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BACKGROUND RESULTS CONCLUSIONS Ligusticum chuanxiong Hort., with over 2000 years of medicinal use and cultivation history, is extensively used in clinical settings for treating heart disease, headache, dysmenorrhea, and amenorrhea. Constructing the geographic distribution pattern of L. chuanxiong and identifying the environmental factors limiting its range, as well as clarifying the effects of key environmental factors on the content of major active constituents and transcription regulation, could provide a scientific foundation for the conservation and effective management of this valuable medicinal resource.The results reveal that the predominant environmental factors influencing the distribution were the minimum temperature of the coldest month (Bio6) and solar radiation (Srad), with cumulative account for 87.46% of the importance. Correlation analysis further reveals significant negative correlations between Bio6 and the content of major active constituents in L. chuanxiong, with Srad exhibiting a negative correlation with these constituents. The gene differential expression analysis indicated that the expression levels of some genes associated with growth and active constituent biosynthesis pathways, such as RPT2_13888, UVR8_16871, CLPB3_3155, and 4CLL5_116, varied significantly among locations influenced by differing key environmental factors. Consequently, alterations in the environment were found to influence the gene expression levels within these pathways, resulting in variations in the content of active constituents.These findings contribute to an enhanced understanding of how environmental factors impact the distribution and quality of medicinal plants and offer a theoretical reference for the introduction, cultivation, quality improvement, resource utilization and management of L. chuanxiong. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

To develop and validate the predictive effects of stable ferroptosis‐ and pyroptosis‐related features on the prognosis and immune status of breast cancer (BC). We retrieved as well as downloaded ferroptosis‐ and pyroptosis‐related genes from the FerrDb and GeneCards databases. The minimum absolute contraction and selection operator (LASSO) algorithm in The Cancer Genome Atlas (TCGA) was used to construct a prognostic classifier combining the above two types of prognostic genes with differential expression, and the Integrated Gene Expression (GEO) dataset was used for validation. Seventeen genes presented a close association with BC prognosis. Thirteen key prognostic genes with prognostic value were considered to construct a new expression signature for classifying patients with BC into high‐ and low‐risk groups. Kaplan–Meier analysis revealed a worse prognosis in the high‐risk group. The receiver operating characteristic (ROC) curve and multivariate Cox regression analysis identified its predictive and independent features. Immune profile analysis showed that immunosuppressive cells were upregulated in the high‐risk group, and this risk model was related to immunosuppressive molecules. We successfully constructed combined features of ferroptosis and pyroptosis in BC that are closely related to prognosis, clinicopathological and immune features, chemotherapy efficacy and immunosuppressive molecules. However, further experimental studies are required to verify these findings. [ABSTRACT FROM AUTHOR]

Background: The absence of thyroid transcription factor 1 (TTF‐1) is associated with a lower frequency of epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma (LUAD). The aim of this study was to assess the impact of TTF‐1 expression on the clinical response to EGFR‐tyrosine kinase inhibitor (TKI) treatment in patients with advanced LUAD. Methods: The data of patients with advanced LUAD who were admitted to the Beijing Tiantan Hospital and Peking University Cancer Hospital (China) between April 2009 and May 2023 was retrospectively analyzed. Results: A total of 227 patients diagnosed with advanced LUAD were included, of which 28.2% (64/227) had TTF‐1‐negative adenocarcinoma, while 54.6% (124/227) harbored EGFR mutations. Negative TTF‐1 expression significantly correlated with male sex (68.8% vs. 42.3%, p < 0.001), history of heavy smoking (57.8% vs. 36.2%, p = 0.003), poorly differentiated tumors (86.5% vs. 43.2%, p < 0.001), and lower frequency of EGFR mutations (26.6% vs. 65.6%, p < 0.001) compared with TTF‐1 positivity. Multivariable logistic regression showed that low prevalence of EGFR mutations (p < 0.001) and male sex (p = 0.006) were independent predictive factors for the negative expression of TTF‐1. Patients lacking TTF‐1 also exhibited worse overall response rate (ORR; 23.5% vs. 54.2%, p = 0.019), disease control rate (DCR; 58.8% vs. 89.7%, p = 0.003), and median progression‐free survival (PFS; 2.9 vs. 11.6 months, p < 0.001) following treatment with EGFR‐TKIs compared to the TTF‐1‐positive patients with EGFR mutations. Conclusions: Patients with TTF‐1‐negative and EGFR‐mutant LUAD show a diminished response to EGFR‐TKIs. [ABSTRACT FROM AUTHOR]

