Cholangiokines: undervalued modulators in the hepatic microenvironment

The biliary epithelial cells, also known as cholangiocytes, line the intra- and extrahepatic bile ducts, forming a barrier between intra- and extra-ductal environments. Cholangiocytes are mostly known to modulate bile composition and transportation. In hepatobiliary diseases, bile duct injury leads to drastic alterations in cholangiocyte phenotypes and their release of soluble mediators, which can vary depending on the original insult and cellular states (quiescence, senescence, or proliferation). The cholangiocyte-secreted cytokines (also termed cholangiokines) drive ductular cell proliferation, portal inflammation and fibrosis, and carcinogenesis. Hence, despite the previous consensus that cholangiocytes are bystanders in liver diseases, their diverse secretome plays critical roles in modulating the intrahepatic microenvironment. This review summarizes recent insights into the cholangiokines under both physiological and pathological conditions, especially as they occur during liver injury-regeneration, inflammation, fibrosis and malignant transformation processes

Cellular Senescence in Hepatocellular Carcinoma: The Passenger or the Driver?

With the high morbidity and mortality, hepatocellular carcinoma (HCC) represents a major yet growing burden for our global community. The relapse-prone nature and drug resistance of HCC are regarded as the consequence of varying intracellular processes and extracellular interplay, which actively participate in tumor microenvironment remodeling. Amongst them, cellular senescence is regarded as a fail-safe program, leading to double-sword effects of both cell growth inhibition and tissue repair promotion. Particularly, cellular senescence serves a pivotal role in the progression of chronic inflammatory liver diseases, ultimately leading to carcinogenesis. Given the current challenges in improving the clinical management and outcome of HCC, senescence may exert striking potential in affecting anti-cancer strategies. In recent years, an increasing number of studies have emerged to investigate senescence-associated hepatocarcinogenesis and its derived therapies. In this review, we intend to provide an up-to-date understanding of liver cell senescence and its impacts on treatment modalities of HCC

CDK4/6 inhibition enhances T-cell immunotherapy on hepatocellular carcinoma cells by rejuvenating immunogenicity

Abstract Hepatocellular carcinoma (HCC) poses a significant clinical challenge, necessitating the integration of immunotherapeutic approaches. Palbociclib, a selective CDK4/6 inhibitor, has demonstrated promising efficacy in preclinical HCC models and is being evaluated as a novel therapeutic option in clinical trials. Additionally, CDK4/6 inhibition induces cellular senescence, potentially influencing the tumor microenvironment and immunogenicity of cancer cells. In this study, we conducted comprehensive bioinformatic analyses using diverse HCC transcriptome datasets, including bulk and single-cell RNA-sequencing data from public databases. We also utilized human and mouse HCC cells to investigate functional aspects. Primary T cells isolated from mouse blood were employed to assess T cell immunity against HCC cells. Results revealed that CD8+ T-cell infiltration correlates with improved outcomes in HCC patients with suppressed CDK4/6 expression. Moreover, CDK4/6 expression was associated with alterations in the immune landscape and immune checkpoint expression within the liver tumor microenvironment. Furthermore, we found that treatment with Palbociclib and Doxorubicin induces cellular senescence and a senescence-associated secretory phenotype in HCC cells. Notably, pretreatment with Palbociclib augmented T cell-mediated cytotoxicity against HCC cells, despite upregulation of PD-L1, surpassing the effects of Doxorubicin pretreatment. In conclusion, our study elucidates a novel mechanism by which CDK4/6 inhibition enhances T-cell-associated cancer elimination and proposes a potential therapeutic strategy to enhance T-cell immunotherapy on HCC. Graphical abstrac

Genome-wide identification, classification, and expression analysis of the HSF gene family in pineapple (Ananas comosus)

Transcription factors (TFs), such as heat shock transcription factors (HSFs), usually play critical regulatory functions in plant development, growth, and response to environmental cues. However, no HSFs have been characterized in pineapple thus far. Here, we identified 22 AcHSF genes from the pineapple genome. Gene structure, motifs, and phylogenetic analysis showed that AcHSF families were distinctly grouped into three subfamilies (12 in Group A, seven in Group B, and four in Group C). The AcHSF promoters contained various cis-elements associated with stress, hormones, and plant development processes, for instance, STRE, WRKY, and ABRE binding sites. The majority of HSFs were expressed in diverse pineapple tissues and developmental stages. The expression of AcHSF-B4b/AcHSF-B4c and AcHSF-A7b/AcHSF-A1c were enriched in the ovules and fruits, respectively. Six genes (AcHSF-A1a , AcHSF-A2, AcHSF-A9a, AcHSF-B1a, AcHSF-B2a, and AcHSF-C1a) were transcriptionally modified by cold, heat, and ABA. Our results provide an overview and lay the foundation for future functional characterization of the pineapple HSF gene family

Characterization of germline development and identification of genes associated with germline specification in pineapple

