1,399 research outputs found

    Aconitine and its derivatives: bioactivities, structure-activity relationships and preliminary molecular mechanisms

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    Aconitine (AC), which is the primary bioactive diterpene alkaloid derived from Aconitum L plants, have attracted considerable interest due to its unique structural feature. Additionally, AC demonstrates a range of biological activities, such as its ability to enhance cardiac function, inhibit tumor growth, reduce inflammation, and provide analgesic effects. However, the structure-activity relationships of AC are remain unclear. A clear understanding of these relationships is indeed critical in developing effective biomedical applications with AC. In line with these challenges, this paper summarized the structural characteristics of AC and relevant functional and bioactive properties and the structure-activity relationships presented in biomedical applications. The primary temporal scope of this review was established as the period spanning from 2010 to 2023. Subsequently, the objective of this review was to provide a comprehensive understanding of the specific action mechanism of AC, while also exploring potential novel applications of AC derivatives in the biomedical field, drawing upon their structural characteristics. In conclusion, this review has provided a comprehensive analysis of the challenges and prospects associated with AC in the elucidation of structure-bioactivity relationships. Furthermore, the importance of exploring modern biotechnology approaches to enhance the potential biomedical applications of AC has been emphasized

    GXM decreases the trans-endothelial electrical resistance (TEER) and transmigration of <i>C</i>. <i>neoformans</i> through HBECs in a blood brain barrier (BBB) model.

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    Graphic representation of the HBECs and pericytes BBB model used for the (A) TEER measurements and (C) HBEC barrier permeability assay and HBEC model used for the (E) fungal transmigration assay. For A and C, HBECs and pericytes were grown separately (HBECs, 0.4 μm pore insert; pericytes, bottom of a well) and co-incubated using a microtiter transwell system that permits chemotactic exchange through the supernatant. (B) Relative TEER of HBECs incubated with GXM (10, 50, or 100 μg/mL) for 5 h at 37°C and 5% CO2. HBECs incubated alone (negative), with EDTA (10 μg/mL; positive), or with mock extract from acapsular strain cap59 (negative) were used as controls. Time points are the averages of the results for three different TEER measurements (n = 3 wells per group per experiment), and error bars denote SDs. Symbols (*, #, ϕ, and x) indicate P value significance (P (D) Relative HBEC barrier permeability to streptavidin-horseradish peroxidase (HRP) after incubation with GXM (10, 50, or 100 μg/mL) for 30 min at 37°C and 5% CO2. HBECs incubated alone (negative), with EDTA (10 μg/mL; positive), or with mock extract (negative) were used as controls. (E) HBECs were cultured for 2 h with 10 μg/mL of GXM in a microtiter transwell system (5 μm pore insert). Then, 105 cryptococci were added to the well and fungal transmigration through the HBECs was determined for 4 h using CFU. (F) CFU determinations after fungal transmigration are shown. HBECs incubated alone or with EDTA (10 μg/mL) were used as negative and positive controls, respectively. For B, D, and F, bars and error bars denote the means and SDs, respectively. Each symbol denotes a single well measurement (n = 3 wells per group for B and D) or CFU determinations from a single well (n = 5 wells per group for F). Asterisks indicate P-value significance (* P P P P < 0.0001) calculated using one-way ANOVA and adjusted using the Tukey’s post-hoc analysis. These experiments were performed thrice, similar results were obtained each time, and all the results combined are presented.</p

    Respiratory epithelial cell types, states and fates in the era of single-cell RNA-sequencing

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    Standalone and consortia-led single-cell atlases of healthy and diseased human airways generated with single-cell RNA-sequencing (scRNA-seq) have ushered in a new era in respiratory research. Numerous discoveries, including the pulmonary ionocyte, potentially novel cell fates, and a diversity of cell states among common and rare epithelial cell types have highlighted the extent of cellular heterogeneity and plasticity in the respiratory tract. scRNA-seq has also played a pivotal role in our understanding of host–virus interactions in coronavirus disease 2019 (COVID-19). However, as our ability to generate large quantities of scRNA-seq data increases, along with a growing number of scRNA-seq protocols and data analysis methods, new challenges related to the contextualisation and downstream applications of insights are arising. Here, we review the fundamental concept of cellular identity from the perspective of single-cell transcriptomics in the respiratory context, drawing attention to the need to generate reference annotations and to standardise the terminology used in literature. Findings about airway epithelial cell types, states and fates obtained from scRNA-seq experiments are compared and contrasted with information accumulated through the use of conventional methods. This review attempts to discuss major opportunities and to outline some of the key limitations of the modern-day scRNA-seq that need to be addressed to enable efficient and meaningful integration of scRNA-seq data from different platforms and studies, with each other as well as with data from other high-throughput sequencing-based genomic, transcriptomic and epigenetic analyses

