Search Results (287)

Pasteurella multocida (Pm) is a zoonotic pathogen that causes severe hemorrhagic pneumonia in pigs, characterized by vascular injury and systemic inflammatory responses. Our previous studies demonstrated that 18β-glycyrrhetinic acid (GA), a bioactive triterpenoid derived from liquorice, protected against Pm-induced vascular inflammatory injury through suppression of poly(ADP-ribose) polymerase 1 (PARP1)-mediated nuclear factor-kappa B (NF-κB) and high mobility group box 1 (HMGB1) signaling. However, whether GA modulates PARP1-mediated NF-κB p65 nuclear translocation, a critical step in NF-κB activation, remains unclear. This study evaluated the protective effects of GA and its underlying mechanism using a Pm-infected mouse model and immunofluorescence staining of porcine iliac artery endothelial cells. Our results demonstrated that GA treatment attenuated body weight loss, ameliorated hematological and biochemical parameters, and reduced vascular structural damage in Pm-infected mice. Mechanistically, Pm infection induced PARP1 upregulation, accompanied by phospho-p65 (p-p65) nuclear translocation, all of which were suppressed by GA. PARP1 overexpression drove p-p65 nuclear accumulation, which was reversed by GA, whereas PARP1 knockdown suppressed Pm-induced p-p65 nuclear translocation. The findings demonstrated that GA protected against Pm-induced vascular injury by inhibiting PARP1-mediated NF-κB p65 nuclear translocation, supporting its potential as a candidate therapeutic agent for Pm-associated vascular injury. Full article

Background: Tankyrase 1 (TNKS1) is a poly(ADP-ribose) polymerase involved in Wnt/β-catenin signaling, telomere maintenance, and genomic stability, making it an attractive therapeutic target in oncology. This study aimed to develop and apply an integrated computational workflow to identify novel TNKS1 inhibitor candidates. Methods: A curated dataset of experimentally validated TNKS1 inhibitors and property-matched DUD-E decoys was used to develop a consensus supervised machine learning (ML) model prioritization framework for ligand-based virtual screening, integrating Morgan fingerprints with three complementary classifiers. The model screened more than 700,000 compounds, and prioritized hits were evaluated by structure-based virtual screening (SBVS), Prime MM-GBSA binding free-energy refinement, and 500 ns molecular dynamics simulations (MDs). The top candidates were subsequently tested in an in vitro TNKS1 enzymatic inhibition assay. Results: The consensus ML framework prioritized 670 compounds, yielding five candidates for experimental testing. Compound 3 displayed the most favorable computational profile and was experimentally confirmed as a TNKS1 inhibitor candidate, exhibiting approximately 80% TNKS1 inhibition at 0.1 μM, whereas the remaining candidates showed only limited activity. Conclusions: The proposed workflow efficiently reduced a large chemical space to a focused set of TNKS1 inhibitor candidates while substantially reducing the experimental screening burden. Compound 3 represents a promising starting point for future structure–activity relationship studies and lead optimization in the context of TNKS1 inhibition. Moreover, this work highlights the value of integrating consensus ML, SBVS, and experimental validation to accelerate early-stage hit discovery for TNKS1 and other therapeutic targets. Full article

