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Luteolin (LTL) exerts remarkable tumor suppressive activity on various types of cancers, including non-small cell lung cancer (NSCLC). However, it is not completely understood whether the mechanism of its action against NSCLC is related to microRNAs (miRNAs). In the present study, we investigated the anti-tumor effects of LTL on NSCLC in vitro and in vivo. The results revealed that LTL could inhibit cell proliferation and induce apoptosis in both A549 and H460 cells. In a H460 xenograft tumor model of nude mice, LTL significantly suppressed tumor growth, inhibited cell proliferation, and induced apoptosis. miRNA microarray and quantitative PCR (qPCR) analysis indicated that miR-34a-5p was dramatically upregulated upon LTL treatment in tumor tissues. Furthermore, MDM4 was proved to be a direct target of miR-34a-5p by luciferase reporter gene assay. LTL treatment was associated with increased p53 and p21 protein expressions and decreased MDM4 protein expression in both NSCLC cells and tumor tissues. When miR-34a-5p was inhibited in vitro, the protein expressions of Bcl-2 and MDM4 were recovered, while that of p53, p21, and Bax were attenuated. Moreover, caspase-3 and caspase-9 activation induced by LHL treatment in vitro were also suppressed by miR-34a-5p inhibition. Overall, LTL could inhibit tumorigenesis and induce apoptosis of NSCLC cells by upregulation of miR-34a-5p via targeting MDM4. These findings provide novel insight into the molecular functions of LTL that suggest its potential as a therapeutic agent for human NSCLC.

The cardiac autonomic nerve system (CANS) is a potentially potent modulator of the initiation and perpetuation of atrial fibrillation (AF). In this review, we focus on the relationship between the autonomic nervous system (ANS) and the pathophysiology of AF and the potential benefit and limitations of neuromodulation in the management of this arrhythmia from eight aspects. We conclude that Activation and Remodeling of CANS involved in the initiation and maintenance of AF. The network control mechanism, innervation regions, and sympathetic/parasympathetic balance play an important role in AF substrate. And the formation of Complex Fractional Atrial Electrograms also related to CANS activity. In addition, modulating CANS function by potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, and low‐level vagal nerve stimulation, may enable AF to be controlled. Although the role of the ANS has long been recognized, a better understanding of the complex interrelationships of the various components of the CANS will lead to improvement of treatments for this common arrhythmia.

Alzheimer’s disease (AD) is a common age-related neurodegenerative disorder with extremely low drug development success rates, making nutritional intervention a promising strategy. Cerebral energy metabolism dysfunction is a core pathological feature of AD. Odd-chain fatty acids (OCFAs) can generate propionyl-CoA via β-oxidation to replenish the impaired tricarboxylic acid (TCA) cycle. This study characterized the lipid composition of OCFAs-enriched algal oil by UPC2-Q-TOF-MS, evaluated its neuroprotective effects on Caenorhabditis elegans (C. elegans) models with AD, Parkinson’s disease (PD), and Huntington’s disease (HD), and explored the metabolic mechanism of its key component pentadecanoic acid (C15:0) using untargeted metabolomics. Results showed that triglycerides (TAGs) represented the predominant lipid class, accounting for 97.3% of the total lipid content in the algal oil. Among all the identified TAG molecular species, TAGs containing C15:0/C17:0 accounted for more than 90%. OCFAs-enriched algal oil exhibited disease-selective neuroprotection. It significantly improved locomotor function in AD nematodes, moderately ameliorated PD-related deficits, whereas showed no efficacy in HD nematodes. Metabolomics revealed that C15:0 produced propionyl-CoA to rescue TCA cycle dysfunction and energy deficits, upregulated membrane phospholipids to repair membrane integrity, and reduced abnormal metabolites to restore metabolic homeostasis. KEGG analysis confirmed that C15:0 globally regulated core metabolic pathways including amino acid, cofactor, nucleotide, and carbon metabolism. OCFAs-enriched algal oil exerted selective anti-AD effects by repairing energy metabolism, remodeling membrane phospholipids, and restoring metabolic homeostasis, providing a novel nutritional candidate for AD intervention.

