Nanoplastics (NPs) represent a major challenge in environmental contamination resulting from the physical, chemical, and biological degradation of plastics. Their characterization requires advanced and expensive methods, which limit routine analyses. The biological effects of NPs depend on their chemical and physical properties, which influence toxicity and interactions with biological systems. Studies in animal models, such as Daphnia magna and Danio rerio, show that NPs induce oxidative stress, inflammation, DNA damage, and metabolic alterations, often related to charge and particle size. NPs affect endocrine functions by acting as endocrine disruptors, interfering with thyroid and sex hormones and showing potential transgenerational effects through epigenetic modifications, including DNA hyper- and hypomethylation. Behavioral and neurofunctional alterations have been observed in Danio rerio and mouse models, suggesting a link between NP exposure and neurotransmitters such as dopamine and serotonin. Despite limited human studies, the presence of NPs in breast milk and placenta underscores the need for further investigation of health effects. Research focusing on genetic and epigenetic markers is encouraged to elucidate the molecular mechanisms and potential risks associated with chronic exposure.

Gastrointestinal (GI) cancers, which mainly include malignancies of the esophagus, stomach, intestine, pancreas, liver, gallbladder, and bile duct, pose a significant global health burden. Unfortunately, the prognosis for most GI cancers remains poor, particularly in advanced stages. Current treatment options, including targeted and immunotherapies, are less effective compared to those for other cancer types, highlighting an urgent need for novel molecular targets. NEK (NIMA related kinase) kinases are a group of serine/threonine kinases (NEK1-NEK11) that play a role in regulating cell cycle, mitosis, and various physiological processes. Recent studies suggest that several NEK members are overexpressed in human cancers, including gastrointestinal (GI) cancers, which can contribute to tumor progression and drug resistance. Among these, NEK2 stands out for its consistent overexpression in all types of GI cancer. Targeting NEK2 with specific inhibitors has shown promising results in preclinical studies, particularly for gastric and pancreatic cancers. The development and clinical evaluation of NEK2 inhibitors in human cancers have emerged as a promising therapeutic strategy. Specifically, an NEK2 inhibitor, T-1101 tosylate, is currently undergoing clinical trials. This review will focus on the gene expression and functional roles of NEKs in GI cancers, as well as the progress in developing NEK inhibitors.

As key enzymes in the gibberellin (GA) biosynthesis pathway, GAoxs function as regulators of bioactive GA levels and plant architecture, yet little is understood about GAoxs in Gossypium. In this study, 78 GAox genes identified in four cotton species were divided into three subgroups: GA2ox, GA3ox, and GA20ox. Syntenic relationships of GAoxs in Gossypium suggested that divergencies in gene function may be attributed to whole-genome duplication during evolution. Cis-acting element analysis suggested that the GbGAox genes might participate in plant growth, development, and hormone responses. Moreover, transcriptome analysis was performed to characterize the molecular response of the exogenous GA3 application. It was found that DEGs (differentially expressed genes) are widely involved in cell division and cell wall modification, in which the most XTH (xyloglucan endotransglucosylase/hydrolase) and GAox genes responded actively to the exogenous GA3 treatment. Some transcription factors and protein kinases cooperated with those GbGAoxs in response to GA3. These findings underlie the biological function of GAox genes and their responses to GA3 in regulating plant growth in Gossypium barbadense.

Triple-negative breast cancer (TNBC) is a type of breast cancer characterized by high molecular heterogeneity. Owing to the lack of effective therapeutic strategies, patients with TNBC have a poor prognosis. Prunella vulgaris L. has the effects of reducing swelling, dissolving knots and treating breast carbuncles and mammary rocks. Modern pharmacological studies have reported that it can effectively inhibit the growth of breast cancer. The main active antitumor components of Prunella vulgaris are triterpenoids (PVT); however, the role and potential mechanism of PVT in TNBC remain unexplored. Our study aimed to further explore the inhibitory effects of PVT on TNBC and the associated mechanism. The results showed that 19 compounds associated with PVT were identified, 9 of which were triterpenoids. The percentages of ursolic acid and oleanolic acid in PVT were 34.51% and 11.32%, respectively. Triterpenes of Prunella vulgaris significantly inhibited the proliferation, migration and invasion of MDA-MB-231 cells and promoted their apoptosis in a concentration-dependent manner. PVT could also effectively downregulate the mRNA and protein expression levels of Ptp1b, Pi3k, Akt and mtor and upregulate the mRNA and protein expression levels of Il-24 in MDA-MB-231 cells. In mice with tumors of TNBC, PVT significantly reduced tumor growth and the expression levels of PTP1B, CXCL12, CXCR4, PI3K, AKT, mTOR and other proteins in TNBC tumor tissue and upregulated the expression of IL-24. This study showed that PVT played an anti-TNBC role by regulating the PTP1B/PI3K/AKT/mTOR signaling pathway and the IL-24/CXCL12/CXCR4 signaling axis.

