Lung cancer is the leading cause of cancer deaths among American men, even though various treatments are available. The discovery and use of new alternative drugs to treat lung cancers are needed to reduce lung cancer mortality. Phytochemicals are potentially desirable therapeutic agents due to their better safety profiles. Isorhapontigenin (ISO) is an orally bioavailable dietary stilbene. Our studies show that treatment with ISO inhibits human lung cancer cell growth, angiogenesis, invasion, and migration. Neural precursor cell expressed developmentally downregulated 9 (NEDD9), a multi-domain scaffolding protein, regulates various processes crucial for tumorigenesis and metastasis. Our results show that NEDD9 is upregulated in the lung tissues from human lung adenocarcinomas (LUADs) and squamous-cell carcinomas (LUSCs) compared to normal lungs. Overexpression of NEDD9 elevates the invasion and migration of human lung cancer cells. Treatment of human lung cancer cells with ISO decreases NEDD9 protein levels. Our studies have also demonstrated that NEDD9 positively regulates angiogenesis, an essential factor in cancer progression. ISO treatment reduces angiogenesis. Moreover, ISO reduces the protein levels of hypoxia-inducible factor-1α (HIF-1α), a transcription factor critical for angiogenesis. Aberrant high expression of β-Catenin leads to various diseases including cancer. Our results show that ISO treatment reduces the activation of β-Catenin through the downregulation of NEDD9. Studies indicate that ISO decreases NEDD9, causing the suppression of cell growth, angiogenesis, invasion, and migration of human lung cancer cells. ISO is a potent therapeutic agent for lung cancer treatment.

Thyroid hormone (TH) plays a vital role in ovarian follicle development, and glucose-regulated protein 78 (GRP78) is involved in these processes, which is regulated by TH. However, the mechanisms are still unclear. To evaluate the possible mechanism of TH on the regulation of GRP78 expression, Cleavage Under Targets and Tagmentation (CUT & Tag) sequencing, luciferase assays, and Electrophoretic Mobility Shift Assays (EMSA) were employed to delineate the binding sites of thyroid hormone receptor β (TRβ) on the GRP78 promoter and to confirm the interactions. Additionally, Co-Immunoprecipitation (Co-IP) and Immunofluorescence (IF) assays were used to investigate the interactions between TRβ and the coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) after triiodothyronine (T3) treatment with different concentrations. Our findings identified a thyroid hormone response element (TRE) on the GRP78 promoter and demonstrated that TRβ can activate GRP78 expression by interacting with PGC-1α. In order to simulate the condition of hyperthyroidism, granulosa cells (GCs) extracted from rats were treated by T3 with high concentrations, which decreased the expression of PGC-1α, resulting in decreased expressions of GRP78 and other ferroptosis-related markers such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11, xCT), thereby inducing ferroptosis in GCs. Taken together, the present study demonstrates that T3 induces cellular ferroptosis by binding TRE of the GRP78 promoter in ovarian GCs via TRβ. As a switcher, PGC-1α is also involved in these processes.

Resistance to tyrosine kinase inhibitors (TKIs, e.g., sorafenib and lenvatinib) presents a significant hurdle for hepatocellular carcinoma (HCC) treatment, underscoring the need to decipher the underlying mechanisms for improved therapeutic strategies. MicroRNAs (miRNAs) have emerged as critical modulators in HCC progression and TKI resistance. In this study, we report a positive correlation between the expression levels of a tumor suppressor miRNA, miR-142-3p, and increased sensitivity to sorafenib and lenvatinib, supported by clinical data from the BIOSTORM HCC cohort. Overexpression of miR-142-3p in TKI-resistant HCC cells significantly inhibited proliferation and colony formation, induced apoptosis, increased cell cycle arrest at the G2 phase, and reduced migration and invasion by reversing epithelial-mesenchymal transition. Notably, combining miR-142-3p with lenvatinib synergistically inhibited growth in both inherent and acquired TKI-resistant HCC cells by modulating critical signaling pathways, including STAT3, PI3K/AKT, MAPK, YAP1, and by impeding autophagic influx. RNA-sequencing of a TKI-resistant HCC cell line ± miR-142-3p overexpression identified YES1 and TWF1 as direct downstream target genes of miR-142-3p, both of which are key genes associated with drug resistance in HCC. Small interfering RNA (siRNA)-mediated knockdown of these genes mirrored the antitumor effects of miR-142-3p and enhanced TKI sensitivity, with YES1 knockdown decreasing YAP1 phosphorylation, and TWF1 knockdown inhibiting autophagy. Collectively, these findings indicate that restoring miR-142-3p expression or targeting its downstream effectors YES1 and TWF1 offers a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC.

