study revealed that immunity, metabolism, and inflammation are involved in the development of STEMI derived from SCAD, and 6 genes, including MS4A3, KLRC4, KLRD1, AQP9, CD14, and CCR1, could be employed as candidate biomarkers to STEMI.

FUNDAMENTO: O infarto do miocárdio com elevação do segmento ST (IAMCSST) é uma das principais causas de doenças cardiovasculares fatais, que têm sido a principal causa de mortalidade em todo o mundo. O diagnóstico na fase inicial beneficiaria a intervenção clínica e o prognóstico, mas ainda falta a exploração dos biomarcadores do IAMCSST. OBJETIVOS: Neste estudo, conduzimos uma análise bioinformática para identificar potenciais biomarcadores cruciais no progresso do IAMCSST. MÉTODOS: Obtivemos GSE59867 para pacientes com IAMCSST e doença arterial coronariana estável (DACE). Genes diferencialmente expressos (GDEs) foram selecionados com o limiar de |log2fold change| > 0,5 e p < 0,05. Com base nesses genes, conduzimos análises de enriquecimento para explorar a relevância potencial entre genes e para rastrear genes centrais. Posteriormente, os genes centrais foram analisados para detectar miRNAs relacionados e DAVID para detectar fatores de transcrição para análise posterior. Finalmente, o GSE62646 foi utilizado para avaliar a especificidade dos GDEs, com genes demonstrando resultados de AUC superiores a 75%, indicando seu potencial como candidatos a biomarcadores. Posteriormente, os genes centrais foram analisados para detectar miRNAs relacionados e DAVID para detectar fatores de transcrição para análise posterior. Finalmente, o GSE62646 foi utilizado para avaliar a especificidade dos GDEs, com genes demonstrando resultados de AUC superiores a 75%, indicando seu potencial como candidatos a biomarcadores. RESULTADOS: 133 GDEs entre DACE e IAMCSST foram obtidos. Em seguida, a rede PPI de GDEs foi construída usando String e Cytoscape, e análises posteriores determinaram genes centrais e 6 complexos moleculares. A análise de enriquecimento funcional dos GDEs sugere que as vias relacionadas à inflamação, metabolismo e imunidade desempenham um papel fundamental na progressão de DACE para IAMCSST. Além disso, foram previstos miRNAs relacionados, has-miR-124, has-miR-130a/b e has-miR-301a/b regularam a expressão do maior número de genes. Enquanto isso, a análise dos fatores de transcrição indica que EVI1, AML1, GATA1 e PPARG são os genes mais enriquecidos. Finalmente, as curvas ROC demonstram que MS4A3, KLRC4, KLRD1, AQP9 e CD14 exibem alta sensibilidade e especificidade na previsão de IAMCSST. CONCLUSÕES: Este estudo revelou que imunidade, metabolismo e inflamação estão envolvidos no desenvolvimento de IAMCSST derivado de DACE, e 6 genes, incluindo MS4A3, KLRC4, KLRD1, AQP9, CD14 e CCR1, poderiam ser empregados como candidatos a biomarcadores para IAMCSST.

Synergistic B and T lymphocyte interaction: prognostic implications in non-small cell lung cancer.

While T-cell-mediated immune responses in solid tumors have been well-established and have driven major therapeutic advances, our understanding of B-cell biology in cancer is comparatively less developed. A total of 60 lung cancer patients were included, of which 53% were diagnosed at an early stage while 47% were diagnosed at an advanced stage. Flow cytometry was used to analyze the proportion of T and B cells in all blood samples, and the levels of human serum cytokines were also assessed. Compared to the control group, cancer patients showed lower frequencies of IgD+CD27+ marginal B cells and CD32+ B cells, and higher frequencies of T cells with lower CD8+ T cells and higher central memory and naïve CD4+ T cells. Additionally, advanced-stage cancer patients exhibited higher levels of cytokines, a higher proportion of effector memory CD8+ T cells, and a lower frequency of CD27+CD28+CD4+/CD8+ T cells. Linear regression analysis revealed significant correlations between cancer stage and the frequency of B and T cell subsets, leukocyte count, and cytokine levels. Survival analysis demonstrated that patients with higher frequency of class-switched B cells had a worse prognosis, while patients with higher frequency of CD8+ effector T cells and lower frequency of CD4+57+ T cells appeared to have a better survival rate. These findings provide valuable insight into the immunological changes that occur during lung cancer progression and have the potential to inform the development of new immunotherapeutic strategies.

