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Ancient and medieval sources, particularly from Arabic and Mediterranean traditions, reported Citrus aurantifolia (Lime) as antidotes against poison, tonics for digestion, antibacterial and immunomodulatory effects. Moreover, its traditional use as a diuretic and antitoxic agent supports its ethnomedicinal relevance in managing renal ailments such as urolithiasis and toxin-induced nephropathies. Methotrexate (MTX) is consumed in several types of carcinomas. Still, numerous studies have stated MTX side effects, including kidney and liver damage. The purpose of the current study is to elucidate the defending strategies of Citrus aurantifolia (Christm.) Swingle (Rutaceae) essential oil (CAEO) in the amelioration of MTX induced hepatic and kidney toxicities focusing on the Nrf2/HO-1 and JAK2/STAT3/NF-κB pathways. CAEO was extracted and its composition was investigated. After the acclimation period, rats were allocated into five groups. Normal and CAEO groups in which animals were given saline or CAEO orally (10 days). MTX group in which rat were given MTX (20 mg/kg ip, once on 4th day). CAEO-50/MTX and CAEO-100/MTX groups in which animals received oral administration of CAEO 50 and 100 mg/kg for 10 days and MTX (20 mg/kg ip, on 4th day). Histopathological, liver and kidney functions, Cytochrome c release and mitochondrial swelling assessment. Oxidative and nitrosative stress, Lipid peroxidation, Inflammatory mediators and apoptosis markers assessment. Gene expression of JAK2/STAT3/NF-κB and Nrf2/HO-1/NQO1were measured. CAEO showed a monoterpene-dominant profile. Integrated analysis of docking scores suggested that a small group of abundant monoterpenes, supported by selected sesquiterpenes, drives the predicted interaction with JAK2, with comparatively weaker binding to the Keap1-related target. The network pharmacology analysis of CAEO ingredients specified JAK2/STAT3 signaling as one of the key mechanistic insights into how CAEO might counteract MTX-induced organ toxicity. Co-administering CAEO with MTX decreased hepatic and renal function tests caused by MTX and improved liver and kidney architecture. CAEO with MTX increased GST, GSH-Px, GSH-R and SOD and diminished NO and MDA levels. CAEO effectively reserved the MTX associated cytochrome c release from mitochondria and lessened mitochondrial swelling. CAEO instigated the gene expression and levels of Nrf2, HO-1, NQO1 while reduced the gene and protein expressions of JAK2, STAT3 and NF-κB. CAEO reduced inflammatory markers (TNF-α, MPO and ICAM), apoptotic markers (caspase 3 and 9). CAEO considerably alleviated the oxidative and nitrosative stress, mitochondrial dysfunction, inflammatory and apoptosis responses caused by MTX. This shielding effect may be due to the decline in JAK2/STAT3/NF-κB and the triggering in Nrf2/HO-1/NQO1 pathways.
Doxorubicin (DOX) is an effective anthracycline chemotherapeutic agent widely used for treating lymphoma, leukemia, and sarcoma, but its clinical application is severely restricted by dose-dependent cardiotoxicity, hepatotoxicity, and nephrotoxicity. This study aimed to investigate the mechanisms underlying DOX-induced multi-organ toxicity and identify targeted therapeutic natural compounds through an integrated approach combining network toxicology, virtual screening, molecular docking, molecular dynamics simulation, and in vivo validation. Potential targets were obtained by intersecting drug targets from SwissTargetPrediction, SuperPred, PharmMapper, DrugBank, TTD, ChEMBL, PubChem, and DGIdb databases with injury-related targets from GeneCards, OMIM, and TTD databases. Ten protein-protein interaction network analyses were performed to identify core targets, revealing 24 potential targets involved in DOX-induced toxicity. Gene Ontology enrichment analysis identified 1515 biological processes, 44 cellular components, and 90 molecular functions, while KEGG analysis highlighted 107 significant pathways including lipid and atherosclerosis-related signaling. TLR4 was prioritized as the top hub target, and reverse virtual screening of the natural product database identified taxifolin as a high-affinity candidate with favorable ADMET properties. Molecular docking and dynamics simulations confirmed stable taxifolin-TLR4 complex formation. In vivo experiments using a mouse model demonstrated that taxifolin significantly ameliorated serum biomarker elevations and histopathological damage in heart, liver, and kidney tissues while effectively suppressing TLR4 protein expression. These findings establish taxifolin as a promising TLR4-targeted natural therapeutic agent for mitigating DOX-induced multi-organ toxicity.
