Association between the composite dietary antioxidant index and the prevalence and recurrence of kidney stones: results of a nationwide survey.

Aim: This study aims to evaluate the relationship between the Composite Dietary Antioxidant Index (CDAI) and the prevalence and recurrence of kidney stones. Methods: Data from the National Health and Nutrition Examination Survey (NHANES) collected between 2007 and 2014 were used in this cross-sectional analysis. The CDAI was derived by standardizing the intake of dietary antioxidants from 24 h dietary recalls. The study assessed the prevalence and recurrence of kidney stones based on questionnaire responses. The association between the CDAI and both the prevalence and recurrence of kidney stones was investigated using multivariable logistic regression. Subgroup analyses and interaction tests further evaluated the robustness of this relationship. Results: The study included 20,743 participants, and the reported incidence and recurrence rates of kidney stones were 9.09 and 2.90%, respectively. After stratifying the CDAI into tertiles, an inverse trend was observed in both kidney stones' prevalence and recurrence probabilities with increasing CDAI levels. Adjusting for confounding factors, individuals in the top tertile had a 23% lower prevalence of kidney stones (OR = 0.77, 95% CI: 0.66, 0.90, p = 0.0011) and a 39% lower recurrence rate (OR = 0.61, 95% CI: 0.47, 0.80, p = 0.0003) than those in the bottom tertile. In addition, interaction tests showed that age, gender, body mass index, hypertension, and diabetes did not significantly affect the relationship between CDAI levels and kidney stone prevalence and recurrence rates. Conclusion: Our study suggests that increased levels of CDAI are associated with reduced incidence and recurrence rates of kidney stones. Therefore, increasing the intake of dietary antioxidants may be an effective strategy for preventing kidney stones and their recurrence.

Investigating the role of killer cell immunoglobulin-like receptors and human leukocyte antigen genetic variants in hepatitis C virus infection.

The genetic diversity of killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) genes influences the host's immune response to viral pathogens. This study aims to explore the impact of five single nucleotide polymorphisms (SNPs) in KIR3DL2 and HLA-A genes on hepatitis C virus (HCV) infection. A total of 2251 individuals were included in the case-control study. SNPs including KIR3DL2 rs11672983, rs3745902, rs1654644, and HLA-A rs3869062, rs12202296 were genotyped. By controlling various confounding factors using a modified logistic regression model, as well as incorporating stratified analysis, joint effects analysis, and multidimensional bioinformatics analysis, we analyzed the relationship between SNPs and HCV infection. The logistic regression analysis showed a correlation between KIR3DL2 rs11672983 AA, KIR3DL2 rs3745902 TT, and increased HCV susceptibility (p < 0.01). Stratified analysis indicated that KIR3DL2 rs1654644 and HLA-A rs3869062 also heightened HCV susceptibility in certain subgroups. A linear trend of rising HCV infection rates was observed when combining KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT (ptrend = 0.007). Bioinformatics analysis suggested these SNPs' regulatory potential and their role in altering messenger RNA secondary structure, implying their functional relevance in HCV susceptibility. Our findings indicate that KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT are significantly associated with increased susceptibility to HCV infection.

Forest carbon stocks increase with higher dominance of ectomycorrhizal trees in high latitude forests.

Understanding the mechanisms controlling forest carbon accumulation is crucial for predicting and mitigating future climate change. Yet, it remains unclear whether the dominance of ectomycorrhizal (EcM) trees influences the carbon accumulation of entire forests. In this study, we analyzed forest inventory data from over 4000 forest plots across Northeast China. We find that EcM tree dominance consistently exerts a positive effect on tree, soil, and forest carbon stocks. Moreover, we observe that these positive effects are more pronounced during unfavorable climate conditions, at lower tree species richness, and during early successional stages. This underscores the potential of increasing the dominance of native EcM tree species not only to enhance carbon stocks but also to bolster resilience against climate change in high-latitude forests. Here we show that forest managers can make informed decisions to optimize carbon accumulation by considering various factors such as mycorrhizal types, climate, successional stages, and species richness.

