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.

Background: Increasing evidence indicates that N6-methyladenosine (m6A), as one of the common RNA modifications, plays a significant role in inflammatory diseases. However, the specific role of m6A in the occurrence and development of acute pancreatitis remains unclear. This study investigated the role of m6A modifications mediated by METTL3 and IGF2BP2 in acinar cells during acute pancreatitis. Methods: The expression of METTL3 and the m6A modification level in pancreatic tissues and acinar cells from the control and pancreatitis groups were verified using qRT-PCR, western blotting, etc. The differentially expressed m6A-modified genes during pancreatitis were identified through methylation RNA immunoprecipitation sequencing (meRIP-seq). Using RNA immunoprecipitation (RIP) and luciferase activation assays, the recognition role of IGF2BP2 in the m6A modification sites of Bim was verified. Findings: We found that METTL3 is significantly up-regulated, resulting in an increase in m6A methylation of Bim mRNA. This m6A modification, recognized by the “reader” IGF2BP2, enhances Bim mRNA stability, consequently elevating the protein levels of its downstream effectors, BAX and BAK1. The up-regulation of these proteins triggers mitochondrial DNA release into the cytosol. The liberated mtDNA subsequently activates the cGAS/STING/NF-κB signaling pathway, exacerbating pancreatic injury. Inhibition of METTL3 with STM2457 effectively mitigated this cascade and alleviated pancreatic damage. Interpretation: Our findings highlight the METTL3/IGF2BP2/Bim axis as a promising therapeutic target for acute pancreatitis.

Abstract Cisplatin-based chemotherapy combined with bevacizumab (CB) remains the standard first-line treatment for advanced or recurrent cervical cancer, integrating cytotoxic and anti-angiogenic mechanisms to improve clinical outcomes. However, treatment success is frequently undermined by dose-dependent nephrotoxicity caused by cisplatin and bevacizumab-induced vascular alterations. Thus, strategies capable of safeguarding renal function without attenuating antitumor activity are urgently needed to optimize treatment durability and patient survival. We previously developed 31c, a novel dual inhibitor of prolyl hydroxylase domain-containing protein 2 (PHD2) and histone deacetylases (HDACs), as a nephroprotective agent. Therefore, we evaluated the nephroprotective potential of 31c in a HeLa xenograft mouse model. Mice were treated with cisplatin, bevacizumab, or their combination, with or without 31c. Tumor growth kinetics and body weight were monitored to assess therapeutic response and systemic toxicity. Renal function was examined through blood urea nitrogen (BUN), serum creatinine (Scr), and erythropoietin (EPO) levels. Kidney tissues underwent histopathological evaluation using hematoxylin and eosin (H&E) and Masson’s trichrome staining to quantify tubular injury and fibrosis. RNA sequencing (RNA-seq) of kidney samples identified transcriptomic alterations, and immunofluorescence staining validated renal injury markers lipocalin-2 (Lcn2/NGAL) and kidney injury molecule-1 (Havcr1/KIM-1). Co-administration with 31c preserved the antitumor efficacy of the CB regimen, yielding tumor inhibition comparable to CB alone. Notably, 31c markedly reduced renal toxicity. Mice receiving CB alone displayed significant increases in BUN and Scr levels, extensive tubular degeneration, and marked collagen accumulation, hallmarks of acute renal injury and fibrosis. In contrast, 31c significantly reduced these pathological changes and maintained normal tubular structure. Transcriptomic profiling revealed distinct clustering among treatment groups, with 31c partially reversing CB-induced transcriptional dysregulation. Among the most upregulated genes in CB group, Lcn2 and Havcr1 were significantly suppressed by31c, consistent with immunofluorescence validation. The dual PHD2-HDAC inhibitor 31c confers robust nephroprotection against cisplatin-bevacizumab-induced renal injury without compromising antitumor activity. This integrated protective strategy highlights a promising approach to enhance the safety, tolerability, and continuity of platinum-anti-angiogenic therapies. By preserving renal integrity, 31c may support sustained treatment intensity and prolonged therapeutic benefit in patients with advanced cervical cancer and potentially other malignancies treated with similar regimens. Citation Format: Xi Chen, Dongyu Han, Xiaohua Kong, Wenfeng Gou, Yang Song, Huiqiang Wei, Yiliang Li, Yong Qin. Dual PHD2-HDAC inhibitor 31c prevents cisplatin-bevacizumab nephrotoxicity and preserves antitumor efficacy in cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 291.

