Taraxacum mongolicum is rich in phenolic acids and is widely utilized in food and medicine globally. Our previous research demonstrated that the abscisic acid (ABA) hormone significantly enhances chicoric acid accumulation in T. mongolicum. SNF1-related protein kinase 2s (SnRK2s) are extensively involved in ABA signaling and have the potential to regulate the biosynthesis of phenolic acids.

The premature senescence of retinal pigment epithelium (RPE) plays a significant role in the development of age-related macular degeneration. This study aimed to investigate the potential protective effect of Lycium barbarum polysaccharide (LBP) against H2O2-induced premature senescence and to elucidate the underlying mechanisms. The ARPE-19 cell line was subjected to H2O2 exposure to create a model of premature senescence. The modulation of microRNA-34a-5p expression was accomplished using antagomir and agomir, as assessed by quantitative real-time polymerase chain reaction. The senescence model was successfully established by treating cells with 200 μM H2O2 for 2 hours daily over a span of three consecutive days. This oxidative stress resulted in a notable increase in the proportion of senescence-associated beta-galactosidase-positive cells, reaching 33.5%, without significant alterations in cell viability or apoptosis. In the ARPE-19 cells undergoing premature senescence, there was a marked increase in reactive oxygen species (ROS) production and malondialdehyde levels, coupled with a significant decrease in the activity of total superoxide dismutase, glutathione peroxidase, and catalase. Additionally, microRNA-34a-5p was found to be overexpressed in these cells. Treatment with LBP alleviated H2O2-induced premature senescence, diminished the overexpression of microRNA-34a-5p, and suppressed ROS production. Moreover, the incubation with ago-34a reversed the protective effect of LBP in ARPE-19 cells. In conclusion, the overexpression of microRNA-34a-5p contributes to the H2O2-induced premature senescence of ARPE-19 cells. LBP appears to mitigate this premature senescence, at least in part, by downregulating microRNA-34a-5p expression and reducing oxidative stress.

To investigate the effect and molecular mechanism of ezetimibe on colorectal cancer (CRC), our study found that ezetimibe significantly inhibited the proliferation and progression of CRC. Further study showed that RPS6KA2 might be the target gene of ezetimibe treatment on CRC. RPS6KA2 expression was significantly lower in human CRC tissue samples and associated with T classification and vascular invasion of tumor cells. RPS6KA2 inhibited proliferation, migration, and invasion of CRC cells. The underlying mechanisms indicated that interaction between RPS6KA2 and PCSK9 was observed within the cytoplasmic compartment of CRC cells. RPS6KA2 suppressed PCSK9 and MAPK signaling pathway in CRC cells. BI-D1780 which is an inhibitor of RPS6KA2 increased PCSK9 and MAPK signaling pathway related proteins expression in SW620 cells. However, an inhibitor or stimulator of MAPK did not affect RPS6KA2 and PCSK9 expression, respectively. In vivo, CRC cells with RPS6KA2 or PCSK9 overexpression could inhibit or promote tumor growth and metastasis, respectively. PCSK9 promoted proliferation, migration, and invasion of CRC cells. PCSK9 expression was higher in human CRC samples and associated with N classification and TNM stage of CRC. In conclusion, our study firstly suggests that ezetimibe suppresses CRC progression by upregulating RPS6KA2 while downregulating PCSK9/MAPK signaling pathway.

The morphological intricacies of avian feathers make them an ideal model for investigating embryonic patterning and morphogenesis. In particular, the sonic hedgehog (Shh) pathway is an important mediator of feather outgrowth and branching. However, functional in vivo evidence regarding its role during feather development remains limited. Here, we demonstrate that an intravenous injection of sonidegib, a potent Shh pathway inhibitor, at embryonic day 9 (E9) temporarily produces striped domains (instead of spots) of Shh expression in the skin, arrests morphogenesis, and results in unbranched and non-invaginated feather buds-akin to proto-feathers-in embryos until E14. Although feather morphogenesis partially recovers, hatched treated chickens exhibit naked skin regions with perturbed follicles. Remarkably, these follicles are subsequently reactivated by seven weeks post-hatching. Our RNA-sequencing data and rescue experiment using Shh-agonism confirm that sonidegib specifically down-regulates Shh pathway activity. Overall, we provide functional evidence for the role of the Shh pathway in mediating feather morphogenesis and confirm its role in the evolutionary emergence and diversification of feathers.