Cas1 mediates the interference stage in a phage-encoded CRISPR-Cas system.

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas systems are prokaryotic adaptive immune systems against invading phages and other mobile genetic elements. Notably, some phages, including the Vibrio cholerae-infecting ICP1 (International Center for Diarrheal Disease Research, Bangladesh cholera phage 1), harbor CRISPR-Cas systems to counteract host defenses. Nevertheless, ICP1 Cas8f lacks the helical bundle domain essential for recruitment of helicase-nuclease Cas2/3 during target DNA cleavage and how this system accomplishes the interference stage remains unknown. Here, we found that Cas1, a highly conserved component known to exclusively work in the adaptation stage, also mediates the interference stage through connecting Cas2/3 to the DNA-bound CRISPR-associated complex for antiviral defense (Cascade; CRISPR system yersinia, Csy) of the ICP1 CRISPR-Cas system. A series of structures of Csy, Csy-dsDNA (double-stranded DNA), Cas1-Cas2/3 and Csy-dsDNA-Cas1-Cas2/3 complexes reveal the whole process of Cas1-mediated target DNA cleavage by the ICP1 CRISPR-Cas system. Together, these data support an unprecedented model in which Cas1 mediates the interference stage in a phage-encoded CRISPR-Cas system and the study also sheds light on a unique model of primed adaptation.

Natural variation of domestication-related genes contributed to latitudinal expansion and adaptation in soybean.

Soybean is a major source of protein and edible oil worldwide. Originating from the Huang-Huai-Hai region, which has a temperate climate, soybean has adapted to a wide latitudinal gradient across China. However, the genetic mechanisms responsible for the widespread latitudinal adaptation in soybean, as well as the genetic basis, adaptive differentiation, and evolutionary implications of theses natural alleles, are currently lacking in comprehensive understanding. In this study, we examined the genetic variations of fourteen major gene loci controlling flowering and maturity in 103 wild species, 1048 landraces, and 1747 cultivated species. We found that E1, E3, FT2a, J, Tof11, Tof16, and Tof18 were favoured during soybean improvement and selection, which explained 75.5% of the flowering time phenotypic variation. These genetic variation was significantly associated with differences in latitude via the LFMM algorithm. Haplotype network and geographic distribution analysis suggested that gene combinations were associated with flowering time diversity contributed to the expansion of soybean, with more HapA clustering together when soybean moved to latitudes beyond 35°N. The geographical evolution model was developed to accurately predict the suitable planting zone for soybean varieties. Collectively, by integrating knowledge from genomics and haplotype classification, it was revealed that distinct gene combinations improve the adaptation of cultivated soybeans to different latitudes. This study provides insight into the genetic basis underlying the environmental adaptation of soybean accessions, which could contribute to a better understanding of the domestication history of soybean and facilitate soybean climate-smart molecular breeding for various environments.

The Horizons of Medical Mineralogy: Structure-Bioactivity Relationship and Biomedical Applications of Halloysite Nanoclay.

Medical mineralogy explores the interactions between natural minerals and living organisms such as cells, tissues, and organs and develops therapeutic and diagnostic applications in drug delivery, medical devices, and healthcare materials. Many minerals (especially clays) have been recognized for pharmacological activities and therapeutic potential. Halloysite clay (Chinese medicine name: Chishizhi), manifested as one-dimensional aluminum silicate nanotubes (halloysite nanotubes, HNTs), has gained applications in hemostasis, wound repair, gastrointestinal diseases, tissue engineering, detection and sensing, cosmetics, and daily chemicals formulations. Various biomedical applications of HNTs are derived from hollow tubular structures, high mechanical strength, good biocompatibility, bioactivity, and unique surface characteristics. This natural nanomaterial is safe, abundantly available, and may be processed with environmentally safe green chemistry methods. This review describes the structure and physicochemical properties of HNTs relative to bioactivity. We discuss surface area, porosity and surface defects, hydrophilicity, heterogeneity and charge of external and internal surfaces, as well as biosafety. The paper provides comprehensive guidance for the development of this tubule nanoclay and its advanced biomedical applications for clinical diagnosis and therapy.

