Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2) expression, represents a therapeutic challenge due to its aggressive nature and limited treatment options. Here, we identified the cholesterol-lowering drug lovastatin (LV) as a potent apoptosis-inducing agent in TNBC. Mechanistically, LV disrupts the interaction between the deubiquitinating enzyme USP14 and Survivin, a key anti-apoptotic protein, enhancing polyubiquitination and the proteasomal degradation of Survivin. The overexpression of USP14 was found to stabilize Survivin and rescue LV-induced apoptosis and tumor suppression in vitro and in vivo, whereas USP14 silencing or inhibition with IU1 (a USP14-specific inhibitor) enhanced Survivin turnover and synergized with LV to suppress colony formation in TNBC cells. Clinical relevance was demonstrated through bioinformatic analysis and immunohistochemistry, revealing that elevated Survivin expression in TNBC tissues correlated with poor prognosis and is significantly upregulated in TNBC versus non-TNBC tissues. Our findings identify the USP14-Survivin axis as a potential therapeutic target and highlight LV as a promising candidate for TNBC treatment.

Previous studies have shown that walnut-derived peptide TW-7 is a powerful antioxidant, which can significantly improve the embryonic development potential of vitrified mouse MII oocytes. However, the underlying mechanism is still unknown. RNA sequencing indicated that the differentially expressed genes of the parthenogenetic two-cell embryos in the fresh, vitrification, and TW-7 treatment groups were significantly enriched in cell death pathways like apoptosis and necroptosis. Further analysis of the genes enriched in the cell death pathway found that mapk10, a key regulatory gene of apoptosis, showed high expression in the vitrification group but obviously low expression in the fresh and TW-7 treatment groups. Immunofluorescence staining and western blot revealed that TW-7 downregulates JNK3, mapk10-encoded protein, and p-JNK in parthenogenetic two-cell embryos from MII oocyte vitrification. TW-7 improves suppressed embryo development by reducing p-JNK expression. Furthermore, an H2O2 induced oxidative stress model displayed that TW-7 downregulated the expression levels of JNK3 and p-JNK probably by the antioxidant pathway. These findings suggest that TW-7 can suppress the elevated oxidative stress caused by cryopreservation, alleviate apoptosis by regulating the expression of apoptosis-related proteins like JNK3, and promote embryonic development, which provides theoretical support for the application of TW-7 in animal reproduction.

As a member of the chaperonin-containing tailless complex polypeptide 1 (TCP1) complex, which plays a pivotal role in ensuring the accurate folding of numerous proteins, chaperonin-containing TCP1 subunit 6A (CCT6A) participates in various physiological and pathological processes. However, its effects on cell death and cancer therapy and the underlying mechanisms need further exploration in colorectal cancer (CRC) cells.

The recent study by Chen et al highlights the paradoxical role of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in esophageal squamous cell carcinoma (ESCC), revealing its promotion of epithelial-mesenchymal transition (EMT) and tumor migration via the BRD4/c-Myc/endoplasmic reticulum (ER)-stress pathway. While HDACis are traditionally considered anti-tumor agents, these findings underscore the need for alternative therapeutic strategies. In this commentary, we discuss the potential of traditional medicine-derived compounds, such as berberine, curcumin, and resveratrol, in modulating epigenetic regulators and mitigating TSA-induced oncogenic pathways. Additionally, we emphasize the prognostic significance of histone acetylation markers, particularly acetylated histone H3, which could serve as predictive biomarkers for ESCC progression and HDACi therapy responsiveness. Further, we explore the role of ER stress in tumor aggressiveness and suggest that compounds like quercetin and baicalein, known for their ER stress-alleviating properties, warrant further investigation. Integrating traditional medicine-based interventions with biomarker-driven targeted therapy may enhance ESCC treatment efficacy while minimizing HDACi-associated risks. We advocate for future research focusing on the interplay between epigenetic modulation, natural compounds, and biomarker identification to refine personalized therapeutic strategies for ESCC.