Sorafenib has demonstrated great efficacy in liver cancer, however, its application as first-line treatment has been hampered due to the emerging drug resistance. This study is aimed to investigate the mechanism underlying acquired sorafenib resistance in liver cancer. Based on GSE109211 and TCGA datasets, bioinformatics analysis was conducted to find the potential genes implicated in the sorafenib resistance in liver cancer. mCherry-/eGFP-LC3B dual-fluorescent system was used to assess autophagic state. Wild and mutant types of HA-labeled ubiquitin (K27, K29, K33, K48, K63, K29R and K48R) were used to identify the type of polyubiquitin chains added to p27 by CUL1. Herein, we identified that F-box protein (SCF) ubiquitin ligase complexes (CUL1 and SKP2) and NEDD8 were highly expressed in sorafenib-resistant tissues using both the public data and clinical samples. NEDD8-mediated CUL1 neddylation enhanced SCF ubiquitin ligase complex to target p27 and subsequently linked K29-linked polyubiquitin chains to p27. Furthermore, NBR1 facilitated the degradation of ubiquitinated p27 protein by enhancing autophagy flux. Knocking down of CUL1 could prevent ubiquitination- and autophagy-mediated p27 protein degradation. The resistance to sorafenib was suppressed with CUL1 knockdown both in vitro and in vivo. In conclusion, our findings indicated that blocking neddylation or autophagy can restore drug sensitivity, thus providing a potential strategy for overcoming sorafenib resistance in the future.

The increase in tocopherol (vitamin E) biosynthesis in Arabidopsis during drought and osmotic stress, but not during high light or nitrogen deprivation, is mediated by abscisic acid. Plants increase the production of antioxidants including tocochromanols (vitamin E) during stress. To study the regulation of tocochromanol synthesis, Arabidopsis plants were exposed to drought, osmotic stress stimulated by polyethylene glycol, abscisic acid (ABA), nitrogen deprivation, and high light. ABA treatment resulted in increased contents of tocochromanols, and expression of the key tocopherol biosynthesis genes VTE2 and HPPD was upregulated, indicating that tocochromanol accumulation was regulated by ABA. Under drought and osmotic stress, the ABA and tocochromanol contents as well as VTE2 and HPPD expression were also increased. ABA levels did not change during nitrogen deprivation or high light treatment, indicating that tocochromanol accumulation under these conditions was ABA-independent. Tocochromanol accumulation during drought or osmotic stress was not compromised in the ABA-deficient aba1-6, aba2-1 and aba3-2 mutants, suggesting that tocochromanol synthesis under these conditions was mostly regulated in an ABA-independent way. Therefore, the accumulation of tocochromanols in Arabidopsis can be regulated by ABA-dependent and ABA-independent signaling pathways, based on the specific conditions.

Despite the identification of numerous therapeutic targets in lung cancer, achieving significant efficacy has been challenging. TNFRSF21 plays an important role in various cancers. We investigated the function of TNFRSF21 in lung adenocarcinoma (LUAD).

Terpinen-4-ol (T4O), a key constituent of tea tree essential oil and various aromatic plants, has shown promising antiproliferative and pro-apoptotic effects in melanoma and other cancer types. However, its efficacy against cutaneous squamous cell carcinoma (cSCC) remains unclear. Thus, in this study, we investigated the in vivo and in vitro effects of T4O on cSCC cell lines and preliminarily explored its impacting pathways.