INTRODUCTION:The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and inflammasomes were long regarded as distinct innate immune modules that respond to different classes of danger signals. However, accumulating evidence now reveals extensive, bidirectional crosstalk between these pathways, forming an integrated regulatory network that critically shapes the magnitude, quality, and outcome of immune responses. The balance of this network determines whether the host mounts effective pathogen control and tumor immunosurveillance, or instead succumbs to excessive inflammation, tissue injury, or autoimmune pathology. RESULTS AND DISCUSSION:In this review, we synthesize current mechanistic understanding of STING-inflammasome interactions, highlighting how shared upstream triggers - particularly cytosolic DNA - coordinate the activation, amplification, or restraint of these pathways. We further examine how this axis exerts context-dependent, dualistic functions across diverse disease settings, including cancer, autoimmunity, neurodegeneration, chronic infection, and aging. From a pharmacological perspective, we discuss emerging therapeutic strategies aimed at modulating key regulatory nodes within this signaling network, ranging from STING agonists for cancer immunotherapy to selective STING or the NLR family pyrin domain-containing 3 (NLRP3) inhibitors for autoimmune and inflammatory diseases. CONCLUSION:Together, these insights provide a conceptual and translational foundation for the rational development of next-generation immunomodulatory agents targeting the STING-inflammasome axis.

Introduction The chemical analysis of QizhenShengbai Compound (QZSBC) liquid was conducted using ultra-high pressure liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) to investigate the material basis of QZSBC. Additionally, network pharmacology and molecular docking were employed to predict the potential mechanisms underlying its anti-radiation effects on the hematopoietic system. Methods The UPLC-Q-TOF-MS/MS method was employed to analyze the chemical components of QZSBC. Additionally, a network pharmacology approach was used to construct a 'drug-active ingredient-target-disease' topological network. A protein-protein interaction (PPI) network was constructed for the disease targets to identify key proteins. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed on these key targets, and the network was validated through molecular docking. Results GO enrichment analysis revealed significant enrichment in biological processes, such as DNA damage repair, cell cycle regulation, and inflammatory response; KEGG analysis indicated high association with pathways including JAK-STAT, PI3K-Akt, and cell cycle. Molecular docking demonstrated that the active components in QZSBC exhibited strong binding affinity with the core targets.Discussion Among the 10 core proteins screened, the HSP90 family and SRC were identified as critical nodes in radiation-induced DNA damage repair; the JAK-STAT pathway, mediated by STAT3, plays a central role in the survival and differentiation of hematopoietic stem/progenitor cells, which is highly consistent with the enrichment results. Among the active components, quercetin, luteolin, and others were found to alleviate radiation damage through antioxidant effects and the promotion of DNA repair, while amide compounds, such as Aurantiamide acetate, were reported to bind to HSP90, suggesting a novel mechanism of action. Conclusion QZSBC may exert its radioprotective effects on the hematopoietic system by acting on key targets, such as HSP90AA1, SRC, and STAT3, through active ingredients, such as Aurantiamide acetate, Licarin A, and Quercetin, thereby interfering with signaling pathways, including DNA damage repair, JAK-STAT, and PI3K-Akt.