Apyrases (APYs) directly regulate intra- and extra-cellular ATP homeostasis and play a key role in the process of plants adapting to various stresses. In this study, we identified and characterized soybean APY (GmAPY) family members at the genomic level. The results identified a total of 18 APYRASE homologous genes with conserved ACR domains. We conducted a bioinformatics analysis of GmAPYs, including sequence alignment, phylogenetic relationships, and conserved motifs. According to the phylogenetic and structural characteristics, GmAPYs in soybeans are mainly divided into three groups. The characteristics of these GmAPYs were systematically evaluated, including their collinearity, gene structure, protein motifs, cis-regulatory elements, tissue expression patterns, and responses to aluminum stress. A preliminary analysis of the function of GmAPY1-4 was also conducted. The results showed that GmAPY1-4 was localized in the nucleus, presenting relatively high levels in roots and root nodules and demonstrating high sensitivity and positive responses under aluminum stress circumstances. Further functional characterization revealed that the overexpression of GmAPY1-4 in hairy roots not only induced root growth under normal growth conditions but also significantly prevented root growth inhibition under aluminum stress conditions and contributed to maintaining a relatively higher fresh root weight. By contrast, RNAi interference with the expression of GmAPY1-4 in hairy roots inhibited root growth under both normal and aluminum stress conditions, but it exerted no significant influence on the dry or fresh root weight. To sum up, these findings support the significant functional role of GmAPY1-4 in root growth and the aluminum stress response. These findings not only enhance our comprehension of the aluminum stress response mechanism by identifying and characterizing the APY gene family in the soybean genome but also provide a potential candidate gene for improving aluminum tolerance in soybeans in the future.

Afatinib-induced tumor and microenvironment modifications in head and neck squamous cell carcinoma were evaluated by spatial transcriptomics in surgical specimens and RNA-sequencing in tumor biopsies of patients included in the EORTC-90111-24111 window-of-opportunity study. The aim was to explore tumor evolution and composition under anti-HER therapy. Based on our previous investigations by RNA-seq on tumor biopsies, surgical slides of ID08 and ID15 from the epithelial-to-mesenchymal (EMT) cluster and ID30 from the non-EMT cluster were investigated with spatial transcriptomics. Dimension reduction in ID30 revealed 14 clusters, with clusters overlapping three tumor nodules and the stroma. Differential expression analysis between tumor nodules showed enrichment of the hallmark EMT genelist, with 123 genes in common between the analyses. These genes were involved in PDGF and MET signaling pathways. By comparing gene expression in paired tumor biopsies and the 123 genes from differential analyses obtained in ID30, a list of 13 genes involved in cancer pathways and EMT emerged, which were also highly expressed in ID08 and ID15. These results show a progressive apparition of genes implicated in EMT, MET, and PDGF pathways in tumors after afatinib. Notably, a list of 13 genes emerged which may contain targets to prevent tumor evolution after anti-HER therapy.

To successfully metastasize, cancer cells must evade detachment induced cell death, known as anoikis. Unraveling the mechanisms that gastric cancer (GC) circumvent anoikis and achieve peritoneal metastasis especially during unanchored growth, could significantly improve patient outcomes. Our study reveals that GC cells exhibit increased lipid peroxidation, MDA production, and cell death during suspension culture, which can be mitigated by the intervention with liproxstatin-1 and ferrostatin-1. We discovered that oleic acid (OA) or adipocytes stimulate lipid accumulation in GC cells, thereby inhibiting lipid peroxidation and cell death. Lipid mass spectrometry confirmed an upregulation of triglyceride synthesis, indicating that the accumulation of lipid droplet may confer resistance to ferroptosis during suspension growth. In vitro assays demonstrated that OA not only induces lipid droplet accumulation but also upregulates the expression of ferroptosis suppressor protein 1 (FSP1), a process that can be abrogated by the double knockout of GPD1/1L genes. Additionally, we have demonstrated that a decrease in the ubiquitination of FSP1 in GC cells upon lipid droplet accumulation, as well as silencing or pharmacological targeting FSP1, promotes ferroptosis and disrupts the peritoneal metastatic potential of GC cells. Collectively, our findings highlight the potential of FSP1 as a promising therapeutic target for metastatic gastric cancer.