Overuse of acetaminophen (APAP) can induce acute liver injury (ALI), and its mechanism is closely related to ferroptosis. 4'-O-β-d-glucosyl-5-O-methylvisamminol (5-O) is a natural coumarin glycoside with anti-inflammatory and antioxidant activities, but whether it can alleviate liver injury through intervention in ferroptosis and multi-dimensional mechanisms remains unclear. To explore whether 5-O can alleviate APAP-induced ALI through multiple mechanisms such as inhibiting ferroptosis, regulating inflammation, promoting lipid metabolism, and reshaping the intestinal microbiota . Through in vitro and in vivo experiments, combined with CCK-8, Western blot, whole transcriptome sequencing, 16S rRNA sequencing, FMT and other techniques and methods, the mechanism of 5-O was evaluated from multiple levels such as cells, tissues, metabolism and flora. 5-O downregulated Tfrc/Slc39a14 in cells to reduce iron intake and upregulated Slc7a11/GPX4 to enhance antioxidant capacity. It reduced serum ALT/AST, alleviated liver tissue pathological damage, inhibited the expression of chemokines and inflammatory factors, and activated the PPARα-Fabp1/Me1 axis to promote lipid metabolism. Whole transcriptome analysis revealed that 5-O intervention was associated with upregulation of miR-30e-3p and downregulation of Tfrc, suggesting a potential role in modulating iron metabolism. Concurrently, the analysis indicated that 5-O treatment was linked to inhibition of the ferroptosis pathway and activation of the PPAR pathway. In addition, 5-O reshaped the intestinal microbiota, inhibited pro-inflammatory bacterial genera, and promoted the colonization of the probiotic Lactobacillus. This study systematically clarified that the hepatoprotective effect of 5-O against APAP-induced liver injury is associated with a multi-dimensional network involving "ferroptosis-inflammation-metabolism-flora". The innovation lies in systematically elucidating the multi-faceted actions of a natural product, which may involve regulating ferroptosis through miR-30e-3p associated changes, cross-organ metabolic reprogramming, and microecological modulation. This work provides a candidate drug with multi-dimensional synergistic potential for the prevention and treatment of liver injury.
Cytokine Release Syndrome (CRS) is a life-threatening complication of T-cell-engaging immunotherapies, causing vascular leakage and multi-organ dysfunction. Standard Interleukin-6 (IL-6) blockade often fails in severe cases by leaving the upstream initiator, Tumor Necrosis Factor-α (TNF-α), unchecked. TNF-α drives early macrophage activation and endothelial injury, whereas IL-6 amplifies systemic inflammation. To decisively interrupt this inflammatory feedback loop, we developed IDC007, a novel bispecific antibody simultaneously neutralizing TNF-α and IL-6 receptor (IL-6R). We evaluated the neutralizing effects of IDC007 in an in vitro CRS model utilizing OKT3/R848-stimulated human peripheral blood mononuclear cells and human umbilical vein endothelial cells. Furthermore, we utilized an OKT3-induced humanized CRS mouse model to assess in vivo target engagement and therapeutic efficacy. In vitro, IDC007 effectively suppressed pro-inflammatory cytokine secretion (e.g., TNF-α, IFN-γ) and prevented endothelial barrier dysfunction. In vivo, IDC007 successfully engaged both targets. Administration mitigated physiological deterioration, including hypothermia and weight loss, leading to improved survival. Dual inhibition effectively prevented immune hyperactivation, evidenced by the significant attenuation of splenomegaly and lung-specific organ damage. These findings serve as a preclinical proof-of-concept demonstrating that dual targeting of TNF-α and IL-6R offers a potent mechanistic approach to attenuate severe CRS by preserving vascular endothelial integrity and overcoming the therapeutic limitations of conventional monotherapies.