BACKGROUND:Radiation-induced colitis (RC) poses a substantial clinical challenge with limited therapeutic options. Taxifolin (TAX), a natural flavonoid, exhibits potential anti-inflammatory properties; however, its clinical application is hindered by poor oral bioavailability and an unclear mechanism of action in the context of radiation injury. PURPOSE:This study aims to investigate the therapeutic potential and underlying mechanisms of the flavonoid monomer TAX in the context of RC, with a particular focus on the gut microbiota-BAs-FXR/NLRP3 axis. METHODS:We employed a 13 Gy total abdominal irradiation (TAI) mouse model and HIEC-6 cells. Multi-omics approaches, including 16S rRNA sequencing and untargeted metabolomics, were used to map microbiota and metabolic profiles. Crucially, to establish causality, fecal microbiota transplantation (FMT) was performed to assess the microbiota's mediating role, and the specific FXR antagonist DY268 was utilized to verify the dependency on FXR signaling. Molecular interactions were confirmed via molecular docking, drug affinity responsive target stability (DARTS), and co-immunoprecipitation (Co-IP) assays. RESULTS:TAX significantly mitigated RC, characterized by preserved intestinal barrier integrity and reduced inflammatory cytokine production. It reshaped microbial homeostasis, specifically enriching bile acid (BA)-metabolizing genera (such as Lachnoclostridium) and promoting the accumulation of specific FXR-activating BAs, including glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), and ursodeoxycholic acid (UDCA). FMT from TAX-treated donors successfully recapitulated the radioprotective phenotype in recipient mice, confirming the causal role of the gut microbiota. Mechanistically, both TAX and the enriched BAs directly bound to the farnesoid X receptor (FXR), inducing conformational changes that enhanced its physical interaction with NLRP3, thereby inhibiting inflammasome assembly and downstream signaling. Importantly, pharmacological blockade of FXR by DY268 abolished the protective effects of TAX, confirming that FXR activation is indispensable for its therapeutic action. CONCLUSIONS:TAX mitigates RC not merely as an antioxidant, but as a microecological modulator. Importantly, TAX acts as a natural modulator of the "gut microbiota-BAs-FXR/NLRP3" signaling axis for RC therapy. TAX-induced microbiota changes promote the production of specific bile acids that amplify intestinal FXR signaling to suppress inflammation. This study provides a robust mechanistic basis for using TAX as an orally active radioprotectant targeting the gut-liver axis.

BACKGROUND:Mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) have remarkable potential in alleviating the severity of pancreatic inflammation. However, most transplanted MSCs undergo apoptosis shortly after in vivo administration, producing apoptotic EVs (ApoEVs). Our study investigated the potential role and molecular mechanisms of ApoEVs derived from apoptotic MSCs in ameliorating severe acute pancreatitis (SAP). METHODS:DiO-labeled peripancreatic adipose-derived stem cells (P-ADSCs) were administered to rats with SAP to monitor P-ADSC apoptosis. ApoEVs were isolated from P-ADSCs subjected to apoptosis induction, and conventional EVs were obtained from untreated P-ADSCs. The morphology, size distribution and marker protein expression of ApoEVs and EVs were characterized, and functional differences were assessed via transcriptomic and proteomic analyses to compare their gene and protein compositions. The rat pancreatic acinar cell (PAC) line AR42J was used to assess cellular responses to ApoEVs, and an SAP rat model was used to compare the therapeutic efficacy of ApoEVs in ameliorating SAP. Specific inhibitors and small interfering RNA were used to perform loss-of-function assays. RESULTS:P-ADSCs underwent apoptosis in the pancreas within 72 h after being injected into rats with SAP. Notably, ApoEVs exhibited superior therapeutic effects in ameliorating SAP than conventional EVs. Transcriptomic and proteomic analyses revealed that ApoEVs carry numerous autophagy-lysosome-related genes and proteins, enabling them to efficiently traverse the circulatory system and reach the pancreatic tissues. Following internalization by pancreatic acinar cells, ApoEVs effectively restored the impaired autophagic function of damaged acinar cells. In rats with SAP, ApoEVs treatment effectively alleviated both systemic and local tissue inflammation associated with SAP. Mechanistically, ApoEVs attenuated SAP by enhancing the transcription factor EB (TFEB)-mediated autophagy-lysosomal pathway. CONCLUSION:Given the high yield and ease of obtaining ApoEVs from P-ADSCs, our findings underscore the significant therapeutic potential of ApoEVs from dying P-ADSCs in treating SAP, highlighting their broad relevance for cell-free therapeutic approaches.

The aim of this study was to conduct a comprehensive analysis of the relationship between the fingerprint of Tremella fuciformis polysaccharides (TFPs) sourced from China and their bioactivities, with an emphasis on identifying the most bioactive TFP variety that significantly mitigated radiation-induced intestinal injury (RIII). Firstly, the multi-fingerprints we developed indicated that TFPs were classified as acidic, primarily consisting of mannose, rhamnose, glucuronic acid, glucose, xylose, and fucose, with average molecular weight (Mw) ranging from 1.65 × 103 to 2.50 × 103 kDa. Subsequently, in vitro activity evaluations demonstrated variability in the antioxidant activities and the inhibitory effects on cancer cell proliferation among TFPs. Multiple linear regression analysis indicated a significant correlation between monosaccharide composition of TFPs and their bioactivity, whereas Mw did not exhibit a similar relationship. Notably, TFP sourced from Zhenjinhui (Gutian, Fujian) (i.e., TFP-2) and Shengkuo (Tongjiang, Sichuan) (i.e., TFP-23) exhibited the most significant bioactivities, both effectively mitigating RIII in mice, with TFP-23 proving to be more effective. Further investigations indicated that TFP-23 provided radioprotective benefits by rectifying RIII-induced dysbiosis of intestinal microbiota and increasing probiotic abundance. Consequently, this study not only clarifies the fingerprint-activity relationship of TFPs but also promotes the potential of TFP-23 as innovative agents for radiation protection.

