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.

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.

The human body is highly dependent on adequate oxygenation of the cellular space for physiologic homeostasis mediation. The insufficient oxygenation of the cellular space leads to hypoxia. Hypobaric hypoxia (HH) is the reduction in oxygen partial pressure and atmospheric pressure during ascent to high altitudes. This state induces a maladaptive response. Women and how hormones like estrogen influence hypoxia have not been explored with most research being conducted on males. In this study, we investigated the effects of estrogen and GPER on HIF-1a and MIF expression, cardiac arrhythmias, and inflammation during hypobaric hypoxia.

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.

Several studies have shown that Parkinson's disease causative gene products, including α-synuclein (α-syn), display tight links with the tumor suppressor p53. The purpose of this study is to determine the implication of α-syn in glioblastoma development and elucidate how it elicits a tumor suppressor function. We show that the expression of α-syn, a TP53 transcriptional target and a key molecular player in Parkinson's disease, is detected in 1p/19q-codeleted and isocitrate dehydrogenase (IDH)-mutant oligodendroglioma and in IDH-wild-type glioblastoma, while reduced in glioblastoma biopsies, corroborating the link of α-syn expression with a better prognosis among all glioma patients. Accordingly, protein expression is drastically reduced in oligodendrogliomas and glioblastoma biopsies. This could be accounted for by a reduction of p53 transcriptional activity in these samples. Interestingly, genetic manipulation of p53 in glioblastoma cells and in mouse brain shows that p53 up-regulates α-synuclein, a phenotype fully abolished by the prominent p53 hot spot mutation R175H. Downstream to its p53-linked control, α-syn lowers cyclin D1 protein and mRNA levels and reduces glioblastoma cells proliferation in a cyclin D1-dependent-manner. Further, in temozolomide (TMZ)-resistant U87 cells, α-syn reduces O6-methylguanine-DNA methyltransferase (MGMT) expression and rescues drug sensitivity by a mechanism implying its transcriptional activation by X-box binding protein 1 (XBP1), an effector of the UPR response. Furthermore, α-syn lowers MGMT and cyclin D1 (CCDN1) expressions and reduces tumor development in allografted mice. Overall, our data reveals a new role of α-syn as an oligodendroglioma biomarker and as a glioblastoma tumor suppressor capable of either potentiate TMZ effect or avoid TMZ-associated resistance.

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.

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.

Prostate cancer (PCa) is a leading cause of cancer-related mortality in men globally. While androgen deprivation therapy (ADT) can extend the asymptomatic phase and overall survival of patients with metastatic PCa, prolonged ADT often leads to the development of castration-resistant prostate cancer (CRPC) within 18-24 months. The mechanisms underlying CRPC remain incompletely understood, presenting a significant challenge in clinical prostate cancer treatment.

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.

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) represents a critical global health challenge, making the SaeRS two-component system (TCS), a key regulator of S. aureus virulence, an ideal target for novel therapeutic approaches. In this study, virtual screening and thermal shift assays identified Baohuoside I (BI), a flavonol glycoside, as a potent inhibitor of the SaeR response regulator. BI significantly attenuated S. aureus pathogenicity without bactericidal effects, suppressing the expression of key virulence factors, such as hemolysin A (Hla) and Panton-Valentine leukocidin (PVL), while modulating immune evasion pathways. Additionally, BI disrupted biofilm formation, promoting the development of porous, less structured biofilms. Biochemical assays, including EMSA, CETSA, fluorescence quenching, and SPR, confirmed strong binding interactions between SaeR and BI. In vivo, BI demonstrated therapeutic efficacy in Galleria mellonella and rat MRSA models. These findings establish BI as a promising lead for nonbactericidal therapies to combat MRSA infections and mitigate resistance.

Targeting the dependency of MLL-rearranged (MLLr) leukemias on menin with small molecule inhibitors has opened new therapeutic strategies for these poor-prognosis diseases. However, the rapid development of menin inhibitor resistance calls for combinatory strategies to improve responses and prevent resistance. Here we show that leukemia stem cells (LSCs) of MLLr acute myeloid leukemia (AML) exhibit enhanced guanine nucleotide biosynthesis, the inhibition of which leads to myeloid differentiation and sensitization to menin inhibitors. Mechanistically, targeting inosine monophosphate dehydrogenase 2 (IMPDH2) reduces guanine nucleotides and rRNA transcription, leading to reduced protein expression of LEDGF and menin. Consequently, the formation and chromatin binding of the MLL-fusion complex is impaired, reducing the expression of MLL target genes. Inhibition of guanine nucleotide biosynthesis or rRNA transcription further suppresses MLLr AML when combined with a menin inhibitor. Our findings underscore the requirement of guanine nucleotide biosynthesis in maintaining the function of the LEDGF/menin/MLL-fusion complex and provide a rationale to target guanine nucleotide biosynthesis to sensitize MLLr leukemias to menin inhibitors.