Lymphatic metastasis is a well-known factor for initiating distant metastasis of head and neck squamous cell carcinoma (HNSCC), which caused major death in most patients with cancer. Meanwhile, metabolic reprogramming to support metastasis is regarded as a prominent hallmark of cancers. However, how metabolic disorders drive in HNSCC remains unclear. We firstly established a new classification of HNSCC patients based on metabolism gene expression profiles from the TCGA and GEO database, and identified an enriched carbohydrate metabolism subgroup which was significantly associated with lymphatic metastasis and worse clinical outcome. Moreover, we found that highly activated pyruvate metabolism endowed tumors with EPHB2 upregulation and promoted tumor lymphangiogenesis independently of VEGF-C/VEGFR3 signaling pathway. Mechanically, high nuclear acetyl-CoA production from pyruvate metabolism promoted histone acetylation, which in turn transcriptionally upregulated EPHB2 expression and secretion in tumor cells. EPHB2 bound with EFNB1 in lymphatic endothelial cells promoted YAP/TAZ cytoplasmic retention, which alleviated YAP/TAZ-mediated prospero homeobox protein 1 (PROX1) transcriptional repression, and then triggered tumor lymphangiogenesis. Importantly, combined treatment with EFNB1-Fc and VEGFR3 inhibitor synergistic abrogated lymphangiogenesis in vitro and in vivo, suggesting that targeting EPHB2 might be a potential strategy to patients with no or slight response to VEGFR3 inhibitor. These findings uncover the mechanism by which pyruvate metabolism is linked to lymphatic metastasis of tumor and provides a promising therapeutic strategy for the prevention of HNSCC metastasis.

Sweet sorghum (Sorghum bicolor Moench) seedling emergence and growth are significantly impeded by physical soil crusts (PSCs) in saline-alkaline soils. Abscisic acid (ABA) is a potent seed priming agent known for modulating plant physiological and metabolic responses under salinity stress. However, the influence of ABA priming on seedling emergence in PSCs remains unclear. This study conducted both pot and field experiment to examine the effects of ABA priming on enhancing seedling emergence under PSC conditions. ABA priming altered the balance of at least 24 endogenous phytohormones, including abscisic acid, jasmonic acid, gibberellins, ethylene, auxins, and cytokinins. Additionally, it reprogrammed starch and sucrose metabolism, resulting in the differential expression of genes encoding key enzymes such as AMY, BAM, and INV, which are crucial for converting complex sugars into readily available energy sources, thereby supporting seedling growth. Furthermore, 52 differentially expressed metabolites (DEMs) of flavonoids were identified in germinating seedlings, including 15 anthocyanins, 3 flavones, 7 flavonols, 6 isoflavones, 7 flavanones, and 14 other flavonoids. Genetic and metabolic co-expression network analysis, along with flavonoid biosynthesis pathway exploration, revealed that the biosynthesis of 17 key DEMs-including liquiritigenin, apigenin, kaempferide, syringetin, phloretin, formononetin, dihydrokaempferol, and xanthohumol-was regulated by 10 differentially expressed genes (DEGs) associated with flavonoid biosynthesis. These DEGs encoded 7 enzymes critical for this pathway, including chalcone synthase, shikimate O-hydroxycinnamoyltransferase, bifunctional dihydroflavonol 4-reductase, naringenin 7-O-methyltransferase, and anthocyanidin reductase. This regulation, along with reduced levels of superoxide anion (O2-) and malondialdehyde and increased antioxidant enzyme activities, suggested that flavonoids played a vital role in mitigating oxidative stress. These findings demonstrate that ABA priming can effectively enhance sweet sorghum seedling emergence in PSCs by accelerating emergence and boosting stress resistance.

The ability of plant growth-promoting rhizobacteria (PGPR) to alleviate iron deficiency-induced chlorosis in plants has been widely reported, but the role of siderophores in the re-greening process has rarely been investigated. In this study, the Priestia megaterium ZS-3 (ZS-3) siderophore was first characterized, and a 100-fold concentration of the crude extract of the siderophore was extracted by solid-phase extraction and used to inoculate Arabidopsis thaliana to investigate whether the ZS-3 siderophore could alleviate plant iron deficiency-induced chlorosis in the presence of an insoluble iron source and to determine how it promoted plant growth.

