Search Results (282)

Ulcerative colitis is a chronic inflammatory bowel disease that requires new treatment approaches beyond traditional anti-inflammatory drugs. In this study, we analyzed publicly available single-cell RNA sequencing data from a DSS-induced colitis mouse model and identified pyroptosis as a key biological process linked to epithelial damage. Based on this, we screened marine-derived brominated indoles for potential pyroptosis inhibitors and identified 6-bromoindole-3-acetonitrile as a promising candidate. Our results show that this compound significantly alleviates DSS-induced colitis in mice, with notable body weight recovery and a drop in Disease Activity Index (DAI) scores from about 8.5 to below 4 (p < 0.05). At the molecular level, it lowers the mRNA levels of Nlrp3, Caspase-1, and other pyroptosis-related genes, indicating suppression of the pyroptotic pathway. Moreover, treatment helps restore the intestinal barrier by supporting goblet cell regeneration and strengthening tight junctions. Molecular docking suggests that 6-bromoindole-3-acetonitrile binds stably to the active site of myeloperoxidase (MPO), with a binding energy of −18.1 kcal/mol, offering a possible structural basis for its anti-inflammatory effects. Together, these findings point to a marine-derived compound that reduces both inflammation and pyroptosis, representing a promising strategy for treating ulcerative colitis. Notably, these results come from preclinical studies and need further validation in clinical settings. Full article

Intervertebral disc degeneration (IDD) is a fundamental pathological basis of low back pain, yet its pathogenic mechanisms remain incompletely understood. Infection by low-virulence anaerobic bacteria has recently been recognized as a potential etiological factor. In this study, Cutibacterium acnes (C. acnes) was detected in 13.7% of degenerated intervertebral disc (IVD) tissues, and its presence was significantly associated with younger patients and Modic changes. In vitro experiments demonstrated that C. acnes supernatant induces oxidative stress, apoptosis, and extracellular matrix (ECM) degradation in nucleus pulposus (NP) cells in a dose-dependent manner. RNA sequencing and functional validation further indicated that these pathological effects are mediated through activation of the p38 MAPK signaling pathway. Pharmacological inhibition of p38 with the specific inhibitor BIRB-796 effectively reversed the observed cellular damage. Wogonin exhibited negligible cytotoxicity toward NP cells and significantly attenuated C. acnes supernatant-induced oxidative stress, apoptosis, and ECM metabolic imbalance by inhibiting the phosphorylation of p38, JNK, and ERK1/2 within the MAPK pathway. Furthermore, in vivo experiments confirmed that Wogonin alleviated disc height loss, reduced T2-weighted signal attenuation, and mitigated histological damage induced by C. acnes in rat models, thereby restoring the balance between ECM synthesis and degradation. Collectively, this study demonstrates for the first time that C. acnes supernatant exacerbates IDD through activation of the p38 MAPK signaling pathway. It further shows that Wogonin can specifically inhibit this pathway and effectively ameliorate C. acnes-mediated IDD damage in both in vitro and in vivo models. These findings expand the theoretical framework of infection-related mechanisms underlying IDD and identify potential therapeutic targets and candidate agents for the treatment of IDD associated with C. acnes infection. Low back pain is a common health issue affecting populations worldwide, with intervertebral disc degeneration as its core etiology. However, the pathogenic causes in some patients, especially young individuals, remain incompletely understood. This study found that Cutibacterium acnes, a low-virulence bacterium commonly colonizing human skin and mucous membranes, produces metabolic products that can induce damage to the core cells of the intervertebral disc, exacerbate disc degeneration, and this process is associated with the abnormal activation of specific cellular signaling pathways. Through clinical sample detection, cell experiments, and animal model validation, we confirmed that infection with this bacterium is closely related to young patients and specific spinal imaging changes. Meanwhile, we identified Wogonin, a natural compound extracted from Scutellaria baicalensis, which can effectively inhibit the aforementioned abnormal signaling pathways, alleviate cell damage caused by bacterial metabolic products, and improve the pathological state of intervertebral disc degeneration. This study not only reveals the role of low-virulence bacterial infection in intervertebral disc degeneration and provides a new explanation for the pathogenic mechanism in young patients but also offers a natural antibiotic-free candidate for addressing bacterial resistance. It holds significant reference value for the clinical diagnosis and treatment of spinal diseases as well as the development of related drugs. Full article