Suillus: an emerging model for the study of ectomycorrhizal ecology and evolution.

Research on mycorrhizal symbiosis has been slowed by a lack of established study systems. To address this challenge, we have been developing Suillus, a widespread ecologically and economically relevant fungal genus primarily associated with the plant family Pinaceae, into a model system for studying ectomycorrhizal (ECM) associations. Over the last decade, we have compiled extensive genomic resources, culture libraries, a phenotype database, and protocols for manipulating Suillus fungi with and without their tree partners. Our efforts have already resulted in a large number of publicly available genomes, transcriptomes, and respective annotations, as well as advances in our understanding of mycorrhizal partner specificity and host communication, fungal and plant nutrition, environmental adaptation, soil nutrient cycling, interspecific competition, and biological invasions. Here, we highlight the most significant recent findings enabled by Suillus, present a suite of protocols for working with the genus, and discuss how Suillus is emerging as an important model to elucidate the ecology and evolution of ECM interactions.

Zhilong Huoxue Tongyu Capsule regulates the macrophage polarization and inflammatory response via the let-7i/TLR9/MyD88 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhilong Huoxue Tongyu Capsule (ZL) is clinically prescribed for acute ischemic stroke (AIS). However, only a few studies have addressed the mechanisms of ZL in treating AIS. AIM OF THE STUDY: To explore the underlying mechanism of macrophage polarization and inflammation mediated by ZL, and to provide a reference for AIS treatment. MATERIALS AND METHODS: Sixteen SD rats were fed with different dose of ZL (0, 0.4, 0.8, and 1.6 g/kg/d) for 4 days to prepare ZL serum. After 500 ng/mL lipopolysaccharide (LPS) stimulation, RAW264.7 cells were administrated with ZL serum. Then, experiments including ELISA, flow cytometry, real-time quantitative PCR and Western blot were performed to verify the effects of ZL on macrophage polarization and inflammation. Next, let-7i inhibitor was transfected in RAW264.7 cells when treated with LPS and ZL serum to verify the regulation of ZL on the let-7i/TLR9/MyD88 signaling pathway. Moreover, the interaction between let-7i and TLR9 was confirmed by the dual-luciferase assay. RESULTS: ZL serum significantly decreased the expression of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), and increased the expression of IL-10 and transforming growth factor ß1 (TGF-ß1) of LPS stimulated-macrophages. Furthermore, ZL serum polarized macrophages toward M2, decreased the expressions of TLR9, MyD88, and iNOS, as well as increased the expressions of let-7i, CHIL3, and Arginase-1. It is worth mentioning that the effect of ZL serum is dose-dependent. However, let-7i inhibitor restored all the above effects in LPS stimulated-macrophages. In addition, TLR9 was the target of let-7i. CONCLUSIONS: ZL targeted let-7i to inhibit TLR9 expression, thereby inhibiting the activation of the TLR9/MyD88 pathway, promoting the M2 polarization, and inhibiting the development of inflammation in AIS.

[Meta-analysis and trial sequential analysis of Tanreqing Injection in treatment of severe pneumonia in elderly].