Severe Acute Pancreatitis (SAP) is a critical gastrointestinal inflammatory disease. Mesenchymal stem cells (MSCs), multipotent cells exhibiting diverse biological properties including directional migration, paracrine signaling, immunosuppression, and anti-inflammatory effects. Adipose tissue-derived mesenchymal stem cells (ADSCs) are particularly valuable in regenerative medicine and tissue engineering. Previous studies have demonstrated that ADSCs can mitigate pancreatic damage during acute pancreatitis (AP). However, given the complexity of SAP pathophysiology, which involves a dysregulated systemic inflammatory response and multiorgan failure, the therapeutic differences and underlying mechanisms of ADSCs derived from distinct harvesting sites. The SAP rat model was created by retrograde injection of a 4

INTRODUCTION:The innate immune system's complement system and cGAS-STING pathway play crucial roles in pathogen defense and immune response modulation. Complement's role in cancer is multifaceted, affecting myeloid cells and T cell activities, while intracellular complement (complosome) participates in cellular processes like metabolism and autophagy. STING's activation influences tumor dynamics through NF-κB pathway interactions, enhancing or suppressing tumor responses. The interplay between complement and cGAS-STING pathways suggests potential regulatory crosstalk affecting immune responses, warranting further investigation. AREAS COVERED:We review the functions of the complement system and the cGAS-STING pathway in pathogen clearance and tumor development. The focus is on exploring the intricate interplay between these pathways and discussing its implications for disease pathogenesis ;(PubMed: 1983-2024). EXPERT OPINION:Such insights into these pathways could guide therapeutic strategies targeting immune modulation in oncology and autoimmune disorders, emphasizing the need to understand their complex roles in health and disease.

The biological damage caused by ionizing radiation (IR) depends not only on the time and doses of exposure to tissue components but also on the developmental state of the cells. Currently, amifostine is the only radiation-protective agent used for clinical indications related to radiation therapy, but this compound has multiple drawbacks including high toxicity, short half-life and no protective effect on the nervous system. Ursolic acid (UA), a natural pentacyclic triterpenoid that exhibits multiple protective effects including anti-inflammatory, anticarcinogenic, and antioxidant effects. Due to its poor solubility and bioavailability, UA is mostly administered with liposomes. In this study we investigated the impact of UA312, an optimized derivative of UA, on radiation-induced developmental toxicity in zebrafish embryos and larvae. Embryo and larvae survival were observed at 4, 24, 48, and 72 hpf. UA312 was administered at 3 hpf, while embryos were irradiated with 6 Gy of γ-irradiation (dose rate: 0.88 Gy/min) at 4 hpf, then the embryos were moved to a fresh buffer. We determined that 40 µM of UA312 was a safe concentration for zebrafish embryos and larvae. We found that treatment with UA312 (40 µM) restored IR-induced early developmental dysplasia of the zebrafish embryos and larvae. Transcriptomic analysis revealed that exposure to IR inhibited multiple pathways related to neurodevelopment and cardiomyocyte function in zebrafish, which were validated by assessing abnormal cardiac morphology, variations in neurotransmitter levels and alterations in locomotor behavior; and that UA312 treatment ameliorated these alterations. We demonstrated that UA312 treatment significantly reversed the related signaling pathways by targeting chrna3 and grik5. In conclusion, this study identified a promising radioprotective drug, UA312, which alleviates IR-induced cardiotoxicity and neurodevelopmental toxicity in zebrafish by targeting chrna3 and grik5. UA312 may be developed as a novel radioprotective agent against acute IR damage in humans.