Unlike mammals, adult zebrafish undergo spontaneous recovery after major spinal cord injury. Whereas reactive gliosis presents a roadblock for mammalian spinal cord repair, glial cells in zebrafish elicit pro-regenerative bridging functions after injury. Here, we perform genetic lineage tracing, assessment of regulatory sequences and inducible cell ablation to define mechanisms that direct the molecular and cellular responses of glial cells after spinal cord injury in adult zebrafish. Using a newly generated CreERT2 transgenic line, we show that the cells directing expression of the bridging glial marker ctgfa give rise to regenerating glia after injury, with negligible contribution to either neuronal or oligodendrocyte lineages. A 1 kb sequence upstream of the ctgfa gene was sufficient to direct expression in early bridging glia after injury. Finally, ablation of ctgfa-expressing cells using a transgenic nitroreductase strategy impaired glial bridging and recovery of swim behavior after injury. This study identifies key regulatory features, cellular progeny, and requirements of glial cells during innate spinal cord regeneration. [ABSTRACT FROM AUTHOR]

Cohesin is a ring-shaped protein complex and plays a critical role in sister chromosome cohesion, which is a key event during mitosis and meiosis. Meiotic recombination protein REC8 is one of the subunits of the cohesion complex. Although REC8 genes have been characterized in some plant species, little is known about them in Gossypium. In this study, 89 REC8 genes were identified and analyzed in 16 plant species (including 4 Gossypium species); 12 REC8 genes were identified in Gossypium. hirsutum, 11 in Gossypium. barbadense, 7 in Gossypium. raimondii, and 5 in Gossypium. arboreum. In a phylogenetic analysis, the 89 RCE8 genes clustered into 6 subfamilies (I–VI). The chromosome location, exon-intron structure, and motifs of the REC8 genes in the Gossypium species were also analyzed. Expression patterns of GhREC8 genes in various tissues and under abiotic stress treatments were analyzed based on public RNA-seq data, which indicated that GhREC8 genes might have different functions in growth and development. Additionally, qRT-PCR analysis showed that MeJA, GA, SA, and ABA treatments could induce the expression of GhREC8 genes. In general, the genes of the REC8 gene family of cotton were systematically analyzed, and their potential function in cotton mitosis, meiosis, and in response to abiotic stress and hormones were preliminary predicted, which provided an important basis for further research on cotton development and resistance to abiotic stress. [ABSTRACT FROM AUTHOR]

Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia in the general population, and stroke is the most severe complication of AF. Exosomal miRNAs have been reported to be candidates as biomarkers for cardiovascular diseases, including AF and stroke. This study aimed to identify differentially expressed miRNAs (DEMs) in serum exosomes of AF and AF-associated ischemic stroke (AF-IS) patients and evaluate their potential in distinguishing AF and AF-IS patients. Methods: Serum exosomes were isolated from 8 healthy individuals with sinus rhythm (SR controls), 8 AF patients, and 8 AF-IS patients. miRNA-seq was performed to identify DEMs, and qRT-PCR analysis was performed to confirm the sequencing results. A support vector machine (SVM) model was developed using Python to distinguish AF and AF-IS patients. Results: 68 and 86 DEMs were identified in serum exosomes of AF patients compared to AF-IS patients and SR controls, respectively. Levels of miR-641 and miR-30e-5p were found significantly higher in AF-IS patients. The SVM model achieved an accuracy of 100%, with an area under curve of 1. Conclusions: The results indicated that miRNA expression profiles of serum exosomes in AF patients were distinct from those in AF-IS patients, and based on the distinction, AF and AF-IS patients can be distinguished. [ABSTRACT FROM AUTHOR]

