Search Results (2,307)

Heart failure (HF) is the leading cause of morbidity and mortality worldwide, while myocardial fibrosis acts as a pivotal hallmark, which exacerbates ventricular dysfunction and remodeling in HF. In this study, we found FGF23, a critical endocrine regulator, which regulates phosphate and vitamin D metabolism, was significantly upregulated in fibrotic mouse hearts after transverse aortic constriction (TAC). By using the FGF23 monoclonal antibody, we found that inhibition of FGF23 alleviated TAC-induced cardiac fibrosis, while injection of recombinant FGF23 (rFGF23) protein exacerbated tissue fibrosis in mouse hearts after TAC. RNA sequencing indicated that FGF23 may promote cardiac fibroblast proliferation and activation in stressed mouse hearts. In human primary cardiac fibroblasts, rFGF23 treatment further upregulated the expression of Ki67, Cyclin D1, Cyclin E1, PCNA, α-SMA, and collagen 1A1 after TGF-β stimulation. Further results indicated that FGF23 promoted cardiac fibroblast proliferation and activation through FGFR4 and activated the downstream MAPK/ERK signaling. This study suggests a role of FGF23 in the regulation of myocardial fibrosis, which shows the potential of targeting FGF23 in the treatment of HF and cardiac fibrosis. Full article

WD repeat and HMG-box DNA-binding protein 1 (WDHD1) has been identified as a crucial oncogene in various tumors, but its role in pancreatic cancer remains unexplored. This study investigated the mechanisms by which WDHD1 contributes to pancreatic cancer progression. Differential analysis of the Cancer Genome Atlas (TCGA) pancreatic cancer samples identified abnormally expressed genes. Cellular assays, including cell proliferation, flow cytometry, and apoptosis assays, demonstrated WDHD1’s oncogenic role. WDHD1 expression was significantly elevated in pancreatic cancer cells and tissues compared to normal counterparts. Knockdown of WDHD1 inhibited cell proliferation, induced apoptosis, and caused G1-phase cell-cycle arrest. In vivo xenograft models further validated that WDHD1 knockdown suppressed the growth of pancreatic cancer cells. Mechanistically, WDHD1 knockdown resulted in significant reductions in CDK4 and cyclin D1 protein levels, whereas WDHD1 overexpression produced the opposite effects. Additionally, E2F1 overexpression increased the expression of WDHD1 at both mRNA and protein levels. Rescue experiments revealed that WDHD1 knockdown could reverse the E2F1-induced upregulation of CDK4 and cyclin D1 protein levels. In conclusion, E2F1 promotes pancreatic cancer cell proliferation and cell-cycle progression by upregulating WDHD1, which in turn enhances the expression of the CDK4–cyclin D1 complex. Full article

Baloxavir has emerged as a breakthrough anti-influenza therapy, owing to its single-dose regimen and rapid viral clearance. Nevertheless, clinical adverse effects have been reported, while the underlying cellular mechanisms remain unclear. In this study, we demonstrate that baloxavir acid rapidly induces mitochondrial morphological abnormalities. This mitochondrial dysfunction subsequently initiates a cascade of cellular events, including G0/G1 cell cycle arrest mediated by the downregulation of cyclin D3 and CDK4, and apoptosis via the Bak-caspase-3 pathway. Co-treatment with the antioxidant N-acetylcysteine alleviated baloxavir-induced mitochondrial abnormalities and the decreased expression level of cyclin D3. In contrast, the prodrug baloxavir marboxil exhibited minimal mitochondrial toxicity, underscoring the advantage of the prodrug strategy in reducing adverse effects. Our findings identify mitochondrial impairment as a key mechanism for baloxavir-induced cytotoxicity and provide molecular insights that may help explain its clinical adverse profile. Full article