The liver is a critical organ in drug metabolism and detoxification. Ganoderma lingzhi triterpenoids, a major class of bioactive compounds in G. lingzhi extracts, exhibit liver protective effects with pharmaceutical potential. In this study, we established an acute liver injury model in mice via intraperitoneal injection of 0.25% Carbon tetrachloride(CCl₄) olive oil. Prophylactic and therapeutic administration of G. lingzhi triterpenoid extracts were evaluated using alanine aminotransferase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and hepatic histopathology. Western blot analysis assessed protein expression of anti-inflammatory and antioxidant stress-related pathways (Nrf2/Keap1 and MyD88/NF-κB-p65). Intervention effects on acute liver injury were determined by measuring protein molecular weight following triterpenoid treatment. In summary, G. lingzhi triterpenoids significantly alleviate oxidative stress and inflammatory responses in mice with acute liver injury by activating the KEAP1-Nrf2 antioxidant pathway and inhibiting the NF-κB-p65 and MyD88-mediated inflammatory pathways. These triterpenoids reduced serum transaminase levels, improved hepatic histopathological damage, and exerted effective protective effect on liver tissue. This study provides experimental support for the comprehensive evaluation of G. lingzhi’s anti-inflammatory and antioxidant effects. Full article

The inappropriate use of antibiotics in aquaculture has exacerbated antimicrobial resistance in pathogens, thereby reducing the efficiency of aquaculture production. Therefore, it is crucial to develop effective antibiotic alternatives capable of inhibiting pathogenic bacteria. Against this background, the present study investigated the efficacy and underlying mechanism of carvacrol against Vibrio harveyi in the mariculture of the marine fish Sebastes schlegelii, aiming to provide data support for the development of green fishery drugs to replace antibiotics. The results indicated that pre-treatment with carvacrol increased the survival rate of infected S. schlegelii. Meanwhile, post-infection administration of carvacrol alleviated intestinal pathological damage. Carvacrol regulated host immunity by modulating the transcription of the immune-related genes NF-κB/RelA and IL-15. Carvacrol did not significantly alter the activities of SOD, MDA, or CAT, suggesting that the oxidative defense pathway was not primarily involved. Analysis of intestinal Vibrio load confirmed that carvacrol could inhibit the growth and colonization of intestinal Vibrio, thereby maintaining microbial homeostasis. Immunohistochemistry and peripheral blood flow cytometry showed that carvacrol enhanced the adaptive immunity of fish by increasing the proportions of CD4-1⁺ T cells and CD79a/CD79b⁺ B cells in tissues and peripheral blood. In conclusion, carvacrol enhances the resistance of S. schlegelii against V. harveyi by inhibiting pathogenic bacteria, improving intestinal morphological structure, reducing pathogenic bacterial load to maintain microbial homeostasis, and enhancing the adaptive immunity of the organism. This study provides a theoretical basis and data support for the substitution of antibiotics and the development of green feed additives in aquaculture. Full article

Purpose: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder strongly associated with intestinal microbial dysregulation. Although 5-aminosalicylic acid (5-ASA) is widely used in the clinical management of IBD, its therapeutic efficacy is often limited. To address this, the present study aimed to develop a bifidobacterium-derived extracellular vesicle-based drug delivery system (B-MVs@5-ASA) to enhance the therapeutic outcomes of IBD. Methods: B-MVs were isolated by PEG precipitation and loaded with 5-ASA via sonication to obtain B-MVs@5-ASA. Their morphology, particle size, zeta potential, and encapsulation efficiency were analyzed using TEM, DLS, and UV spectrophotometry. Cellular uptake, cytotoxicity (LDH and NO assays), and anti-inflammatory effects were assessed in RAW 264.7 and Caco-2 cells. A DSS-induced colitis mouse model was established to evaluate therapeutic efficacy. Cytokines (ELISA), colon histopathology (H&E), tight-junction proteins (IF), and gut microbiota composition (16S rRNA sequencing) were systematically analyzed. Results: B-MVs@5-ASA exhibited a particle size of 104.3 ± 2.81 nm and an encapsulation efficiency of 11.14% ± 3.63%. B-MVs@5-ASA exhibited the strongest anti-inflammatory effect in vitro and most effectively alleviated DSS-induced colitis in vivo, outperforming monotherapies in reducing inflammation, tissue damage, and enhancing barrier integrity. B-MVs@5-ASA further promoted goblet cell regeneration and beneficially modulated the gut microbiota by enriching Akkermansia and suppressing Escherichia, thereby restoring microbial homeostasis. Conclusions: B-MVs@5-ASA provides potent anti-inflammatory and mucosal-protective effects by modulating cytokine balance, enhancing epithelial barrier function, and reshaping gut microbiota. These findings highlight probiotic vesicle-based nanoplatforms as a safe and promising strategy for targeted IBD therapy. Full article