    LncRNA MIR31HG fosters stemness malignant features of non-small cell lung cancer via H3K4me1- and H3K27Ace-mediated GLI2 expression

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    Non-coding RNAs are responsible for oncogenesis and the development of stemness features, including multidrug resistance and metastasis, in various cancers. Expression of lncRNA MIR31HG in lung cancer tissues and peripheral sera of lung cancer patients were remarkably higher than that of healthy individuals and indicated a poor prognosis. Functional analysis showed that MIR31HG fosters stemness-associated malignant features of non-small cell lung cancer cells. Further mechanistic investigation revealed that MIR31HG modulated GLI2 expression via WDR5/MLL3/P300 complex-mediated H3K4me and H3K27Ace modification. In vivo MIR31HG repression with an antisense oligonucleotide attenuated tumor growth and distal organ metastasis, whereas MIR31HG promotion remarkably encouraged cellular invasion in lung and liver tissues. Our data suggested that MIR31HG is a potential diagnostic indicator and druggable therapeutic target to facilitate multiple strategic treatments for lung cancer patients

    Pegylated Gold Nanoparticles Conjugated with siRNA: Complexes Formation and Cytotoxicity

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    Drug delivery systems such as dendrimers, liposomes, polymers or gold/silver nanoparticles could be used to advance modern medicine. One significant pharmacological problem is crossing biological barriers by commonly used drugs, e.g., in the treatment of neurodegenerative diseases, which have a problem of the blood-brain barrier (BBB) restricting drug delivery. Numerous studies have been conducted to find appropriate drug carriers that are safe, biocompatible and efficient. In this work, we evaluate pegylated gold nanoparticles AuNP14a and AuNP14b after their conjugation with therapeutic siRNA directed against APOE4. This genetic risk factor remains the strongest predictor for late-onset Alzheimer’s disease. The study aimed to assess the biophysical properties of AuNPs/siAPOE complexes and to check their biological safety on healthy cells using human brain endothelial cells (HBEC-5i). Techniques such as fluorescence polarization, circular dichroism, dynamic light scattering, ζ-potential measurements and gel retardation assay showed that AuNPs form stable complexes with siRNA. Subsequently, cytotoxicity assays proved the biological safety of formed conjugates. Obtained results enabled us to find effective concentrations of AuNPs when complexes are formed and non-toxic for healthy cells. One of the studied nanoparticles, AuNP14b complexed with siRNA, displayed lower cytotoxicity (MTT assay, cells viability −74.8 ± 3.1%) than free nanoparticles (44.7 ± 3.6%). This may be promising for further investigations in nucleic acid delivery and could have practical use in treating neurodegenerative diseases

    MDC1 maintains active elongation complexes of RNA polymerase II

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    The role of MDC1 in the DNA damage response has been extensively studied; however, its impact on other cellular processes is not well understood. Here, we describe the role of MDC1 in transcription as a regulator of RNA polymerase II (RNAPII). Depletion of MDC1 causes a genome-wide reduction in the abundance of actively engaged RNAPII elongation complexes throughout the gene body of protein-encoding genes under unperturbed conditions. Decreased engaged RNAPII subsequently alters the assembly of the spliceosome complex on chromatin, leading to changes in pre-mRNA splicing. Mechanistically, the S/TQ domain of MDC1 modulates RNAPII-mediated transcription. Upon genotoxic stress, MDC1 promotes the abundance of engaged RNAPII complexes at DNA breaks, thereby stimulating nascent transcription at the damaged sites. Of clinical relevance, cancer cells lacking MDC1 display hypersensitivity to RNAPII inhibitors. Overall, we unveil a role of MDC1 in RNAPII-mediated transcription with potential implications for cancer treatment

    Air Pollution: Role of Extracellular Vesicles-Derived Non-Coding RNAs in Environmental Stress Response

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    Air pollution has increased over the years, causing a negative impact on society due to the many health-related problems it can contribute to. Although the type and extent of air pollutants are known, the molecular mechanisms underlying the induction of negative effects on the human body remain unclear. Emerging evidence suggests the crucial involvement of different molecular mediators in inflammation and oxidative stress in air pollution-induced disorders. Among these, non-coding RNAs (ncRNAs) carried by extracellular vesicles (EVs) may play an essential role in gene regulation of the cell stress response in pollutant-induced multiorgan disorders. This review highlights EV-transported ncRNAs’ roles in physiological and pathological conditions, such as the development of cancer and respiratory, neurodegenerative, and cardiovascular diseases following exposure to various environmental stressors
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