Keyu Sun

Management of sepsis‐associated acute lung injury (S‐ALI) remains challenging due to complex inflammatory cascades, oxidative stress amplification, and limited therapeutic delivery to injured pulmonary tissues. Here, we developed a biomimetic “dual‐lock‐inspired” nanoplatform (M@ORNP) that integrates a neutrophil‐mimetic membrane interface with an OR‐based encapsulated prodrug core to enable inflammation‐associated pulmonary targeting and coordinated therapeutic regulation. The platform consists of a self‐assembled ester‐linked prodrug composed of 4‐octyl‐itaconate and retinol, encapsulated within a membrane derived from differentiated HL‐60 cells. The neutrophil‐mimetic membrane endows M@ORNPs with enhanced interaction with inflammatory endothelial cells and promotes preferential accumulation within injured lung tissues. Following cellular internalization, M@ORNPs exhibited progressive dissociation from lysosomal compartments, consistent with altered endo‐lysosomal trafficking behavior and potential intracellular release of therapeutic components. In vitro and in vivo studies demonstrated that M@ORNPs coordinated the suppression of reactive oxygen species (ROS) accumulation and inflammatory signaling pathways, including NF‐κB, STAT1, and the NLRP3 inflammasome, in macrophage‐associated inflammatory models. In murine S‐ALI models, M@ORNP treatment reduced inflammatory responses, alleviated pulmonary injury, and improved survival outcomes under lethal challenge conditions. Collectively, this study presents a biomimetic nanotherapeutic strategy that combines inflammatory‐site accumulation with complementary anti‐inflammatory and antioxidant activities, providing a platform for the treatment of severe inflammatory disorders.

Lipopolysaccharide (LPS)-activated pro-inflammatory responses play a critical role in sepsis, a life-threatening condition. This study investigates the role of origin recognition complex subunit 6 (ORC6) in LPS responses in macrophages and monocytes. Silencing ORC6 using targeted shRNA significantly reduced LPS-induced expression and production of IL-1β (interleukin-1 beta), TNF-α (tumor necrosis factor alpha), and IL-6 (interleukin-6) in THP-1 human macrophages, peripheral blood mononuclear cells (PBMCs), and bone marrow-derived macrophages (BMDMs). Additionally, ORC6 knockout (KO) via the CRISPR/Cas9 method in THP-1 macrophages inhibited LPS-induced pro-inflammatory responses, while ectopic overexpression of ORC6 enhanced LPS-induced expression and production of pro-inflammatory cytokines. ORC6 is crucial for the activation of the nuclear factor kappa B (NFκB) signaling cascade in macrophages and monocytes. LPS-induced NFκB activation was largely inhibited by ORC6 silencing or KO, but potentiated following ORC6 overexpression. Mechanistically, ORC6 associated with nuclear p65 after LPS stimulation, an interaction necessary for NFκB activation. Overexpression of ORC6 did not recover the reduced pro-inflammatory response to LPS in THP-1 macrophages with silenced p65. Furthermore, the NFκB inhibitor BMS-345,541 nearly eliminated the pro-inflammatory response enhanced by ORC6 overexpression in response to LPS. Further studies revealed that ORC6 depletion inhibited NFκB activation induced by double-stranded RNA (dsRNA) and high mobility group box 1 (HMGB1) in THP-1 macrophages. In vivo experiments demonstrated that macrophage-specific knockdown of ORC6 protected mice from LPS-induced septic shock and inhibited LPS-stimulated production of IL-1β, TNF-α, and IL-6 in mouse serum. ORC6 silencing also inhibited LPS-induced NFκB activation in ex vivo cultured PBMCs following macrophage-specific knockdown of ORC6. These findings highlight ORC6 as a pivotal mediator in LPS-induced NFκB activation and the pro-inflammatory response in sepsis, suggesting that targeting ORC6 could be a novel therapeutic strategy for managing sepsis and related inflammatory conditions.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating condition caused by a putative mechanism associated with the activation of the mammalian target of rapamycin (mTOR). The current study aims to unravel the signaling pathway leading to CTEPH on the basis of mTOR activation. Methods: In vivo CTEPH models were established from rats exposed to repeated autologous thromboembolization. The rats were subjected to right ventricular pressure (RVP) and mean pulmonary artery pressure (mPAP) measurement as well as histopathological examination. To establish CTEPH cellular models for in vitro experiments, pulmonary artery endothelial cells were isolated from CTEPH rats and identified via immunofluorescence/flow cytometry. AZD8055, an mammalian target of rapamycin complex 1 (mTORC1) inhibitor, was used to treat both in vivo and in vitro models. Activating transcription factor 4 (ATF4) was overexpressed in in vitro models. Viability and apoptosis were detected using cell counting kit-8 assay and flow cytometry. Expression of mTOR, ATF4 and monocyte chemoattractant protein-1 (MCP-1) in pulmonary artery tissues/cells was measured by means of immunohistochemistry, Western blotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA). The interaction between ATF4 and MCP-1 was predicted with bioinformatics approach and validated using Chromatin immunoprecipitation (ChIP) assay. Results: CTEPH rats exhibited elevated mPAP, activated mTORC1-ATF4-MCP-1 pathway, increased area/total area of pulmonary artery, and enhanced apoptosis and thromboembolism in the pulmonary artery tissues, which were all reversed by AZD8055 treatment. In in vitro models, ATF4 overexpression decreased cell viability, enhanced apoptosis and upregulated MCP-1 level, while AZD8055 exerted an opposite effect, normalizing these changes and suppressing the mTORC1-ATF4-MCP-1 pathway. ATF4 could bind to MCP-1 promoter region. Conclusion: The mTORC1-ATF4-MCP-1 pathway induces endothelial dysfunction and pulmonary artery thromboembolism to promote the development of CTEPH in rats.