Abstract: This work aims to discuss the possibility that disordered CUL4B was involved in the pathogenesis of adjuvant-induced arthritis (AIA) in rats. Synovium and FLS from AIA rats both showed increased CUL4B and β-catenin, and up-regulated CUL4B enhanced the canonical Wnt signaling by targeting the GSK3β. Increased CUL4B promoted the FLS abnormal proliferation, activated the secretion of IL-1β and IL-8, and promoted the production of AIA pathology gene MMP3 and fibronectin. Furthermore, miR-101-3p was significantly down-regulated in AIA rats compared with controls, and transfection of AIA FLS with miR-101-3p mimics significantly down-regulated the CUL4B expression, whereas transfection with miR-101-3p inhibitors resulted in an opposite observation. The dual-luciferase reporter assay confirmed that the CUL4B was a direct target of miR-101-3p, and further analysis suggested that lowly expressed miR-101-3p contributed to disordered CUL4B activating the canonical Wnt signaling pathway and further promoting the development of AIA rats. Thus clarification of the CUL4B roles in the pathogenesis of AIA rats and corresponding mechanisms will contribute to the disease diagnosis and treatment for rheumatoid arthritis (RA) patients.Key messages: CUL4B expression is up-regulated in synovium and FLS from AIA rats.Increased CUL4B promotes the canonical Wnt signaling.Increased CUL4B promotes the pathogenesis of AIA rats.Decreased miR-101-3p contributes to disordered CUL4B. [ABSTRACT FROM AUTHOR]

The production and accumulation of secondary metabolites of medicinal plants are regulated by environmental factors. Analyzing the effects of climate change on the suitable habitats and active compound of Nardostachys jatamansi (D. Don) DC. is essential for their future conservation and cultivation. This study predicted changes in the scale of distribution of N. jatamansi under different Shared Socio-economic Pathway (SSP) scenario models over time. In addition, this study analyzed differences in active compound content by high performance liquid chromatography (HPLC) methods and changes in gene expression by transcriptome sequencing across different habitats. The results reveal that elevation, mean temperature of coldest quarter, and precipitation of warmest quarter cumulatively contributed 90.1% to the species distribution models (SDMs), and were the critical environmental variables affecting the distribution of N. jatamansi. The SDMs predicted that N. jatamansi habitats will decrease in the future. Under the SSP5–8.5 scenario, highly suitable areas in China for N. jatamansi growth will decrease to 7.734375 × 104 km2 by the 2061–2080 s period. This study also observed that the contents of active compounds increased with ecological suitability, with the nardosinone content in N. jatamansi reaching 0.67% in highly suitable areas. Analysis of differential gene expression in N. jatamansi indicated that the expression levels of genes in the terpene synthesis pathway genes were significantly different across grades of suitable areas. Together, the combined results of SDMs analysis, chemical analysis, and transcriptome analysis in N. jatamansi reveal that environmental changes affect the expression levels of genes related to terpene gene synthesis pathways, thereby changing the contents of active compounds. Overall, these findings provide a reference for the conservation of wild resources of N. jatamansi and the improvement of the quality of cultivated N. jatamansi. • The distribution of Nardostachys jatamansi is affected by various types of environmental factors. • The distribution of N. jatamansi based on species distribution models will decrease in the future. • Positive correlation between highly suitable areas and active compound contents. • Environmental changes affect gene expression levels of samples, changing the contents of active compounds. [ABSTRACT FROM AUTHOR]