Bladder cancer (BCa) is the second most common cancer of the genitourinary tract globally. It has limited treatment options, high recurrence rate, and acquires resistance to platinum-based therapy. Therefore, identifying novel therapeutic targets is urgently needed. Analysis of the TCGA data revealed that the enzyme galactokinase-1 (GALK1) is overexpressed (p < 0.0001) in bladder tumors compared to normal tissue. Our data also confirmed GALK1 protein upregulation in multiple human BCa cell lines and rodent bladder tumors. However, the precise role of GALK1 in BCa progression and effects of its specific inhibitor remain unexamined. In this study, we demonstrate that GALK1 gene silencing using shRNA resulted in a significant reduction in BCa cell proliferation, migration, and invasion. Pharmacological inhibition of GALK1 using small molecule Cpd36 resulted in anticancer efficacy against BCa. Cpd36 inhibited proliferation, migration, and invasion of BCa cells. Further, Cpd36 induced G1 phase cell cycle arrest, apoptosis, mitochondrial membrane depolarization, and ROS production in the BCa cells. Mechanistically, Cpd36-induced reduction in cell proliferation was associated with a decrease in expression of GALK1, PCNA proteins. Inhibition of metastatic potential was accompanied by decreased migration, invasion, and MMP-9 expression. Cell cycle arrest was associated with decrease in Cyclin D1 and increased expression of p21 and p27. Induction of apoptosis was linked with increased expression of cleaved caspase-3 and cleaved PARP, while downregulating p-AKT. Additionally, Cpd36 in combination with cisplatin or gemcitabine showed a strong synergistic effect on BCa cells. Taken together, our findings suggest that GALK1 plays a significant role in BCa cell survival and validates its inhibitors as promising therapeutic options for managing this disease. Full article

Background: This study aims to evaluate the real-world efficacy and safety of dalpiciclib in patients with hormone receptor-positive (HR+) advanced breast cancer and explore the impact of different clinical characteristics on treatment outcomes. Methods: This was a two-center, retrospective cohort study involving 76 patients treated with dalpiciclib between January 2022 and June 2024 at two affiliated hospitals of Anhui Medical University in China. Data on progression-free survival (PFS), adverse events, and key clinical factors were collected and analyzed. Kaplan–Meier estimates were used for statistical analysis. Results: The median PFS (mPFS) for the entire cohort was 12.00 months (95% CI: 10.09–13.91 months). Patients receiving dalpiciclib as first-line therapy had significantly better outcomes (mPFS: 17.00 months, 95% CI: 9.19–24.81 months) than those receiving later-line therapy (p < 0.001). Patients with prior exposure to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and those with endocrine resistance had poorer outcomes. Multivariate Cox proportional hazards regression analysis confirmed that earlier treatment line (HR for second-line vs. first-line: 3.89, p = 0.015; HR for third-line or later vs. first-line: 5.56, p = 0.006) and prior CDK4/6i treatment (HR = 3.42, p = 0.040) were independent predictors of PFS. The most common adverse events were hematologic toxicities, including leukopenia (76.6%) and neutropenia (72.4%), mostly grade 1–2. No febrile neutropenia cases were reported, indicating a manageable safety profile. Conclusions: Dalpiciclib combined with endocrine therapy is associated with favorable efficacy and safety in real-world settings, with early-line treatment and lower tumor proliferative activity associated with better outcomes. While findings suggest potential for clinical application, further large-scale prospective studies are needed to validate its effectiveness in different patient subgroups and optimize treatment strategies. Full article

Apostichopus japonicus undergoes evisceration in response to adverse environmental stimuli, and its coelomocytes undergo rapid regeneration within 6–24 h to restore innate immune function. FOS, an immediate early gene, regulates cell proliferation and cycle, but its role in A. japonicus coelomocyte regeneration after evisceration is unclear. In this study, AjFOSL from A. japonicus was cloned, which harbors a 609 bp open reading frame (ORF) encoding 202 amino acids (aa) with a conserved bZIP domain and is localized on chromosome 14. It shares 58% homology with FOS from Holothuria leucospilota and Lytechinus pictus. Phylogenetic analysis revealed that AjFOSL clusters closely with FOS from Magallana gigas and Mytilus edulis. Tissue distribution analysis showed that AjFOSL was widely expressed in various tissues, with the highest expression level detected in the tentacles. Temporal expression profiling demonstrated that AjFOSL was significantly upregulated by 1.75-fold at 6 h after evisceration. After AjFOSL knockdown, the peak expression of Cyclin A, Cyclin B, and E2F was delayed and the coelomocyte number was consistently reduced compared with that in the evisceration-only group. The AjFOSL acted as an immediate early response gene and was associated with the regulation of coelomocyte regeneration by modulating the expression of cell cycle-related genes. This study provides novel insights into the molecular associations underlying coelomocyte regeneration and the evolutionary adaptation of FOS genes in echinoderms. Full article