A phenotypic screen of fungal filtrates on developing zebrafish embryos identified metabolites from the fungus Ceratocystis populicola to induce ectopic tail formation, including a split notochord and a duplicated caudal fin. Chemical analyses led to the identification of monoterpene alcohols, in particular geraniol, as the active compounds. Tüpfel long fin zebrafish embryos were more susceptible to geraniol-induced ectopic tail formation than Wild Indian Karyotpe zebrafish embryos. RNA-sequencing on tail buds of 15-somite-stage embryos revealed downregulation of essential genes of the retinoic acid signaling pathway. Differential expression of cyp26a1, fgf8a and downstream hox-genes was validated. Time-lapse imaging revealed that Kupffer's vesicle-derived cells failed to migrate after Kupffer's vesicle collapse upon geraniol treatment. These cells failed to merge with progenitors from the tail bud and contributed to an ectopic tail, expressing markers for presomitic mesoderm, somite and notochord tissue. Strikingly, ablation of Kupffer's vesicle by tbxta-morpholino injection rescued ectopic tail formation. Taken together, our data suggest that Kupffer's vesicle cells harbor tail progenitor capacity, and proper migration of these cells is essential for normal tail morphogenesis.

Hypothalamic neuropeptides play a pivotal role in regulating appetite and energy homeostasis. Extracellular ATP, a key signaling molecule in the hypothalamus, is associated with neuronal activity and metabolic processes. However, its role in appetite control remains unclear. This study explored how sustained extracellular ATP regulates the expression of hypothalamic orexigenic neuropeptides Agrp and Npy. The administration of ATP alone reduced food intake, body weight, and orexigenic neuropeptide expression in mice. Conversely, inhibition of ATP conversion into AMP using the ectonucleoside triphosphate diphosphohydrolase inhibitor ARL67156 caused a transient increase in these parameters. Prolonged extracellular ATP was shown to upregulate Agrp and Npy expression via purinergic P2X4 receptor (P2X4R) activation in AGRP/NPY-expressing cells. Activation of P2X4R induced CaMKII phosphorylation, which subsequently led to CREB phosphorylation and upregulation of orexigenic neuropeptides. Our findings reveal a mechanism whereby extracellular ATP accumulation promotes appetite through P2X4R-CaMKII-CREB signaling, shedding light on how extracellular ATP impacts hypothalamic appetite control.

Extracellular vesicles (EVs) play a crucial role in intercellular communication. While the effects of EVs released from living or non-dying cancer cells are well characterized, the impact of EVs released from chemotherapy-treated or apoptotic cancer cells is less understood. This study investigated the effects of the chemotherapy agent cisplatin on EV release and miRNA content in apoptotic medulloblastoma cells, as well as their influence on the growth of drug-naïve recipient cancer cells.

In recent years, the role of epigenetic modifications, especially N6-methyladenosine (m6A) modifications, in the occurrence and development of cancer has received increasing attention. This study aims to elucidate the role of m6A modification in colorectal cancer (CRC), focusing on the effect of METTL3 on STC2 expression and its effects on cell proliferation, drug resistance and metastasis. Using MeRIP-seq, mRNA-seq, EdU staining, CCK-8 (Cell Counting Kit-8) assay, Transwell assay, Western blot and flow cytometry, this study confirmed that RNA methylation was predominantly located in the CDS region and that STC2 was overexpressed in advanced cancer and 5-FU (5-Fluorouracil)-resistant cell lines. Knockdown of STC2 increased the sensitivity of cells to 5-FU, reduced cell proliferation and metastatic capacity, and indicated that METTL3 positively regulates STC2 m6A modification. Further experiments showed that METTL3 knockdown reduced the IC50 (Half Maximal Inhibitory Concentration) of 5-FU-resistant CRC cells, inhibited cell proliferation, ERS (Endoplasmic Reticulum Stress) and oxidative stress, and reduced KRAS G12 and G13 mutations, and these effects were reversed by STC2 overexpression. In vivo, METTL3 knockdown enhanced the efficacy of 5-FU and inhibited tumor metastasis, whereas STC2 overexpression counterbalanced these benefits. Overall, our findings suggest the METTL3/STC2 axis as a promising therapeutic target to combat drug resistance and metastasis in colorectal cancer.