Proteasome is an essential organelle responsible for maintaining cellular protein homeostasis, but its relationship with DNA methylation remains unknown. In this study, we assessed DNA methylation of colorectal cancer (CRC) cells following treatment with proteasome inhibitors, and investigated the underlying mechanism of DNA methylation changes and the biological effects on CRC cells. We established that inhibition of proteasome leads to significant alterations in DNA methylation profile in CRC by suppressing the synthesis of DNA methyltransferases (DNMTs). We found that treating CRC cells with proteasome inhibitors results in attenuated translation of DNMT1 and DNMT3B, mediated by the inactivation of AKT and mammalian target of rapamycin (mTOR), which is dependent on the accumulation of p300, an acetyltransferase that inhibits AKT through acetylation modification. Furthermore, we demonstrated that downregulation of DNMT1 and DNMT3B confers protection against proteasome inhibitor treatment, potentially through reprogramming the transcriptome of CRC cells, highlighting the significant role of DNMTs in response to disruptions in protein homeostasis. Interestingly, it appears that the proteasome inhibitor-induced downregulation of DNMT1 and DNMT3B is specific to CRC. Altogether, our findings reveal an epigenetic effect of proteasome on DNA methylation in CRC through its regulation of DNA methyltransferase synthesis.

Objective. It is known that inhibition of the endoplasmic reticulum transmembrane signaling protein (ERN1) suppresses the glioblastoma cells proliferation. The present study aims to investigate the impact of inhibition of ERN1 endoribonuclease and protein kinase activities on the TOB1, HBEGF, and TWIST1 gene expression in U87MG glioblastoma cells with an intent to reveal the role of ERN1 signaling in the regulation of expression of these genes. Methods. The U87MG glioblastoma cells with inhibited ERN1 endoribonuclease (dnrERN1) or both enzymatic activities of ERN1 (endoribonuclease and protein kinase; dnERN1) were used. Cells transfected with empty vector served as controls. Wild-type glioblastoma cells were used for mRNA silencing. The expression level of the TOB1, HBEGF, and TWIST1 genes and microRNA were studied by quantitative RT-PCR. Results. We found that inhibition of ERN1 endoribonuclease activity led to a strong down-regulation of HBEGF gene expression in glioblastoma cells and did not significantly change the expression of TOB1 and TWIST1 genes. At the same time, inhibition of both enzymatic activities of ERN1 strongly increased the expression of the TOB1 gene and down-regulated HBEGF and TWIST1 genes in glioblastoma cells. The expression of TWIST1 gene increased, but HBEGF and TOB1 genes significantly decreased in cells with silencing of ERN1 mRNA by specific siRNA. At the same time, silencing of XBP1 mRNA reduced the expression of HBEGF gene only. In addition, in glioblastoma cells with ERN1 knockdown, the level of miR-96-5p was suppressed, but miR-182-5p was increased and could promote post-transcriptional expression of TWIST1, HBEGF, and TOB1 mRNAs. Conclusion. The results of the present study demonstrate that inhibition of ERN1 strongly up-regulated the expression of the anti-proliferative TWIST1 gene through protein kinase activity of ERN1 and that decreased HBEGF and TOB1 genes expression was also controlled preferentially by ERN1 protein kinase activity. These changes in the expression level of TWIST1, HBEGF, and TOB1 genes may also contribute to ERN1 knockdown-mediated suppression of glioblastoma cells proliferation.

The emergence and rapid spread of multidrug-resistant Botrytis cinerea strains pose a great challenge to the quality and safety of agricultural products and the efficient use of pesticides. Previously unidentified fungicides and targets are urgently needed to combat B. cinerea-associated infections as alternative therapeutic options. In this study, the promising compound Z24 demonstrated efficacy against all tested plant pathogenic fungi. Thiamine thiazole synthase (Bcthi4) was identified as a target protein of Z24 by drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) assays. Molecular docking and enzyme activity experiments have demonstrated that Z24 can affect the function of Bcthi4. Last, mechanistic studies show that Z24 inhibits thiamine biosynthesis by binding to Bcthi4 and induces up-regulation of alternative splicing [alternative 5' splice site (A5SS)] of the Bcthi4 gene. In conclusion, by targeting Bcthi4, Z24 has the potential to be developed as a previously unidentified anti-B. cinerea candidate.