Microcystin-LR (MC-LR) is a potent hepatotoxin that has been shown to cause liver damage even at doses lower than the established Low Observable Adverse Effect Level (LOAEL) of 200 μg/kg in animal models. We have previously observed that low-dose exposure to MC-LR in animals with diet-induced Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and subsequent treatment with antioxidants like N-acetylcysteine (NAC) and the Na⁺/K⁺ ATPase-Src kinase inhibitor pNaKtide significantly alleviated hepatic infiltration of immune cells, downregulated markers of inflammation and hepatotoxicity, increased the breakdown of the toxin molecule, and restored phase I and II drug metabolism pathways, including the glutathione pathway. Because the liver is composed of heterogeneous cell types, this study aimed to determine the specific role of hepatocytes in the uptake and metabolism of MC-LR, especially in the setting of MASLD. To address this, we used two well-established hepatocyte cell lines—AML-12 murine hepatocytes and human Hep3B hepatocytes. Preliminary dose comparison studies with AML-12 cells showed that MC-LR at 10 μM concentration showed a significant upregulation in the genetic expression of the markers of hepatotoxicity—OSMR (p ≤ 0.01) and SerpinE (p ≤ 0.0001)—in comparison to Vehicle. Treatment with pNaKtide (1 µM) and/or NAC (10 mM) in the presence of MC-LR significantly reduced the expression of both OSMR (p ≤ 0.0001) and SerpinE (p ≤ 0.01 and p ≤ 0.0001, respectively). To model steatotic hepatocytes characteristic of the MASLD phenotype, Hep3B hepatocytes were first treated with 500 µM of oleic acid (OA) before exposing them to the toxin in the presence and absence of antioxidants. MC-LR exposure, induced markers of inflammation and hepatotoxicity to be elevated significantly in the presence of OA as compared to MC-LR exposure alone. This elevation of the genetic markers of inflammation and hepatotoxicity was significantly attenuated on treatment with pNaKtide (1 µM) and NAC (10 mM). Quantification of human SERPINE1 (PAI1) and 8-OHdG, a stable marker of oxidative stress, in the spent media of Hep3B cells corroborated the trends observed in the genetic markers of hepatotoxicity. These observations support the central role that hepatocytes play in the uptake and metabolism of MC-LR, which is complicated by the presence of MASLD-like conditions and can help in the development of future therapeutic strategies. Full article

Celastrol (CSL), a natural triterpenoid extracted from Tripterygium wilfordii, demonstrates a wide range of biological activities. In this study, we explored whether CSL alleviates kidney damage in spontaneously hypertensive rats (SHRs) through the modulation of the Nrf2/Ho-1 pathway, a crucial target in renal injury models. A total of 40 male SHRs, aged 6–8 weeks, were randomly allocated to four groups: the control group (CON, serving as the healthy control), the spontaneously hypertensive rat group (SHR), the SHR group treated with low-dose CSL (L-CSL + SHR, 0.5 mg/kg/d), and the SHR group treated with high-dose CSL (H-CSL + SHR, 1 mg/kg/d). All drugs were formulated using physiological saline as the solvent and administered via intraperitoneal injection. The control group received an equivalent volume of physiological saline via intraperitoneal injection, and all groups underwent continuous daily administration for 6 weeks. The results indicated that, in comparison with the control group, the serum levels of angiotensin, angiotensin-converting enzyme, and aldosterone in the SHR group were relatively high, and CSL treatment further downregulated these indices. Simultaneously, CSL downregulated pro-inflammatory factors (tumor necrosis factor-α and interleukin-1β) and upregulated interleukin-6. Regarding renal function-related indicators, CSL reduced malondialdehyde levels and enhanced the activities of antioxidant enzymes, such as superoxide dismutase, glutathione peroxidase, and catalase. Moreover, CSL inhibited the overexpression of Keap1. Significantly, the mRNA levels of Nrf2, Nqo1, and Ho-1 in the CSL-treated groups were notably higher than those in the SHR group. These findings suggest that CSL mitigates renal pathological damage in SHR by activating the Nrf2/Ho-1 pathway, offering a potential therapeutic approach for hypertension-induced renal injury. Full article