The success of assisted reproductive technology is contingent upon the growth potential of embryos post-vitrification process. When compared to in vivo embryos, it has been found that the high intracellular lipid accumulation inside the in vitro-derived embryos results in poor survival during vitrification. Based on this finding, the present study assessed the impact of incorporating forskolin and linoleic acid (FL) entering in vitro culture (IVC) on the embryos' cryo-survival, lipid content, and viability throughout vitrification. Lipid metabolomics and single-cell RNA sequencing (scRNA-seq) techniques were used to determine the underlying mechanism that the therapies were mimicking. It was observed that out of 726 identified lipids, 26 were expressed differentially between the control and FL groups, with 12 lipids upregulated and 14 lipids downregulated. These lipids were classified as Triacylglycerol (TG), Diacylglycerol (DG), Phosphatidylcholine (PC), and so on. A total of 1079 DEGs were detected between the FL and control groups, consisting of 644 upregulated genes and 435 downregulated genes. These DEGs were significantly enhanced in the arachidonic acid metabolism, lipolysis, fatty acid metabolism, cAMP signaling pathway, and other critical developmental pathways. Based on the observation, it was concluded that forskolin and linoleic acid decreased the droplet content of embryos by modulating lipid metabolism, thus enhancing the vitrified bovine embryos' cryo-survival.

Tramadol, a widely used analgesic, has recently been explored for its potential anti-cancer effects. However, the antitumor dosage of tramadol is over its current clinical application. Its primary metabolite, O-desmethyltramadol, has greater μ-opioid receptor affinity and stronger pharmacological activity. Hence, we sought to examine whether the cytotoxic effect of O-desmethyltramadol was better than tramadol on breast cancer cells. Our results showed that O-desmethyltramadol significantly reduced cell viability in breast cancer cells, with IC50 values of 64.2 μg/mL (MDA-MB-231) and 96.7 μg/mL (MCF-7), demonstrating over ten-fold greater potency than tramadol. The presence of a μ-opioid receptor antagonist Alvimopan did not alter the cytotoxic effects of tramadol and O-desmethyltramadol, indicating a non-opioid receptor-mediated mechanism. Compared with antitumor activity of tramadol mediated through ER stress, we confirmed that O-desmethyltramadol induced ER stress proteins, including the p-eIF2α/eIF2α ratio, ATF4, and CHOP. In MDA-MB-231 cells, O-desmethyltramadol treatment elevated mRNA expression levels of ATF4, CHAC1, and DDIT3 by approximately 2-fold. In MCF-7 cells, the induction was even more pronounced, with ATF4 increased 1.7-fold, CHAC1 12-fold, and DDIT3 9-fold. Beyond the opioid receptor-mediated pathway, we further analyzed the differential functions of O-desmethyltramadol than tramadol using the RNA-seq analysis. The pathway enrichment analyses revealed that O-desmethyltramadol influenced immune and inflammatory pathways, such as TNF and IL-6/JAK/STAT3 signaling in MDA-MB-231 cells, while in MCF-7 cells, it affected metabolic and transcriptional pathways, including mTOR and MAPK signaling. Gene Set Enrichment Analysis further highlighted O-desmethyltramadol's role in interferon response and tumor microenvironment modulation. Four upregulated genes and five downregulated genes were modulated by O-desmethyltramadol in MDA-MB-231 and MCF-7 cells. Overall, our findings indicated that O-desmethyltramadol exerted potent anti-cancer effects through multiple non-opioid mechanisms, with distinct response from tramadol depending on breast cancer subtype. These findings not only highlight the therapeutic potential of O-desmethyltramadol as a novel adjunct in breast cancer treatment, but also emphasize the need for further investigation into its safety and clinical applicability in oncology.

