Chlorolipids are produced during the neutrophil respiratory burst as a result of myeloperoxidase (MPO)-generated hypochlorous acid (HOCl) targeting the vinyl ether bond of plasmalogen phospholipids. The initial products of this reaction are 2-chlorofatty aldehydes (2-ClFALDs), which are subsequently oxidized to 2-chlorofatty acids (2-ClFAs). 2-Chlorohexadecanoic acid (2-ClHA) is the 16-carbon 2-ClFA species, and previous studies have shown that increased levels of plasma 2-ClHA associate with acute respiratory distress syndrome (ARDS)-caused mortality in human sepsis. 2-ClHA causes endothelial barrier dysfunction and increases neutrophil and platelet adherence to the endothelium. In this study, click chemistry analogs of 2-ClHA and hexadecanoic acid (HA) were used to identify proteins covalently modified by 2-ClHA and HA in human lung microvascular endothelial cells (HLMVECs). Eleven proteins were specifically modified by 2-ClHA, and an additional one hundred and ninety-four proteins were modified by both 2-ClHA and HA. STRING analysis of 2-ClHA-modified proteins revealed a network of proteins with RhoA as a hub. RhoA is one of the proteins specifically modified by 2-ClHA and not HA. The RhoA inhibitors, Rhosin and C3, inhibited both 2-ClHA-elicited HLMVEC barrier dysfunction and angiopoietin-2 (Ang-2) release from HLMVEC. Further studies showed 2-ClHA activates HLMVEC RhoA activity. The specificity of the 2-ClHA-RhoA pathway for endothelial activation was further confirmed since HA did not cause HLMVEC barrier dysfunction, Ang-2 release and RhoA activation. Collectively, these studies have identified multiple proteins modified exclusively by 2-ClHA in HLMVECs, including RhoA. These proteomics studies led to the key finding that RhoA is an important mediator of 2-ClHA-caused endothelial barrier dysfunction.

Recent studies show that metabolites, beyond their metabolic roles, can induce significant changes in cell behavior. Herein, we investigate the non-canonical role of nicotinamide (vitamin B3) on glioblastoma (GB) cell behavior. Nicotinamide induced senescence in GB cells, characterized by reduced proliferation, chromatin reorganization, increased DNA damage, enhanced beta-galactosidase activity, and decreased Lamin B1 expression. Nicotinamide-induced senescence was accompanied by an unexpected reprogramming of its metabolism, marked by simultaneous downregulated transcription of NNMT (nicotinamide N-methyltransferase) and NAMPT (nicotinamide phosphoribosyl-transferase). Nicotinamide effects on GB cells were mediated by decreased levels of SOX2. Consistently, analyses of patients' single cell transcriptome datasets showed that GB cells with low NNMT and NAMPT expression levels were enriched in gene modules related to senescence. Remarkably, senescent GB cells retained tumor-forming ability in vivo, albeit to a lesser extent compared to control cells. Further experiments at the single-cell level and transcriptomic analyses demonstrated that nicotinamide-induced senescence in GB cells is fully reversible. Overall, our findings identify a novel reversible senescent state in GB tumors and highlight the non-canonical role of nicotinamide as a key driver of cancer cell plasticity.

Androgen deprivation therapy remains a cornerstone in managing prostate cancer. However, its recurrence often leads to the more aggressive castration-resistant prostate cancer (CRPC). Although second-line androgen receptor signaling inhibition treatments such as enzalutamide and abiraterone are available, their effectiveness against CRPC is only transient. High-dose testosterone (Hi-T) has recently emerged as a promising treatment for CRPC, primarily through the suppression of E2F and MYC signaling. However, the roles of Rb family proteins in influencing this therapeutic response remain debated. In this study, we utilized a CRPC patient-derived xenograft model that includes both Rb pathway-proficient and -deficient cell populations based on the positive or negative expression of RB family genes. Single-cell RNA sequencing analysis revealed that Rb-proficient cells displayed a robust response to Hi-T, whereas Rb-deficient cells exhibited significant resistance. Notably, our analysis indicated increased enrichment of the hypoxia signature in the Rb-deficient cell population. Further studies in RB1-silenced CRPC cell lines showed that treatment with a hypoxia-inducible factor-1α inhibitor can restore the sensitivity of Rb-deficient cells to high-dose dihydrotestosterone treatment. In conclusion, our research provides new molecular insights into CRPC tumor cell responses to Hi-T and proposes a new strategy to resensitize Rb-deficient CRPC cells to Hi-T treatment.