The emergence of antibiotic resistance in pathogens, including Salmonella typhimurium, poses a major challenge to animal health and safety. Andrographolide is well known for its antibacterial properties and therefore offers potential as an antimicrobial treatment to lessen the damage caused by Salmonella. PANoptosis is defined as an inflammatory coordinated cell death pathway encompassing apoptosis, pyroptosis, and necroptosis. To reduce the organ and tissue damage caused by bacterial infection and reduce antibiotic resistance, this study investigated the effect of andrographolide on liver damage in Salmonella-infected mice. We used a mouse model infected with Salmonella typhimurium for in vivo experiments, which involved the detection of the bacterial load in the liver, liver injury indicators, and expression of related PANoptosis-related genes and proteins. Here, our finding indicated that andrographolide effectively inhibited markers associated with apoptosis, pyroptosis, and necroptosis in mouse hepatocytes, alleviated liver injury and clinical symptoms caused by Salmonella typhimurium in mice, and thus exerted therapeutic effects. In this study, we observed that andrographolide modulated the markers associated with these three pathways, indicating their involvement in PANoptosis. These results suggest that andrographolide significantly relieve Salmonella-induced liver injury by inhibiting PANoptosis, highlighting the potential significance of andrographolide as an effective drug for the treatment of Salmonella. Full article

Background/Objectives: The frequent use of antibiotics has led to increasing drug resistance in Aeromonas hydrophila; therefore, there is an urgent need to develop novel antimicrobial agents to prevent and control bacterial diseases in aquaculture. Allicin E (ALE) is derived from garlic (Allium sativum L.), a plant extensively used in traditional medicine for treating infections. This study aimed to evaluate the potential of ALE against A. hydrophila, a major aquaculture pathogen, by investigating its antibacterial efficacy, mechanisms of action, and in vivo protective effects. Methods: The minimum inhibitory and bactericidal concentrations (MIC/MBC) were determined by broth microdilution. Antibacterial mechanisms were investigated through ROS detection, electron microscopy, fluorescent staining, and content leakage measurement. In vivo efficacy was evaluated in Carassius auratus gibelio by monitoring survival rates and bacterial loads, analyzing immune and antioxidant biomarkers, and histopathological analysis after A. hydrophila challenge. Results: ALE exhibited potent antibacterial activity (MIC = MBC = 8 μg/mL), achieving complete bacterial elimination within 1 h and showing a low resistance propensity. Mechanistically, ALE induced ROS accumulation, causing oxidative damage that disrupted membrane integrity and facilitated the leakage of cellular contents. In vivo, ALE significantly enhanced fish survival, reduced bacterial loads, modulated inflammatory cytokines, boosted antioxidant enzyme activities (SOD and CAT), and alleviated tissue damage. Conclusions: ALE possesses potent in vitro antibacterial activity and exerts an inhibitory effect on bacteria-induced inflammatory responses, effectively combating A. hydrophila through a multi-target mechanism and enhancing host resistance. Full article

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), characterized by immune system disorders and multiple organ damage. Current clinical treatment of LN requires a complex multi-drug combination, which is often associated with severe side effects and low patient compliance. The aim of this study was to design a self-nanoemulsifying drug delivery system (SNEDDS) co-loading total glucosides of Paeonia (TGP) and dihydroartemisinin (DHA) to increase the solubility of the drug as well as achieve synergistic anti-inflammatory and immunomodulatory effects for LN therapy. Network pharmacology, molecular docking and molecular dynamics simulations were employed to predict the core therapeutic targets and related signaling pathways. The SNEDDS co-loaded with TGP and DHA was optimized via central composite design response surface methodology (CCD-RSM). Its physicochemical properties, particle size and the polydispersity index (PDI) of the optimized formulation were characterized. In vivo therapeutic efficacy was evaluated in MRL/lpr mice by measuring disease-related indicators (urinary protein, serum ANA, and anti-ds-DNA) and inflammatory cytokines (TNF-α, IL-6, and IL-1β). Renal tissue pathology was also examined. All data were analyzed by one-way analysis of variance (ANOVA) with p < 0.05 considered statistically significant. The core therapeutic targets predicted with high relevance were AKT1, MAPK1, MAPK3, and RELA. The optimized SNEDDS achieved a high loading capacity of 16.11 ± 0.43 mg/g for TGP and 12.79 ± 1.33 mg/g for DHA, with a particle size of (25.84 ± 0.30) nm and PDI of (0.07 ± 0.02). In MRL/lpr mice, SNEDDS treatment significantly reduced urinary protein levels (p < 0.01), serum ANA (p < 0.01) and anti-ds-DNA titers (p < 0.01) compared with the model group. Additionally, the levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) were markedly decreased (p < 0.05), and renal tissue damage was alleviated. Conclusions: The SNEDDS co-loaded TGP and DHA is a promising oral nanotherapeutic strategy for LN, offering synergistic anti-inflammatory and immunomodulatory effects. Full article