Cadmium (Cd) contamination, through induction of oxidative stress, severely impairs plant growth. Using primary roots of Vicia faba, we investigated how a 24 h incubation in CdCl₂ solution (175 µM) affects mitotic progression in meristems and assessed whether thyme essential oil (TO; 0.03%, v/v), as a natural antioxidant, can protect proliferating cells during simultaneous Cd exposure. Cd strongly inhibited root growth, reduced mitotic index tenfold (to 0.6%), induced chromatin condensation, decreased CDKA protein levels and CycB transcripts and proteins, caused pronounced microtubule bundling and alterations in their arrangement, disorganization of actin filaments, and disturbances in histone H3 phosphorylation (H3T3Ph, H3S10Ph). TO led to a partial recovery of mitotic index (to ~50% of the control), normalization of chromosome condensation, maintenance of cell-cycle regulators at near-control levels, preservation of proper cytoskeletal organization, and restoration of the correct H3 phosphorylation pattern. This enabled cells to progress from metaphase to anaphase and maintain phase proportions close to the control, resulting in normal root growth. These findings indicate that TO protects the mitotic cellular environment against Cd-induced disturbances. To the best of our knowledge, this is the first evidence that TO safeguards the plant mitotic apparatus under Cd stress, highlighting its potential as a natural bioprotective agent supporting plant growth. Full article

Transcription-associated cyclin-dependent kinases (tCDKs) precisely control the gene transcription process (initiation, elongation, and termination) by mediating RNA polymerase II phosphorylation. In several cancers, disrupted transcriptional control is emerging as a hallmark. In this review we summarize research studies of tCDKs’ role in gastrointestinal (GI) tumors, particularly, in the biology of esophageal, gastric, pancreatic, and hepatobiliary cancers. Across these tumor types, tCDKs are implicated as activators of super enhancer (SE) regions and contribute to the “transcriptional addiction” that not only drives cancer cell growth but is also attributed to therapeutic vulnerabilities. Overall, expression of tCDKs is increased in GI tumor tissues, indicating a rational target for therapeutics. We further describe emerging approaches, including genetic manipulation, small-molecule inhibitors or targeted protein degradation that disrupt tCDK functions in GI malignancies. We conclude by describing key challenges in targeting tCDKs and future treatment directions. Full article

Context: S-phase kinase-associated protein 2 (SKP2) is an oncogene and cell cycle regulator that mediates the ubiquitination of cell cycle regulators. Curcumol, a sesquiterpene natural product, has been reported to regulate SKP2-mediated ubiquitination degradation to overcome drug resistance in cancer cells. However, whether the cell cycle arrest effect of curcumol is related to SKP2’s function in cancer cells and its mechanisms are still unclear. Objective: To investigate the role of SKP2 in curcumol-induced cell cycle arrest and its underlying mechanisms. Materials and Methods: Transcriptomic and proteomic analyses were used to screen the ubiquitination-related factors in curcumol treated hepatocellular carcinoma cells. Lentiviral overexpression, co-immunoprecipitation assays, ubiquitination analysis, and cell-line-derived xenograft (CDX) models were used to dissect the role and mechanisms of the identified ubiquitination-related factor in the cell cycle arrest effect of curcucmol. Results: Curcumol modulated the expression of CDK4, CDK6, Cyclin D1, p27 and SKP2. SKP2 was one candidate target of curcumol selected by multi-omics. Overexpressed SKP2 partially reversed curcumol-induced growth inhibition and G1-phase arrest. The increased expression of p27 induced by curcumol was attenuated by overexpressed SKP2. Curcumol impaired the interaction between SKP2 and p27, and led to the ubiquitination and degradation of p27. In vivo, curcumol effectively reduced tumor growth, and its antitumor effect was significantly mitigated by SKP2 overexpression. Discussion and Conclusions: Curcumol reduced SKP2 expression, weakened the interaction between SKP2 and p27, inhibited degradation of p27, and then induced G1 phase cell-cycle arrest in SK-Hep-1 cells. Full article

Gastric cancer (GC) is a highly prevalent and rapidly progressing cancer with a poor prognosis, primarily due to chemoresistance and treatment-related toxicity. Moracin D (MD), a benzofuran extracted from Morus alba L., has shown potential antitumor effects in various malignancies, although its impact on GC remains limited. The aim of this study was to assess the anticancer potential of MD in human gastric cancer cell lines and subcutaneous xenograft models. We examined cell proliferation, clonogenic ability, cell cycle progression, and apoptosis using MTT, BrdU, colony formation assays, flow cytometry, Western blotting, and immunohistochemistry. Our findings suggest that MD selectively inhibited GC cell proliferation and reduced DNA synthesis in vitro. It also inhibited colony formation and tumor growth in vivo, affecting GC cell clonogenicity without affecting body weight or vital organs, and without overt toxicity under the experimental conditions tested. Mechanistically, MD was found to induce G₂/M cell-cycle arrest, potentially through modulation of cyclin B1 and CDK1, and to trigger apoptosis in GC cells, which may involve the mitochondrial pathway as suggested by changes in Bcl-2 and pro-apoptotic protein levels. While Bcl-2 overexpression partially reversed MD-induced inhibition of proliferation and apoptosis, further studies are required to confirm its role as a mediator. Additionally, MD enhances the anticancer effects of 5-fluorouracil (5-FU) through synergistic mechanism. This study highlights the observed antiproliferative and proapoptotic effects of MD in preclinical models and suggests its potential as monotherapy or in combination with 5-FU as a promising therapeutic approach in the treatment of gastric cancer. Full article