BackgroundPatients with heart failure with reduced ejection fraction (HFrEF) and atrial fibrillation are mostly elderly patients, and persistent atrial fibrillation (PerAF) with multiple comorbidities tends to have a worse clinical prognosis. However, there is a lack of randomised trial to investigate the impact of catheter ablation (CA) on outcomes in older PerAF combined with HFrEF.ObjectiveThis study aims to compare the effects of CA versus medical rate control (MRC) on severity indicators of HFrEF.MethodsOlder patients with PerAF and HFrEF underwent transthoracic echocardiography and were randomly assigned to receive either AF ablation or MRC. The primary outcome was changes in left ventricular ejection fraction (LVEF).ResultsA total of 89 patients (mean age 69.5±3.9 years) were randomly allocated to the CA group (n=45) and MRC group (n=44). Baseline characteristics were similar between the two groups. After 12 months, worsening heart failure requiring unplanned hospitalisation occurred less frequently in the CA group (p=0.019). In CA group, LVEF (from baseline 36.1%±2.7% to 48.9%±7.1%; p<0.00 L) improved higher compared with the MRC group (8.7 (5.9 to 11.5)), p<0.001. Compared with baseline, New York Heart Association functional class and AF burden also showed improvement in CA group than MR group. At a follow-up period of 12 months, sinus rhythm rate was higher in CA group than MRC group, 51.1% versus 20.4%.ConclusionThis limited small-scale randomised study showed that CA in older patients with PerAF and HFrEF was associated with a lower likelihood of unplanned hospitalisations due to worsening heart failure with improvement in LVEF and lower AF burden.Trial registration number NCT05827172.

This study aimed to describe the landscape of Immune checkpoint inhibitors (ICIs)-related adverse events (AEs) in a predominantly Chinese cohort. We searched electronic datasets including PubMed, Web of Science and Embase to identify and recruit relevant trials up to September 2, 2019. Clinical trials focusing on ICIs in Chinese patients or a predominantly Chinese population were included. Incidences of treatment-related AEs (TRAEs) and immune-related AEs (irAEs) were pooled and compared. In total, we recruited 13 trials consisting of 1063 patients, with 922 (86.7%) receiving ICI monotherapy and 141 (13.3%) receiving combination of ICI with chemotherapy or anti-angiogenesis. The pooled incidence of any grade TRAEs, grade 1–2, grade 3–5 TRAEs, any grade irAEs, grade 1–2 irAEs and grade 3–5 irAEs in all 1063 patients were 84.1%, 63.3%, 20.9%, 43.3%, 40.0% and 3.0%, respectively. Moreover, 4.3% (44/1018) of patients experienced treatment discontinuation and only 8 (0.8%) patients experienced treatment-related death. Compared to ICI monotherapy, combination significantly increased grade 3–5 TRAEs (46.1% vs. 17.0%, P  < 0.001) and grade 3–5 irAEs (7.1% vs. 2.0%, P  = 0.015). By comparing the toxicity profiles between different ICIs, we found some drug-specific AEs such as reactive capillary haemangiomas for camrelizumab (58.6%), hyperglycemia for toripalimab (55.6%) and pyrexia for tislelizumab (54.3%). Additionally, nivolumab has the lowest incidence of any grade (64.1%) and grade 3–5 (11.8%) TRAEs. ICI-related AEs were generally mild and tolerable for a predominantly Chinese cohort. However, we should pay attention to the combination of ICI with chemotherapy as it could increase grade 3–5 TRAEs and irAEs.