Ultraviolet B (UVB) irradiation is a major environmental factor contributing to skin photoaging by inducing oxidative stress, apoptosis, inflammation, and extracellular matrix degradation in dermal fibroblasts. This study investigated the photoprotective effects of Thua Nao, a Thai fermented soybean, against UVB-induced human dermal fibroblast damage, and explored its underlying mechanisms. The dichloromethane fraction of Thua Nao (TN-DC) most effectively mitigated UVB-induced cell death. HPLC analysis identified daidzein and glycitein as the major constituent isoflavones in TN-DC that protect fibroblasts against UVB-induced cellular damage. Mechanistically, they reduced apoptosis by suppressing caspase-9 and poly (ADP-ribose) polymerase activation and preserving mitochondrial membrane potential. Additionally, they suppressed inflammatory mediators including interleukin-6, interleukin-8, inducible nitric oxide synthase, and cyclooxygenase-2 and prevented collagen loss. These protective outcomes correlated with decreased intracellular reactive oxygen species and upregulated endogenous antioxidant enzymes including superoxide dismutase 1 and heme oxygenase. Signaling pathway analysis revealed that TN-DC activated the pro-survival extracellular-signal-regulated kinase and Akt pathways in UVB-exposed cells. Conversely, daidzein and glycitein selectively attenuated c-Jun N-terminal kinase activation, downregulating downstream pro-inflammatory cytokines and mediators. Collectively, these findings demonstrate that TN-DC protects human dermal fibroblasts against UVB-induced photoaging primarily by enhancing endogenous antioxidant defense, thereby preserving cellular homeostasis through coordinated regulation of oxidative stress-responsive signaling pathways. Full article

Natural products represent a valuable source of anticancer agents, although their mechanisms of action are often incompletely understood. In this study, we evaluated the cytotoxic effects of the ethyl acetate (EA) fraction derived from Schima superba bark. The EA fraction exhibited selective cytotoxicity against HepG2 and MCF-7 cancer cells, with minimal effects on normal HEK293 cells, and induced apoptosis as evidenced by time- and dose-dependent activation of caspase-3. Phytochemical profiling by UPLC-QTOF-MS/MS identified 18 major constituents, predominantly phenylethanoid glycosides and triterpenoids. To gain insight into the underlying mechanism, molecular docking, 200 ns molecular dynamics simulations, and MM-PBSA analyses were performed targeting poly (ADP-ribose) polymerase 1 (PARP1) and caspase-3. Among the identified compounds, cistanoside D displayed favorable binding affinity toward both targets, but formed a more stable and energetically favorable complex with PARP1 during molecular dynamics simulations, whereas its interaction with caspase-3 was comparatively weak. These findings suggest that cistanoside D may preferentially interact with PARP1, while the observed activation of caspase-3 is likely associated with downstream apoptotic processes rather than direct enzymatic modulation. This study provides an integrated evaluation of the phytochemical composition and anticancer potential of Schima superba bark extract, and identifies cistanoside D as a promising candidate for further investigation. These results contribute to a better understanding of the molecular basis underlying the bioactivity of this medicinal plant and support its potential as a source of anticancer agents. Full article

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation in which excessive cell death and the release of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1) amplify mucosal injury. Although necrosis—particularly regulated forms including necroptosis and ferroptosis—has emerged as a contributor to IBD pathogenesis, the therapeutic potential of targeting necrotic cell death remains incompletely explored. We investigated whether MIT-001 (previously known as NecroX-7), a mitochondria-targeted reactive oxygen species (ROS) scavenger with anti-necrotic activity, ameliorates intestinal inflammation in an acute dextran sulfate sodium (DSS)-induced colitis model. In vitro, MIT-001 reduced hydrogen peroxide-induced necrotic cell death in IEC-18 intestinal epithelial cells and was associated with a qualitative reduction in the 55-kDa cleaved poly(ADP-ribose) polymerase-1 (PARP-1) fragment (a marker of necrosis), with no apparent change in the apoptosis-related 89-kDa fragment. In vivo, oral administration of MIT-001 to C57BL/6 mice with DSS-induced colitis was associated with preservation of colon length, reduced histological injury, and a marked decrease in HMGB1-positive cells in colonic tissue. Among pro-inflammatory cytokines, IL-1β expression was significantly reduced, while IL-12, monocyte chemoattractant protein-1 (MCP-1), and TNF-α showed non-significant downward trends. These findings indicate that MIT-001 ameliorates DSS-induced colitis in association with reduced HMGB1 and IL-1β expression, supporting further investigation of mitochondria-targeted anti-necrotic strategies as a potential adjunctive approach in IBD. Full article