Therapeutic resistance remains a major obstacle to durable cancer control, with functional reprogramming of the DNA damage response (DDR) network playing a central role. The poly(ADP-ribose) polymerase (PARP) family, particularly PARP1 and PARP2, is crucial for maintaining genomic integrity. By exploiting synthetic lethality, PARP inhibitors (PARPi) selectively target tumors with homologous recombination deficiency (HRD) and are integral to precision therapy in ovarian, breast, and prostate cancers. However, over 40% of patients with BRCA1/2 alterations develop resistance, and patient eligibility remains limited by the low prevalence of HRD mutations. In this review, we summarize the molecular mechanisms of PARPi action, resistance pathways, and emerging combination strategies. PARPi resistance arises through HR restoration (e.g., BRCA1/2 reversion mutations), replication fork protection, RAD51-mediated strand invasion, and metabolic reprogramming. Combination therapies, integrating PARPi with histone deacetylase inhibitors, cyclin-dependent kinase inhibitors, immune checkpoint blockade, or radiation, enhance efficacy by converging on DNA repair pathways and the tumor immune microenvironment. A deeper understanding of coordinated DDR regulation and rationally designed combination regimens will be essential for overcoming PARPi resistance and advancing adaptive, precision-based therapeutic strategies. Full article

Following the establishment of the four molecular subtypes of breast cancer, additional biomarkers are required to further refine prognostication and patient stratification. Krüppel-like factors (KLFs), components of Wnt signaling, estrogen receptor beta (ERβ) isoforms, cyclin D1, and E-cadherin have been implicated in epithelial–mesenchymal transition, tumor proliferation, and disease progression. In this monocentric retrospective cohort study, tissue microarrays from 153 patients with histologically confirmed breast cancer were analyzed by immunohistochemistry to assess the expression of cytoplasmic Dkk1, β-catenin, and E-cadherin, as well as nuclear cyclin D1, KLF-4, KLF-5, and ERβ isoforms, using the Remmele and Stegner immunoreactive score. Associations between protein expression patterns with clinicopathological characteristics and survival outcomes using univariable and multivariable Cox regression analyses were examined. High cytoplasmic E-cadherin expression was associated with improved overall survival [hazard ratio (HR) 0.37, 95% confidence interval (95% CI) 0.18–0.77, p = 0.008], whereas high nuclear expression of KLF-4 (HR 2.63, 95% CI 1.32–5.22, p = 0.006) and KLF-5 (HR 2.16, 95% CI 1.01–4.65, p = 0.048) was associated with reduced overall survival. High ERβ1 expression showed a marginally protective association with the development of metastases (log-rank test p = 0.045). Importantly, nuclear KLF-4 expression remained independently associated with adverse overall survival after adjustment for tumor stage, lymph node status, molecular subtype, and other molecular markers (adjusted HR 4.09, 95% CI 1.93–8.67, p < 0.001). These findings identify nuclear KLF-4 as an adverse prognostic marker in breast cancer and support its potential relevance for molecular patient stratification. Full article