Steroid-induced osteonecrosis of the femoral head (SONFH) is a challenging orthopedic disease worldwide. Previous research has long focused on bone structure repair; however, bone and muscle are now recognized as functionally interconnected units coupled through biomechanics throughout the lifespan. Recent studies suggest that SONFH is not an isolated single-organ disorder but rather aligns with a systemic comorbid state characterized by the synergistic decline of bone and muscle function. Understanding the pathophysiology of bone and muscle crosstalk in SONFH is essential for its prevention and treatment. In this review, we propose an integrated pathological framework-the four-axis pathological mechanism of bone and muscle crosstalk in SONFH. We elaborate in detail on the mechanisms of bone and muscle crosstalk along four pathological axes-blood supply, lipid metabolism homeostasis, inflammation-immune regulation, and mechanical transduction-as well as the cross-tissue signaling-mediated synergistic damage among these axes: Imbalance in the blood supply axis may contribute to parallel ischemia in bone and muscle via shared pathways such as decreased HIF-1α/VEGF and inhibited NO/eNOS, which has been associated with endothelial dysfunction and impaired angiogenesis; Dysregulation of the lipid metabolism axis promotes bone marrow adiposity and muscular lipid accumulation by modulating key factors such as PPARγ and PGC-1α, as well as signaling pathways including PI3K/Akt/mTOR; Activation of the inflammation-immune axis exacerbates bone resorption and muscle atrophy through pathways such as NF-κB and STAT3, along with imbalanced immune cell polarization; Abnormalities in the mechanical axis create a vicious cycle of bone-muscle co-deterioration due to reduced bone load-bearing capacity and diminished muscular support function. This review further highlights current research gaps, including the insufficient systematic analysis of multi-axis interactive mechanisms, the lack of in-depth verification of bone-muscle crosstalk via multi-dimensional technologies, and the limited research on multi-target combined interventions targeting the bone-muscle unit. It proposes that future studies should strengthen systematic investigation into the interactive mechanisms among multiple pathological axes and develop combined intervention strategies targeting both bone and muscle. This will provide important insights for establishing an integrated diagnostic and therapeutic model addressing both structure and function, as well as for developing future hip-preserving treatment strategies for SONFH.
Docetaxel (DTX) is an efficient and normally used anticancer drug. But it results in systemic organ toxicity and damages various non-target organs of the body. Vanillic acid (VA) is a biologically active phenolic acid that exhibits potential therapeutic properties. This research was conducted to understand the protective effects of VA against DTX-induced liver damage in rats. Forty male Sprague Dawley rats were randomly assorted into four groups. One group was the control, and the other groups were as follows: DTX group, DTX + VA group, and VA group. Thirty milligrams per kilogram DTX was given once on the first day of the trial while VA (50 mg/kg) was given on a daily basis via intragastric gavage for 7 days. The results showed that DTX disrupted TLR4/MyD88/TRAF6, NF-κB, and JAK/STAT signaling pathways and caused oxidative stress, inflammation, and apoptosis as well as mitochondrial and histological damages in liver. However, the supplementation of VA protected the hepatic tissues from these damages by mitigating the effects of DTX. VA protected the hepatic tissues by reducing the expressions of TLR4, MyD88, TRAF6, NF-κB, and other inflammatory cytokines, while upregulating the expressions of IκB. Importantly, it lowered the levels of ALT and AST by 29.10% and 44.46%, respectively, while significantly reducing the levels of inflammatory markers, i.e., TNF-α (36.60%) and IL-6 (40.94%). Additionally, ELISA evaluation showed it lowered the levels of p-STAT3, and NF-κB (p-65) and normalized BAX, BCL-2 and CASPASE-3 expressions and levels. Furthermore, VA restored antioxidant defenses and preserved mitochondrial and histological architecture. Hence, VA may protect hepatic tissues from chemotherapeutic drug, i.e., DTX-induced damage through modulating JAK/STAT, and NF-κB/TLR4 signaling pathways.
Traumatic Brain Injury (TBI) is a critical neurological condition that severely affects the brain and extracranial organs. Secondary damages such as BBB disruption, oxidative stress, and inflammation in the brain can induce systemic pathophysiological changes in multiple organs, primarily in the heart, lungs, liver, and kidneys, known as Multiple Organ Dysfunction Syndrome (MODS). Systemic hyperinflammation, autonomic dysfunction, and immunosuppression collectively play a crucial role in the progression of MODS. The current study aimed to investigate the therapeutic efficacy of the polyphenolic compound, sinapic acid (SA), against this complex disease. The Weight Drop model was used to induce TBI in Swiss albino mice, which were divided into four groups: control, TBI, SA 30, and SA 50. SA was administered orally to the test groups at doses of 30 mg/kg and 50 mg/kg for 21 days post-injury. Several behavioural, biochemical, molecular, and histopathological parameters were assessed at days 1 and 21 post-injury. The results highlighted that SA treatment significantly improved animal behaviour, restored BBB and lung integrity, reduced oedema, oxidative stress, and inflammation, as well as catecholamine spill. It also restored the normal organ functions, preserved cellular architecture, and upregulated PDL-1 and IL-10 mRNA expression. These findings suggest that SA is a multi-target therapeutic compound having neuroprotective and organoprotective properties, making it a promising candidate that mitigates TBI-induced MODS.