Objective To investigate the potential protective effects of dihydromyricetin (DHM), a primary bioactive compound derived from Ampelopsis grossedentata, against radiation-induced hematopoietic damage. Methods The in virto antioxidant capacity of DHM was evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2ʹ-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) assays. Survival rate and hematopoietic damage experiments were conducted on 130 mice. To assess the protective effects of DHM, a lethal dose of 7.5 ​Gy was delivered to 60 mice, and their 30-d survival rates were assessed and survival time were recorded. The mice were divided into 6 groups in survival analysis: DHM-only (200 ​mg/kg), IR, IR ​+ ​low-dose DHM (50 ​mg/kg), IR ​+ ​moderate-dose DHM (100 ​mg/kg), IR ​+ ​high-dose DHM (200 ​mg/kg), and IR ​+ ​amifostine (200 ​mg/kg). Subsequently, a hematopoietic injury model was established by subjecting 70 mice to whole-body irradiation (WBI) at a dose of 4 ​Gy. The mice were divided into 7 groups in the hematopoietic damage experiment: control, DHM-only (200 ​mg/kg), IR, IR ​+ ​low-dose DHM (50 ​mg/kg), IR ​+ ​moderate-dose DHM (100 ​mg/kg), IR ​+ ​high-dose DHM (200 ​mg/kg), and IR ​+ ​amifostine (200 ​mg/kg), with 10 mice in each group. The effects of DHM on body weights, blood routine indices, femoral nucleated cell counts, organ indices, and splenic nodules were analyzed. Using hematoxylin and eosin (H&E) staining, the effects of DHM on the spleen and bone marrow were examined. Furthermore, the antioxidant effects of DHM were evaluated by measuring biochemical markers including glutathione (GSH) and superoxide dismutase (SOD). Results DHM exhibited strong in vitro antioxidant activity (92.17 ​% in the ABTS assay and 90.75% in the DPPH assay). It significantly improved both the survival time and rates of mice exposed to irradiation at a lethal dose (20% for the IR ​+ ​low-dose DHM group, 40% for the IR ​+ ​moderate-dose DHM group, and 50% for the IR ​+ ​high-dose DHM group; P ​< ​0.05). In the hematopoietic injury experiment, DHM greatly improved blood routine indices, including the white blood cell count and the lymphocyte percentage (P ​< ​0.01). Moreover, DHM considerably increased organ indices, the number of splenic nodules, and the nucleated cell count in the femoral bone marrow. H&E staining revealed that DHM significantly alleviated radiation-induced damage to the spleen and bone marrow. Additionally, DHM treatment greatly enhanced the hepatic GSH and SOD levels of the irradiated mice, reaching 219.01 μmol/g prot and 199.53 U/mg prot, respectively (P ​< ​0.05). Conclusions Owing to its free radical scavenging potential, DHM can enhance the survival rates of mice exposed to radiation at a lethal dose and mitigate radiation-induced damage to the hematopoietic system. This study serves as a valuable reference for the application of traditional Chinese medicine in radioprotection.

