Axitinib resistance remains a serious challenge in the treatment of advanced renal cell carcinoma (RCC), and the underlying mechanisms are not fully understood. Here, we constructed an in vivo axitinib-resistant RCC model and identified the long non-coding RNA STX17-DT as a driver of therapy resistance in RCC. The expression of STX17-DT was significantly elevated in axitinib-resistant RCC cells and correlated with poorer prognosis in RCC patients. Elevated levels of STX17-DT contributed to the development of resistance to axitinib both in vitro and in vivo. Mechanistically, STX17-DT modulated the stability of IFI6 mRNA by recruiting and binding to hnRNPA1, leading to decreased accumulation of mitochondrial reactive oxygen species (ROS) and attenuated ferroptosis. Meanwhile, STX17-DT was packaged into extracellular vesicles through hnRNPA1, thus transmitting axitinib resistance to other cells. Compared with axitinib monotherapy, combined treatment of axitinib and STX17-DT-targeted in vivo siRNA demonstrated enhanced therapeutic efficacy. These findings indicate a novel molecular mechanism of axitinib resistance in RCC and suggest that STX17-DT may serve as a prognostic indicator and potential therapeutic target to overcome resistance to targeted therapy.

Cancer-associated fibroblasts (CAFs) play a key role in oxaliplatin resistance in pancreatic ductal adenocarcinoma (PDAC). However, the potential mechanisms by which CAFs promote chemotherapy resistance have not yet been explored. In this study, we found that circABCC4 (hsa_circ_0030582) was positively correlated with poor platinum-chemotherapeutic response and a shorter progression-free survival (PFS) time in late-stage PDAC patients. CircABCC4 enhanced the ability of CAFs to induce oxaliplatin resistance in pancreatic cancer cells through glycolysis reprogramming. Mechanistically, circABCC4 enhanced the interaction between PKM2 and KPNA2 to promote PKM2 nuclear translocation in CAFs, leading to the transcription of glycolysis-related genes. The glycolytic reprogramming of CAFs promoted the secretion of IL-8, which in turn enhanced DNA damage repair in pancreatic cancer. Blocking PKM2 nuclear translocation abolished circABCC4-driven oxaliplatin resistance of pancreatic cancer in vivo. Collectively, our study reveals a circRNA-mediated glycolysis reprogramming of CAFs to induce oxaliplatin resistance and highlights circABCC4 as a potential therapeutic target.

Depression, often stress-induced, is closely related to neuroinflammation, in which microglia, the brain's immune cells, are the leading players. Microglia shift between a quiescent and an active state, promoting both pro- and anti-inflammatory responses. Cannabinoid type 2 (CB2) receptor encoded by the CNR2 gene is a key player to modulate inflammatory activity. CB2 receptor is highly controlled at the epigenetic level, especially in response to stressful stimuli, positioning it between stress, neuroinflammation, and depression. The following review addresses how epigenetic regulation of CNR2 expression affects depression and the dissection, further, of molecular pathways driving neuroinflammation-related depressive states. The present study emphasizes the therapeutic potential of CB2 receptor agonists that selectively interact with activated microglia and opens a new avenue for the treatment of depression associated with neuroinflammation. The review, therefore, provides a framework of underlying mechanisms for developing novel therapeutic strategies that focus on relieving symptoms by modulating the neuroinflammatory response. Finally, this review underlines the possibilities of therapeutic interventions taking into account CB2 receptors in combating depression.

Epigenetics is currently considered the investigation of inheritable changes in gene expression that do not rely on DNA sequence alteration. Significant epigenetic procedures are involved, such as DNA methylations, histone modifications, and non-coding RNA actions. It is confirmed through several investigations that epigenetic changes are associated with the formation, development, and metastasis of various cancers, such as colorectal cancer (CRC). The difference between epigenetic changes and genetic mutations is that the former could be reversed or prevented; therefore, cancer treatment and prevention could be achieved by restoring abnormal epigenetic events within the neoplastic cells. These treatments, consequently, cause the anti-tumour effects augmentation, drug resistance reduction, and host immune response stimulation. In this article, we begin our survey by exploring basic epigenetic mechanisms to understand epigenetic tools and strategies for treating colorectal cancer in monotherapy and combination with chemotherapy or immunotherapy.

Soil salinization represents the most prevalent abiotic stress, severely impacting a severe impact on plant growth and crop yield. Consequently, delving into the mechanism through which exogenous substances enhance plant salt tolerance holds significant importance for the stabilization and augmentation of crop yield.