Triple-negative breast cancer (TNBC), particularly when associated with breast cancer susceptibility gene 1/2 (BRCA1/2) alterations or homologous recombination deficiency (HRD), remains therapeutically challenging because DNA repair vulnerabilities coexist with molecular heterogeneity, resistance, and toxicity constraints. This narrative review synthesizes mechanistic, preclinical, clinical, and translational evidence on DNA damage response (DDR)-targeted and synthetic lethality-based strategies in TNBC. We summarize TNBC biological heterogeneity, current biomarker-guided treatment options, mechanisms of poly(ADP-ribose) polymerase (PARP) inhibition and resistance, and emerging DDR targets, including ataxia telangiectasia and Rad3-related/checkpoint kinase 1 (ATR/CHK1), WEE1, DNA-dependent protein kinase (DNA-PK), RAD51, DNA polymerase theta (POLQ), neddylation-related pathways, and targeted protein degradation. The review highlights that PARP inhibitors and platinum agents provide clinically validated examples of exploiting HRD in selected populations, whereas most next-generation DDR inhibitors remain preclinical, investigational, or in early clinical trials. Resistance mechanisms, including BRCA reversion, homologous recombination restoration, replication fork stabilization, and checkpoint adaptation, limit durable benefit. Safety, target selectivity, overlapping toxicities, and the lack of standardized functional biomarkers further constrain translation. Future progress will require prospective biomarker validation, dynamic HRD assessment, rational scheduling of combinations, and medicinal chemistry approaches that improve therapeutic index rather than a broad application of DDR inhibition across all TNBC. Full article

Background/Objectives: Poly (ADP-ribose) polymerase (PARP), particularly PARP-1, is overexpressed in prostate cancer and linked to poor prognosis. PARP inhibitors show efficacy in homologous recombination deficiency (HRD)-positive tumors, but 30–70% of patients develop resistance, often due to low PARP expression. Tissue biopsies have limitations in assessing PARP levels, highlighting the need for noninvasive imaging tools. This study aimed to develop a novel [⁶⁸Ga]Ga-PARP-targeted radiotracer for prostate cancer visualization and therapy monitoring, with potential implications for targeted radionuclide therapy. Methods: PET/CT imaging was conducted in 22RV1 prostate cancer xenograft-bearing mice using the [⁶⁸Ga]Ga-FL9-7 probe. Imaging was performed at 1, 2, and 3 h post-injection. Standardized uptake values (SUV) were quantified to evaluate tumor and organ uptake, and tumor-to-normal tissue (T/NT) contrast ratios were calculated. Results: [⁶⁸Ga]Ga-FL9-7 rapidly accumulated in tumors, with optimal imaging contrast achieved at 3 h post-injection. Normal organ uptake (e.g., kidneys) peaked at 1 h and subsequently declined, while tumor uptake increased over time. This differential clearance and retention resulted in the highest T/NT ratio at the 3 h time point. Conclusions: The [⁶⁸Ga]Ga-FL9-7 probe enables effective noninvasive visualization of PARP-1 expression in prostate cancer, demonstrating clinical potential for tumor localization and monitoring of PARP-targeted therapies. This work also lays the groundwork for further development of PARP-targeted radionuclide therapy strategies. Full article

Ischemic stroke triggers a severe redox disequilibrium that critically shapes cell survival within the penumbra. Although oxidative DNA damage arises from excessive ROS production, the capacity to repair such lesions is tightly constrained by cellular metabolic status. Growing evidence indicates that astrocytes, key metabolic regulators of the neurovascular unit, modulate neuronal susceptibility to genomic injury through redox buffering, NAD⁺ maintenance, and metabolic support. In the metabolically impaired yet structurally preserved penumbra, astrocytic control of glutathione turnover, mitochondrial function, and lactate shuttling may determine whether oxidative DNA lesions are efficiently repaired or progress toward energetic collapse. Poly(ADP-ribose) polymerase 1 activation following DNA strand breaks couples genomic stress to NAD⁺ depletion and bioenergetic failure, forming a critical interface between redox biology and metabolism. This framework posits that astrocytes preserve genomic integrity not by directly altering DNA repair pathways but by sustaining the energetic capacity required for an effective DNA damage response. Elucidating this astrocyte-centered redox–metabolic axis may reveal therapeutic strategies to stabilize penumbral tissue and improve stroke outcomes. Full article