Softening process greatly affects fruit texture and shelf life. Expansins (EXPs) are a group of structural proteins participating in cell wall loosening, which break the hydrogen bonding between cellulose microfibrils and hemicelluloses. However, our knowledge on how EXP genes are regulated in fruit ripening, especially in non-climacteric fleshy fruits, is limited. Here, we have identified the EXP genes in both the octoploid cultivated strawberry (Fragaria × ananassa) and one of its diploid progenitor species, woodland strawberry (Fragaria vesca). We found that EXP proteins in F. × ananassa were structurally more divergent than the ones in F. vesca. Transcriptome data suggested that FaEXP88, FaEXP114, FveEXP11 and FveEXP33 were the four candidate EXP genes more likely involved in fruit softening, whose transcript levels dramatically increased when firmness decreased during fruit maturation. Phylogenetic analyses showed that those candidate genes were closely clustered, indicating the presence of homoeolog expression dominance in the EXP gene family in strawberry. Moreover, we have performed chromatin immunoprecipitation (ChIP) experiments to investigate the distribution of histone modifications along the promoters and genic regions of the EXP genes in F. vesca. ChIP data revealed that the transcript levels of EXP genes were highly correlated with the enrichment of H3K9/K14 acetylation and H3K27 tri-methylation. Collectively, this study identifies the key EXP genes involved in strawberry fruit softening and reveals a regulatory role of histone modifications in their transcriptional regulation, which would facilitate functional studies of the EXP genes in the ripening of non-climacteric fruits.

Background Aortic stiffness shares a similar profile of risk factors with left ventricular hypertrophy (LVH) and can also lead to LVH by itself. Published data have demonstrated the correlation between aortic stiffness and LVH. Recent data have revealed estimated pulse wave velocity (ePWV) to be a simple and cost-effective marker of the severity of aortic stiffness. Our analysis aimed to explore the association between ePWV and LVH prevalence, and to investigate the incremental value of ePWV for the identification of LVH prevalence. Methods The present analysis based on a cross-sectional survey which included 11,597 participants from rural areas of southeastern China between Sep 2020 and Feb 2021. ePWV was formulated based on mean blood pressure and age according to a published algorithm. Results The prevalence of LVH was 14.56%. With the adjustment of age, sex, education, income and physical activity level, current drinking and smoking status, BMI, waist circumference, serum creatinine, total cholesterol, high density cholesterol, mean blood pressure, fasting plasma glucose, anti-hypertensive therapy, anti-diabetic therapy, lipid-lowering therapy, and cardiovascular disease history, every standard deviation increment of ePWV associated with a 2.993 times risk of LVH prevalence. When dividing ePWV into quartiles, the top quartile had a 4.520 times risk of LVH prevalence when compared with the bottom quartile. Furthermore, smooth spline analysis displayed that the association was linear in the whole range of ePWV ( p for non-linearity = 0.073). Additionally, subgroup analysis revealed the association was robust to sex, obesity and diabetes, and younger people and hypertensive population were more vulnerable to the increase of ePWV than their corresponding counterparts. Finally, ROC analysis showed a significant advancement when introducing ePWV into established risk factors (0.787 vs. 0.810, p for comparison < 0.001), and reclassification analysis also confirmed significant improvement from ePWV to identify LVH prevalence (category-free net reclassification analysis = 0.421, p  < 0.001; integrated discrimination index = 0.023, p  < 0.001). Conclusion Our analysis demonstrated a linear association between ePWV and LVH prevalence. Furthermore, our results suggest younger people and hypertensive population are more likely to have LVH prevalence with the increase of ePWV. More importantly, our findings implicate the incremental value of ePWV to optimize the identification of LVH prevalence in a general Chinese population.

The genus Laccaria is a type of cosmopolitan and ecologically important fungal group. Members can form ectomycorrhizal associations with numerous trees, and some species are common edible fungi in local markets. Although some new species from China are recently published, the species diversity of Laccaria is still unclear in China. In this study, some samples of Laccaria were collected from southern China, and morphological characteristics and phylogenetic analyses based on the multilocus dataset of ITS-LSU-tef1-rpb2 confirmed five new species. Laccaria miniata, L. nanlingensis and L. neovinaceoavellanea were collected from subtropical broad-leaved forests, and L. rufobrunnea and L. umbilicata were collected from subtropical mixed forests of southwest China. Full descriptions, illustrations, comparisons with similar species and phylogenetic analysis are provided.