Chalcones, potential anticancer agents, have shown promise in the suppression of multidrug resistance due to the inhibition of drug efflux driven by certain adenosine triphosphate (ATP)-binding cassette (ABC) transporters. The gene and protein expression of chosen ABC transporters (multidrug resistance protein 1, ABCB1; multidrug resistance-associated protein 1, ABCC1; and breast cancer resistance protein, ABCG2) in human colorectal cancer cells (COLO 205 and COLO 320, which overexpress active ABCB1) was mainly studied in this work under the influence of a novel synthetic acridine-based chalcone, 1C. While gene expression dropped just at 24 h, compound 1C selectively suppressed colorectal cancer cell growth and greatly lowered ABCB1 protein levels in COLO 320 cells at 24, 48, and 72 h. It also reduced ABCC1 protein levels after 48 h. Molecular docking and ATPase tests show that 1C probably acts as an allosteric modulator of ABCB1. It also lowered galectin-1 (GAL1) expression in COLO 205 cells at 24 h. Functional tests on COLO cells revealed ABCB1 and ABCC1/2 to be major contributors to multidrug resistance in both. Overall, 1C transiently lowered GAL1 in COLO 205 while affecting important functional ABC transporters, mostly ABCB1 and to a lesser extent ABCC1 in COLO 320 cells. COLO 320's absence of GAL1 expression points to a possible yet unknown interaction between GAL1 and ABCB1.

Although a myocardial infarction occurs roughly every minute in the U.S. alone, medical research has yet to unlock the key to fully enabling post-hypoxic myocardial regeneration. Thymosin beta-4 (TB4), a short, secreted peptide, was shown to possess a beneficial impact regarding myocardial cell survival, coronary re-growth and progenitor cell activation following myocardial infarction in adult mammals. It equally reduces scarring, however, the precise mechanisms through which the peptide assists this phenomenon have not been properly elucidated. Accordingly, the primary aim of our study was to identify novel molecular contributors responsible for the positive impact of TB4 during the remodeling processes of the infarcted heart. We performed miRNA profiling on adult mice hearts following permanent coronary ligation with or without systemic TB4 injection and searched for targets and novel mechanisms through which TB4 may mitigate pathological scarring in the heart. Our results revealed a significant increase in miR139-5p expression and identified ROCK1 as a potential target protein aligned. Real-time PCR, Western blot and immunostaining on adult mouse hearts and human cardiac cells revealed the peptide indirectly or directly modulates ROCK1 protein levels both in vivo and in vitro. We equally discovered TB4 may reverse or inhibit fibroblast/myofibroblast transformation and the potential downstream mechanisms by which TB4 alters cellular responses through ROCK1 are cell type specific. Given the beneficial effects of ROCK1 inhibition in various cardiac pathologies, we propose a potential utilization for TB4 as a ROCK1 inhibitor in the future.