Epigenetic dysregulation is prevalent in human cancers, affecting gene expression and metabolic patterns to meet the demands of malignant evolution and abnormal epigenetic processes, and resulting in a protumor immune microenvironment. Tumors require a steady supply of methionine for maintaining epigenetic flexibility, which is the only exogenous precursor of methyl donor S-adenosylmethionine for methylation, crucial for their resistance to therapies and survival in a nutrient-deficient microenvironment. Thus, tumor cells upregulate the Lat4 transporter to compete and deprive methionine in the microenvironment, sustaining their malignant phenotypes and also impairing immune cell functions. Addressing this methionine addiction is the key to overcoming drug resistance and improving immune response. Despite the challenge of lacking specific Lat4 inhibitors, an oxaliplatin prodrug crosslinked fluorinated polycation/anti-Lat4 small interfering RNA complex nanoregulator (AS-F-NP) has been designed and developed here. This nanoregulator restricted the greedy methionine uptake of tumor cells by knocking down Lat4, which in turn inhibited the malignant evolution of the tumor while restoring the viability and function of tumor-infiltrating immune cells.

Multiple myeloma (MM) is a hematological malignancy with the proliferation of malignant plasma cells. Numerous studies have highlighted the critical role of ferroptosis in MM. However, how to use ferroptosis-related genes (FRGs) for prognostic prediction and treatment guidance in MM remains unknown.

3-hydroxy-3-methylglutaryl-coenzymOHBe A(HMG-CoA) lyase (HMGCL) catalyzes the cleavage of HMG-CoA into acetyl-CoA and acetoacetic acid and serves as a rate-limiting enzyme in the metabolism of ketone bodies. While HMGCL is involved in various biological processes, its specific role in osteosarcoma remains unclear.

Malignant mesothelioma (MM) is a rare and aggressive form of cancer that affects the mesothelial surfaces, associated with exposure to asbestos fibres. To date, no cure is available for MM and therapeutically approved treatments are based on the use of platinum compounds often used in combination with other drugs. We have previously analysed the efficacy of a cisplatin/piroxicam (CDDP/P) combined treatment showing that this treatment was able to reduce in vivo tumor growth. Several studies reported that platinum-drug sensitivity in cancer is connected to modulation of the expression of non-coding RNAs. In this study we analysed if the CDDP/P treatment was able to modulate miRNAs expression in MM.

Salmonella Typhimurium is an invasive intracellular pathogen that employs various factors for its survival within host cells. To mitigate S. Typhimurium survival, it is crucial to identify factors that influence bacterial survival and to develop drugs that inhibit these factors. In this study, we investigated the effects of nafcillin and diosmin, both of which have been identified as inhibitors of Lon protease, on the intracellular survival of S. Typhimurium and its survival under various stress conditions. Additionally, we examined the expression of genes associated with the type II toxin-antitoxin system to enhance our understanding of the impact of these systems on the bacterium's survival. Our findings indicate that while nafcillin and diosmin did not affect S. Typhimurium attachment, they significantly reduced bacterial intracellular survival, particularly in Hep2 cells after 16 h. These inhibitors were also effective in decreasing bacterial survival under oxidative and acidic stress conditions. Furthermore, gene expression analysis revealed that although there were variations in the expression of TA system genes in S. Typhimurium across different cell lines, the relEB system emerged as the most effective among those studied, exhibiting the highest increase in expression. This study highlights the efficacy of nafcillin and diosmin in reducing the intracellular survival of S. Typhimurium as well as its survival under stress conditions. These findings suggest potential new strategies for developing therapies aimed at preventing S. Typhimurium infections.

In the cultivation and production of sweet cherry, the cost of picking fruit is high due to inconsistency in the maturation period, which has affected the development of the cherry industry. In this study, the effects of exogenous abscisic acid (ABA) on the sweet cherry variety 'Luying 3' fruit quality and maturation stage were observed and recorded, and the physiological and molecular mechanisms were explored to systematically analyze the effects of ABA on sweet cherry fruit ripening to promote the development of the cherry industry. Exogenous ABA (400 mg L-1) enhanced the color of 'Luying 3' fruit in the developing stage but had no significant effect on the fruit weight, soluble solid content, titratable acid content, and sugar-acid ratio in the mature stage. The application of ABA significantly promoted the secretion of endogenous ABA, gibberellin (GA) and salicylic acid (SA). A total of 766 differentially expressed genes (DEGs) were obtained between the treatment group and the control group at 47 and 54 d after flowering. The DEGs were significantly enriched in plant hormone signal transduction pathway, MAPK plant signal transduction pathway and glycolysis pathway. Six genes related to the synthesis of endogenous hormones were screened, of which five were upregulated and one was downregulated. Four DEGs related to the sweet cherry fruit metabolic rate were upregulated by ABA, which positively regulated fruit ripening. Eight differentially expressed AP2/ERF transcription factors were identified, of which 5 were upregulated and 3 were downregulated. This study provides a theoretical foundation for the application of ABA in promoting the consistency of cherry fruit maturity.