Sodium-glucose co-transporter (SGLT) inhibitors are a novel class of glucose-lowering drugs with beneficial pleiotropic effects that have been widely investigated in the past decade in several experimental models and patients in the absence of diabetes. There are two types of transporters: the SGLT1 isoform that is distributed across a broad range of tissues, including the cardiovascular system, and the SGLT2 isoform, which is mostly expressed in renal proximal tubular cells. It is known that inflammation and oxidative stress are key contributors to vascular damage and the progression of atherosclerosis. SGLT inhibitors have demonstrated multiple benefits that contribute to improved vascular health, including alleviation of endothelial function, anti-inflammatory and antioxidative effects, and mitigation of arterial stiffness, all contributing to blood pressure decrease. An increasing body of research has tackled the molecular and cellular mechanisms of their chronic and, more recently, acute cardiovascular beneficial effects. This narrative review specifically delves into the direct vasculoprotective effects of SGLT2 and dual SGLT1/2 inhibitors, summarizing their off-target mechanisms described in various experimental settings (animal models, animal and human cell lines/samples). Full article

Objective: The therapeutic efficacy of the classic antibiotic combination trimethoprim/sulfamethoxazole (TMP/SMZ) is often limited by the significant pharmacokinetic mismatch. In this study, a polyethylene glycol-polylactic-co-glycolic acid (PEG-PLGA) nanodelivery system was employed to improve the pharmacokinetic matching of TMP and SMZ. The investigation also evaluated the enhanced in vivo antibacterial efficacy of this formulation. Methods: Ultra-High Performance Liquid Chromatography–Tandem Mass Spectrometry (UPLC-MS/MS) was employed to systematically characterize the absorption, distribution, and excretion profiles of PEG-PLGA-loaded TMP nanoparticles (NPs) in rats. In vitro antibacterial activity was assessed against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). In vivo efficacy and biosafety of the TMP NPs/SMZ regimen were evaluated using a murine E. coli infection model via survival monitoring, biochemical assays, and histopathology. Results: Pharmacokinetic analysis revealed that TMP NPs achieved a relative bioavailability of 193.05% and extended the elimination half-life by 3.37-fold compared to free TMP. Tissue distribution showed significantly increased drug accumulation in the liver, spleen, and kidneys, with renal clearance as the primary excretion pathway (73.89%). In vitro, the nano-formulation reduced the minimum inhibitory concentration (MIC) by 2-4-fold and shortened the bactericidal duration from 12 to 8 h. In vivo, the TMP NPs/SMZ combination significantly improved survival rates, accelerated recovery, and alleviated infection-induced organ damage without systemic toxicity. Conclusions: This nanotechnology-based strategy effectively aligns the pharmacokinetics of TMP and SMZ, prolongs their synergistic window, and enhances biosafety, offering a viable approach to revitalize classic antibiotic combinations. Full article