Uncoupling protein 2 (UCP2) plays an important role in normal cells because it mitigates the cytotoxic effect of reactive oxygen species (ROS). However, its overexpression in cancer cells is related to drug resistance and increased cell proliferation due to a decrease in ROS production. In this context, molecules that regulate or block UCP2 have potential as anticancer agents. (-)-Epicatechin, a flavonoid that inhibits cell proliferation, increases ROS, and induces apoptosis in cancerous cells, was evaluated for its effects on UCP2 gene expression. For this purpose, the real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting were performed in MDA-MB-231 and MCF-10A cells to determine the effects of (-)-epicatechin on UCP2 expression. Furthermore, the impact of (-)-epicatechin on cell viability was also determined. To analyze the transcriptional regulation of the UCP2 gene by (-)-epicatechin, a 5'-region of the human UCP2 gene (-2093/+297) was amplified, sequenced, cloned, and inserted into a reporter plasmid. To analyze the promoter activity and regulatory motif involved in the effects of (-)-epicatechin, several deletions of the UCP2 promoter were generated and transfected into MDA-MB-231 and MCF-10A cells. An electrophoretic mobility shift assay (EMSA) was carried out to detect the interaction between DNA and proteins involved in the effect of (-)-epicatechin. The increased expression of the UCP2 gene in MDA-MB-231 cells was decreased by (-)-epicatechin, and the opposite effect was observed in MCF-10A cells. The promoter region of the human UCP2 gene (-2093/+297) showed activity, which was decreased by (-)-epicatechin. A sequence of 117 bp located at position -109 b to +8 b has a fragment of 90 bp that is related to the (-)-epicatechin effect. Bioinformatics analysis and EMSA of this sequence revealed the presence of a regulatory site for a protein with zinc fingers. The presence of a response element to (-)-epicatechin in the human UCP2 promoter revealed that the inhibition of this gene in MDA-MB-231 breast cancer cells occurred at the transcriptional level. In this study, we propose the mechanism of action of (-)-epicatechin that could aid in cancer treatment.

Chronic oxidative distress results in cellular damage, necessitating adaptive mechanisms for redox balance. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is pivotal in the regulation of key antioxidant and cytoprotective genes. Under normal conditions, Nrf2 undergoes rapid degradation through polyubiquitination. However, it can be activated during oxidative eustress and distress via modifications of its inhibitor Kelch-like ECH-associated protein 1 (KEAP1). Activation of the Nrf2-Keap1 signaling pathway may decelerate aging-related muscle degeneration, such as sarcopenia and cachexia. In this study, we investigated the efficacy of two muscle-active endogenous factors, creatine and L-β-aminoisobutyric acid (L-BAIBA), as well as two natural phytochemicals, luteolin and silibinin, to induce Nrf2 in the murine myoblast cell line C2C12. Our results revealed that only luteolin significantly enhances Nrf2 activity in both proliferating and differentiated C2C12 cells, leading to increased expression of Nrf2 target genes in proliferating C2C12 cells. In contrast, the other three compounds had either no or only minor effects on Nrf2 activity or target gene expression. Our results underscore the distinct responses of C2C12 cells to different Nrf2 activators, emphasizing the significance of cellular context in their biological effects and highlight luteolin as a potential future treatment option to counteract muscle wasting associated with sarcopenia and cachexia.

Bisphenol A (BPA) is a common synthetic chemical compound classified as an endocrine disruptor. It affects multiple physiological systems in the body, including the female reproductive system, particularly granulosa cells (GCs) in the ovaries, where steroidogenesis occurs. This study investigated the impact of various BPA concentrations (environmentally relevant concentrations of 0.001 µM and 0.1 µM and toxicological concentration of 100 µM) and exposure times (24 and 72 h) on cell viability and counts and in vitro production of estradiol and progesterone in human GCs collected from waste follicular fluid of IVF patients. Gene expression analysis of 182 genes associated with steroidogenesis and apoptosis was performed in GCs using PCR arrays, followed by protein expression analysis by Western blot. Our results demonstrate that after longer BPA exposure (72 h), a higher concentration of BPA (100 µM) negatively affects the cellular viability and counts and significantly alters steroid hormone biosynthesis in vitro, leading to reduced concentrations of estradiol and progesterone in the culture medium. We found that all BPA concentrations altered the expression of different steroidogenesis- and apoptosis-related genes in GCs. At 0.001 μM, BPA exposure decreased the expression of TRIM25, UGT2B15, CASP3, and RPS6KA3 genes and increased the expression of NR6A1 and PPID genes. At 0.1 μM, BPA increased the expression of AR, HSD3B1, BID, IKBKG, and PPID genes while reducing the expression of TRIM25 and CASP3 genes. At the highest concentration of 100 μM, BPA upregulated the expression of AR, GPER30, BID, IKBKG, and PPID genes and downregulated the expression of FOXO1 and UGT2B15 genes. These results highlight BPA's concentration-specific effects on steroidogenesis and apoptosis and show its potential to compromise GC function, with possible negative implications for female fertility and ovarian health, even at environmentally relevant concentrations.