Deoxynivalenol (DON), a prevalent mycotoxin contaminating agricultural commodities worldwide, poses substantial risks to both public health and animal production. While recognized as a primary contaminant in chicken feed, the mechanistic basis of its multi-organ toxicity remains incompletely elucidated. This study employed an integrated approach combining network pharmacology, molecular docking, in silico ADME prediction, and in vivo experiments to systematically investigate the common molecular mechanisms underlying DON-induced damage in broilers, focusing on the liver, spleen, breast muscle, and cecum. Bioinformatic analysis identified 20 core target genes, with KEGG enrichment highlighting the MAPK and Rap1 signalling pathways as central regulatory hubs. In vivo results demonstrated that DON exposure significantly compromised growth performance, evident through reduced body weight and organ coefficients. Histopathological and serological analyses confirmed extensive tissue damage: hepatic injury (elevated AST/ALT, structural lesions), immunotoxicity (increased IgA/IgM, splenic abnormalities), myotoxicity (elevated CK/LDH, muscle degeneration), and intestinal inflammation (upregulated IL-1β/TNF-α, villous atrophy). Critically, DON dysregulated the expression of eight key genes within the MAPK/Rap1 axis, upregulating BRAF, CDC42, CSF1R, IKBKB, PDGFRA, and THBS1 while downregulating IGF1R and MAP2K1, along with increased phosphorylated MAPK protein level. Molecular docking simulations further validated strong binding affinities between DON and these core targets. Complementary ADME prediction further supported the physiological plausibility of these interactions, indicating DON's favorable drug-likeness and potential for intracellular target accessibility. Collectively, this work establishes that DON induces coordinated multi-organ toxicity in broilers primarily through regulation of the Rap1/MAPK signalling network, providing a crucial theoretical foundation for developing targeted interventions against DON exposure in (especially poultry) production, food safety and beyond.
Poria cocos (Fuling), a classic edible and medicinal fungus with a 2000-year clinical application history in traditional Chinese medicine, is well-documented for its core efficacies of "invigorating the spleen and relieving diarrhea", which is highly consistent with the core clinical manifestations of infectious colitis including persistent diarrhea, intestinal barrier impairment and mucosal inflammation. Poria cocos polysaccharides (PCP) are recognized as the primary bioactive component of Poria cocos, with proven anti-inflammatory and immunomodulatory activities. However, whether PCP exerts its anti-colitis effect via regulating the tryptophan (Trp) metabolism-aryl hydrocarbon receptor (AhR) signaling axis remains largely uncharacterized. This study aimed to investigate the therapeutic effect of PCP on Salmonella-induced infectious colitis in mice, and systematically elucidate its underlying molecular mechanism focusing on the Trp metabolism-AhR-redox signaling axis. A Salmonella typhimurium-induced infectious colitis mouse model was established to evaluate the protective effect of PCP (100, 200, 400 mg/kg) via oral administration. Targeted metabolomics was performed to profile the changes of intestinal Trp metabolites in colitis mice. Histopathological examination, immunohistochemistry, immunofluorescence, western blot, and real-time quantitative PCR were conducted to assess intestinal barrier integrity, intestinal redox status, and the activation of relevant signaling pathways. Molecular docking simulation was used to verify the direct interaction between the key differential metabolite and its target proteins. PCP administration significantly alleviated the clinical symptoms of infectious colitis, restored colon length and organ indices (P < 0.05), and ameliorated colonic pathological damage in a dose-dependent manner. PCP markedly reinforced intestinal epithelial barrier integrity via upregulating the protein expression of tight junction proteins including ZO-1, Occludin and Claudin (P < 0.01). Targeted metabolomics analysis revealed that PCP intervention effectively remodeled the disordered intestinal Trp metabolic profile, especially significantly enriched the endogenous AhR ligand indole-3-lactic acid (I3LA) by 5.5-fold compared with the model group (P < 0.05). Mechanistically, PCP promoted the nuclear translocation of AhR, normalized the aberrant NRF2/HO-1 signaling pathway to restore intestinal redox homeostasis, and subsequently suppressed the hyperactivation of JAK/STAT3 and NF-κB inflammatory cascades, with the mRNA levels of core pro-inflammatory cytokines IL-6 and TNF-α reduced by more than 70% (P < 0.01). Collectively, these findings demonstrate that PCP ameliorates Salmonella-induced infectious colitis via remodeling the intestinal Trp metabolic microenvironment to enrich I3LA, which acts as a molecular switch to activate the AhR-redox axis and further suppress mucosal inflammatory responses. This study provides modern scientific evidence for the traditional "invigorating the spleen and relieving diarrhea" clinical application of Poria cocos, and supports the potential of PCP as a safe and effective prebiotic agent for the prevention and treatment of intestinal inflammatory diseases.