Novel treatment options are needed for the gastric pathogen Helicobacter pylori due to its increasing antibiotic resistance. The vitamin K analogue menadione has been extensively studied due to interest in its anti-bacterial and anti-cancer properties. Here, we investigated the effects of menadione on H. pylori growth, viability, antibiotic resistance, motility and gene expression using clinical isolates. The MIC of menadione was 313 µM for 11/13 isolates and 156 µM for 2/13 isolates. The minimum bactericidal concentrations were 1.25-2.5 mM, indicating that concentrations in the micromolar range were bacteriostatic rather than bactericidal. We were not able to experimentally evolve resistance to menadione in vitro. Sub-MIC menadione (16 µM for 24 h) did not significantly inhibit bacterial growth but significantly (P<0.05) changed the expression of 1291/1615 (79.9%) genes encoded by strain 322A. The expression of the virulence factor genes cagA and vacA was downregulated in the presence of sub-MIC menadione, while genes involved in stress responses were upregulated. Sub-MIC menadione significantly (P<0.0001) inhibited the motility of H. pylori, consistent with the predicted effects of the observed significant (P<0.05) downregulation of cheY, upregulation of rpoN and changes in the expression of flagellar assembly pathway genes seen in the transcriptomic analysis. Through in-depth interrogation of transcriptomic data, we concluded that sub-MIC menadione elicits a general stress response in H. pylori with survival in the stationary phase likely mediated by the upregulation of surE and rpoN. Sub-MIC menadione caused some modest increases in H. pylori susceptibility to antibiotics, but the effect was variable with strain and antibiotic type and did not reach statistical significance. Menadione (78 µM) was minimally cytotoxic to human gastric adenocarcinoma (AGS) cells after 4 h but caused a significant loss of cell viability after 24 h. Given its inhibitory effects on bacterial growth, motility and expression of virulence- and colonization-associated genes, menadione at low micromolar concentrations may have potential utility as a virulence-attenuating agent against H. pylori.

A previously reported clinical trial in familial adenomatous polyposis (FAP) patients treated with erlotinib plus sulindac (ERL + SUL) highlighted immune response/interferon-γ signaling as a key pathway. In this study, we combine intermittent low-dose ERL ± SUL treatment in the polyposis in rat colon (Pirc) model with mechanistic studies on tumor-associated immune modulation. At clinically relevant doses, short-term (16 weeks) and long-term (46 weeks) ERL ± SUL administration results in near-complete tumor suppression in Pirc colon and duodenum (p < 0.0001). We identify a low-dose threshold for significant antitumor activity in Pirc rats given SUL at 125 ppm in the diet plus ERL at 5 mg/kg body weight via twice-weekly oral gavage (SUL125 + ERL5 × 2). Longitudinal analyses show diminished expression of MHC class I and II genes in polyps larger than Grade 5, a novel finding in the Pirc model. Treatment with ERL ± SUL upregulates the corresponding MHC and immune-associated factors in a subset of Pirc colon polyps, Pirc tumor cell lines, murine colon carcinoma cells, and FAP patient-derived organoids, with Nlrc5 playing a critical role in this effect. Imaging mass cytometry reveals that SUL125 + ERL5 × 2 increases tumor-associated Cd4+ T cells by ~2.6-fold (p < 0.05), with no apparent effect on Cd8+ T cells. The treatment also increases tumor-associated Cd68+ cells (p < 0.05) and decreases Foxp3+ (p < 0.01) and Arg1+ (p < 0.05) cells. Thus, intermittent low-dose ERL + SUL treatment enhances tumor-associated MHC expression and remodels the immune cell niche toward a more permissive "helper" immune microenvironment. We conclude that early immune-interception strategies targeting interferon-γ signaling may benefit FAP patients at drug doses below the clinical standard of care.

Ageing is a major risk factor for cognitive and physical decline, but its mechanisms remain poorly understood. This study aimed to detect early cognitive and physical changes, and to analyze the pathway involved by monitoring two groups of mice: a young and an adult group. The study has identified the types of molecules involved in the hippocampus. Adult mice (47 weeks) showed significantly reduced exploratory behavior compared to young mice (11 weeks), although spatial working memory showed no difference. In terms of physical function, grip strength was significantly reduced in adult mice. The Frailty Index (FI) further highlighted age-related changes in adult mice. To investigate the causes of cognitive decline, adult mice were categorized based on their declining cognitive function. Microarray analysis of their hippocampi revealed that the cholinergic receptor nicotinic α3 subunit (Chrna3) was significantly reduced in mice with cognitive decline compared to controls. Subsequent in vitro experiments showed that oxidative stress and cholinesterase inhibitors decreased Chrna3 expression, whereas nicotine and cytisine increased it. These results suggest that Chrna3 is a key factor in age-related cognitive decline. The development of therapeutic strategies targeting Chrna3 expression may offer promising avenues for preclinical and clinical research to mitigate cognitive ageing.