Effect of Origin, Seed Coat Color, and Maturity Group on Seed Isoflavones in Diverse Soybean Germplasm.

Soybeans are grown worldwide owing to their protein, oil, and beneficial bioactive compounds. Genetic and environmental factors influence soybean seed isoflavones. In the present study, we profiled the seed isoflavones in world diverse soybean germplasm grown in two locations over two years in China. Significant differences (p < 0.001) were observed between the accessions, accession origins, seed coat colors, and maturity groups for individual and total isoflavone (TIF) content. TIF content of the soybean accessions ranged from 677.25 µg g-1 to 5823.29 µg g-1, representing an 8-fold difference. USA soybean accessions showed the highest mean TIF content (3263.07 µg g-1), followed by Japan (2521.26 µg g-1). Soybean with black seed coat showed the highest (3236.08 µg g-1) TIF concentration. Furthermore, isoflavone levels were significantly higher in late-maturity groups. Correlation analysis revealed significant positive associations between individual and TIF content. Malonyldaidzin and malonylgenistin showed higher correlations with TIF content (r = 0.92 and r = 0.94, respectively). The soybean accessions identified as having high and stable TIF content can be utilized in the food and pharmaceutical industries and breeding programs to develop soybean varieties with enhanced isoflavone content.

Early menopause and hormone therapy as determinants for lung health outcomes: a secondary analysis using the PLCO trial.

RATIONALE: Early natural menopause (early-M; <45 years of age) increases the risk of lung morbidities and mortalities in smokers. However, it is largely unknown whether early-M due to surgery demonstrates similar effects and whether menopausal hormone therapy (MHT) is protective against lung diseases. OBJECTIVES: To assess the associations of early-M and MHT with lung morbidities and mortalities using the prospective Prostate, Lung, Colorectal and Ovarian (PLCO) trial. METHODS: We estimated the risk among 69 706 postmenopausal women in the PLCO trial, stratified by menopausal types and smoking status. RESULTS: Early-M was associated with an increased risk of most lung disease and mortality outcomes in ever smokers with the highest risk seen for respiratory mortality (HR 1.98, 95% CI 1.34 to 2.92) in those with bilateral oophorectomy (BO). Early-M was positively associated with chronic bronchitis, and all-cause, non-cancer and respiratory mortality in never smokers with natural menopause or BO, with the highest risk seen for BO- respiratory mortality (HR 1.91, 95% CI 1.16 to 3.12). Ever MHT was associated with reduced all-cause, non-cancer and cardiovascular mortality across menopause types regardless of smoking status and was additionally associated with reduced risk of non-ovarian cancer, lung cancer (LC) and respiratory mortality in ever smokers. Among smokers, ever MHT use was associated with a reduction in HR for all-cause, non-cancer and cardiovascular mortality in a duration-dependent manner. CONCLUSIONS: Smokers with early-M should be targeted for smoking cessation and LC screening regardless of menopause types. MHT users had a lower likelihood of dying from LC and respiratory diseases in ever smokers.

Decoding the immune landscape: a comprehensive analysis of immune-associated biomarkers in cervical carcinoma and their implications for immunotherapy strategies.