Progressive aniridia associated keratopathy is worsening visual acuity of congenital aniridia subjects lifelong. Restoration of PAX6 expression in PAX6 haploinsufficient limbal epithelial cells could be one therapeutic option. In a previous study using aniridia-like CRISPR/Cas9 genome-edited corneal epithelial cells, the antipsychotic drugs duloxetine and ritanserin increased PAX6 mRNA and protein expression. Our purpose was to investigate the effect of duloxetine and ritanserin on cultured primary limbal epithelial cells (pLECs) without and with PAX6 knockdown. pLECs were isolated from 11 aniridia patients and corneoscleral rims of 8 healthy human donors and were treated with 5 µM duloxetine or ritanserin for 24 hours. In addition, pLECs were transfected with small interfering RNA (siRNA) (PAX6 knockdown) in the siRNA-based aniridia cell model and were also treated by 5 µM duloxetine or ritanserin for 24 hours. Gene and protein expression were analyzed using qPCR and Western blot. In both primary aniridia limbal epithelial cells and the siRNA-based aniridia cell model, the expression of PAX6 at the transcriptional or translational level did not show significant changes through duloxetine or ritanserin treatment (p > 0.5). The target genes of PAX6 such as KRT3, KRT12, DSG1, ALDH1A1, ADH7, FABP5, ABCG2 also did not change significantly (p ≥ 0.2). Our study shows that primary cultures of limbal epithelial cells from both aniridia patients and healthy donors were unresponsive to drug treatment. Therefore, our data suggest that different aniridia cell models or cell culture conditions exhibit varying responses to duloxetine and ritanserin. The use of in vivo models could further enhance our understanding of duloxetine and ritanserin treatment in aniridia-associated keratopathy.

Salvia officinalis (sage) extract has demonstrated potential as a functional ingredient for skin care application. However, its effect and mechanism in regulating skin pigmentation remain largely unclear. This study investigated the effects of sage ethanol extract (SGE) on melanogenesis and its underlying molecular mechanisms. Treatment with SGE in a human skin equivalent model (3D-skin) suppressed melanin production. To clarify the mechanism of action, the study focused on senescence-associated secretory phenotype (SASP) factors, which are implicated in age-related pigmentation changes. q-PCR and ELISA analyses showed that SGE inhibits melanogenesis by suppressing the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), a known SASP factor in keratinocytes. Interestingly, a similar effect was observed with L-ascorbic acid 2-glucoside (AG), previously identified as a tyrosinase inhibitor. Importantly, p38 and JNK MAP-kinase were identified as upstream regulators of GM-CSF that are suppressed by SGE. These findings provide new insights into how SGE and AG regulate pigmentation via keratinocyte-derived GM-CSF, highlighting their potential in modulating skin tone and pigmentation through cellular signaling pathways.

Rice blast, caused by Magnaporthe oryzae, is a major threat to global rice production. This study explores the antifungal potential of the immunosuppressant FK506 and identifies its target protein, MoFpr1 (FK506-binding protein 1B). FK506 inhibited mycelial growth, appressorium formation, and pathogenicity of M. oryzae in an MoFpr1-dependent manner. Mechanistic analyses revealed that FK506 impairs autophagy and ubiquitination, supported by transcriptomic and metabolomic data. Structural studies using X-ray crystallography and site-directed mutagenesis confirmed the direct interaction between FK506 and MoFpr1, highlighting the importance of residues Gly95 and Ile97. Furthermore, FK506 demonstrated broad-spectrum antifungal activity against various plant pathogens and effectively controlled rice blast in laboratory, net-chamber, and field trials with minimal phytotoxicity. These findings position FK506 as a promising antifungal agent and offer insights into its molecular mechanism, suggesting its potential for sustainable plant disease management.

Dendrobium polysaccharide (DOP) as a glucomannan has significant probiotic effects on microbiota. Here, we optimize the preparation of low-molecular-weight Dendrobium oligosaccharides (DMOS) using developed endomannosidase Thms, which increased proliferation efficiency of Lactobacillus plantarum FN107 by >50 % compared to glucose. Utilization mechanism of DMOS by L. plantarum FN107 is investigated through transcriptomic analysis, results showed that DMOS significantly affect 46 key genes involved in glycolysis/gluconeogenesis, fatty acid biosynthesis and pyruvate metabolism pathways. Further bioinformatics analysis indicated the 5'-Untranslated region of these genes harbor catabolite responsive elements (cre) that are rigorously regulated by catabolite control protein A (CcpA). Characterization of these cre reveals significant inhibition by 1.63-5.29 folds under glucose, but almost completely avoided cre-mediated carbon catabolite repression (CCR) under DMOS. Those findings demonstrate probiotic potential of low-molecular-weight DMOS for microorganisms and provide valuable insight into the growth-promoting mechanism.