Background and Purpose: Macrophage infiltration and activation is a critical step during acute pancreatitis (AP). NLRP3 inflammasomes in macrophages plays a critical role in mediating pancreatic inflammatory responses. Qing-Yi Decoction(QYD)has been used for many years in clinical practice of Nankai Hospital combined with traditional Chinese and western medicine treatment of acute pancreatitis. Although QYD has a well-established clinical efficacy, little is known about its bioactive ingredients, how they interact with different therapeutic targets and the pathways to produce anti-inflammatory effects. Here, we elucidate the therapeutic effects of QYD against acute pancreatitis and reveal its mechanism of action. Methods: The main components of QYD were identified using UHPLC-Q-Orbitrap MS. Network pharmacology was employed to predict potential therapeutic targets and their mechanisms of action. C57BL/6 mice were randomly divided into control group, model group, low, medium and high dose (6, 12, 24 g/kg) QYD groups, with 10 mice in each group. The therapeutic effect of QYD on cerulein-induced acute pancreatitis. (CER-AP) was evaluated by histopathological score, immunohistochemistry, serum amylase and cytokines detection by ELISA. The protein expressions of MyD88/NF-kappa B/NLRP3 signaling pathway were detected by Western blotting. Along with molecular docking of key bioactive compounds and targets, RAW264.7 cells stimulated with 1 mu g/ml LPS is used to screen components with more potent effects on target proteins. AR42 J cells were stimulated with 100 nM dexamethasone (dexa) combined with 10 nM cerulein (CN) as s a cell-culture model of acute pancreatitis. Inhibitory effects of the main chemical composition Wogonoside on NLRP3 inflammasomes were analyzed by qRT-PCR and Western blots. Results: Using UHPLC-Q-Orbitrap MS, 217 compounds were identified from QYD, including Wogonoside, Catechins, Rhein, etc. A visualization network of QYD-compounds-key targets-pathways-AP show that QYD may modulate PI3K-Akt signaling pathway, NOD-like receptor signaling pathway, MAPK signaling pathway, Ras signaling pathway and Apoptosis signaling pathway by targeting TNF, IL1 beta, AKT1, TP53 and STAT3 exerting a therapeutic effect on AP. QYD administration effectively mitigated CER-induced cytokine storm, pancreas edema and serum amylase. QYD (12 mg/kg) showed better effect. The protein expression levels of MyD88, NF-kappa B, NLRP3, Caspase-1 and GSDMD in pancreatic tissue were significantly decreased. Through molecular docking and LPS-RAW264.7 inflammation model, the selected Wogonoside significantly decreased IL-1 beta mRNA. The expression levels of NLRP3/Caspase-1/GSDMD pathway-related proteins were also decreased on AR42J-AP. Conclusion: The results of network pharmacology indicate that QYD can inhibit AP through multiple pathways and targets. This finding was validated through in vivo tests, which demonstrated that QYD can reduce AP by inhibiting NLRP3 inflammasomes, additionally, it should be noted that 12mg/kg was a relatively superior dose. One of the main chemical compositions Wogonoside regulated NLRP3 inflammasome activation to protect against AP. This study is the first to verify the intrinsic molecular mechanism of QYD in treating AP by combining network pharmacology and animal experiments. The findings can provide evidence for subsequent clinical research and drug development.

Large neutral amino acid transporter 1 (LAT1) is a family of transmembrane proteins that recognize and transport large neutral amino acids. Overexpression of LAT1 has been implicated in the pathogenesis of diverse cancers, primarily owing to its role in facilitating the cellular uptake of essential amino acids for tumour growth. Consequently, pharmacological intervention targeting LAT1 functionality has emerged as a therapeutically promising approach for cancer treatment. This review elaborates on the structural characteristics and biological activities of diverse LAT1-targeting compounds, including natural and synthetic amino acid derivatives. Additionally, radionuclides are attached to LAT1 inhibitors and utilized in tumour targeted therapy and imaging. In this review, small molecular LAT1 inhibitors/radiopharmaceuticals developed over the past 15 years are comprehensively overviewed.

Target identification is crucial for drug screening and development because it can reveal the mechanism of drug action and ensure the reliability and accuracy of the results. Chemical biology, an interdisciplinary field combining chemistry and biology, can assist in this process by studying the interactions between active molecular compounds and proteins and their physiological effects. It can also help predict potential drug targets or candidates, develop new biomarker assays and diagnostic reagents, and evaluate the selectivity and range of active compounds to reduce the risk of off-target effects. Chemical biology can achieve these goals using techniques such as changing protein thermal stability, enzyme sensitivity, and molecular structure and applying probes, isotope labeling and mass spectrometry. Concurrently, computational biology employs a diverse array of computational models to predict drug targets. This approach also offers innovative avenues for repurposing existing drugs. In this paper, we review the reported chemical biology and computational biology techniques for identifying different types of targets that can provide valuable insights for drug target discovery.

Cyclin-dependent kinase 19 (CDK19) has been identified as a promising target due to its high expression in prostate cancer (PCa) cells. This study focuses on optimizing the structure of CDK19-targeted imaging tracers. The linker of the lead compound was optimized based on previous structure-activity relationships and cyclization strategy. Incorporating the spirocyclic structure optimized the binding conformation and increased the binding effect of the ligands, which was also reflected in its increased IC50 value. Mice imaging showed clearer tumor lesions and acceptable tissue safety. In addition, 68Ga-IRM-8c identified three distinct lesions in two advanced CRPC patients, located in the pelvis, sacrum, and prostate. The SUVmax values of these lesions were 3.31, 2.93, and 2.73, respectively, with tumor-to-nontumor (T/NT) ratios of 2.30, 2.59, and 2.42. In conclusion, 68Ga-IRM-8c not only effectively detected lesions in PCa patients, but also preliminarily demonstrated tissue safety, further highlighting the potential of CDK19 in PCa diagnosis.