The high incidence of cardiovascular events in chronic kidney disease (CKD) exhibits an epidemic character, affecting patients in predialysis, hemodialysis, and post-transplant stages, accounting for approximately 50% of deaths, with a mortality rate around 9% per year. Statins are primarily used in the treatment of dyslipidemia and possess pleiotropic effects that are not yet fully understood. Moreover, there is insufficient evidence to support their use in attenuating cardiovascular outcomes or their potential role in modulating the ABCA-1 transporter in CKD. Thus, the aim of this study was to investigate the effect of statins on ABCA-1 modulation in cultures of human umbilical vein endothelial cells (HUVEC) incubated with uremic serum from CKD patients. The results demonstrate that statins influence the inflammatory response of HUVEC exposed to a uremic environment by reducing TNF-α secretion compared to baseline levels. Furthermore, the uremic environment was found to decrease the expression of LxR-β and RxR-α, leading to a consequent reduction in ABCA-1 expression in HUVEC. Cells pre-treated with simvastatin exhibited increased expression of ABCA-1, LxR-β, and RxR-α, along with a significant increase in the transcription of ABCA-1, LXR-β, and RxR-α, indicating that statins may exert a positive modulation on LxR-β and RxR-α receptors, activating ABCA-1 transcription.

Antimony (Sb), a non-essential heavy metal, exerts severe toxic effects on the growth and development of plants. This study investigated the response of Brassica napus to Sb(III) stress under hydroponic conditions, focusing on Sb accumulation, physiological indexes, and transcriptome sequencing. Sb accumulation in different B. napus varieties showed consistent trends with physiological indicators (SOD, POD, CAT, MDA) in XZY512 root tissue. Both parameters increased with Sb concentration, reaching a peak at 75 mg/L before declining, suggesting that 75 mg/L Sb may be the optimal concentration for B. napus adaptation. Transcriptomic analysis identified 8,802 genes in root tissues and 13,612 genes in leaf tissues responsive to Sb stress, predominantly involved in oxidative stress responses, ABC transporters, glutathione metabolism, plant hormone signaling, and MAPK pathways. Physiological index changes were associated with upregulation of genes linked to antioxidants, including as CATs, GPXs, PERs, and GSTUs, in root tissues, whereas photosynthesis-related genes were mostly downregulated in leaf tissues. This work shows the potential of B. napus for phytoremediation efforts and offers important insights into its response mechanisms to Sb stress.

In recent years, abiotic stresses, including droughts, floods, high temperatures, and salinity, have become increasingly frequent and severe. These stresses significantly hinder crop yields and product quality, posing substantial challenges to sustainable agriculture and global food security. Simultaneously, the rapidly growing global population exacerbates the need to enhance crop production under worsening environmental conditions. Consequently, the development of effective strategies to strengthen the resilience of crop plants against high temperatures, water scarcity, and extreme environmental conditions is critical for mitigating the impacts of abiotic stress. Plants respond to these environmental challenges by reprogramming their transcriptome and metabolome. Common strategies for developing stress-tolerant plants include screening germplasm, generating transgenic crop plants, and employing genome editing techniques. Recently, chemical treatment has emerged as a promising approach to enhance abiotic stress tolerance in crops. This technique involves the application of exogenous chemical compounds that induce molecular and physiological changes, thereby providing a protective shield against abiotic stress. Forward and reverse genetic approaches have facilitated the identification of chemicals capable of modulating plant responses to abiotic stresses. These priming agents function as epigenetic regulators, agonists, or antagonists, playing essential roles in regulating stomatal closure to conserve water, managing cellular signaling through reactive oxygen species and metabolites to sustain plant growth, and activating gluconeogenesis to enhance cellular metabolism. This review summarizes recent advancements in the field of chemical priming and explores strategies to improve stress tolerance and crop productivity, thereby contributing to the enhancement of global food security.