This study aimed to systematically evaluate the effectiveness and safety of Tanreqing Injection in the treatment of severe pneumonia in the elderly. Eighteen randomized controlled trials(RCTs) involving 1 457 elderly patients with severe pneumonia were included in the study after conducting searches in both Chinese and English databases as well as clinical trial registration platforms. The quality of the included studies was assessed using the Cochrane risk of bias assessment tool. Meta-analysis were conducted using RevMan 5.4 and Stata 17 software, and trial sequential analysis(TSA) was performed using TSA 0.9.5.10 beta software. Meta-analysis results showed that compared with conventional western medicine treatment, Tanreqing Injection + conventional western medical significantly improved the clinical effectiveness in elderly patients with severe pneumonia(RR=1.26, 95%CI[1.20, 1.32], P<0.000 01), arterial oxygen partial pressure(SMD=6.23, 95%CI[3.29, 9.18], P<0.000 1), oxygenation index(SMD=11.72, 95%CI[4.41, 19.04], P=0.002), reduce procalcitonin(SMD=-6.16, 95%CI[-8.10,-4.21], P<0.000 01), C-reactive protein(SMD=-8.50, 95%CI[-11.05,-5.96], P<0.000 01), white blood cell count(SMD=-4.56, 95%CI[-5.73,-3.39], P<0.000 01), and shortened the duration of fever(SMD=-3.12, 95%CI[-4.61,-1.63], P<0.000 1), cough(SMD=-4.84, 95%CI[-6.90,-2.79], P<0.000 01), lung rales(SMD=-0.99, 95%CI[-1.54,-0.44], P=0.000 4), and mechanical ventilation time(SMD=-3.26, 95%CI[-5.03,-1.50], P=0.000 3), increase CD4~+ T-cell levels(SMD=6.73, 95%CI[5.23, 8.23], P<0.000 01) and CD8~+ T-cell levels(SMD=7.47, 95% CI[5.32, 9.61], P<0.000 01) with no significant adverse reactions. TSA confirmed the stability and reliability of the results related to clinical effectiveness. This study suggests that Tanreqing Injection, as a Chinese medicinal preparation, has a significant therapeutic effect and good safety profile in the treatment of severe pneumonia in elderly patients. Due to the limited quality of the included studies, high-quality RCT is still needed to provide evidence support for the above conclusions.

Discovery of digallic acid as XOD/URAT1 dual target inhibitor for the treatment of hyperuricemia.

The development of XOD/URAT1 dual target inhibitors has emerged as a promising therapeutic strategy for the management of hyperuricemia. Here, through virtual screening, we have identified digallic acid as a novel dual target inhibitor of XOD/URAT1 and subsequently evaluated its pharmacological properties, pharmacokinetics, and toxicities. Digallic acid inhibited URAT1 with an IC50 of 5.34 ± 0.65 µM, which is less potent than benzbromarone (2.01 ± 0.36 µM) but more potent than lesinurad (10.36 ± 1.23 µM). Docking and mutation analysis indicated that residues S35, F241 and R477 of URAT1 confer a high affinity for digallic acid. Digallic acid inhibited XOD with an IC50 of 1.04 ± 0.23 µM. Its metabolic product, gallic acid, inhibited XOD with an IC50 of 0.91 ± 0.14 µM. Enzyme kinetic studies indicated that both digallic acid and gallic acid act as mixed-type XOD inhibitors. It shares the same binding mode as digallic acid, and residues E802, R880, F914, T1010, N768 and F1009 contribute to their high affinity. The anion group (carboxyl) of digallic acid contribute significantly to its inhibition activity on both XOD and URAT1 as indicated by docking analysis. Remarkably, at a dosage of 10 mg/kg in vivo, digallic acid exhibited a stronger urate-lowering and uricosuric effect compared to the positive drug benzbromarone and lesinurad. Pharmacokinetic study indicated that digallic acid can be hydrolyzed into gallic acid in vivo and has a t1/2 of 0.77 ± 0.10 h. Further toxicity evaluation indicated that digallic acid exhibited no obvious renal toxicity, as reflected by CCK-8, biochemical analysis (CR and BUN) and HE examination. The findings of our study can provide valuable insights for the development of XOD/URAT1 dual target inhibitors, and digallic acid deserves further investigation as a potential anti-hyperuricemic drug.