Background and aims: Cervical cancer, a prevalent gynecological malignant tumor, poses a significant threat to women's health and lives. Immune checkpoint inhibitor (ICI) therapy has emerged as a promising avenue for treating cervical cancer. For patients with persistent or recurrent metastatic cervical cancer, If the sequence of dead receptor ligand-1 (PD-L1) is positive, ICI show significant clinical efficacy. PD-L1 expression serves as a valuable biomarker for assessing ICI therapeutic efficacy. However, the complex tumor immune microenvironment (TIME), encompassing immune cell composition and tumor-infiltrating lymphocyte (TIL) status, also exerts a profound influence on tumor immunity and prognosis. Given the remarkable strides made by ICI treatments in improving the survival rates of cervical cancer patients, it becomes essential to identify a comprehensive biomarker that integrates various TIME aspects to enhance the effectiveness of ICI treatment. Therefore, the quest for biomarkers linked to multiple facets of TIME in cervical cancer is a vital pursuit. Methods: In this study, we have developed an Immune-Associated Gene Prognostic Index (IRGPI) with remarkable prognostic value specifically for cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). The Cancer Genome Atlas CESC dataset (n = 305) was meticulously analyzed to pinpoint key immune-related genes via weighted gene co-expression network analysis and differential gene expression assays. Subsequently, we employed Cox regression analysis to construct the IRGPI. Furthermore, the composition of immune cells and TIL status were examined using CIBERSORT and TIDE. Tumor expression of Epigen, LCN10, and P73 were determined with immunohistochemistry. Results: The resulting IRGPI, composed of EPGN, LCN10, and TP73 genes, displayed a strong negative correlation with patient survival. The discovery was validated with a patient cohort from our hospital. The IRGPI not only predicts the composition of immune cell subtypes such as Macrophages M1, NK cells, Mast cells, Plasma cells, Neutrophils, Dendritic cells, T cells CD8, and T cells CD4 within CESC, but also indicates TIL exclusion, dysfunction, and PD-1 and PD-L1 expression. Therefore, the IRGPI emerges as a promising biomarker not only for prognostic assessment but also for characterizing multiple immune features in CESC. Additionally, our results underscored the significant associations between the IRGPI and immune cell composition, TIL exclusion, and dysfunction, along with PD-1 and PD-L1 expression in the TIME. Conclusion: Consequently, the IRGPI stands out as a biomarker intimately connected to both the survival and TIME status of CESC patients, offering potential insights into immunotherapy strategies for CESC.

BTA2 regulates tiller angle and the shoot gravity response through controlling auxin content and distribution in rice.

Tiller angle is a key agricultural trait that establishes plant architecture, which in turn strongly affects grain yield by influencing planting density in rice. The shoot gravity response plays a crucial role in the regulation of tiller angle in rice, but the underlying molecular mechanism is largely unknown. Here, we report the identification of the BIG TILLER ANGLE2 (BTA2), which regulates tiller angle by controlling the shoot gravity response in rice. Loss-of-function mutation of BTA2 dramatically reduced auxin content and affected auxin distribution in rice shoot base, leading to impaired gravitropism and therefore a big tiller angle. BTA2 interacted with AUXIN RESPONSE FACTOR7 (ARF7) to modulate rice tiller angle through the gravity signaling pathway. The BTA2 protein was highly conserved during evolution. Sequence variation in the BTA2 promoter of indica cultivars harboring a less expressed BTA2 allele caused lower BTA2 expression in shoot base and thus wide tiller angle during rice domestication. Overexpression of BTA2 significantly increased grain yield in the elite rice cultivar Huanghuazhan under appropriate dense planting conditions. Our findings thus uncovered the BTA2-ARF7 module that regulates tiller angle by mediating the shoot gravity response. Our work offers a target for genetic manipulation of plant architecture and valuable information for crop improvement by producing the ideal plant type.

Network pharmacology in combination with bibliometrics analysis on the mechanism of compound Kushen injection in the treatment of radiation pneumonia and lung cancer.