Osteosarcoma (OS), a malignant bone tumor with limited treatment options, exhibits low sensitivity to immune checkpoint therapy (ICT). Through genomics and transcriptomics analyses, we identify a subgroup of OS with methylthioadenosine phosphorylase (MTAP) deletion, which contributes to ICT resistance, leading to a "cold" tumor microenvironment. MTAP-deleted OS relies on methionine metabolism and is sensitive to methionine intervention, achieved through either dietary restriction or inhibition of methionine adenosyltransferase 2a (MAT2A), a key enzyme in methionine metabolism. We further demonstrate that methionine intervention triggers programmed death-ligand 1 (PD-L1) transcription factor IKAROS family zinc finger 1 (IKZF1) and enhances PD-L1 expression in MTAP-deleted OS cells. Methionine intervention also activates the immune-related signaling pathways in MTAP-deleted OS cells and attracts CD8+ T cells, thereby enhancing the efficacy of ICT. Combining methionine intervention with ICT provides a significant survival benefit in MTAP-deleted OS murine models, suggesting a rationale for combination regimens in OS ICT.

Cisplatin (DDP) is a key chemotherapeutic agent in the treatment of gastric cancer; however, its efficacy is often limited by chemoresistance, a notable challenge in clinical oncology. The present study aimed to investigate the influence of exosomes derived from M2‑polarized macrophages, which promote this resistance, on the response of gastric cancer cells to DDP, examining both the effects and the underlying mechanisms. M2 macrophages, differentiated from mouse bone marrow cells with interleukin (IL)‑13 and IL‑4, were identified using immunofluorescence staining for CD206 and CD163. Exosomes derived from these macrophages were characterized using transmission electron microscopy and protein markers, including calnexin, tumor susceptibility gene 101 and CD9. The role of exosomal microRNA (miR)‑3681‑3p in DDP resistance was assessed using Cell Counting Kit‑8 and apoptosis assays, while a luciferase reporter assay was used to elucidate the interaction between miR‑3681‑3p and MutL protein homolog 1 (MLH1). Co‑culturing gastric cancer cells with M2 macrophages enhanced DDP resistance, an effect amplified by exosomes from M2 macrophages enriched with miR‑3681‑3p. This microRNA directly targeted and reduced MLH1 protein expression. Overexpression of miR‑3681‑3p through mimic transfection, along with MLH1 silencing by small interfering RNA transfection, significantly increased DDP resistance, as evidenced by elevated IC50 values in AGS cells. By contrast, the overexpression of MLH1 effectively reversed the drug resistance of AGS cells to DDP caused by miR‑3681‑3p mimic transfection, as evidenced by a decrease in the IC50 value. In conclusion, exosomal miR‑3681‑3p from M2 macrophages may have a key role in conferring DDP resistance to gastric cancer by suppressing MLH1, offering a new therapeutic target for overcoming chemoresistance.

CALGB 40903 (Alliance) was a phase II single arm multicenter trial conducted in postmenopausal patients diagnosed with estrogen-receptor (ER) positive breast ductal carcinoma in situ (DCIS) without invasion. Patients were treated with the aromatase inhibitor (AI) letrozole for 6 months prior to surgery with change in magnetic resonance imaging (MRI) enhancement volume compared to baseline as the primary endpoint. In the current study, we performed sequence analysis of pre- and post-treatment specimens to determine gene expression and DNA copy number parameters associated with treatment and response.

Maternal antenatal corticosteroid treatment is standard care to accelerate fetal maturation. However, there are growing concerns that antenatal corticosteroid administration may harm fetal neurodevelopment. Quantitative assessments of the effects of antenatal corticosteroid on the neonates have not been performed and poorly understood about their complex biology.

The increasing use of synthetic chemical herbicides has resulted in environmental, human and animal health issues. This has also led to the development of herbicide resistance in weed populations. The use of essential oils (EOs) can contribute to the development of effective, eco-friendly and nature-based alternatives to these chemical products due to their phytotoxicity and multisite action. Our study aimed to evaluate the proteomic response of Arabidopsis thaliana (A. thaliana) leaves to the application of a cinnamon essential oil (CEO) emulsion. The results showed that the application of CEO emulsion at a concentration of 6% severely impacted the proteomic profile of A. thaliana, especially for membrane proteins and those involved in the photosynthesis process. Interestingly, 40 proteins were identified and listed as the most differentially accumulated proteins in the leaves of A. thaliana. CEO decreased the expression of all the proteins associated with catabolism and anabolism processes while simultaneously increasing the expression levels of proteins involved in the response to oxidative stress. Overall, these findings allowed us to obtain a global view of the proteome response to CEO, opening promising perspectives for the development of natural herbicides, especially given the low probability of developing resistant weed populations.