Bordetella pertussis infects human upper airways and deploys an array of immunosuppressive virulence factors, among which the adenylate cyclase toxin (CyaA) plays a prominent role in disarming host phagocytes. CyaA binds the complement receptor-3 (CR3 aka αMβ2 integrin CD11b/CD18 or Mac-1) of myeloid cells and delivers into their cytosol an adenylyl cyclase enzyme that hijacks cellular signaling through unregulated conversion of cytosolic ATP to cAMP. We found that the action of as little CyaA as 22 pM (4 ng/mL) blocks macrophage colony-stimulating factor (M-CSF)-driven transition of migratory human CD14+ monocytes into macrophages. Global transcriptional profiling (RNAseq) revealed that exposure of monocytes to 22 pM CyaA for 40 hours in culture with 20 ng/mL of M-CSF led to upregulation of genes that exert negative control of monocyte to macrophage differentiation (e.g., SERPINB2, DLL1, and CSNK1E). The sustained CyaA action yielded downregulation of numerous genes involved in processes crucial for host defense, such as myeloid cell differentiation, chemotaxis of inflammatory cells, antigen presentation, phagocytosis, and bactericidal activities. CyaA-elicited signaling also promoted deacetylation and trimethylation of lysines 9 and 27 of histone 3 (H3K9me3 and H3K27me3) and triggered the formation of transcriptionally repressive heterochromatin patches in the nuclei of CyaA-exposed monocytes. These effects were partly reversed by the G9a methyltransferase inhibitor UNC 0631 and by the pleiotropic HDAC inhibitor Trichostatin-A, revealing that CyaA-elicited epigenetic alterations mediate transcriptional reprogramming of monocytes and play a role in CyaA-triggered block of monocyte differentiation into bactericidal macrophage cells.IMPORTANCETo proliferate on host airway mucosa and evade elimination by patrolling sentinel cells, the whooping cough agent Bordetella pertussis produces a potently immunosubversive adenylate cyclase toxin (CyaA) that blocks opsonophagocytic killing of bacteria by phagocytes like neutrophils and macrophages. Indeed, chemotactic migration of CD14+ monocytes to the infection site and their transition into bactericidal macrophages, thus replenishing the exhausted mucosa-patrolling macrophages, represents one of the key mechanisms of innate immune defense to infection. We show that the cAMP signaling action of CyaA already at a very low toxin concentration triggers massive transcriptional reprogramming of monocytes that is accompanied by chromatin remodeling and epigenetic histone modifications, which block the transition of migratory monocytes into bactericidal macrophage cells. This reveals a novel layer of toxin action-mediated hijacking of functional differentiation of innate immune cells for the sake of mucosal pathogen proliferation and transmission to new hosts.

In plants, basic-region/leucine-zipper (bZIP) transcription factors are key regulators of stress responses mediated by various phytohormone signalling pathways. However, the roles of bZIP transcription factors in pepper, particularly those associated with ABA signalling and drought stress, remain poorly understood. In this study, we isolated the CaADBZ1 (Capsicum annuum ABA and Dehydration-Induced bZIP transcription factor 1) gene, a member of the group A family, and analysed its functions in response to dehydration stress and ABA signalling. The expression of CaADBZ1 was specifically induced by dehydration and exogenous ABA treatment, not salinity and osmotic stress. CaADBZ1 was found to have transactivation activity in yeast cells, which was dependent on the N-terminal of CaADBZ1 (amino acids 1-112), harbouring a highly conserved C1 domain. Notably, a dual-luciferase reporter assay revealed that CaADBZ1 modulated the expression of CaOSR1, a dehydration stress-responsive gene in pepper plants. Functional studies in both pepper and Arabidopsis plants revealed that the modulation of CaADBZ1 expression level affected dehydration stress resistance in pepper and Arabidopsis plants. CaADBZ1-silenced pepper Arabidopsis plants showed dehydration stress-sensitive phenotypes characterized by higher transpiration rates and reduced expression of dehydration-responsive genes compared to control plants. Conversely, overexpression of the CaADBZ1 gene in Arabidopsis plants enhanced dehydration stress resistance. Moreover, CaADBZ1-overexpressing Arabidopsis transgenic plants showed increased ABA sensitivity during the seedling stage. Collectively, our findings suggest that CaADBZ1 plays a crucial role in enhancing dehydration stress tolerance in plants by positively regulating ABA sensitivity and dehydration-responsive gene expression.