Programmed cell death (PCD) pathways of innate immunity serve to protect host cells from invading viruses. Parthanatos is a novel form of PCD triggered by excessive host cell DNA damage that leads to overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) which in turn stimulates poly(ADP-ribose) (PAR) polymer formation. PAR translocates to the cytoplasm, where it induces release of apoptosis-inducing factor (AIF) from mitochondria, that then travels back to the nucleus, where it mediates large-scale DNA fragmentation and cell death. Little information is available regarding parthanatos as a cell death mechanism to dampen herpesvirus replication at the host cell level. A series of studies were therefore performed to clarify a possible role for parthanatos during productive replication of murine cytomegalovirus (MCMV) and herpes simplex virus type 1 (HSV-1) in diverse cell types. These included mouse embryo fibroblasts, mouse lung fibroblasts, mouse microglial (BV-2) cells, and human retinal pigment epithelial (ARPE-19) cells. We report that PAR protein production is surprisingly cell type specific. Moreover, MCMV or HSV-1 infection may suppress parthanatos as observed for other PCD pathways, such as apoptosis, necroptosis, and pyroptosis, in a dose-dependent and cell type-specific manner. We conclude that the operation of parthanatos at the host cell level during herpesvirus replication is more complex than originally thought but offers new targets for possible therapeutic interventions. Full article

Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with more than 90% patients dying from metastasis due to limited treatment options. Although miRNA-based therapeutics represent a promising strategy, their clinical application has been hindered by poor stability in vivo and the lack of efficient organ-specific delivery systems. Methods: In this study, we developed a lung-targeted lipid nanoparticle (LuT-LNP) platform for the delivery of a chemically modified miRNA, AM22, which demonstrated enhanced tumor-suppressive activity. By replacing cholesterol and helper lipids with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), the most abundant lipid in pulmonary surfactant, and systematically optimizing the ratios of ionizable and cationic lipids, we obtained a LuT-LNP formulation with superior lung tropism. Results: The resulting LuT-LNPs exhibited excellent stability, biocompatibility, and efficient encapsulation and protection of AM22. Both in vitro and in vivo, AM22-loaded LuT-LNP (AM22@LuT-LNP) significantly inhibited the proliferation and migration of CRC cells and markedly suppressed lung metastasis in a mouse model. Mechanistic studies revealed that AM22 acts by targeting Poly (ADP-ribose) polymerase 1 (PARP1), inducing DNA damage, and inhibiting the epithelial-mesenchymal transition (EMT) process. Conclusions: These findings established a lung-targeted delivery platform for miRNA-based therapy, offering a promising strategy for the treatment of colorectal cancer pulmonary metastasis (CRPM). Full article

