Cyclin E1 (CCNE1) amplification is associated with poor prognosis of ovarian carcinomas across histological subtypes. Inhibitors targeting PLK1 or WEE1 are emerging as promising therapeutic agents for cancer treatment that disrupt the critical G2/M checkpoint, leading to cancer cell death. However, biomarkers that predict the response to these inhibitors are not well defined. Here, we evaluated the efficacy of the PLK1 inhibitor, volasertib, and the WEE1 inhibitor, adavosertib, along with the biomarker potential of cyclin E1 in ovarian cancer cells. Both inhibitors suppressed the proliferation of cyclin E1-overexpressing cells to a greater extent than that of cells exhibiting low cyclin E1 expression. TP53 silencing did not increase the sensitivity to these inhibitors. In cyclin E1-overexpressing cells, PLK1 inhibition reduced the proportion of cells in the G1 phase and increased those in the G2/M and sub-G1 phases. WEE1 inhibition reduced G1 phase cells without a clear peak in the S-G2/M phase and increased the sub-G1 phase cells. Both inhibitors suppressed the growth of cyclin E1-overexpressing tumors in vivo. Taken together, cyclin E1 overexpression, regardless of TP53 status, may serve as a predictive biomarker for the efficacy of these inhibitors, offering potential personalized treatment strategies for ovarian cancer.

Psoriasis is an immune-mediated inflammatory skin disease. IL-22, a proinflammatory cytokine, is implicated in psoriasis pathogenesis; however, there is currently no established biological treatment targeting IL-22 or its receptor, IL-22Rα. Alloferon is a short peptide that has an antiinflammatory effect on skin disorders; however, little is known about its anti-inflammatory activity in psoriasis. We investigated the regulatory role of alloferon in the development of psoriasis in an imiquimod (IMQ)-induced psoriasis model through the regulation of IL-22Rα expression. The expression of IL-22Rα was analyzed by immunofluorescence staining in primary human keratinocytes. The effect of alloferon on the development of psoriasis was investigated in IMQ-induced wild-type and IL-22Rα KO mice. We found that alloferon decreased the expression of IL-22Rα in psoriasis-like keratinocytes treated with TNF-α, while epidermal hyperplasia was observed in IMQ-induced wild-type and IL-22Rα KO mice. In addition, the expression of IL-1β, IL-19, and IL-33 was suppressed when IL-22Rα KO mice were treated with alloferon. The findings of this study indicate that alloferon could be an effective potential drug for the treatment of psoriasis by interrupting IL-22 signaling and factors related to skin inflammation.

Metformin, widely used for the treatment of type 2 diabetes, has recently gained attention for its potential anticancer properties. Several studies have shown that metformin treatment inhibits cell viability in colon adenocarcinoma (COAD); however, the research related to the tumor-node-metastasis (TNM) stage is limited. As COAD is frequently diagnosed at an advanced stage, understanding the genetic factors that regulate the pathogenesis of COAD at each TNM stage and the effects of metformin for potential treatment. Therefore, we identified differentially expressed factors at the TNM stage in metformin-treated COAD cells and investigated their regulatory mechanisms using microRNAs (miRNAs). Through bioinformatics analyses, four-jointed box kinase 1 (FJX1) and hsa-miR-1306-3p were identified as differentially expressed in COAD upon metformin treatment. Metformin treatment significantly reduced cell viability, with an observed decrease of approximately 50%. Analysis using quantitative real-time PCR showed an increase in hsa-miR-1306-3p and a decrease in FJX1 expression upon metformin treatment compared to untreated cells. Luciferase assay confirmed the sequence-specific binding of hsa-miR-1306-3p to FJX1. These findings highlight the potential of metformin as a therapeutic agent for COAD by modulating FJX1 expression via upregulation of hsa-miR-1306-3p, revealing novel avenues for COAD treatment.