Background: Inflammatory bowel disease (IBD) involves chronic intestinal inflammation, epithelial barrier disruption, and dysbiosis, with environmental factors playing a significant role in its pathogenesis. Previous work revealed that cold exposure alleviates colitis in mice; this study extends that finding by demonstrating that cold exposure enhances intestinal regeneration even in healthy mice, upregulating proliferation markers (Mki67, PCNA, Cyclin D1). Methods: Applying this pro-regenerative effect to a colitis model, we investigated the underlying mechanisms through multi-omics analysis, transmission electron microscopy (TEM), immunofluorescence, and pathological staining as well as 16S rRNA sequencing. Results: We found that cold exposure activates intestinal epithelial proliferation pathways. Further analysis indicated that cold exposure induces colonic stem cell regeneration, upregulating stem cell markers Lgr5 and Ascl2. Notably, colonic transcriptomic profiling revealed the emergence of a Paneth-like cell phenotype, characterized by altered expression of specific lineage genes. Furthermore, cold exposure simultaneously promoted the accumulation of secretory granules and upregulated the expression of antimicrobial peptide genes (such as Lysozyme and Defa) in ileal Paneth cells. This enhanced ileal antimicrobial defense effectively reshaped the gut microbiota in inflamed intestines. Conclusions: This research elucidates a mechanism whereby cold adaptation promotes mucosal repair by integrating localized colonic epithelial regeneration with enhanced ileal Paneth cell-mediated antimicrobial defense. This offers compelling new perspectives on how environmental factors, such as cold exposure, could influence the pathophysiology of IBD and contribute to intestinal regeneration, which may provide foundational theoretical support for the future diagnosis and treatment of IBD. Full article

Background: Danhong injection (DHI), a standardized traditional Chinese medicine formulation, has shown clinical benefits in treating cerebrovascular diseases. Blood–brain barrier (BBB) disruption is a key pathological feature of ischemic stroke, but its modulation by DHI under hyperlipidemic conditions remains unclear. This study aimed to investigate the protective effects and mechanisms of DHI in cerebral ischemia/reperfusion injury (CI/RI) under hyperlipidemia, focusing on BBB integrity and the Wnt/β-catenin signaling pathway. Methods: Rats were divided into control, ischemic, hyperlipidemic, and treatment subgroups to evaluate DHI’s dose-dependent effects and pathway specificity using DKK1 inhibition. Assessments included neurological scores, TTC and Nissl staining, TEM, and molecular analyses (qRT-PCR/Western blot/immunofluorescence/immunohistochemistry). Results: DHI significantly improved neurological function, reduced cerebral infarct size, and alleviated cortical damage. DHI treatment upregulated the expression of tight junction proteins (Claudin-5, Occludin, ZO-1) and downregulated MMP-9 expression. Mechanistically, DHI promoted the nuclear translocation of β-catenin and increased the expression of Wnt3α, p-GSK-3β, and Cyclin D1, thereby activating the Wnt/β-catenin pathway. Additionally, DHI treatment increased the count of NeuN-positive neurons, suppressed astrocyte activation, and markedly reduced IgG infiltration in the ischemic cerebral cortex. These effects were reversed by DKK1. Conclusions: The results indicate that DHI protects BBB integrity and alleviates CI/RI in hyperlipidemic rats independently of direct lipid-lowering activity. Specifically, DHI activates the Wnt/β-catenin pathway by enhancing β-catenin nuclear translocation, which in turn mediates the upregulation of tight junction proteins and suppression of MMP-9, ultimately preserving BBB integrity. These findings support its therapeutic potential in ischemic stroke with comorbid hyperlipidemia. Full article

Taxifolin, a natural flavonoid, consistently exerts cytoprotective effects against various oxidative stresses. In this study, we systematically evaluated its photoprotective efficacy and underlying mechanisms against ultraviolet B (UVB)-induced injury in human immortalized keratinocytes (HaCaT). Cell viability and apoptosis were assessed by MTT, fluorescence staining, and flow cytometry, while integrative transcriptomic and proteomic analyses were employed to identify core pathways and key mediators. Taxifolin exhibited antioxidant capacity comparable to that of ascorbic acid under identical in vitro radical-scavenging assays. Moreover, it displayed a strong absorption peak at 289 nm that overlaps the UVB spectrum (280–320 nm), enabling it to act as a chemical sunscreen. In UVB-challenged HaCaT cells, taxifolin markedly reduced intracellular reactive oxygen species (ROS) and attenuated JNK/p38 MAPK activation, as evidenced by Western blot, thereby breaking the ROS-MAPK vicious cycle. Multi-omics revealed that taxifolin was associated with attenuation of UVB-imposed G1/S arrest concomitant with restored Cyclin expression, while up-regulating MYC, FOXQ1, HMOX1 and AP-1 components c-Jun/c-Fos and thereby switching on a pro-survival transcriptional program. Consequently, apoptosis was suppressed and survival was significantly improved. Collectively, taxifolin integrated chemical filtration, ROS scavenging and signaling modulation to support a multi-target photoprotective network, which provides mechanistic insight into taxifolin-mediated cytoprotection and identifies candidate molecular nodes for further validation. Full article