Radiation pneumonia is a common adverse reaction during radiotherapy in lung cancer patients, which negatively impacts the quality of life and survival of patients. Recent studies have shown that compound Kushen injection (CKI), a traditional Chinese medicine (TCM), has great anti-inflammatory and anticancer potential, but the mechanism is still unclear. We used CiteSpace, the R package "bibliometrix," and VOSviewers to perform a bibliometrics analysis of 162 articles included from the Web of Science core collection. A network pharmacology-based approach was used to screen effective compounds, screen and predict target genes, analyze biological functions and pathways, and construct regulatory networks and protein interaction networks. Molecular docking experiments were used to identify the affinity of key compounds and core target. The literature metrology analysis revealed that over 90% of the CKI-related studies were conducted by Chinese scholars and institutions, with a predominant focus on tumors, while research on radiation pneumonia remained limited. Our investigation identified 60 active ingredients of CKI, 292 genes associated with radiation pneumonia, 533 genes linked to lung cancer, and 37 common targets of CKI in the treatment of both radiation pneumonia and lung cancer. These core potential targets were found to be significantly associated with the OS of lung cancer patients, and the key compounds exhibited a good docking affinity with these targets. Additionally, GO and KEGG enrichment analysis highlighted that the bioinformatics annotation of these common genes mainly involved ubiquitin protein ligase binding, cytokine receptor binding, and the PI3K/Akt signaling pathway. Our study revealed that the main active components of CKI, primarily quercetin, luteolin, and naringin, might act on major core targets, including AKT1, PTGS2, and PPARG, and further regulated key signaling pathways such as the PI3K/Akt pathway, thereby playing a crucial role in the treatment of radiation pneumonia and lung cancer. Moreover, this study had a certain promotional effect on further clinical application and provided a theoretical basis for subsequent experimental research.

Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation.

Low-density lipoprotein receptor-related protein-1 (LRP1) is an endocytic/signaling cell-surface receptor that regulates diverse cellular functions, including cell survival, differentiation, and proliferation. LRP1 has been previously implicated in the pathogenesis of neurodegenerative disorders, but there are inconsistencies in its functions. Therefore, whether and how LRP1 maintains brain homeostasis remains to be clarified. Here, we report that astrocytic LRP1 promotes astrocyte-to-neuron mitochondria transfer by reducing lactate production and ADP-ribosylation factor 1 (ARF1) lactylation. In astrocytes, LRP1 suppressed glucose uptake, glycolysis, and lactate production, leading to reduced lactylation of ARF1. Suppression of astrocytic LRP1 reduced mitochondria transfer into damaged neurons and worsened ischemia-reperfusion injury in a mouse model of ischemic stroke. Furthermore, we examined lactate levels in human patients with stroke. Cerebrospinal fluid (CSF) lactate was elevated in stroke patients and inversely correlated with astrocytic mitochondria. These findings reveal a protective role of LRP1 in brain ischemic stroke by enabling mitochondria-mediated astrocyte-neuron crosstalk.

CT-determined low skeletal muscle index predicts poor prognosis in patients with colorectal cancer.

BACKGROUND: Sarcopenia is highly prevalent among patients with colorectal cancer (CRC). Computed tomography (CT)-based assessment of low skeletal muscle index (SMI) is widely used for diagnosing sarcopenia. However, there are conflicting findings on the association between low SMI and overall survival (OS) in CRC patients. The objective of this study was to investigate whether CT-determined low SMI can serve as a valuable prognostic factor in CRC. METHODS: We collected data from patients with CRC who underwent radical surgery at our institution between June 2020 and November 2021. The SMI at the third lumbar vertebra was calculated using CT scans, and the cutoff values for defining low SMI were determined using receiver operating characteristic curves. Univariate and multivariate analyses were performed to assess the associations between clinical characteristics and postoperative major complications. RESULTS: A total of 464 patients were included in the study, 229 patients (46.7%) were classified as having low SMI. Patients with low SMI were older and had a lower body mass index (BMI), a higher neutrophil to lymphocyte ratio (NLR), and higher nutritional risk screening 2002 (NRS2002) scores compared to those with normal SMI. Furthermore, patients with sarcopenia had a higher rate of major complications (10.9% vs. 1.3%; p < 0.001) and longer length of stay (9.09 ± 4.86 days vs. 8.25 ± 3.12 days; p = 0.03). Low SMI and coronary heart disease were identified as independent risk factors for postoperative major complications. Moreover, CRC patients with low SMI had significantly worse OS. Furthermore, the combination of low SMI with older age or TNM stage II + III resulted in the worst OS in each subgroup analysis. CONCLUSIONS: CT-determined low SMI is associated with poor prognosis in patients with CRC, especially when combined with older age or advanced TNM stage.