Influenza A virus (IAV) infection constitutes a major public health threat. Severe influenza virus infection can induce intense inflammatory responses and lung injury, leading to serious clinical symptoms or even death. The utility of current anti-influenza drugs is often limited by side effects and the emergence of drug-resistant strains. Based on the critical role of L-type voltage-gated calcium channels (L-VGCCs) in influenza virus replication, this study investigates the antiviral activity and mechanism of verapamil, a classic L-type calcium channel antagonist, against H1N1-UI182 virus. Verapamil, an L-type calcium channel blocker, is widely used in the treatment of cardiovascular diseases and has a well-established safety profile. Through molecular dynamics (MD) simulation and network pharmacology analysis, we predicted the stable binding mode of verapamil to the target protein (PDB id: 6JPA) and its potential multi-target network. In vitro, verapamil exhibited antiviral activity against H1N1-UI182 in MDCK cells, enhancing the survival rate of infected cells and reducing viral nucleoprotein (NP) expression. In a lethal H1N1-UI182 infection mouse model, verapamil treatment markedly improved survival rates, alleviated weight loss and lung pathological damage, exhibiting a dose-dependent protective effect. Lung tissue analysis showed that verapamil effectively reduced the lung index and viral load, suppressed the activation of the Nuclear factor kappa B (NF-κB) signaling pathway, and decreased the expression of key inflammatory factors, thereby mitigating the cytokine storm. A comparison of administration regimens indicated that pre-treatment yielded optimal efficacy, suggesting verapamil acts primarily during the early stage of the viral life cycle. This study systematically elucidates that verapamil exerts antiviral and immunomodulatory effects by regulating the NF-κB pathway. Network pharmacology analysis suggested the potential involvement of multiple targets and pathways, including EGFR, SRC, and phospholipase D signaling, providing hypotheses for future mechanistic investigation. This paper supports a drug repurposing strategy against drug-resistant influenza viruses and highlights its significant potential for clinical translation. Full article

Oxidative stress-induced endometrial injury has been shown to contribute to infertility; however, effective strategies that can simultaneously scavenge reactive oxygen species (ROS) and restore mitochondrial and antioxidant homeostasis remain elusive. In this study, we isolated extracellular nanovesicles from Artemisia argyi (A-NVs) and investigated their protective effects on H₂O₂-damaged human endometrial stromal cells (hESCs). We discovered that A-NVs possess a typical lipid bilayer structure and contain a variety of bioactive components. Our metabolomic analysis indicates that A-NVs can be regarded as a “natural drug reservoir”, in which flavonoids account for approximately 10.8%. We demonstrate that A-NVs can be efficiently taken up by cells, improve cell viability, reduce intracellular and mitochondrial ROS levels, enhance superoxide dismutase (SOD) activity, upregulate the expression of catalase (CAT), SOD1, and SOD2, and partially restore mitochondrial membrane potential. Mechanistically, A-NVs exert antioxidant effects by activating the SIRT1/PGC-1α/Nrf2 signaling axis. SIRT1 activation further alleviates H₂O₂-induced premature senescence, as evidenced by a 71.8% reduction in SA-β-Gal-positive cells compared with the H₂O₂ group, together with downregulation of p53 and p21 expression. These positive protective effects can be blocked by the SIRT1 inhibitor EX-527, confirming the central role of this pathway. Collectively, our findings demonstrate that A-NVs can maintain redox and mitochondrial homeostasis while inhibiting oxidative stress-related senescence progression, underscoring their application potential in endometrial repair and functional recovery. Full article

No US Food and Drug Administration (FDA)-approved prophylaxis is currently available for Acute Radiation Syndrome (ARS), which remains a significant threat to military and civilian populations. In this study, we investigated Vasculotide (VT), a Tie2 receptor agonist mimic, as a novel pre-exposure prophylaxis designed to stabilize the vascular endothelium, one of primary targets of radiation-induced damage. To evaluate its efficacy, female B6D2F1/J mice were exposed to 9.5 Gy total body irradiation (TBI), with VT administered subcutaneously at 12 and 2 h prior to exposure. Assessments included 30-day survival, biomarkers of vascular injury, proinflammatory cytokine/chemokine profiling, and evaluation of hematopoietic (H) and gastrointestinal (GI) recovery. Our findings demonstrate that VT significantly increased 30-day survival in a dose-dependent manner, achieving a 30% survival advantage at the 20 μg/kg dose. Furthermore, VT provided robust protection against radiation-induced vascular activation and injury, effectively alleviating damage to the bone marrow (BM) and GI tract. Taken together, these results identify VT as a promising prophylactic countermeasure for ARS. By targeting the Tie2 pathway to preserve vascular integrity, VT addresses a critical gap in medical countermeasures, offering a viable strategy to enhance survival and accelerate multi-organ recovery in radiological mass-casualty scenarios. Full article