Cancer is a complex and evolutionary disease, with the development of different types of cancers leading to various different defective gene mutations. Synthetic lethality is a genetic-level precision medical strategy. Currently, treating BRCA (BReast CAncer)-mutated breast or ovarian cancer cells with a chemical inhibitor (Poly(ADP-ribose) polymerase, PARPi) is a typical synthetic lethal application in clinical practice. However, PARPi therapy has been found to cause off-target effects and therapy-induced immune escape driven by PD-L1 upregulation, allowing for cancer cells to escape attack from the immune response. To overcome these challenges, we developed a core–shell structure comprising a hydrophobic core of quercetin (Q)-mediated PARP inhibition and iron oxide nanoparticles (IONPs), enveloped by a hydrophilic fucoidan (Fu) shell to encapsulate short hairpin RNA targeting Programmed Death Ligand 1 (shPD-L1) for efficient gene transfection (shPD-L1@QIO@Fu). Structurally, the incorporation of quercetin into the intermediate hydrophobic layer enables modulate of the PARP effect, while the inner aqueous core with shPD-L1 gene silencing can inhibit the expression of PD-L1 protein. In this study, we proved that shPD-L1@QIO@Fu demonstrated a dual therapeutic mechanism against BRCA-mutant cancer cells by inducing extensive DNA double-strand breaks and promoting apoptosis. Furthermore, the combined action of quercetin-mediated DNA damage and shPD-L1-driven PD-L1 suppression led to a significant reduction in PD-L1 mRNA to approximately 5% at 72 h and decreased surface PD-L1 below baseline by 96 h. This effectively suppresses PARPi-induced PD-L1 upregulation and enhances antitumor immunity. These findings demonstrate the therapeutic efficacy of shPD-L1@QIO@Fu nanomedicine, providing a promising foundation for advanced co-delivery strategies to synergize PARP inhibition mediated synthetic lethality with immune checkpoint blockade in next-generation precision medicine. Full article

Deoxynivalenol (DON) is a globally prevalent mycotoxin that threatens food and feed safety via severe multi-organ toxicity. Previous studies indicate that DON induces cellular energy metabolism dysregulation by triggering oxidative stress and impairing mitochondrial function. During this process, nicotinamide adenine dinucleotide (NAD⁺), a central coenzyme in cellular energy metabolism, frequently exhibits significantly decreased intracellular levels or even complete depletion. However, the molecular mechanisms underlying the disruption of NAD⁺ homeostasis by DON exposure, as well as the development of targeted countermeasures, remain elusive. Using human embryonic kidney 293T (HEK293T) cells as an in vitro renal toxicity model, we dissected DON-induced NAD⁺ dysregulation and evaluated the protective potential of nicotinamide (NAM). DON caused significant NAD⁺ depletion in porcine serum (in vivo) and HEK293T cells (in vitro), which was confirmed as a key driver of cytotoxicity. Mechanistically, although DON binds and inhibits nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD⁺ salvage pathway, neither NAMPT knockdown and overexpression nor nicotinamide mononucleotide (NMN) supplementation rescued DON-induced toxicity. Instead, DON dose-dependently activated poly(ADP-ribose) polymerase 1 (PARP1), the primary intracellular NAD⁺-consuming enzyme, to accelerate NAD⁺ depletion. PARP1 knockdown markedly attenuated DON-induced cytotoxicity, identifying PARP1 hyperactivation as the core toxic mechanism. NAM dose-dependently suppressed PARP1 activity, replenished NAD⁺ pools, and reversed cell injury. These findings establish PARP1-driven NAD⁺ depletion as an important mechanism of DON-induced renal toxicity, providing a promising intervention candidate for mitigating DON toxicity in food safety. Full article

Selective inhibition of poly(ADP-ribose) polymerase 1 (PARP1) may reduce the hematologic toxicity associated with dual PARP1/PARP2 inhibition. We performed molecular dynamics simulations for five selective inhibitors in complexes with PARP1 and PARP2, using three independent 50 ns runs per complex after docking and equilibration, followed by protein–ligand interaction fingerprint and statistical analyses. All complexes remained dynamically stable, with ligand root-mean-square deviation values generally within 0.3 nm. Comparative analysis identified three αF-helix residue pairs with nominally reduced interaction frequencies in PARP2: Asn767/Ala336, Leu769/Gly338, and Asp770/Asp339 (p < 0.05). After Benjamini–Hochberg correction for multiple comparisons, Leu769/Gly338 remained significant (q < 0.05), indicating that this pair represents the most statistically robust interaction difference within this region. Using palacaparib as the most selective inhibitor, these differences were associated with weakened or lost hydrophobic, van der Waals, and cation–π interactions in PARP2. Selective binding of modern PARP1 inhibitors appears to be associated with αF-helix-dependent interaction patterns, providing a mechanistic basis for the rational design of next-generation selective inhibitors with improved selectivity and potentially reduced toxicity. Full article