Metallothioneins (MTs) are low-molecular-weight metal-binding proteins potentially involved in the detoxification of heavy metals, protection against oxidative stress, and other biological processes. This study examined progesterone's influence on Mt gene expression in rat adipose tissue. Wistar rats (females and males) received 100 mg of progesterone per rat. MT mRNA and protein levels were quantified by real-time PCR and Western blotting methods. Using radioimmunoassay, the serum progesterone level was measured. In this study, progesterone administration to female rats led to a 2.5-fold increase in serum progesterone concentration and significant increases in MT-1, MT-2A mRNA, and protein levels in inguinal WAT (WATi), compared to untreated female rats. RU 486 (progesterone receptor antagonist) abolished progesterone's influence on Mt-1 and Mt-2A gene expression in female WATi. Progesterone administration did not alter the level of Mt-3 gene expression in WATi or Mt-1 and Mt-2A in retroperitoneal WAT or brown adipose tissue in female rats.

Tissue culture-based rapid propagation is critical for genetic improvement and virus-free production of strawberries (Fragaria × ananassa). This study evaluated the optimal concentration of thidiazuron (TDZ) for shoot multiplication and explored the underlying molecular mechanisms. Strawberry explants were treated with TDZ at concentrations of 0, 0.025, 0.05, 0.1, and 0.4 mg·L-1 in vitro, and growth, physiological changes, and transcriptomic profiles were analyzed after four weeks. The results identified 0.05 mg·L-1 TDZ as the most effective concentration for shoot proliferation, yielding a significant increase in leaf number. However, TDZ application inhibited plant height and reduced chlorophyll, carotenoid, and soluble sugar contents. Physiological analyses revealed that TDZ decreased endogenous cytokinin levels while elevating auxin concentrations. Transcriptomic analysis showed that TDZ suppressed cytokinin biosynthesis and up-regulated cytokinin oxidase expression, thereby modulating hormone homeostasis. Additionally, TDZ enhanced the cytokinin signaling pathway, which is crucial for cell division and shoot initiation, and influenced auxin, gibberellin, and brassinosteroid pathways to regulate differentiation. These findings suggest that TDZ promotes strawberry shoot multiplication primarily through hormone signal transduction, providing insights for optimizing tissue culture protocols.