Exertional heat stroke (EHS) is a life‑threatening condition characterized by hyperthermia, systemic inflammation and central nervous system injury, particularly in desert dry‑heat environments. Excessive activation of inflammatory signaling pathways, notably the Toll‑like receptor (TLR)4/myeloid differentiation factor 88 (MyD88)/NF‑κB axis, critically contributes to brain damage and neuroendocrine dysfunction in EHS. Curcumin exhibits anti‑inflammatory and neuroprotective effects; however, poor bioavailability limits its clinical application. Notably, nanocrystal formulations may improve the therapeutic efficacy of curcumin. In the present study, network pharmacology and molecular docking were employed to identify the potential therapeutic targets of curcumin in EHS. A rat model of desert dry‑heat‑induced EHS was established and nanocurcumin was administered intravenously following heat exposure. Histopathological examination, ELISA analyses of neuroendocrine hormones and inflammatory cytokines, serum biochemical assays and western blotting were subsequently performed. These evaluations assessed brain injury, hypothalamic‑pituitary‑adrenal and hypothalamic‑pituitary‑thyroid axes functions, systemic inflammation, peripheral organ injury indicators and activation of the TLR4/MyD88/NF‑κB signaling pathway. Network analysis revealed 138 overlapping target genes between curcumin and EHS, identifying AKT1, TNF, EGFR, BCL2, STAT3, SRC and NFKB1 as key hub genes. Kyoto Encyclopedia of Genes and Genomes pathway analysis highlighted enrichment of the 'Toll‑like receptor signaling pathway' and 'NF‑κB signaling pathway'. Molecular docking indicated favorable binding affinities of curcumin to essential inflammatory proteins, including TLR4, MyD88 and NFKB1. In vivo experiments demonstrated that nanocurcumin reduced neuronal injury in the cerebral cortex and hypothalamus of rats. Furthermore, nanocurcumin significantly decreased serum concentrations of corticotropin‑releasing hormone, corticosterone, thyrotropin‑releasing hormone and thyroid‑stimulating hormone, and restored adrenocorticotropic hormone, total triiodothyronine and free triiodothyronine levels. Nanocurcumin also lowered serum TNF‑α, IL‑6 and IL‑1β levels, and improved biochemical markers of liver, kidney and tissue injury (alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatine kinase and lactate dehydrogenase). Within the 4‑h observation period, medium and high doses of nanocurcumin did not worsen biochemical markers compared with those in the EHS or saline groups. Additionally, nanocurcumin administration dose‑dependently inhibited TLR4, MyD88 and NF‑κB protein expression in brain tissues. In conclusion, nanocurcumin may alleviate brain injury, neuroendocrine dysfunction and systemic inflammation associated with desert dry‑heat‑induced EHS, and may improve biochemical indicators of peripheral organ damage; these effects likely involve suppression of the TLR4/MyD88/NF‑κB signaling pathway. These findings support the use of nanocurcumin as a promising adjunctive therapy for managing EHS.
Diabetes mellitus and its complications represent one of the most critical global public health challenges, with their pathogeneses involving complex multi-system and multi-level regulatory networks. Modern medical research confirms that diabetes mellitus not only manifests as glucose metabolism disorders characterized by insulin resistance and β-cell dysfunction but also involves progressive systemic pathological changes including microcirculation disorders(encompassing microvascular complications) and organ fibrosis(macrovascular complications). On the basis of the "Qi pathway-collateral axis" theory and the trunk-branch coupling mechanism, this study thoroughly investigates the pathogenesis and treatment of diabetes mellitus and its complications. Research findings demonstrate that Qi pathway, as the main channel for Qi and blood circulation, directly contributes to insulin resistance and β-cell dysfunction when its function is disrupted. Collaterals, as the finer branches of Qi and blood circulation, play a key pathological role in diabetic microvascular and macrovascular complications when being obstructed. Through the analysis of the trunk(Qi pathway)-branch(collateral vessel) coupling mechanism, this study reveals the intrinsic connection between central metabolic regulation and target organ damage. In terms of traditional Chinese medicine(TCM) treatment, an intervention system focusing on regulating Qi pathway to restore metabolic balance, dredging collateral vessels to improve microcirculation, and coordinating trunk-branch interactions to prevent complications has been established. This approach aims to restore the normal function of Qi pathway and collaterals while harmonizing the trunk-branch system, thereby providing new perspectives and methods for the prevention and treatment of diabetes mellitus and its complications. By constructing the "Qi pathway-collateral axis" theoretical framework, this study not only offers innovative TCM diagnostic and therapeutic insights for the management of diabetes mellitus but also paves new ways for the modernization and clinical application of TCM theory, providing unique theoretical foundations and practical guidance for improving the prevention and treatment of diabetes mellitus and its complications.