The emergence of resistance to antitumor drugs in cancer cells presents a notable obstacle in cancer therapy. Metabolic reprogramming is characterized by enhanced glycolysis, disrupted lipid metabolism, glutamine dependence and mitochondrial dysfunction. In addition to promoting tumor growth and metastasis, metabolic reprogramming mediates drug resistance through diverse molecular mechanisms, offering novel opportunities for therapeutic intervention. Non‑coding RNAs (ncRNAs), a diverse class of RNA molecules that lack protein‑coding function, represent a notable fraction of the human genome. Due to their distinct expression profiles and multifaceted roles in various cancers, ncRNAs have relevance in cancer pathophysiology. ncRNAs orchestrate metabolic abnormalities associated with drug resistance in cancer cells. The present review provides a comprehensive analysis of the mechanisms by which metabolic reprogramming drives drug resistance, with an emphasis on the regulatory roles of ncRNAs in glycolysis, lipid metabolism, mitochondrial dysfunction and glutamine metabolism. Furthermore, the present review aimed to discuss the potential of ncRNAs as biomarkers for predicting chemotherapy responses, as well as emerging strategies to target ncRNAs that modulate metabolism, particularly in the context of combination therapy with anti‑cancer drugs.

Sorafenib (Sfb) is a multikinase inhibitor regularly used for the management of patients with advanced hepatocellular carcinoma (HCC) that has been shown to increase very modestly life expectancy. We have shown that Sfb inhibits protein synthesis at the level of initiation in cancer cells. However, the global snapshot of mRNA translation following Sorafenib-treatment has not been explored so far. In this study, we performed a genome-wide polysome profiling analysis in Sfb-treated HCC cells and demonstrated that, despite global translation repression, a set of different genes remain efficiently translated or are even translationally induced. We reveal that, in response to Sfb inhibition, translation is tuned, which strongly correlates with the presence of established mRNA cis-acting elements and the corresponding protein factors that recognize them, including DAP5 and ARE-binding proteins. At the level of biological processes, Sfb leads to the translational down-regulation of key cellular activities, such as those related to the mitochondrial metabolism and the collagen synthesis, and the translational up-regulation of pathways associated with the adaptation and survival of cells in response to the Sfb-induced stress. Our findings indicate that Sfb induces an adaptive reprogramming of translation and provides valuable information that can facilitate the analysis of other drugs for the development of novel combined treatment strategies based on Sfb therapy.

Cervical cancer (CC) is the second cause of death by a neoplasia in woman in Mexico. Among the factors that contribute to its development are prolonged infection by a high-risk HPV type and the use of estrogens. It is well known that diagnosis at early stages is extremely important since, in most cases, progression towards carcinogenesis could be prevented, hence the importance of finding candidates that serve as early biomarkers. Several studies have shown that the expression level of the tumor suppressor miR-218 is diminished in CC while oncomiR miR-21 is overexpressed. On the other hand, it has been reported that the Potassium calcium-activated channel subfamily M alpha 1 (Kcnma1) oncogene, a known target gene of miR-218, is overexpressed in CC. However, there are few studies on the expression of this oncogene in Cervical Intraepithelial Neoplasia 1 (CIN 1). In this study, the analysis of the K14E7HPV16 carcinogenesis model in young mice (1.5-month-old), showed that a single-dose of 17β-estradiol (E2) increased both the cell proliferation and the Bcl-2 oncogene expression, as well as promoted the development of CIN 1. Interestingly, the hormonal stress and the E7 expression, favor the physiological response of the organism in transgenic young mice by decreasing the expression levels of the tumor suppressor miR-218 and increasing the expression of the Kcnma1 and Bcl-2 mRNA oncogenes in both, cervical tissue and serum. This work demonstrates the significance of a single E2 stimulation and the expression of the HPV E7 oncoprotein in the early stage of cervical carcinogenesis. In addition, we provide strong evidence about Kcnma1 oncogene as a target gene of miR-218 and that both could be used as early circulating biomarkers of CC.

A hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes.

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.