Evolutionary history encompasses both genetic and phenotypic bacterial differences; however, the extent to which this history influences drug response and antimicrobial resistance (AMR) adaptation remains unclear. Historical contingencies arise when elements from an organism's past leave lasting effects on the genome, altering the paths available for adaptation. Here, we compare two diverging reference strains of Acinetobacter baumannii, representative of archaic and contemporary infections, to study the impact of deep historical differences shaped by decades of adaptation in varying antibiotic and host pressures. We evaluated these effects by comparing immediate and adaptive responses to the last-resort antibiotic, tigecycline (TGC). The strains demonstrated divergent transcriptional responses, suggesting that baseline transcript levels may dictate global responses to antibiotics. Experimental evolution in TGC revealed clear differences in population dynamics, with hard sweeps in populations founded by one strain and no mutations reaching fixation in the other strain. AMR was acquired through predictable mechanisms of increased efflux and drug target modification; however, efflux targets were dictated by strain background. Genetic adaptation may outweigh historic differences in transcriptional networks, as evolved populations no longer show transcriptomic signatures of drug response. Importantly, fitness-resistance trade-offs were only observed in lineages evolved from the archaic strain, while the contemporary reference isolate suffered no fitness defects. This suggests that decades of adaptation to antibiotics resulted in pre-existing compensatory mechanisms in the more contemporary isolate, an important example of a beneficial effect of historical contingencies.

Lung cancer is strongly associated with malnutrition and detrimental changes in muscle mass (MM), which can lead to reduced quality of life and reduced tolerance to and efficacy of antineoplastic treatment. The loss of MM and myosteatosis (fat infiltration into muscle) have been linked to inflammation in cancer, and n-3 polyunsaturated fatty acids (PUFA) found in fish oil are known to modulate inflammatory response, lean mass, microbiota, and epigenetic mechanisms.

Chlorogenic acid (CGA) exerts immunomodulatory effects by regulating the proportion of regulatory T cells (Tregs), and T-cell dysregulation is a known feature of post-traumatic osteomyelitis (PTO). This study explored the mechanism of CGA in the treatment of PTO from the perspective of T-cell immunity.

Aluminum (Al) toxicity is a major limiting factor leading to crop yield reduction in acidic soils. The pectic polysaccharides, key components of plant cell walls, are considered the primary binding site for Al ions. Oligogalacturonide (OGA), the oligomers of alpha-1,4-linked galacturonosyl residues originating from the degradation of cell wall pectin (homogalacturonan), are able to elicit defense responses and protect plants against biotic stress, such as pathogen infections. However, the involvement of OGA in the plant's response to abiotic stress remains to be elucidated. In this work, we analysed the effects of Al treatment on the endogenous OGA content in pea root tips, as well as the effects of OGA pretreatment on pea root elongation, Al content, and reactive oxygen species (ROS) metabolism, with a working hypothesis being that OGA is causally involved in plant responses to Al toxicity. Hydroponically grown pea (Pisum sativum) plants were used to explore the biological functions of OGA in response to Al toxicity. Our data showed that Al treatment significantly induced the accumulation of endogenous OGA in root tips, primarily in the form of short-chain OGA. Pretreatment with exogenous OGA for 12 h notably improved pea tolerance to Al toxicity, including mitigating Al-induced suppression of root elongation growth and attenuating Al toxicity effects on the root system. OGA also enhanced Al tolerance by regulating redox homeostasis in root tips, reducing Al toxicity-induced accumulation of ROS and by transcriptional upregulation of antioxidant enzyme activities. Overall, this research is the first to demonstrate the role of OGA in plant responses to Al toxicity, offering novel theoretical foundations for understanding plant adaptation to acidic soil conditions.