As antibiotic resistance escalates into a global health crisis, novel therapeutic approaches against infectious diseases are in urgent need. Pseudomonas aeruginosa, an adaptable opportunistic pathogen, poses substantial challenges in treating a range of infections. The quorum-sensing (QS) system plays a pivotal role in orchestrating the production of a large set of virulence factors in a cell density-dependent manner, and the anti-virulence strategy targeting QS may show huge potential. Here, we present a comprehensive investigation into the potential of the synthesized compound 3-(benzo[d][1,3]dioxol-4-yl)oxazolidin-2-one (OZDO, C10H9NO4) as a QS inhibitor to curb the virulence of P. aeruginosa. By employing an integrated approach encompassing in silico screening, in vitro and in vivo functional identification, we elucidated the multifaceted effects of OZDO. Molecular docking predicted that OZDO interfered with three core regulatory proteins of P. aeruginosa QS system. Notably, OZDO exhibited significant inhibition on the production of pyocyanin, rhamnolipid and extracellular proteases, biofilm formation, and cell motilities of P. aeruginosa. Transcriptomic analysis and quantitative real-time PCR displayed the down-regulation of QS-controlled genes in OZDO-treated PAO1, reaffirming the QS-inhibition activity of OZDO. In vivo assessments using a Caenorhabditis elegans-infection model demonstrated OZDO mitigated P. aeruginosa pathogenicity, particularly against the hypervirulent strain PA14. Moreover, OZDO in combination with polymyxin B and aztreonam presented a promising avenue for innovative anti-infective therapy. Our study sheds light on the multifaceted potential of OZDO as an anti-virulence agent and its significance in combating P. aeruginosa-associated infections.

Light is an essential environmental factor that facilitates the robust upward growth of post-germinative seedlings emerging from buried seeds that is partly mediated by the photoreceptors. Salinity stress hampers plant growth and development and reduces yield. However, the involvement and regulatory role of photoreceptors and light signaling factors to salt stress are largely unknown. Here, we report that mutants of the phytochrome B (phyB) photoreceptor showed reduced sensitivity to salt-inhibited hypocotyl elongation in darkness, and that PHYTOCHROME-INTERACTING FACTOR 3 (PIF3) acts downstream of phyB in regulating this process in Arabidopsis thaliana. We also show that SALT OVERLY SENSITIVE 2 (SOS2) regulates phyB protein accumulation under salt stress in darkness. Surprisingly, salt treatment induces phyB nuclear body formation in darkness. Moreover, we found that the phosphorylation at residue Ser-86 of phyB is essential for its function, and the scaffold protein 14-3-3κ is involved in the regulation of phyB under salt stress in darkness. Taken together, our study reveals a regulatory role of the phyB-PIF3 module in mediating post-germination growth in darkness in response to salt stress.

Psilocybin, a psychedelic compound found in specific hallucinogenic mushrooms, is known to induce changes in visual perception and experience in humans. However, there is little knowledge of the molecular mechanisms through which psilocybin affects vision-associated regions in the brain, such as the visual cortex. The current study determined both psilocybin-induced and experience-dependent changes (exposure to light) in visual cortex gene expression in mice. Of great interest, psilocybin induced robust gene expression changes in the visual cortex that closely mirror light-induced gene expression changes, even when the mice are kept in the dark. These gene expression changes correspond to specific molecular pathways, including synaptic functioning, and represent genes expressed in specific subtypes of neurons. In addition, exposure to both psilocybin and light induced synergetic changes in genes involved in epigenetic programming. Overall, the study determined that psilocybin induces robust changes in gene expression in the visual cortex that may have functional consequences in visual perception both in the absence and in synergy with visual experience.