Understanding germline specification in plants could be advantageous for agricultural applications. In recent decades, substantial efforts have been made to understand germline specification in several plant species, including Arabidopsis, rice, and maize. However, our knowledge of germline specification in many agronomically important plant species remains obscure. Here, we characterized the female germline specification and subsequent female gametophyte development in pineapple using callose staining, cytological, and whole-mount immunolocalization analyses. We also determined the male germline specification and gametophyte developmental timeline and observed male meiotic behavior using chromosome spreading assays. Furthermore, we identified 229 genes that are preferentially expressed at the megaspore mother cell (MMC) stage during ovule development and 478 genes that are preferentially expressed at the pollen mother cell (PMC) stage of anther development using comparative transcriptomic analysis. The biological functions, associated regulatory pathways and expression patterns of these genes were also analyzed. Our study provides a convenient cytological reference for exploring pineapple germline development and a molecular basis for the future functional analysis of germline specification in related plant species

Brassinosteroid signaling regulates female germline specification in Arabidopsis

Unlike in humans and animals, plant germlines are specified de novo from somatic cells in the reproductive organs of the flower. In most flowering plant ovules, the female germline starts with the differentiation of one megaspore mother cell (MMC), which initiates a developmental program distinct from adjoining cells. Phytohormones act as a key player in physiological processes during plant development, in particular by providing positional information that supports localized differentiation events. However, little is known about the role of phytohormones for female germline initiation and establishment. Using Arabidopsis as a flowering plant model, we show that brassinosteroid (BR) biosynthesis and signaling components are accumulated in sporophytic cells of ovule primordia but not in the megaspore mother cell representing the precursor of the female germline. We further demonstrate that BR signaling restricts multiple sub-epidermal cells in the distal nucellus region of ovule primordia from acquiring MMC-like cell identity by transiently activating the WRKY23 transcription factor, expressed exclusively in L2 layer cells adjacent to the MMC. This activation is regulated through the BRI1 receptor and directly by the BZR1 transcriptional repressor family. Mutations in BR biosynthesis or signaling components and ectopic activation of BR signaling in MMCs induce multiple MMC-like cells. In summary, our findings elucidate a gene regulatory network that shows how the hormone BR generated in sporophytic ovule primordia cells restricts the origin of the female germline to a single cell

The bZIP Transcription Factor GmbZIP15 Negatively Regulates Salt- and Drought-Stress Responses in Soybean

Soybean (Glycine max), as an important oilseed crop, is constantly threatened by abiotic stress, including that caused by salinity and drought. bZIP transcription factors (TFs) are one of the largest TF families and have been shown to be associated with various environmental-stress tolerances among species; however, their function in abiotic-stress response in soybean remains poorly understood. Here, we characterized the roles of soybean transcription factor GmbZIP15 in response to abiotic stresses. The transcript level of GmbZIP15 was suppressed under salt- and drought-stress conditions. Overexpression of GmbZIP15 in soybean resulted in hypersensitivity to abiotic stress compared with wild-type (WT) plants, which was associated with lower transcript levels of stress-responsive genes involved in both abscisic acid (ABA)-dependent and ABA-independent pathways, defective stomatal aperture regulation, and reduced antioxidant enzyme activities. Furthermore, plants expressing a functional repressor form of GmbZIP15 exhibited drought-stress resistance similar to WT. RNA-seq and qRT-PCR analyses revealed that GmbZIP15 positively regulates GmSAHH1 expression and negatively regulates GmWRKY12 and GmABF1 expression in response to abiotic stress. Overall, these data indicate that GmbZIP15 functions as a negative regulator in response to salt and drought stresses

A Bright Squeezed Light Source for Quantum Sensing

The use of optical sensing for in vivo applications is compelling, since it offers the advantages of non-invasiveness, non-ionizing radiation, and real-time monitoring. However, the signal-to-noise ratio (SNR) of the optical signal deteriorates dramatically as the biological tissue increases. Although increasing laser power can improve the SNR, intense lasers can severely disturb biological processes and viability. Quantum sensing with bright squeezed light can make the measurement sensitivity break through the quantum noise limit under weak laser conditions. A bright squeezed light source is demonstrated to avoid the deterioration of SNR and biological damage, which integrates an external cavity frequency-doubled laser, a semi-monolithic standing cavity with periodically poled titanyl phosphate (PPKTP), and a balanced homodyne detector (BHD) assembled on a dedicated breadboard. With the rational design of the mechanical elements, the optical layout, and the feedback control equipment, a maximum non-classical noise reduction of −10.7 ± 0.2 dB is observed. The average squeeze of −10 ± 0.2 dB in continuous operation for 60 min is demonstrated. Finally, the intracavity loss of degenerate optical parametric amplifier (DOPA) and the initial bright squeezed light can be calculated to be 0.0021 and −15.5 ± 0.2 dB, respectively. Through the above experimental and theoretical analysis, the direction of improving bright squeeze level is pointed out