Synthetic RNA devices are engineered to control gene expression and offer great potential in both biotechnology and clinical applications. Here, we present multidisciplinary structural and biochemical data for a tetracycline (Tc)-responsive RNA device (D43) in both ligand-free and bound states, providing a structure-dynamical basis for signal transmission. Activation of self-cleavage is achieved via ligand-induced conformational and dynamical changes that stabilize the elongated bridging helix harboring the communication module, which drives proper coordination of the catalytic residues. We then show the utility of CRISPR-integrated D43 in EL4 lymphocytes to regulate programmed cell death protein 1 (PD-1), a key receptor of immune checkpoints. Treatment of these cells with Tc showed a dose-dependent reduction in PD-1 by immunostaining and a decrease in messenger RNA levels by quantitative PCR as compared with wild type. PD-1 expression was recoverable upon removal of Tc. These results provide mechanistic insight into RNA devices with potential for cancer immunotherapy or other applications.

Mutations in the TP53 gene may lead to the loss of its tumor suppressor function and the acquisition of oncogenic properties. The enhanced stability of mutant p53 (mutp53) is one of the pivotal factors for its oncogenic functions, rendering proteins implicated in mutp53 stabilization as promising targets for therapeutic intervention. Although deubiquitinases (DUBs) are commonly deregulated in various cancers, their specific impact on mutp53 stabilization remains largely unexplored. In this study, we demonstrated the involvement of DUBs-USP5 and USP9X in-enhancing mutp53 stability while revealing the effects of DUB inhibitor WP1130 in selectively destabilizing different p53 mutants in cancer cells of various origins. Mechanistically, WP1130 induced mutp53 ubiquitination and nuclear aggregation, resulting in its partitioning to the detergent-insoluble fraction. Moreover, combined treatment with the proteasome inhibitor augmented mutp53 accumulation in this fraction, indicating proteasomal degradation of these aggregates. Interestingly, WP1130 did not alter the stability or induce aggregation of WTp53 protein, suggesting its selective targeting of mutp53. Furthermore, WP1130 disrupted the interaction of mutp53 with HSP40 and HSP90 while promoting its association with ubiquitin ligase CHIP, thereby facilitating mutp53 destabilization. Notably, WP1130 reactivated mutp53 via induction of a wild-type-like p53 conformation, upregulating its downstream effectors and inducing apoptosis, possibly due to its targeted binding near the mutation site, as suggested by our in silico analysis. These findings highlight the roles of USP9X and USP5 in mutp53 stabilization and underscore the therapeutic potential of DUB inhibitor WP1130 for the selective targeting of mutp53-expressing cancer cells.

Senile pruritus is a specific type of itching that occurs in elderly persons. Previously, we assessed antagonism of the nonselective ligand-gated cation channel transient receptor potential vanilloid 1 (TRPV1; capsaicin receptor or vanilloid receptor 1) and attenuation of atopic dermatitis by the non-steroidal TRPV1 antagonist PAC-14028 in clinical studies. The findings led us to postulate that PAC-14028 may also reduce itching in elderly people by antagonizing the TRPV1 pathway. In this study, we evaluated whether PAC-14028 modulates inflammatory markers present in senile pruritus.

The increase in metabolic dysfunction-associated steatotic liver disease (MASLD) and its progression to metabolic dysfunction-associated steatohepatitis (MASH) is a worldwide healthcare challenge. Heterogeneity between men and women in the prevalence and mechanisms of MASLD and MASH is related to differential sex hormone signalling within the liver, and declining hormone levels during aging. In this study we used biochemically characterised pluripotent stem cell derived 3D liver spheres to model the protective effects of testosterone and estrogen signalling on metabolic liver disease 'in the dish'. We identified sex steroid-dependent changes in gene expression which were protective against metabolic dysfunction, fibrosis, and advanced cirrhosis patterns of gene expression, providing new insight into the pathogenesis of MASLD and MASH, and highlighting new druggable targets. Additionally, we highlight gene targets for which drugs already exist for future translational studies.