Ovarian cancer is a gynecological malignancy with the highest recurrence and mortality rates. Although niraparib can effectively affect its progression, the challenge of drug resistance remains. Herein, niraparib-resistant ovarian cancer cell lines were constructed to identify the abnormally activated enhancers and associated target genes via RNA in situ conformation sequencing. Notably, the target gene RAD23A was markedly upregulated in niraparib-resistant cells, and inhibiting RAD23A restored their sensitivity. Additionally, abnormal activation of glycolysis in niraparib-resistant cells induced lactate accumulation, which promoted the lactylation of histone H4K12 lysine residues. Correlation analysis showed that key glycolysis enzymes such as pyruvate kinase M and lactate dehydrogenase A were significantly positively correlated with RAD23A expression in ovarian cancer. Additionally, H4K12la activated the super-enhancer (SE) of niraparib and RAD23A expression via MYC transcription factor, thereby enhancing the DNA damage repair ability and promoting the drug resistance of ovarian cancer cells. Overall, the findings of this study indicate that lactic acid accumulation leads to lactylation of histone H4K12la, thereby upregulating SE-mediated abnormal RAD23A expression and promoting niraparib resistance in ovarian cancer cells, suggesting RAD23A as a potential therapeutic target for niraparib-resistant ovarian cancer.

The complete dormancy release determines the quality of bud break, flowering and fruiting. While in tree peony (Paeonia suffruticosa Andr.), the insufficient accumulation of cold temperatures results in incomplete dormancy release and poor flowering quality.

Breast cancer cells have the propensity to metastasize to bone, resulting in altered growth, chemoresistance, and causing skeletal failures, often leading to death in patients. There is a scarcity of effective therapeutics for bone metastasized breast cancer due to the lack of accurate drug screening metastasis models. We utilize a unique 3D in vitro nano clay-based scaffold model as a testbed for bone metastatic breast cancer for drug screening applications. Rhodiola crenulata, a Tibetan plant-based extract, has been previously explored for primary-site breast cancer. However, its effect on bone metastasized breast cancer cells is unknown. In the present study, we evaluated the cytotoxicity of R. crenulata extract on bone metastatic breast cancer using testbeds and compared the results with 2D cultured cells. We observed that R. crenulata induced apoptosis in bone metastasized breast cancer cells grown on a 3D in vitro testbed by upregulating pro-apoptotic proteins, p53, and caspase-9. Alternatively, we observed that bone cells remain unaffected by the treatment of R. crenulata. For the first time, we demonstrated the anticancer capabilities of R. crenulata against bone metastasis of breast cancer. R. crenulata is a robust therapeutic candidate for bone metastasis, shown to induce death in bone metastatic breast cancer while unaffecting healthy bone.

Studies have demonstrated that sialylation changes play a vital part in lung adenocarcinoma (LUAD), yet the specific mechanism is uncertain. Hence, in the present research, we screened sialylation-related biomarkers in LUAD using the bioinformatic strategy, predicted the drugs and performed relevant experiments to explore their role in regulating LUAD. The TCGA-LUAD, GSE31210, and GSE13213 datasets were combined to form LUAD ensemble. The sialylation-related genes (SRGs) linked with LUAD prognosis were determined by univariate Cox regression analysis, and their expressions and mutations in LUAD were analyzed in GSCA database. Then, depending on the consistent clustering of prognostic SRGs, LUAD patients were divided into sialylation-related subgroups, followed by the investigation of survival, immunity, and clinical characteristics in the subgroups. LASSO regression analysis was further employed to identify prognostic gene signatures and to build a sialylation-related model to predict the prognosis of LUAD patients. The gene signature were validated using RT-qPCR and used for predicting target medicines using molecular docking to further investigate the potential therapies for LUAD patients. A total of 26 SRGs in LUAD ensemble were associated with prognosis, and LUAD samples were classified into two sialylation-related subgroups based on these SRGs. Intergroup comparisons revealed that patients in Cluster A had greater survival rates, as well as higher immune infiltration. The risk prognostic model built based on 6 prognostic gene signature was able to effectively predict the survival of LUAD patients. Finally, the experimental findings indicated that Troxerutin exhibits a strong binding energy to the sialylation-related gene EGLN3, which could greatly reduce the growth of LUAD by inhibiting the expression of EGLN3, thus limiting the capacity of LUAD cells in the proliferation, migration, and invasion. Troxerutin could target and lower the expression of sialylation-related gene EGLN3, reducing LUAD cells' ability to proliferate, migrate, and invade, making it an essential reference for LUAD prevention and treatment.