Feeding low crude protein (LCP) diets supplemented with crystalline amino acids improves environmental and welfare parameters of broilers. However, increased body fat contents in broilers fed LCP diets have become a concern. Black soldier fly larvae oil (BSFLO), rich in lauric acid, has been reported to inhibit lipogenesis and reduce body fat. A 3 × 2 factorial experiment was conducted to evaluate the effect of BSFLO on performance, blood biochemistry, carcass quality, fat metabolism gene expression, and litter quality in broilers fed protein-reduced diets. A total of 288 broilers were divided into 6 treatments: three CP levels (200, 185, or 170 g/kg; high [HCP], medium [MCP], or low [LCP]) and two oil sources (BSFLO and Crude Palm Oil [CPO]), with 6 replicate pens of 8 birds each. Results showed a 15 g/kg CP reduction had no effect on body weight and feed intake (P > 0.05) but increased FCR (P = 0.001). A 30 g/kg CP significantly reduced the body weight and feed intake with inferior FCR (P < 0.05). However, negative effect of low CP diets on FCR was mitigated by BSFLO (P = 0.008). Reducing CP by 30 g/kg increased fat pads (P = 0.033), whereas BSFLO reduced fat pads (P = 0.049) at all three CP levels. Protein-reduced diets increased blood cholesterol (P = 0.002), HDL (P < 0.001), and LDL (P = 0.002). BSFLO decreased blood triglyceride (P = 0.026) and cholesterol (P < 0.001). Reducing 30 g/kg CP increased meat cooking loss (P = 0.035), while BSFLO decreased cooking loss (P < 0.001). BSFLO increased meat protein (P < 0.001) and decreased cholesterol (P = 0.003). The inclusion of BSFLO in protein-reduced diet down-regulated the gene expression of FAS, ACC, SREBP-1, and HMGR in broilers (P < 0.001). Reducing CP levels decreased litter pH (P = 0.011), nitrogen (P < 0.001), ammonia (P < 0.001) and moisture (P = 0.018). The study concludes that BSFLO reduced body fat by down-regulating the lipogenesis gene expression. In addition, BSFLO enhanced feed efficiency in broilers fed protein-reduced diet.

The development of resistance to chemotherapy in the case of aggressive glioblastoma multiforme (GBM) presents a significant treatment challenge. Dysregulation of the Notch signalling pathway promotes tumour proliferation in GBM cells. This study was that targeting the Notch signalling pathway could be a potential therapeutic approach for GBM. Initially, temozolomide-(TMZ)-resistant GBM cells were generated, and the effect of Notch1 on the expression of multiple resistance proteins within these cells was investigated. Subsequently, the expression of Notch-1 in GBM cells was reduced using siRNA. Results revealed a significant reduction in TMZ sensitivity in TMZ-resistant GBM cells, accompanied by a substantial increase in the expression of major vault protein-(MVP), O6-methylguanine-DNA-methyltransferase-(MGMT), and ATP-binding-cassette transporter-G2-(ABCG2). Furthermore, TMZ-resistant U87-R and U251-R cells exhibited higher proliferation rates compared to their parental control cells (U87 and U251). Additionally, we observed that downregulating Notch-1 signalling inhibited the proliferation of TMZ-resistant U87-R and U251-R cells. This downregulation led to the inactivation of MGMT, ABCG2, and MVP. Importantly, it increased chemosensitivity to TMZ, particularly by downregulating MVP expression. Consequently, Notch1 could serve as a potential therapeutic target for GBM cells and may be effective in preventing TMZ resistance by targeting MVP, as well as MGMT and ABCG2 in GBM cells.

Triple-negative breast cancer (TNBC) poses a significant challenge due to its high mortality rates, primarily attributed to resistance against chemotherapy regimens containing taxanes like paclitaxel. Thus, developing combinatorial strategies to override resistance is a pressing need. By taking advantage of a library screening with various kinase inhibitors, we found that the small-molecule inhibitor enzastaurin targeting protein kinase C (PKC) could overcome resistance in TNBC cells. Mechanistically, dual treatment with paclitaxel and enzastaurin resulted in efficient mitotic arrest and subsequent cell death by restoring AURKB expression. Further analysis revealed that the GCN2-p-eIF2α axis was responsible for the posttranscriptional accumulation of AURKB upon combinatorial treatment. Finally, we confirmed that combinatorial regimens synergistically suppressed tumour growth in vivo in mouse models. Moreover, the efficiency of dual treatment was largely determined by AURKB, implying that AURKB could be a potential predictive marker for stratifying patients who may benefit from the combinatorial treatment. Collectively, our study not only unravels a novel underlying mechanism for paclitaxel resistance in TNBC but also provides a new potential combinatorial therapeutic strategy in the clinic.