Objective To investigate the protective effects of dihydromyricetin (DHM) against radiation-induced intestinal injury (RIII) and its underlying mechanism by both in vivo and in vitro experiments. Methods Sixty male mice were randomly divided into 6 groups: control group, whole-abdominal irradiation (WAI)+0.5% sodium carboxymethyl cellulose (CMCNa) group, WAI ​+ ​DHM (50 ​mg/kg) group, WAI ​+ ​DHM (100 ​mg/kg) group, WAI ​+ ​DHM (200 ​mg/kg) group, and WAI ​+ ​amifostine (100 ​mg/kg) group. An animal model of RIII was then established by administering 12 ​Gy abdominal local irradiation to all groups. The protective effects of DHM was evalauted by hematoxylin and eosin staining (HE), villin staining, and the FITC-dextran method. The in vitro radioprotective effects of DHM was further evaluated by colony formation assay. Flow cytometry was used to analyze cell cycle distribution, apoptosis, and reactive oxygen species (ROS) levels. Western blot assay was used to examine the expression of proteins related to apoptosis, ferroptosis, ROS, DNA damage, and autophagy. Additionally, immunofluorescence staining was performed to detect γ-H2AX foci formation as a marker of DNA double-strand breaks. Finally, the effect of DHM on colon cancer radiosensitivity was tested by in vitro and in vivo colony formation and tumor-bearing experiments. Results In the RIII model, DHM showed radioprotective effects by increasing colon length, ameliorating villus injury, promoting crypt cell proliferation, and mitigating mucosal barrier damage (P ​< ​0.05). In vitro experiment indicated that DHM significantly reduced radiation-induced apoptosis (control: 4.27 ​± ​0.61, DHM: 3.46 ​± ​1.31, IR: 23.46 ​± ​0.89, IR ​+ ​DHM: 12.47 ​± ​0.36, P ​< ​0.001), ROS accumulation (P ​< ​0.05), and DNA damage (P ​< ​0.001). The radioprotective effects of DHM might be closely associated with autophagy regulation and Nrf2 pathway activation. Moreover, DHM showed antitumor activity against colon cancer cells without conferring radioprotective effects on them. Conclusions DHM can effectively alleviate RIII indicated by both in vivo and in vitro experiments, suggesting its potential to be used as a radioprotective agent.

Ionizing radiation (IR) poses a significant threat to both the natural environment and biological health. Exposure to specific doses of ionizing radiation early in an organism's development can lead to developmental toxicity, particularly neurotoxicity. Through experimentation with Xenopus laevis (X. laevis), we examined the effects of radiation on early developmental stage. Our findings revealed that radiation led to developmental abnormalities and mortality in X. laevis embryos in a dose-dependent manner, disrupting redox homeostasis and inducing cell apoptosis. Additionally, radiation caused neurotoxic effects, resulting in abnormal behavior and neuron damage in the embryos. Further investigation into the underlying mechanisms of radiation-induced neurotoxicity indicated the potential involvement of the neuroactive ligand-receptor interaction pathway, which was supported by RNA-Seq analysis. Validation of gene expression associated with this pathway and analysis of neurotransmitter levels confirmed our hypothesis. In addition, we further validated the important role of this signaling pathway in radiation-induced neurotoxicity through edaravone rescue experiments. This research establishes a valuable model for radiation damage studying and provides some insight into radiation-induced neurotoxicity mechanisms.

Cyclin-dependent kinase 19 (CDK19) is overexpressed in prostate cancer, making it an attractive target for both imaging and therapy. Since little is known about the optimized approach for radioligands of nuclear proteins, linker optimization strategies were used to improve pharmacokinetics and tumor absorption, including the adjustment of the length, flexibility/rigidity, and hydrophilicity/lipophilicity of linkers. Molecular docking was conducted for virtual screening and followed by IC50 determination. Both BALB/c mice and P-16 xenografts were used for tissue distribution and PET/CT imaging. The ligand 68Ga-10c demonstrated high absorption in tumor 5 min after injection and sustains long-term imaging within 3 h. Furthermore, 68Ga-10c exhibited slow clearance within the tumor and was predominantly metabolized in both the liver and kidneys, showing the potential to alleviate metabolic pressure and enhance tissue safety. Therefore, the linker optimization strategy is well suited for CDK19 and provides a reference for the radioactive ligands of other nuclear targets.