The biological roles of CD47 in ovarian cancer progression.

Ovarian cancer is one of the most lethal malignant tumors, characterized by high incidence and poor prognosis. Patients relapse occurred in 65-80% after initial treatment. To date, no effective treatment has been established for these patients. Recently, CD47 has been considered as a promising immunotherapy target. In this paper, we reviewed the biological roles of CD47 in ovarian cancer and summarized the related mechanisms. For most types of cancers, the CD47/Sirpα immune checkpoint has attracted the most attention in immunotherapy. Notably, CD47 monoclonal antibodies and related molecules are promising in the immunotherapy of ovarian cancer, and further research is needed. In the future, new immunotherapy regimens targeting CD47 can be applied to the clinical treatment of ovarian cancer patients.

Association of metabolic syndrome and its components with Parkinson's disease: a cross-sectional study.

BACKGROUND: The interrelation between metabolic syndrome (MetS) and Parkinson's disease (PD) likely arises from shared pathological mechanisms. This study thus aims to examine the impact of MetS and its components on PD. METHODS: This study utilized data extracted from the National Health and Nutrition Examination Survey database spanning 1999 to 2020. The random forest algorithm was applied to fill in the missing data. Propensity score optimal full matching was conducted. The data were adjusted by total weights derived from both sampling and matching weights. The weighted data were utilized to create multifactor logistic regression models. Odds ratios (ORs) and average marginal effects, along with their corresponding 95% confidence intervals (CIs), were calculated. RESULTS: MetS did not significantly affect the risk of PD (OR: 1.01; 95% CI: 0.77, 1.34; P = 0.92). Hypertension elevated the risk of PD (OR: 1.33; 95% CI: 1.01, 1.76; P = 0.045), accompanied by a 0.26% increased probability of PD occurrence (95% CI: 0.01%, 0.52%; P = 0.04). Diabetes mellitus (DM) had a 1.38 times greater likelihood of developing PD (OR:1.38; 95% CI: 1.004, 1.89; P = 0.046), corresponding to a 0.32% increased probability of PD occurrence (95% CI: -0.03%, 0.67%; P = 0.07). Nevertheless, no correlation was observed between hyperlipidemia, waist circumference and PD. CONCLUSION: MetS does not affect PD; however, hypertension and DM significantly increase the risk of PD.

Mitochondrial DNA copy number mediated the associations between perfluoroalkyl substances and breast cancer incidence: A prospective case-cohort study.

Epidemiologic studies have reported the relationships between perfluoroalkyl substances (PFASs) and breast cancer incidence, yet the underlying mechanisms are not well understood. This study aimed to elucidate the mediation role of mitochondrial DNA copy number (mtDNAcn) in the relationships between PFASs exposure and breast cancer risk. We conducted a case-cohort study within the Dongfeng-Tongji cohort, involving 226 incident breast cancer cases and a random sub-cohort (n = 990). Their plasma concentrations of six PFASs [including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroheptanoic acid (PFHpA), perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS)], and peripheral blood levels of mtDNAcn, were detected at baseline by using ultraperformance liquid chromatography-tandem mass spectrometry and quantitative real-time PCR, respectively. Linear regression and Barlow-weighted Cox models were employed separately to assess the relationships of mtDNAcn with PFASs and breast cancer risk. Mediation analysis was further conducted to quantify the mediating effects of mtDNAcn on PFAS-breast cancer relationships. We observed increased blood mtDNAcn levels among participants with the highest PFNA and PFHpA exposure [Q4 vs. Q1, ß(95%CI) = 0.092(0.022, 0.162) and 0.091(0.022, 0.160), respectively], while no significant associations were observed of PFOA, PFDA, PFOS, or PFHxS with mtDNAcn. Compared to participants within the lowest quartile subgroup of mtDNAcn, those with the highest mtDNAcn levels exhibited a significantly increased risk of breast cancer and postmenopausal breast cancer [Q4 vs. Q1, HR(95%CI) = 3.34(1.80, 6.20) and 3.71(1.89, 7.31)]. Furthermore, mtDNAcn could mediate 14.6 % of the PFHpA-breast cancer relationship [Indirect effect, HR(95%CI) = 1.02(1.00, 1.05)]. Our study unveiled the relationships of PFNA and the short-chain PFHpA with mtDNAcn and the mediation role of mtDNAcn in the PFHpA-breast cancer association. These findings provided insights into the potential biological mechanisms linking PFASs to breast cancer risk.