Abstract: Despite the substantial impact of sleep disturbances on human health and the many years of study dedicated to understanding sleep pathologies, the underlying genetic mechanisms that govern sleep and wake largely remain unknown. Recently, the authors completed large-scale genetic and gene expression analyses in a segregating inbred mouse cross and identified candidate causal genes that regulate the mammalian sleep-wake cycle, across multiple traits including total sleep time, amounts of rapid eye movement (REM), non-REM, sleep bout duration, and sleep fragmentation. Here the authors describe a novel approach toward validating candidate causal genes, while also identifying potential targets for sleep-related indications. Select small-molecule antagonists and agonists were used to interrogate candidate causal gene function in rodent sleep polysomnography assays to determine impact on overall sleep architecture and to evaluate alignment with associated sleep-wake traits. Significant effects on sleep architecture were observed in validation studies using compounds targeting the muscarinic acetylcholine receptor M3 subunit ( Chrm3) (wake promotion), nicotinic acetylcholine receptor alpha4 subunit ( Chrna4) (wake promotion), dopamine receptor D5 subunit ( Drd5) (sleep induction), serotonin 1D receptor ( Htr1d) (altered REM fragmentation), glucagon-like peptide-1 receptor ( Glp1r) (light sleep promotion and reduction of deep sleep), and calcium channel, voltage-dependent, T type, alpha 1I subunit ( Cacna1i) (increased bout duration of slow wave sleep). Taken together, these results show the complexity of genetic components that regulate sleep-wake traits and highlight the importance of evaluating this complex behavior at a systems level. Pharmacological validation of genetically identified putative targets provides a rapid alternative to generating knock out or transgenic animal models, and may ultimately lead towards new therapeutic opportunities. [ABSTRACT FROM AUTHOR]

The primary aim of this study is to evaluate the clinical significance of E-cadherin protein expression and the methylation status in CDH1 promoter in endometrial cancer. The expression of E-cadherin and methylation in its promoter region was analyzed, retrospectively, in 152 clinical tissue samples from patients with endometrial lesions. We found that the hypermethylation of CDH1 promoter, which caused low expression of E-cadherin in endometrial cancer, was associated with not only clinicopathological progress of endometrial cancer but also with the overall 5-year clinical survival rate. The findings provide the potential therapeutic and prognostic target molecule for patients with endomethrial cancer. [ABSTRACT FROM AUTHOR]

Abstract: Telomerase is almost universally required for cellular immortality and is permissive for tumorigenesis. Accumulating evidence suggests that telomerase may have roles in cellular processes independent of its role in telomere maintenance. However, the biochemical properties and the mechanisms of telomerase non-telomeric functions are unknown. In this report, we show that the telomerase catalytic component hTERT is capable of activating transcription of VEGF. We further demonstrated that the activation of VEGF expression by hTERT was independent of telomerase activity and telomere maintenance. These results suggest that hTERT has non-telomeric activity in the regulation of gene expression and provide additional insights into the role of telomerase in aging and cancer. [Copyright &y& Elsevier]

Endothelin is a vasoconstricting peptide that plays a key role in vascular homeostasis, exerting its biologic effects via two receptors, the endothelin receptor A (ETA) and endothelin receptor B (ETB). Activation of ETA and ETB has opposing actions, in which hyperactive ETA is generally vasoconstrictive and pathologic. Selective ETA blockade has been shown to be beneficial in renal injuries such as diabetic nephropathy and can improve proteinuria. Atrasentan is a selective pharmacologic ETA blocker that preferentially inhibits ETA activation. In this study, we evaluated the efficacy of ETA blockade by atrasentan in ameliorating proteinuria and kidney injury in murine adriamycin nephropathy, a model of human focal segmental glomerulosclerosis. We found that ETA expression was unaltered during the course of adriamycin nephropathy. Whether initiated prior to injury in a prevention protocol (5 mg/kg/day, i.p.) or after injury onset in a therapeutic protocol (7 mg/kg or 20 mg/kg three times a week, i.p.), atrasentan did not significantly affect the initiation and progression of adriamycin-induced albuminuria (as measured by urinary albumin-to-creatinine ratios). Indices of glomerular damage were also not improved in atrasentan-treated groups, in either the prevention or therapeutic protocols. Atrasentan also failed to improve kidney function as determined by serum creatinine, histologic damage, and mRNA expression of numerous fibrosis-related genes such as collagen-I and TGF-β1. Therefore, we conclude that selective blockade of ETA by atrasentan has no effect on preventing or ameliorating proteinuria and kidney injury in adriamycin nephropathy. [ABSTRACT FROM AUTHOR]