Retinal ischemic disorders present significant threats to vision, characterized by inadequate blood supply oxygen-glucose deprivation (OGD), oxidative stress, and cellular injury, often resulting in irreversible injury. Catalpol, an iridoid glycoside derived from Rehmannia glutinosa, has demonstrated antioxidative and neuroprotective effects. This study aimed at investigating the protective effects and mechanisms of catalpol against oxidative stress or OGD in vitro and retinal ischemia in vivo, focusing on the modulation of key biomarkers of retinal ischemia, including HIF-1α, vascular endothelial growth factor (VEGF), angiopoietin-2, MCP-1, and the Wnt/β-catenin pathway. Cellular viability was assessed using retinal ganglion cell-5 (RGC-5) cells cultured in DMEM; a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed. H2O2 (1 mM)/OGD was utilized. Vehicle or different catalpol concentrations were administered 15 min before the ischemic-like insults. The Wistar rat eyes' intraocular pressure was increased to 120 mmHg for 60 min to induce retinal ischemia. Intravitreous injections of catalpol (0.5 or 0.25 mM), Wnt inhibitor DKK1 (1 μg/4 μL), anti-VEGF Lucentis (40 μg/4 μL), or anti-VEGF Eylea (160 μg/4 μL) were administered to the rats' eyes 15 min before or after retinal ischemia. Electroretinogram (ERG), fluorogold retrograde labeling RGC, Western blotting, ELISA, RT-PCR, and TUNEL were utilized. In vitro, both H2O2 and OGD models significantly (p < 0.001/p < 0.001; H2O2 and OGD) induced oxidative stress/ischemic-like insults, decreasing RGC-5 cell viability (from 100% to 55.14 ± 2.19%/60.84 ± 4.57%). These injuries were insignificantly (53.85 ± 1.28% at 0.25 mM)/(63.46 ± 3.30% at 0.25 mM) and significantly (p = 0.003/p = 0.012; 64.15 ± 2.41%/77.63 ± 8.59% at 0.5 mM) altered by the pre-administration of catalpol, indicating a possible antioxidative and anti-ischemic effect of 0.5 mM catalpol. In vivo, catalpol had less effect at 0.25 mM for ERG amplitude ratio (median [Q1, Q3] 14.75% [12.64%, 20.48%]) and RGC viability (mean ± SE 63.74 ± 5.13%), whereas (p < 0.05 and p < 0.05) at 0.5 mM ERG's ratio (35.43% [24.35%, 43.08%]) and RGC's density (74.34 ± 5.10%) blunted the ischemia-associated significant (p < 0.05 and p < 0.01) reduction in ERG b-wave amplitude (6.89% [4.24%, 10.40%]) and RGC cell viability (45.64 ± 3.02%). Catalpol 0.5 mM also significantly protected against retinal ischemia supported by the increased amplitude ratio of ERG a-wave and oscillatory potential, along with recovering a delayed a-/b-wave response time ratio. When contrasted with DKK1 or Lucentis, catalpol exhibited similar protective effects against retinal ischemia via significantly (p < 0.05) blunting the ischemia-induced overexpression of β-catenin, VEGF, or angiopoietin-2. Moreover, ischemia-associated significant increases in apoptotic cells in the inner retina, inflammatory biomarker MCP-1, and ischemic indicator HIF-1α were significantly nullified by catalpol. Catalpol demonstrated antiapoptotic, anti-inflammatory, anti-ischemic (in vivo retinal ischemia or in vitro OGD), and antioxidative (in vitro) properties, counteracting retinal ischemia via suppressing upstream Wnt/β-catenin and inhibiting downstream HIF-1α, VEGF, and angiopoietin-2, together with its decreasing TUNEL apoptotic cell number and inflammatory MCP-1 concentration.

Most women with ovarian cancer (OC) develop resistance to platinum chemotherapy, posing a significant challenge to treatment. Matrix metalloproteinase 3 (MMP3) is overexpressed in High-Grade Serous Ovarian Cancer (HGSOC) and is associated with poor survival outcomes; however, its role in platinum resistance remains underexplored. We evaluated the baseline and cisplatin-induced MMP3 transcript and protein levels in cisplatin-resistant OC cells, revealing significantly higher MMP3 levels in cisplatin-resistant cells than in cisplatin-sensitive cells. siRNA-mediated MMP3 knockdown in cisplatin-resistant OC cells significantly reduced viability, proliferation, and invasion, and these effects were further enhanced when combined with cisplatin treatment, indicating a possible synergistic impact on reducing cancer cell aggressiveness; however, chemical MMP3 inhibition did not replicate these effects. RNA sequencing of MMP3-siRNA-treated cisplatin-resistant HGSOC cells revealed 415 differentially expressed genes (DEGs) compared to the negative control, with an additional 440 DEGs identified in MMP3-siRNA HGSOC cells treated in combination with cisplatin. These DEGs were enriched in pathways related to cell cycle regulation, apoptosis, metabolism, stress response, and extracellular matrix organization. Co-immunoprecipitation-coupled mass spectroscopy (IP-MS) identified MMP3-interacting proteins that may contribute to cell survival and chemoresistance in cisplatin-resistant OC. While MMP3-siRNA monotherapy did not reduce tumor growth in vivo, its combination with cisplatin significantly inhibited tumor growth in a cisplatin-resistant HGSOC xenograft model. These findings underscore the multifaceted role of MMP3 in cisplatin resistance, suggesting its involvement in critical cellular processes driving chemoresistance and highlighting the challenges associated with direct MMP3 targeting in therapeutic strategies.