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro.

Hippocampal neurons maintain the ability of proliferation throughout life to support neurogenesis. Deoxynivalenol (DON) is a mycotoxin that exhibits brain toxicity, yet whether and how DON affects hippocampal neurogenesis remains unknown. Here, we use mouse hippocampal neuron cells (HT-22) as a model to illustrate the effects of DON on neuron proliferation and to explore underlying mechanisms. DON exposure significantly inhibits the proliferation of HT-22 cells, which is associated with an up-regulation of cell cycle inhibitor p21 at both mRNA and protein levels. Global and site-specific m6A methylation levels on the 3'UTR of p21 mRNA are significantly increased in response to DON treatment, whereas inhibition of m6A hypermethylation significantly alleviates DON-induced cell cycle arrest. Further mechanistic studies indicate that the m6A readers YTHDF1 and IGF2BP1 are responsible for m6A-mediated increase in p21 mRNA stability. Meanwhile, 3'UTR of E3 ubiquitin ligase TRIM21 mRNA is also m6A hypermethylated, and another m6A reader YTHDF2 binds to the m6A sites, leading to decreased TRIM21 mRNA stability. Consequently, TRIM21 suppression impairs ubiquitin-mediated p21 protein degradation. Taken together, m6A-mediated upregulation of p21, at both post-transcriptional and post-translational levels, contributes to DON-induced inhibition of hippocampal neuron proliferation. These results may provide new insights for epigenetic therapy of neurodegenerative diseases.

Arginine Regulates Skeletal Muscle Fiber Type Formation via mTOR Signaling Pathway.

The composition of skeletal muscle fiber types affects the quality of livestock meat and human athletic performance and health. L-arginine (Arg), a semi-essential amino acid, has been observed to promote the formation of slow-twitch muscle fibers in animal models. However, the precise molecular mechanisms are still unclear. This study investigates the role of Arg in skeletal muscle fiber composition and mitochondrial function through the mTOR signaling pathway. In vivo, 4-week C56BL/6J male mice were divided into three treatment groups and fed a basal diet supplemented with different concentrations of Arg in their drinking water. The trial lasted 7 weeks. The results show that Arg supplementation significantly improved endurance exercise performance, along with increased SDH enzyme activity and upregulated expression of the MyHC I, MyHC IIA, PGC-1α, and NRF1 genes in the gastrocnemius (GAS) and quadriceps (QUA) muscles compared to the control group. In addition, Arg activated the mTOR signaling pathway in the skeletal muscle of mice. In vitro experiments using cultured C2C12 myotubes demonstrated that Arg elevated the expression of slow-fiber genes (MyHC I and Tnnt1) as well as mitochondrial genes (PGC-1α, TFAM, MEF2C, and NRF1), whereas the effects of Arg were inhibited by the mTOR inhibitor rapamycin. In conclusion, these findings suggest that Arg modulates skeletal muscle fiber type towards slow-twitch fibers and enhances mitochondrial functions by upregulating gene expression through the mTOR signaling pathway.