Light stress is a risk factor leading to retinal diseases such as age-related macular degeneration. However, the mechanism underlying the stress response to light in the retina has yet to be elucidated. We have reported that exposure to blue light-emitting diode light induces excessive production of reactive oxygen species and activates the unfolded protein response, robustly increasing activating transcription factor 4 (ATF4) expression. These processes result in photoreceptor cell death. This study investigates the effects of Pentadecyl, a bioactive product obtained from Aurantiochytrium limacinum, on either chemical-induced or blue light-induced endoplasmic reticulum (ER) stress. Pentadecyl suppressed cell death induced by either thapsigargin or tunicamycin in a concentration-dependent manner. Pentadecyl also suppressed the expression of unfolded protein response target genes, including Atf4 and ER chaperones. Consistently, immunoblotting revealed that Pentadecyl suppressed the increased expression of ATF4 at the protein level. Pentadecyl also protected 661W cells from blue light-induced damage but did not protect against hydrogen peroxide (H2O2)-induced oxidative stress. These results indicated that Pentadecyl has a novel function that protects against ER stress induced by photodamage.

This study aimed to elucidate how adding uracil to the culture medium enhanced the freeze-drying resistance of Lactiplantibacillus plantarum YR07. The results showed that uracil significantly increased the number of viable cells and the freeze-drying survival rate of L. plantarum YR07 (P < 0.05). This effect was primarily achieved through the regulation of several key genes, including those involved in energy production (pyrR, pyrB, purQ, purN, adhE), cell barrier protection (fabG, serS), cell repair (oppA, uvrC), and oxidative stress response (cysK). Specifically, uracil promoted energy production and substrate availability by upregulating genes related to carbohydrate metabolism and purine biosynthesis. Additionally, uracil enhanced the synthesis of unsaturated fatty acids and glutamine biosynthesis by regulating the expression of genes related to the cell wall and membrane, thereby strengthening the physical protective barrier. Furthermore, by promoting the expression of genes involved in DNA and protein repair, uracil provided the raw materials necessary for cellular repair and helped restore damaged structures by influencing nucleotide metabolism and protein synthesis. Uracil also stimulated the production of sulfur-containing amino acids, which helped L. plantarum YR07 resist oxidative stress and reduce cellular damage. Together, these regulatory mechanisms significantly enhanced the adaptive capacity of L. plantarum YR07 under harsh environmental conditions.

Diet is the primary source of riboflavin (B2) for humans. It can also be produced by lactic acid bacteria ingested with foods and by gut microbial commensals, including some bifidobacteria. Herein an in silico analysis of potential regulatory mechanisms affecting ribD transcription and translation in Bifidobacterium longum subsp. infantis is presented. Riboflavin-overproducing strains were selected by treatment with roseoflavin of B. longum susbp. infantis CECT4551T and its spontaneous derivative IPLA60011. Whole genomes of both parental strains and the sequencing of the rib clusters of the riboflavin-overproducing ones were conducted. Punctual mutations affecting different stem-loops in the aptamer region of the FMN-riboswitch involved in the regulation of the rib expression were detected. Riboflavin overproduction of the derivative strains was confirmed through HPLC quantification in RAMc and MRSc cultures, ranging from 64.9 to 441.2 μg/L. These levels correlated to predicted secondary folding and stability of the aptamer region and/or expression platform of the rib FMN riboswitch. Safety and technological properties of the riboflavin-overproducing derivatives, in terms of antibiotic resistance profile and carbohydrate utilization capabilities, were not altered following roseoflavin exposure, thus confirming the potential aptitude of the riboflavin-overproducing derivatives to produce biofortified foods such as those formulated on dairy matrixes.

Lupus nephritis (LN) is characterised by renal endothelial dysfunction, which contributes to progressive kidney injury. Endothelial nitric oxide synthase (eNOS) plays a modulating role in LN, as genetic ablation of the eNOS enzyme worsens disease. Serum from patients with active LN induces uncoupling of eNOS homodimers, leading to superoxide (SO) rather than nitric oxide (NO) production by eNOS. This uncoupling is reversed with L-sepiapterin (L-Sep). This study was designed to further examine changes in gene expression in glomerular endothelial cells induced by LN serum and whether treatment with L-Sep can ameliorate these changes.