Persistence of drug-resistant breast cancer stem cells (brCSCs) after a chemotherapeutic regime correlates with disease recurrence and elevated mortality. Therefore, deciphering mechanisms that dictate their drug-resistant phenotype is imperative for designing targeted and more effective therapeutic strategies. The transcription factor SOX2 has been recognized as a protagonist in brCSC maintenance, and previous studies have confirmed that inhibition of SOX2 purportedly eliminated these brCSCs. However, pharmacological targeting of transcription factors like SOX2 is challenging due to their structural incongruities and intrinsic disorders in their binding interfaces. Therefore, transcriptional co-activators may serve as a feasible alternative for effectively targeting the brCSCs. Incidentally, transcriptional co-activators YAP/TAZ were found to be upregulated in CD44+/CD24-/ALDH+ cells isolated from patient breast tumors and CSC-enriched mammospheres. Interestingly, it was observed that YAP/TAZ exhibited direct physical interaction with SOX2 and silencing YAP/TAZ attenuated SOX2 expression in mammospheres, leading to significantly reduced sphere forming efficiency and cell viability. YAP/TAZ additionally manipulated redox homeostasis and regulated mitochondrial dynamics by restraining the expression of the mitochondrial fission marker, DRP1. Furthermore, YAP/TAZ inhibition induced DRP1 expression and impaired OXPHOS, consequently inducing apoptosis in mammospheres. In order to enhance clinical relevance of the study, an FDA-approved drug verteporfin (VP), was used for pharmacological inhibition of YAP/TAZ. Surprisingly, VP administration was found to reduce tumor-initiating capacity of the mammospheres, concomitant with disrupted mitochondrial homeostasis and significantly reduced brCSC population. Therefore, VP holds immense potential for repurposing and decisively eliminating the chemoresistant brCSCs, offering a potent strategy for managing tumor recurrence effectively.

Tea plants (Camellia sinensis) tend to accumulate excessive amounts of fluoride (F) compared to other plants. However, the specific mechanisms of F tolerance or detoxification in tea plants remain insufficiently understood. This study employed ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) to identify critical metabolites involved in F detoxification across two distinct tea plant cultivars with varying F accumulation capacities. Notably, malic acid and citric acid emerged as key metabolites that differentially accumulated under F-stressed conditions. Weighted gene co-expression network analysis indicated that C. sinensis aluminum (Al)-activated malate transporter genes CsALMT9 and CsALMT14 may be implicated in the response to F stress in C. sinensis. Further investigations revealed that CsALMT14 localized to the plasma membrane and exhibited significant transcriptional induction upon exposure to F toxicity. Moreover, heterologous expression of CsALMT14 enhanced F tolerance by mitigating F accumulation in transgenic yeast and Arabidopsis thaliana. Additionally, silencing of CsALMT14 by antisense oligodeoxynucleotide and virus-induced gene silencing reduced the content of malic acid but increased the accumulation of citric acid in tea plants, which might be attributed to the down-regulated expression of malic acid synthesis- and citric acid degradation-related genes. These findings suggest that CsALMT14 confers tolerance to F toxicity through F efflux and regulation of malic acid and citric acid metabolism-related gene expression, thereby providing a novel strategy for F detoxification in tea plants.

Lynch syndrome (LS) is a hereditary disorder that increases the risk of colorectal cancer (CRC) due to constitutional pathogenic variants in mismatch repair (MMR) genes. When coupled with somatic mutations in the same gene, MMR deficiency occurs. However, the mechanisms driving cancer development remain unclear. This study aimed to identify distinct molecular drivers in LS-associated and sporadic CRC. We found that PI3K-Akt signalling is dysregulated in LS-associated CRC, while Wnt signalling predominates in sporadic CRC. Moreover, our findings highlight the therapeutic potential of PI3K-Akt pathway inhibitors, such as taselisib, for LS-associated CRC patients with high pathway dependency. Similarly, Wnt signalling pathway inhibitors, such as XAV939, offer a promising therapeutic approach for sporadic CRC. These findings underscore the importance of understanding the biological basis of disease for developing targeted therapies tailored to CRC subtype-specific oncogenic pathways.

The specificity of the ubiquitination process is mediated by the E3 ligases. Discriminating genuine substrates of E3s from mere interacting proteins is one of the major challenges in the field. We previously developed BioE3, a biotin-based approach that uses BirA-E3 fusions together with ubiquitin fused to a low-affinity AviTag to obtain a site-specific and proximity-dependent biotinylation of the substrates. We proved the suitability of BioE3 to identify targets of RING and HECT-type E3 ligases.