The mediating roles of depressive symptoms and social participation in the relationship between the effects of pain and cognitive function among Chinese older adults: A longitudinal study.

Decline in cognitive function poses a substantial burden on individuals, families, and society. However, the longitudinal potential mechanism underlying the link of pain and cognitive function remains unclear. Using data of 4247 participants aged 60 years and over from the China Health and Retirement Longitudinal Study in 2011, 2013, 2018, and 2020, we discussed the longitudinal predictive effect of pain on cognitive function and the mediating effects of depressive symptoms and social participation. The longitudinal mediation model analysis revealed that pain could not directly influence cognitive function, but it could indirectly predict cognitive function through the independent mediation effects of depressive symptoms and social participation. Moreover, the association between pain and cognitive function was serially mediated by depressive symptoms and social participation. Diversified interventions aimed at relieving pain and depressive symptoms, and increasing social participation in older adults would be beneficial for their cognitive function.

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability.

Gout and hyperuricemia are metabolic diseases characterized with high serum uric acid (SUA) levels that significantly impact human health. Lesinurad, a uricosuric agent, is limited to concurrent use with xanthine oxidase inhibitors (XOIs) in clinical practice due to its restricted efficacy and potential nephrotoxicity. Herein, extensive structural modifications of lesinurad were conducted through scaffold hopping and substituent modification strategies, affording 54 novel derivatives containing pyrimidine-fused cyclic structures. Notably, the thienopyrimidine compound 29 demonstrated a remarkable 2-fold increase in SUA-lowering in vivo activity compared to lesinurad, while exhibiting potent inhibitory activity against the urate transporter 1 (URAT1, IC50 = 2.01 µM) and glucose transporter 9 (GLUT9, IC50 = 18.21 µM). Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable safety profile without any apparent acute toxicity at doses of 1000 mg/kg, and improved pharmacokinetic properties. Overall, we have discovered an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption with favorable pharmacokinetic profiles.

Protecting against ferroptosis in hyperuricemic nephropathy: The potential of ferrostatin-1 and its inhibitory effect on URAT1.

Hyperuricemic nephropathy (HN) is characterized by renal fibrosis and tubular necrosis caused by elevated uric acid levels. Ferroptosis, an iron-dependent type of cell death, has been implicated in the pathogenesis of kidney diseases. The objective of this study was to explore the role of ferroptosis in HN and the impact of a ferroptosis inhibitor, ferrostatin-1 (Fer-1). The study combined adenine and potassium oxonate administration to establish a HN model in mice and treated HK-2 cells with uric acid to simulate HN conditions. The effects of Fer-1 on the renal function, fibrosis, and ferroptosis-associated molecules were investigated in HN mice and HK-2 cells treated with uric acid. The HN mice presented with renal dysfunction characterized by elevated tissue iron levels and diminished antioxidant capacity. There was a significant decrease in the mRNA and protein expression levels of SLC7A11, GPX4, FTL-1 and FTH-1 in HN mice. Conversely, treatment with Fer-1 reduced serum uric acid, serum creatinine, and blood urea nitrogen, while increasing uric acid levels in urine. Fer-1 administration also ameliorated renal tubule dilatation and reduced renal collagen deposition. Additionally, Fer-1 also upregulated the expression levels of SLC7A11, GPX4, FTL-1, and FTH-1, decreased malondialdehyde and iron levels, and enhanced glutathione in vivo and in vitro. Furthermore, we first found that Fer-1 exhibited a dose-dependent inhibition of URAT1, with the IC50 value of 7.37 ± 0.66 µM. Collectively, the current study demonstrated that Fer-1 effectively mitigated HN by suppressing ferroptosis, highlighting the potential of targeting ferroptosis as a therapeutic strategy for HN.