Vandetanib, a critical therapy for advanced thyroid and RET-driven cancers, is limited by life-threatening hepato-cardiotoxicity. This study identifies lysosomal protease cathepsin B (CTSB) as the central mediator of vandetanib-induced organ damage through STAT3-driven transcriptional activation. CTSB triggers mitochondrial apoptosis by cleaving the lysosomal calcium channel mucolipin TRP cation channel 1 (MCOLN1), disrupting calcium/AMP-activated protein kinase (AMPK) signaling and autophagy flux. Crucially, the natural compound tannic acid directly binds and inhibits CTSB, completely protecting against hepato-cardiotoxicity without compromising vandetanib's antitumor efficacy in preclinical models. Overall, our findings establish CTSB-mediated lysosomal dysfunction and MCOLN1-calcium-AMPK axis disruption as the core mechanism of vandetanib-induced hepato-cardiotoxicity, and identify tannic acid as a readily translatable adjuvant strategy to prevent this toxicity. These findings redefine CTSB as a druggable target for kinase inhibitor toxicities and position tannic acid as a clinically translatable adjuvant to enhance vandetanib's safety profile. By preserving lysosomal function and calcium homeostasis, this strategy addresses a critical unmet need in precision oncology, enabling prolonged, safer use of vandetanib and related tyrosine kinase inhibitors. The discovery of shared lysosomal injury mechanisms across organs also opens avenues for preventing multi-organ toxicities in broader cancer therapies.
Heart transplantation is an optimal therapeutic regimen for terminal-stage cardiac failure. However, cold ischemia-reperfusion injury (CIRI) remains an unavoidable and outstanding challenge, which is a significant obstacle to early graft dysfunction and long-term survival. Blockage of complement, apoptosis, and inflammation by small interfering RNA is considered a strategy for attenuating CIRI and protecting cardiac function. However, their delivery to the donor organ is still a serious challenge due to the polyanionic nature and high molecular weight properties. Here, we have designed a novel functionalized gene delivery system of direct delivery and sustained release of siRNAs targeting complement C3 (C3), Caspase-3, and nuclear factor κB (NF-κB) to treat the donor organ prior to transplantation. The functionalized gene delivery system (siRNA-TNPs), composed of CaCO3/CaP/TAT embellished carboxymethyl chitosan (CaCO3/CaP/TCMC) and synthesized through the co-precipitation method, efficiently encapsulates siRNAs during self-assembly. The siRNA-TNPs safeguards siRNAs from biological degradation, facilitates intracellular siRNA transfection, promotes lysosomal escape, and enhances the delivery efficiency of siRNA to the donor hearts. Perfusion of donor hearts with siRNA-TNPs prior to transplantation attenuated C3, Caspase-3, and NF-κB genes expression of donor heart for at least 5 days after transplantation. Furthermore, silencing of C3, Caspase-3, and NF-κB genes expression alleviated cell apoptosis, myocardial damage, tissue inflammation, and rejection and improved cardiac function. These data suggest that the multiple-target siRNA-TNPs solution can extend the preservation time for donor grafts, attenuate IRI, and protect cardiac function in murine models of heart transplantation, which provides a principal of concept for potential clinical translation.
Ubiquitination is crucial for regulating diverse cellular functions, including protein degradation, cell cycle progression, signal transduction and gene expression. This intricate process is mediated by the ubiquitin proteasome system. Within this system, ubiquitin‑specific protease 10 (USP10) is a key member that, through its deubiquitinase activity, orchestrates multiple cellular processes, such as DNA damage repair, immune and inflammatory responses, environmental adaptation and autophagy. The biological activity and protein stability of USP10 are extensively regulated by post‑translational modifications, including PARylation, histone methylation and ubiquitination. Functionally, USP10 has a dual role in tumorigenesis: It can either promote or suppress cancer progression and metastasis by influencing oncogenic signaling pathways. Beyond cancer, USP10 has been implicated in the pathogenesis of cardiovascular and neurodegenerative diseases, as well as organ fibrosis, underscoring its broad physiological relevance. Decades of research have spurred the development of a range of USP10 inhibitors, such as Spautin‑1, P22077, HBX19818, Wu‑5 and D1. The present review provides a comprehensive overview of recent advances in understanding the role of USP10 in maintaining homeostasis and dissects the pathological mechanisms in human diseases. The review further highlights the potential of precise USP10‑targeted interventions as promising therapeutic strategies for disease prevention and treatment.