Vitamin D and its metabolites exert anti-cancer properties in various cancers; however, their effects on cervical cancer remain largely unexplored. To investigate this gap, we exposed HeLa adenocarcinoma cervical cells to physiological and the growth inhibition 20% (GI20) concentration of 25-hydroxycholecalciferol, the precursor hormone of active 1,25-dihydroxycholecalciferol. We then assessed its impact on cell health, and the expression of the genes and proteins involved in the activation and catabolism of vitamin D at the cellular level by autocrine vitamin D metabolism via the vitamin D metabolizing system (VDMS). Cell health was evaluated by crystal violet and alamarBlue assays, while cell cycle progression and apoptotic cell death markers were assessed by flow cytometry. Gross morphology and ultrastructure were observed using brightfield microscopy and transmission electron microscopy. Gene and protein analyses of the autocrine VDMS were assessed using reverse transcription polymerase chain reaction and Western blot, respectively. Our findings reveal that 25(OH)D3 inhibits cell growth and induces apoptosis in HeLa cervical cells in a dose-dependent manner through the autocrine upregulation of CYP27B1 and VDR. These autocrine effects most likely promote the bioactivation of 25(OH)D3 and intracellular signaling of pro-apoptotic genomic pathways by liganded VDR. Furthermore, the upregulation of CYP24A1 at GI20 treatment likely increases the catabolism of 25(OH)D3 and 1,25(OH)2D3, and therefore may mitigate the anti-cancer action of the high-treatment dose. In summary, 25(OH)D3 holds immense potential as a complementary therapeutic treatment for cervical cancer.

The dysregulation of the Hippo signaling pathway leads to the aberrant activation of oncogenic YAP and TAZ, driving tumor progression. In breast cancer, this disruption promotes proliferation and metastasis. This study investigates the effects of CA3, a selective YAP inhibitor, on the proteome of triple-negative breast cancer MDA-MB-231 and luminal-A-like MCF7 cells. Proteomic changes were analyzed via nano-LC-MS/MS, while cytotoxicity, apoptosis, and autophagy were assessed through WST-1 assays, flow cytometry, and Western blot analyses. Bioinformatics tools were employed to identify enriched pathways. MDA-MB-231 cells exhibited an increased expression of DNA repair proteins (p < 0.05), indicating a compensatory response to maintain genomic stability. In contrast, MCF7 cells showed a downregulation of DNA repair factors (p < 0.005). Additionally, metabolic reprogramming was apparent in MCF7 cells (p < 0.001). Apoptosis assays revealed a rise in cell death, while cell cycle analysis indicated pronounced G1-phase arrest in MDA-MB-231 cells (p < 0.01). Moreover, autophagic suppression was particularly evident in MCF7 cells. This study, for the first time, provides evidence that breast cancer subtypes exhibit distinct dependencies on YAP-driven pathways, revealing potential therapeutic vulnerabilities. Targeting Hippo signaling alongside DNA repair in triple-negative breast cancer or combining YAP inhibition with metabolic blockade in luminal breast cancer holds significant potential to enhance treatment efficacy.

Hepatoblastoma (HB) is the most common pediatric primary liver tumor. About 20% of affected children have pulmonary metastasis at presentation. Survival rates for these children are dismal, not exceeding 25%. To study this subset of patients, we sequenced a metastatic HB cell line, HLM_2, and identified downregulation of the Liver X Receptor (LXR)/Retinoid X Receptor (RXR) pathway. LXR/RXRs function as transcriptional regulators that influence genes implicated in HB development, including the Wnt/β-catenin signaling pathway. We assessed the effects of a novel LXR/RXR agonist, UAB116, on metastatic HB, hypothesizing that this compound would affect genes governing the Wnt/β-catenin pathway, decreasing the metastatic phenotype of HLM_2 metastatic HB cells. We evaluated its effects on viability, proliferation, stemness, clonogenicity, and motility, and performed RNA sequencing to study differential gene regulation. Treatment with UAB116 for 72 h decreased HLM_2 proliferation, stemness, clonogenicity, and invasion. RNA sequencing identified an eight-fold increase in TRIM29, a gene known to inhibit β-catenin, in cells treated with UAB116. Administration of the LXR/RXR agonist, UAB116, reduces proliferation, stemness, and invasiveness of metastatic HB cells, potentially by upregulation of TRIM29, a known modulator of the Wnt/β-catenin pathway, providing support for further exploration of LXR/RXR agonism as a therapeutic strategy for metastatic HB.