Proline-derived quinoline formamide compounds as human urate transporter 1 inhibitors with potent uric acid-lowering activities.

We report the design and synthesis of a series of proline-derived quinoline formamide compounds as human urate transporter 1 (URAT1) inhibitors via a ligand-based pharmacophore approach. Structure-activity relationship studies reveal that the replacement of the carboxyl group on the polar fragment with trifluoromethanesulfonamide and substituent modification at the 6-position of the quinoline ring greatly improve URAT1 inhibitory activity compared with lesinurad. Compounds 21c, 21e, 24b, 24c, and 23a exhibit potent activities against URAT1 with IC50 values ranging from 0.052 to 0.56 µM. Furthermore, compound 23a displays improved selectivity towards organic anion transporter 1 (OAT1), good microsomal stability, low potential for genotoxicity and no inhibition of the hERG K+ channel. Compounds 21c and 23a, which have superior pharmacokinetic properties, also demonstrate significant uric acid-lowering activities in a mouse model of hyperuricemia. Notably, 21c also exhibits moderate anti-inflammatory activity related to the gout inflammatory pathway. Compounds 21c and 23a with superior druggability are potential candidates for the treatment of hyperuricemia and gout.

Freezing Shrinkage Dynamics and Surface Dendritic Growth of Floating Refractory Alloy Droplets in Outer Space.

The freezing shrinkage and dendritic growth are of great importance for various alloys solidified from high-temperature liquids to solids since they dominate microstructure patterns and follow-up processing. However, the microgravity freezing shrinkage dynamics is scarcely explored on the ground as it is hard to suppress the strong natural convection inside liquid alloys. Here, a series of in-orbit solidification experiments is conducted aboard the China Space Station with a long-term stable 10-5 g0 microgravity condition. The highest temperature up to 2265 K together with substantial liquid undercoolings far from a thermodynamically stable state are attained for both Nb82.7Si17.3 and Zr64V36 refractory alloys. Furthermore, the solidification under microgravity of a droplet is simulated to reveal the liquid-solid interface migration, temperature gradient, and flow field. The microgravity solidification process leads to freezing shrinkage cavities and distinctive surface dendritic microstructure patterns. The combined effects of shrinkage dynamics and liquid surface flow in outer space result in the dendrites growing not only along the tangential direction but also along the normal direction to the droplet surface. These space experimental results contribute to a further understanding of the solidification behavior of liquid alloys under a weaker convection condition, which is often masked by gravity on the ground.

Long-term tropospheric ozone pollution disrupts plant-microbe-soil interactions in the agroecosystem.

Tropospheric ozone (O3 ) threatens agroecosystems, yet its long-term effects on intricate plant-microbe-soil interactions remain overlooked. This study employed two soybean genotypes of contrasting O3 -sensitivity grown in field plots exposed elevated O3 (eO3 ) and evaluated cause-effect relationships with their associated soil microbiomes and soil quality. Results revealed long-term eO3 effects on belowground soil microbiomes and soil health surpass damage visible on plants. Elevated O3 significantly disrupted belowground bacteria-fungi interactions, reduced fungal diversity, and altered fungal community assembly by impacting soybean physiological properties. Particularly, eO3 impacts on plant performance were significantly associated with arbuscular mycorrhizal fungi, undermining their contribution to plants, whereas eO3 increased fungal saprotroph proliferation, accelerating soil organic matter decomposition and soil carbon pool depletion. Free-living diazotrophs exhibited remarkable acclimation under eO3 , improving plant performance by enhancing nitrogen fixation. However, overarching detrimental consequences of eO3 negated this benefit. Overall, this study demonstrated long-term eO3 profoundly governed negative impacts on plant-soil-microbiota interactions, pointing to a potential crisis for agroecosystems. These findings highlight urgent needs to develop adaptive strategies to navigate future eO3 scenarios.