Osteosarcoma (OS) is the most prevalent type of primary malignant bone cancer and currently lacks effective targeted treatments. Increasing evidence indicates that SOX2 overexpression is a primary driver of OS. By screening a small-molecule kinase inhibitor library, we identified AKT as a kinase essential for robust SOX2 expression in OS cells. AKT was found to be frequently overexpressed in OS and positively correlated with SOX2 protein levels. We demonstrated that AKT has no effect on SOX2 transcription but promotes SOX2 protein stability. Mechanistically, AKT binds to and phosphorylates SOX2 at T116, preventing SOX2 ubiquitination and proteasome-dependent degradation by ubiquitin E3 ligases UBR5 and STUB1. Moreover, we found that AKT-SOX2 axis is a significant modulator of cancer stemness and chemoresistance and that the combination of AKT inhibitor MK2206 and cisplatin resulted in a synergistic and potent inhibition of OS tumor growth in the PDX model. In conclusion, we identified a critical role for AKT in promoting SOX2 overexpression, tumor stemness, and chemoresistance in OS, and provided evidence that targeting AKT combined with chemotherapy may hold promise for treating refractory OS. Working model showing that AKT stabilizes SOX2 by phosphorylating T116 site. Phosphorylation by AKT restraints the binding and ubiquitinoylation of SOX2 by the UBR5 and STUB1, thus promoting SOX2 stability and tumorigenic activity. Targeting AKT by MK2206 inhibits T116 phosphorylation and promotes SOX2 ubiquitination pathway, which impairs SOX2 tumorigenic activity. A combined treatment with chemo reagent and AKT inhibitor could achieve better therapeutic effect for SOX2-positive OS.

Esophageal cancer is a significant global health concern, with esophageal squamous cell carcinoma being the predominant subtype in high-incidence regions like China. Despite advances in multidisciplinary treatments, the prognosis for ESCC remains poor, with systemic chemotherapy facing the challenge of drug resistance. Epigenetic alterations, particularly DNA methylation, play a crucial role in ESCC carcinogenesis and therapeutic response. Aberrant DNA methylations, including global hypomethylation and promoter-specific hyper-methylation, disrupt critical pathways such as cell cycle regulation, apoptosis, and DNA repair, contributing to chemoresistance. Several studies have identified methylation markers that predict treatment response, particularly for chemotherapy, targeted therapy and immunotherapy, such as p16 and GPX3 for cisplatin, MTHFR for 5-FU, CHFR for paclitaxel. DNA methyltransferase inhibitors and other epigenetic therapies are being explored to reverse these methylation changes and enhance therapeutic efficacy. However, the clinical utility of these markers remains limited due to the lack of large-scale validation and concerns over off-target effects. This review aims to summarize all aberrant methylation alterations in ESCC and the clinical implications of aberrantly methylated candidate genes identified in ESCC systemic chemotherapy, with the goal of further understanding the underlying molecular mechanisms, refining methylation-targeting therapies, and integrating them with conventional treatments to improve patient outcomes.

Di(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer, and human exposure to phthalates is a major health concern. DEHP, which is widely recognized as an endocrine disruptor, is associated with an increased risk of several diseases, including breast cancer. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, and metastasis is the leading cause of TNBC-related mortality. However, the correlation between DEHP exposure and TNBC metastasis remains elusive. In the present study, we found that prolonged DEHP treatment enhanced the migration and invasion of TNBC cells both in vitro and in vivo. Mechanistically, DEHP exposure induced Musashi RNA binding protein 2 (MSI2) overexpression, which subsequently activated the PI3K/Akt/NF-κB/MMP-9 axis to augment metastatic potential. MSI2 also promoted stemness. Interestingly, we identified a novel function of MSI2 in regulating the expression, distribution, and polarization of vimentin that is independent of its conventional RNA binding and translation regulation. Genetic knockdown of MSI2 potently abolished DEHP-mediated TNBC progression. Moreover, MSI2 depletion inhibited lung metastasis in metastatic mouse models but did not affect proliferation or tumor size. Intriguingly, miR-155-5p downregulation was observed after DEHP exposure, while mimic miR-155-5p treatment inhibited DEHP-induced TNBC migration, accompanied by reduced expression of MSI2 and vimentin. These findings suggested an inverse relationship between miR-155-5p levels and MSI2 expression. Taken together, MSI2 might serve as a potential therapeutic target and function as a prognostic biomarker for TNBC patients.

To adapt to environmental changes, diapausing silkworm eggs remain dormant during the early stages of embryonic development. Various methods have been used to terminate silkworm egg diapause and promote egg hatching.

Paphiopedilum orchids have a high ornamental value, and flower abundance is a key horticultural trait. Most Paphiopedilum plants exhibit weak tillering ability, with their tiller buds often entering a dormant state post-formation. Tiller production plays a crucial role in enhancing flower abundance and is potentially regulated by plant hormones. However, the effect of hormones on tillering in Paphiopedilum plants is still unclear.

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.