Numerous cellular functions, such as apoptosis, proliferation, differentiation, survival, transformation and cell migration, are regulated by a crucial transcription factor called activator protein 1 (AP-1). Growing evidence indicates that AP-1 is involved in severe conditions like fibrosis, cancer, and organ damage, as well as inflammatory diseases, including rheumatoid arthritis, psoriasis, and asthma. In recent years, AP-1 has become a significant focus in drug research. The activation of AP-1 by TNF is crucial for essential components of the inflammatory reaction, including the expression of tissue remodelling proteases such as collagenase, as well as pro-inflammatory cell adhesion molecules like E-selectin. This transcription factor is formed by the assembly of jun-jun homodimers, jun-fos heterodimers, and jun-ATF (Activating Transcription Factor) heterodimers. As a member of the basic leucine zipper (bZIP) class, AP-1 regulates target genes by binding to their promoters in a sequence-specific way. New research suggests that reducing AP-1 function could improve various disease outcomes and treatments. Transfection of decoy oligonucleotides (ODNs) offers an innovative approach to gene therapy by targeting specific gene regulatory elements. Transcription factor decoys mimic the sites where transcription factors bind, competing with promoter regions within the cell nucleus. These molecules can regulate interactions between DNA sequences and transcription factors, which play a role in altering gene activation during both normal and disease-related cellular processes. This review aims to summarize the effects of AP-1-targeted decoys on various conditions. The studies demonstrated the great promising role of AP-1 decoys as therapeutics for various diseases, especially cardiovascular diseases and cancers. Moreover, it was shown that modifications of AP-1 (circular and hairpin as well as phosphorothioate backbones structures) decoys made them more stable and effective.
Drug-induced liver injury accounts for approximately 10% of acute hepatitis and up to 50% of acute liver failure. Despite its clinical significance, treatment remains largely limited to cessation of the offending agent. SLIT/ROBO signaling, known for roles in organ development, angiogenesis, leukocyte migration, and cancer metastasis, has demonstrated protective effects against various organ damage. In mouse models of liver injury induced by acetaminophen (APAP), thioacetamide, bile duct ligation, and serum from patients with toxic liver disease, Slit2 expression significantly increases, while Slit1 and Slit3 remain unchanged. Liver-specific Slit2 knockdown exacerbates liver injury, whereas recombinant SLIT2 alleviates liver damage by reducing oxidative stress via CYP2E1 downregulation and suppressing inflammation through nuclear factor κB inhibition. Notably, among ROBO receptors, only ROBO4 was induced in hepatocytes after APAP exposure. ROBO4 knockdown eliminates the hepatoprotective effects of SLIT2, highlighting the importance of SLIT2/BOBO4 signaling in toxic liver injury. Furthermore, the novel Slit2-derived peptide 5 (SP5), designed from the ROBO4-binding LRR2 domain, significantly reduces liver damage and inflammation. Notably, both recombinant SLIT2 and SP5 confer hepatoprotection even when administered 24 h after APAP challenge. These findings suggest that SLIT2/ROBO4-targeted therapies may offer a promising approach for preventing fulminant hepatitis in the context of toxic liver injury.
As the primary alternatives to brominated flame retardants, chlorinated organophosphorus flame retardants (Cl-OPFRs) have seen surging production and usage. Consequently, they are now widely distributed and persistent in indoor dust, air, water, and food. These pollutants accumulate in human samples and pose significant hazards to living organisms, with increasing evidence identifying the liver as the main target organ. This paper systematically summarises current progress regarding the absorption and metabolic fate of Cl-OPFRs and reviews their hepatic effects. We propose that Cl-OPFRs induce liver damage through multiple pathways: oxidative stress, inflammatory responses, lipid metabolism disruption, mitochondrial dysfunction, gut-liver axis disruption, cell cycle arrest, and apoptosis. Importantly, these mechanisms function synergistically rather than in isolation. Core drivers, particularly oxidative stress and mitochondrial dysfunction, engage in complex interactions that form positive feedback loops, collectively amplifying liver injury. Despite these advances, current research is constrained by the discrepancy between high-dose experimental models and real-world exposures, as well as limited metabolite data. Future research should prioritise environmentally relevant chronic models and investigate non-apoptotic cell death (e.g., ferroptosis), sex-specific vulnerabilities, and metabolite toxicity. In conclusion, this review provides an outlook for future research and offers scientific evidence to support the rational application of Cl-OPFRs and the mitigation of their environmental health risks.