The Synergistic Effect of Compound Sugar with Different Glycemic Indices Combined with Creatine on Exercise-Related Fatigue in Mice.

In this study, a compound sugar (CS) with different glycemic index sugars was formulated via hydrolysis characteristics and postprandial glycemic response, and the impact of CS and creatine emulsion on exercise-related fatigue in mice was investigated. Thirty-five C57BL/6 mice were randomly divided into five groups to supply different emulsions for 4 weeks: initial emulsion (Con), glucose emulsion (62 mg/10 g MW glucose; Glu), CS emulsion (62 mg/10 g MW compound sugar; CS), creatine emulsion (6 mg/10 g MW creatine; Cr), and CS and creatine emulsion (62 mg/10 g MW compound sugar, 6 mg/10 g MW creatine, CS-Cr). Then, the exhaustion time of weight-bearing swimming and forelimb grip strength were measured to evaluate the exercise capacity of mice, and some fatigue-related biochemical indexes of blood were determined. The results demonstrated that the ingestion of CS significantly reduced the peak of postprandial blood glucose levels and prolonged the energy supply of mice compared to ingesting an equal amount of glucose. Mouse exhaustion time was 1.22-fold longer in the CS group than in the glucose group. Additionally, the supplementation of CS increased the liver glycogen content and total antioxidant capacity of mice. Moreover, the combined supplementation of CS and creatine increased relative forelimb grip strength and decreased blood creatine kinase activity. The findings suggested that the intake of CS could enhance exercise capacity, and the combined supplementation of CS and creatine has a synergistic effect in improving performance.

Metastable Liquid Properties and Surface Flow Patterns of Ultrahigh Temperature Alloys Explored in Outer Space.

The metastable liquid properties and chemical bonds beyond 2000 K remain a huge challenge for ground-based research on liquid materials chemistry. We show the strong undercooling capability, metastable liquid properties and surface wave patterns of refractory Nb-Si and Zr-V binary alloys explored in space environment. The floating droplet of Nb82.7Si17.3 eutectic alloy superheated up to 2338 K exhibited an extreme undercooling of 437 K, approaching the 0.2TE threshold for homogeneous nucleation of liquid-solid reaction. The microgravity state endowed alloy droplets with nearly perfect sphericity and thus ensured the high accuracy to determine metastable undercooled liquid properties. A special kind of swirling flow was induced for liquid alloy owing to Marangoni convection, which resulted in the spiral microstructures on Zr64V36 alloy surface during liquid-solid phase transition. The coupled impacts of surface nucleation and surface flow brought in a novel olivary shape for these binary alloys. Furthermore, the chemical bonds and atomic structures of high temperature liquids were revealed to understand the liquid properties in outer space circumstances.

Sestrin2 reduces ferroptosis via the Keap1/Nrf2 signaling pathway after intestinal ischemia-reperfusion.

Sestrins are metabolic regulators that respond to stress by reducing the levels of reactive oxygen species (ROS) and inhibiting the activity of target of rapamycin complex 1 (mTORC1). Previous research has demonstrated that Sestrin2 mitigates ischemia-reperfusion (IR) injury in the heart, liver, and kidneys. However, its specific role in intestinal ischemia-reperfusion (IIR) injury remains unclear. To elucidate the role of Sestrin2 in IIR injury, we conducted an experimental study using a C57BL/6J mouse model of IIR. We noticed an increase in the levels of Sestrin2 expression and indicators associated with ferroptosis. Our study revealed that manipulating Sestrin2 expression in Caco-2 cells through overexpression or knockdown resulted in a corresponding decrease or increase, respectively, in ferroptosis levels. Furthermore, our investigation revealed that Sestrin2 alleviated ferroptosis caused by IIR injury through the activation of the Keap1/Nrf2 signal pathway. This finding highlights the potential of Sestrin2 as a therapeutic target for alleviating IIR injury. These findings indicated that the modulation of Sestrin2 could be a promising strategy for managing prolonged IIR injury.