The significant economic burden of colorectal cancer (CRC) necessitates the development of innovative therapeutic approaches. Interest in the gut microbiota’s role in CRC has increased. Capecitabine, as a chemotherapy, may disrupt the balance of the intestinal microbiota. This study investigated the anticancer effects of capecitabine combined with fecal microbiota transplantation (FMT) in a CRC mouse model caused by azoxymethane and dextran sodium sulfate. FMT was achieved with fecal microbiota from healthy mice through enema. Capecitabine decreased the number and diameter of cancer foci in CRC mice, while FMT supplementation had a more noticeable impact, indicated by increased body weight and survival rate. Capecitabine significantly reduced the abundance of pathogenic bacteria in mice with CRC, such as Bacteroides , Enterorhabdus , Monoglobus , Rodentibacter , uncultured_rumen_bacterium, Turicibacter , and Streptococcus . The supplementation of FMT more effectively reversed the gut microbiota dysbiosis in CRC mice, as demonstrated by the ACE and Chao 1 indices, PCoA analysis, and enhanced normal biological pathways. Microbial dysbiosis induced immunological dysfunction in CRC mice, indicated by abnormal immune cell recruitment and excessive cytokine production. Capecitabine treatment reduced immune cell infiltration, including CD3 + T cells, CD4 + T cells, and CD49b + NK cells, as chemotherapy often suppresses the immune system. The supplement of FMT increased the proportion of CD4 + T cells, CD49b + NK cells, CD8 + T cells, and LY6G + neutrophils, indicating improved immune responses against CRC. Moreover, capecitabine therapy alone reduced the overexpression of IL1a, IL6, IL12a, IL12b, IL17, IL22, FOXP3, STAT3, IFN-γ, TNF-α, TGF-β, GZMA, CXCR4, OPN, PD-1 and PD-L1. FMT supplementation resulted in a higher immune response to CRC, as it had a greater inhibitory effect on the overexpression of inflammatory cytokines and enhanced the production of IL10, IFN-γ, and CXCR4. These cytokines were positively correlated with Azospirillum_sp._47_25 , Romboutsia , Lactococcus , Rikenella_sp._Marseille_P3215 and Turicibacter and negatively correlated with Parabacteroids , unclassified_Oscillospiraceae, Marvinbryantia , unclassified_Clostridia_vadinBB60_group, unclassified_Erysipelatoclostridiaceae, A2 , Roseburia , Rikenellaceae_RC9_gut_group, Acetatifactor and unclassified_Clostridia. The combination of capecitabine and FMT is more effective at preventing CRC than capecitabine alone, as it reverses gut microbial abnormalities and boosts immune responses to CRC.

High salt is positively associated with the risk of many diseases. However, little is known about the mechanisms. Here we showed that high salt increased proinflammatory molecules, while decreased anti-inflammatory and proendocytic molecules in both human and mouse macrophages. High salt also potentiated lipopolysaccharide-induced macrophage activation and suppressed interleukin 4-induced macrophage activation. High salt induced the proinflammatory aspects by activating p38/cFos and/or Erk1/2/cFos pathways, while inhibited the anti-inflammatory and proendocytic aspects by Erk1/2/signal transducer and activator of transcription 6 pathway. Consistent with the in vitro results, high-salt diet increased proinflammatory gene expression of mouse alveolar macrophages. In mouse models of acute lung injury, high-salt diet aggravated lipopolysaccharide-induced pulmonary macrophage activation and inflammation in lungs. These results identify a novel macrophage activation state, M(Na), and high salt as a potential environmental risk factor for lung inflammation through the induction of M(Na).