The liver is extremely vulnerable to endotoxin-induced damage during sepsis. Hydrogen gas (H2) is a colorless and odorless gas molecule with anti-oxidative and anti-inflammatory actions. However, the effects of H2 intraperitoneal injection on sepsis-induced acute liver injury and the possible mechanisms remain unclear. Biochemical analysis, H&E staining, immunoblotting, immunofluorescence, and TUNEL staining were used to investigate the effects and mechanisms of H2 intraperitoneal injection on lipopolysaccharide (LPS)-induced acute liver injury in mice. AML12 cells and pharmacological rescue experiment were used to confirmed the target of H2. H2 pretreatment by intraperitoneal injection improved LPS-induced acute liver injury in mice as indicated by reducing inflammatory cells infiltration in the liver, down-regulating serum ALT and AST levels, decreasing hepatic 3-nitrotyrosine, MDA, and MPO levels, and up-regulating hepatic GSH levels. Mechanistically, H2 suppressed TLR4 to IKK-NF-κB and to MAPK (ERK, p38 and JNK) signaling, and thus reducing pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-18 levels in the liver of LPS-challenged mice. Moreover, the hepatic pyroptosis signaling including NLRP3 inflammasome (NLRP3, ASC, and Caspase-1) to GSDMD, Caspase-8/11 to GSDMD, Caspase-3 to GSDME, and TUNEL staining in LPS-challenged mice were all reversed by H2 treatment. The pharmacological rescue experiments by agonist (nigericin) and antagonist (MCC950) of NLRP3 further confirm the action of H2 on NLRP3 in vitro. H2 pretreatment by intraperitoneal injection alleviated LPS-induced acute liver injury in mice by modulating redox homeostasis, TLR4-mediated innate immune signaling, NLRP3 inflammasome activation and pyroptosis signaling.
Hypoxic lung injury (HLI) remains a significant clinical challenge, primarily characterized by oxidative damage and vascular remodeling. Recent studies have identified ferroptosis as a key contributor to hypoxia-related organ injury, and its inhibition represents a potential therapeutic strategy for HLI. Silkworm pupa (SW) contains diverse bioactive compounds with well-established anti-inflammatory, antioxidant, and anti-apoptotic properties. However, whether SW exerts protective effects against hypoxic lung injury through the regulation of ferroptosis remains unknown. In this study, a murine model of hypoxia was established, and two different doses of SW powder were administered via gavage. Cellular experiments were also conducted to evaluate the effects of SW on cell proliferation, antioxidant capacity, and metabolic and transcriptional reprogramming under hypoxic conditions, as well as to investigate the underlying molecular mechanisms. SW treatment improved lung function and grip strength, reduced HIF-1α levels, alleviated pulmonary edema, and significantly decreased oxidative stress and lipid peroxidation in hypoxic mice. Cellular experiments further demonstrated that SW promoted cell proliferation under hypoxia, enhanced cellular antioxidant capacity, and induced substantial metabolic and transcriptional reprogramming. Mechanistic investigations revealed that SW upregulated the expression of p62, which competitively bound to Keap1, thereby disrupting the Keap1-Nrf2 interaction and leading to the release and subsequent nuclear translocation of Nrf2. The activated nuclear Nrf2 further promoted the expression of its downstream target genes, including xCT, FTH1, and NQO1, as well as enhancing glutathione (GSH) levels. These coordinated events collectively attenuated oxidative stress and ultimately inhibited hypoxia-induced ferroptosis.The use of ferroptosis regulators further confirmed the involvement of ferroptosis in lung injury. SW protects against HLI primarily by activating the Nrf2-mediated antioxidant response pathway and subsequently suppressing ferroptosis.
Environmental molybdenum (Mo) exposure is increasing worldwide. Notably, the lung has been recognized as a key target organ for heavy metal toxicity, yet the mechanisms underlying Mo-induced lung injury remain poorly understood. In this study, we systematically explored the mechanisms underlying Mo-induced lung injury through a multi-omics strategy integrating respiratory function evaluation, histopathology, biochemical analyses, proteomics, and metabolomics. Our results showed that Mo exposure led to significant accumulation of Mo in lung tissue, accompanied by increased respiratory rate and irregular breathing patterns, as well as marked histological damage. Biochemical analyses revealed that Mo exposure markedly impaired pulmonary antioxidant defenses, promoted oxidative stress, and activated inflammatory responses and apoptosis. Further proteomic and metabolomic analyses demonstrated widespread remodeling of protein expression and metabolic profiles in the lung following Mo exposure. Multi-omics integration identified a highly interconnected metabolic regulatory network centered on Glycine, serine and threonine metabolism, which is coordinated with beta-Alanine metabolism, Pentose phosphate pathway, Thiamine metabolism, and Cysteine and methionine metabolism. This network plays a key role in mediating lung injury, oxidative stress, inflammation, and apoptosis. Collectively, our findings demonstrate that environmental Mo exposure induces lung injury by remodeling metabolic networks and disrupts oxidative stress-inflammation homeostasis, providing new insights into the toxicological mechanisms of Mo.