Background: Poly(ADP-ribose) polymerase inhibitors (PARPis) are established maintenance therapies in epithelial ovarian cancer (EOC). Although considered relatively safe, their impact on renal function remains unclear. Increases in serum creatinine (SCr) are frequently observed during treatment, but the clinical significance of these changes is uncertain. We conducted a systematic review and meta-analysis to assess the risk of renal adverse events associated with PARPis in randomized controlled trials (RCTs). Methods: PubMed/MEDLINE, Embase, and the Cochrane Library were searched for phase II–III, placebo-controlled RCTs published through 30 June 2025. Eligible studies enrolled patients with ovarian cancer receiving maintenance monotherapy with olaparib, niraparib, rucaparib, or fuzuloparib and reported renal adverse events. The primary endpoint was creatinine increase (all grades). Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed- or random-effects models according to heterogeneity. Results: Nine high-quality RCTs comprising 2578 patients met the inclusion criteria. PARPi therapy was associated with a significantly increased risk of creatinine elevation compared with placebo (OR 5.04; 95% CI 3.51–7.24; p < 0.001). Heterogeneity was moderate (I² = 31.7%). High-grade renal adverse events (≥grade 3) were rare (<1%) and could not be reliably pooled. No significant publication bias was detected. Conclusions: PARP inhibitors significantly increase the likelihood of SCr elevation in EOC; however, severe nephrotoxicity appears uncommon in RCTs. Observed SCr increases may partly reflect inhibition of renal tubular creatinine transport rather than true reductions in glomerular filtration. Careful renal monitoring and prospective studies incorporating direct GFR assessment are warranted. Full article

Background/Objectives: Poly(ADP-ribose) polymerase 1 (PARP1) is an important therapeutic target in DNA repair-deficient cancers, but discovery of new inhibitors remains constrained by scaffold convergence, tolerability limits, and acquired resistance. This study aimed to develop an interpretable, reliability-stratified cheminformatics workflow for PARP1 potency prioritization and structure-based follow-up. Methods: A curated ChEMBL dataset of 3339 PARP1 inhibitors was encoded using RDKit 2D descriptors and Avalon fingerprints (1143 initial features), then reduced to 132 informative variables by Random Forest-based feature selection. Five regression models were optimized, including a stacked ensemble. Model interpretation was performed using permutation feature importance and SHAP. External near-domain corroboration was assessed using a stringent PubChem similarity expansion (Tanimoto > 0.90) around sub-10 nM seed compounds, followed by comparison with retrievable experimental PARP1 activity values. Top scaffold-diverse candidates were further evaluated by complementary docking against PARP1 (PDB: 4R6E) using AutoDock Vina and cavity-guided docking through the SwissDock platform. Results: The stacked ensemble achieved the best held-out performance (test R² = 0.723; RMSE = 0.610 pIC₅₀ units), with 83.7% of test predictions within ≤0.75 pIC₅₀ units and only 2.7% exceeding 1.5 pIC₅₀ units. PubChem similarity expansion retrieved approximately 32,450 analogs, of which 3349 were predicted to have IC₅₀ ≤ 10 nM. Among 366 compounds with retrievable experimental PARP1 activity values, predicted versus experimental pIC₅₀ showed a positive association (R² = 0.124; Pearson r = 0.479), with RMSE = 0.491 and MAE = 0.330 pIC₅₀ units. Three ligands—CID 168873053, CID 175154210, and CID 172894737—showed the strongest complementary docking support and pocket-consistent poses relative to niraparib. Conclusions: This workflow provides a transparent and practically useful framework for near-domain PARP1 inhibitor prioritization. The combined QSAR, explainability, external corroboration, and docking strategy supports shortlist generation for experimental follow-up. Full article