Skin exposure to arsenicals such as lewisite and phenylarsine oxide leads to severe cutaneous damage. Here, we characterized the molecular pathogenesis of skin injury caused by additionally structurally distinct warfare arsenicals including diphenylchlorarsine (DPCA), diphenylcyanoarsine (DPCYA), diethylchloroarsine (DECA). Cutaneous exposure to DPCA/DPCYA showed marked increase in skin erythema and edema at 6 and 24 h followed by scar formation at 72 h, while DECA did not produce such visual injuries in mouse skin. Clinical observations showed significant increase in Draize score and skin bi-fold thickness in a time-dependent manner. DPCA or DPCYA-exposed skin histology revealed highly inflamed hypodermal areas with infiltrated immune cells at 6 and 24 h, however, epidermal cell necrosis was seen at 72 h. Significantly high number of macrophage infiltration observed at 6 h, whereas peak neutrophil infiltration occurred at 72 h. Number of micro-blisters also increased. However, these effects were nonsignificant following topical DECA exposure. RT-PCR confirmed augmented inflammatory responses in the skin challenged with both DPCA/DPCYA, which accompanied increased ROS and unfolded protein response (UPR) signaling. DECA also increased ROS with changes in UPR. Disrupted tight (Yap/ZO-1) and adherens (Yap/α-Catenin) junction proteins underlie time-dependent apoptotic cell death of epidermal keratinocytes. Thus, these studies identify arsenicals-manifested signaling pathways similar to those of lewisite.

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.

Cell identity plays a pivotal role in embryo development, guiding the process of cellular differentiation essential for tissue and organ formation. Post-translational modification by the ubiquitin-related SUMO protein acts as a chromatin barrier to cell fate conversions. While SUMOylation deficiency is incompatible with mammalian embryonic development, haploinsufficiency for the SUMOylation machinery's E1 enzyme, UBA2, leads to various phenotypic traits in humans, including craniofacial malformations and aplasia cutis congenita. To investigate SUMO's role in organogenesis, SUMOylation was transiently suppressed using a specific pharmacological inhibitor, TAK981, administered during the early post-implantation embryo stage. A high-concentration injection led to embryonic lethality associated with epigenetic scars and alterations in nuclear and nucleolar integrity observed in treated embryo-derived fibroblasts. Lower-concentration injections resulted in viable mice with craniofacial deformities often accompanied by hydrocephalus, syndactyly and an aplasia cutis-like phenotype. Transcriptomic analysis revealed the repression of genes involved in neural crest differentiation in the TAK981-treated embryos as well as the overexpression of the Fgfr gene family in the adult TAK981 progeny. These genes, expressed in neural crest derivatives, are known for their gain-of-function mutations linked to human craniosynostosis syndromes, suggesting that potential overactivation of the FGF signaling pathway may contribute to the malformations observed in TAK981 progeny. Altogether, disruption of the SUMOylation/deSUMOylation equilibrium during a short embryonic period is sufficient to induce persistent cellular defects and transcriptional alterations, resulting in severe offspring malformations. In conclusion, the SUMO inhibitor TAK981 has teratogenic effects, disrupting normal fetal development and causing congenital disabilities reminiscent of traits observed in UBA2-related syndrome.

Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system. Current treatments aim to manage symptoms and slow disease progression, but there is a need for effective interventions that target underlying disease mechanisms. In this study, we investigated the effects of exercise, MitoQ (a mitochondria-targeted antioxidant), and their combination on the gene expression of various biomarkers associated with MS in postmenopausal and premenopausal women. We measured interleukin-6 (IL-6) and key molecular pathways involved in MS pathogenesis, including suppressor of mother against decapentaplegic 2 (SMAD2), signal transducer and activator of transcription 1 (STAT1), and transforming growth factor beta (TGF-β) using real-time polymerase chain reaction. All interventions significantly lowered IL-6 levels and STAT1, especially in premenopausal women. Also, both exercise and MitoQ led to a significant increase in the SMAD2 and TGF-β expression, with a more pronounced effect on premenopausal women. Noteworthy, the effectiveness of the combination of exercise and MitoQ was considerably higher than each one alone. These findings suggest that exercise and MitoQ, either alone or combined, can modulate various biological pathways implicated in MS pathogenesis.

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.

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.

The aim of this study was to investigate the mechanism by which quercetin (Que) affects apoptosis and autophagy in pediatric acute myeloid leukaemia (AML) cells by inhibiting the activation of the PI3K/AKT signaling pathway through the regulation of the miR-224-3p/PTEN axis.

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.