Super-enhancers (SEs) are critical regulators of tumorigenesis and represent promising targets for bromodomain and extra-terminal domain inhibitors (BETi). However, clinical studies across various solid tumors, including triple-negative breast cancer (TNBC), have demonstrated limited BETi efficacy. This study aims to investigate SE heterogeneity in TNBC and its influence on BETi effectiveness, with the goal of advancing BETi precision treatment strategies and enhancing therapeutic efficacy.

As a key aspect of managing of invasive alien species in China, the prevention and control of Spartina alterniflora have become an important part of the work in coastal provinces, and imazapyr acid has been gradually applied in the control work due to its advantages of high efficiency and low toxicity. In this study, we applied 6.0 L/acre of 25% imazapyr acid aqueous stress treatment, and determined and analyzed the physiological activities and transcriptome profiles of S. alterniflora under sustained stress. Chlorophyll fluorescence was used as a technical tool to analyze the mechanism of photosynthesis and the photosynthetic physiological status of S. alterniflora. We analyzed the root system structure of S. alterniflora using a root system imaging system, and characterized the transcriptome of S. alterniflora by high-throughput sequencing technology. Specifically, after imazapyr acid exposure, the fluorescence imaging area of leaves were all decreased, and the fluorescence indexes such as Fv/Fm, Y(II) and PIabs were significantly decreased, while Y(NO) was significantly increased, and Y(NPQ) showed an increase followed by a decrease. Meanwhile, total root length, root surface area and biomass of S. alterniflora were suppressed after imazapyr acid exposure. In transcriptomic analysis, imazapyr acid inhibited the expression of genes involved in phenylpropanoid biosynthesis, nucleotide sugar-related metabolism, valine, leucine and isoleucine biosynthesis, and DNA replication in S. alterniflora. These results indicate that the effects of imazapyr acid stress on the leaves of S. alterniflora are heterogeneous, with the leaves initiating photoprotective mechanisms to ensure the normal functioning of the photosystem in the early stage of stress, and the PSII reaction centers being damaged in the late stage of stress, ultimately destroying the photosynthetic system. Meanwhile, imazapyr acid stress alters basic physiological processes such as metabolism and growth and development of S. alterniflora, thus affecting the growth and development of the plant root system, and ultimately leading to the death of S. alterniflora.

Ductular reaction is associated with liver disease progression, but there are no drugs targeting ductular reaction. Vitamin D deficiency is common in chronic liver diseases and related to disease progression, but the underlying mechanisms by which vitamin D regulates liver diseases progression remain unclear. Here, we show that vitamin D plasma levels are negatively correlated with the degree of ductular reaction in patients with chronic liver diseases. 1,25(OH)2D3, the active form of vitamin D, reduces 3,5-diethoxycarbonyl-1,4-dihydrocollidin (DDC)-induced ductular reaction, liver inflammation, and fibrosis in female mice and upregulates the vitamin D target gene, TXNIP (encoding thioredoxin-interacting protein), in ductular cells. Cholangiocyte-specific Txnip-knockout female mice are more susceptible to DDC-induced ductular reaction, inflammation, and fibrosis. Deletion of Txnip in cholangiocytes promotes proliferation and suppressed death. Furthermore, Txnip deficiency increases TNF-α and TGF-β secretion by cholangiocytes to stimulate Kupffer cells and hepatic stellate cells, consequently leading to inflammation and collagen deposition. Biliary Txnip deficiency abolishes the protective effects of vitamin D, and TXNIP overexpression attenuates DDC-induced ductular reaction and inflammation and fibrosis. Collectively, our findings identify new mechanism how vitamin D ameliorates liver diseases and suggest that the vitamin D/TXNIP axis is a therapeutic target for addressing ductular reaction and liver diseases.