Background: Procyanidin B1 can attenuate inflammation, but its specific impact and mechanism on sepsis-related acute lung injury (ALI) are obscure. Therefore, this study aimed to explore the effect and mechanism of Procyanidin B1 on the lipopolysaccharide (LPS)-mediated human pulmonary alveolar epithelial cells (HPAEpiCs) injury. Methods: The effect of varying concentrations of Procyanidin B1 (50, 100, 150, or 200 μM) on the viability of HPAEpiCs cells and LPS-mediated HPAEpiCs was assessed using cell counting kit-8. After Procyanidin B1 treatment, the proliferation and apoptosis of LPS-mediated HPAEpiCs, and angiogenesis of human umbilical vein endothelial cells (HUVEC) were evaluated employing colony formation assay, flow cytometer, and angiogenesis experiments. Endothelial nitric oxide synthase (eNOS)/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway and inflammation were examined using quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA), and western blot analysis. The effects of Procyanidin B1 and L-N-nitro-L-arginine methyl ester (L-NAME) on inflammation and eNOS/NO/cGMP pathway were assessed employing ELISA, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. Results: Different concentrations of Procyanidin B1 (50, 100, 150, or 200 μM), which was not toxic to normal cells, enhanced LPS-mediated HPAEpiCs activity (p < 0.05), proliferation (p < 0.05), and eNOS expression (p < 0.01). However, Procyanidin B1 reduced apoptosis of LPS-mediated HPAEpiCs (p < 0.05) and stimulated angiogenesis of HUVEC (p < 0.01). Moreover, Procyanidin B1 repressed inflammation, endothelin-1 (ET-1), and inducible nitric oxide synthase (iNOS) levels and enhanced the NO production, cGMP, eNOS, and phosphorylated eNOS levels in LPS-mediated HPAEpiCs (p < 0.05). However, these effects were counteracted by L-NAME (p < 0.05). Conclusions: Procyanidin B1 protected HPAEpiCs from LPS-mediated inflammation damage by modulating the eNOS/NO/cGMP pathway.

Diquat poisoning is a fatal condition that is becoming increasingly common. The mortality risk of patients taking lethal doses of diquat is extremely high. It typically leads to rapid dysfunction of multiple organs, including the kidneys, heart, lungs, and brain. Acute kidney injury is usually the first manifestation of this poisoning. However, the optimal treatment strategy for diquat poisoning remains uncertain. Additionally, the mechanism of multiple organ dysfunction syndrome caused by diquat poisoning may resemble the progression of sepsis. In this report, we present 3 cases of diquat poisoning, all of which resulted in death. We emphasize that acute kidney injury is the primary cause of death, and suggest that some strategies used in the treatment of sepsis could be beneficial in managing diquat poisoning-induced acute kidney injury.

Lung cancer and asthma are both global health problems with significant economic consequences. Recent studies have demonstrated that asthma may be a risk factor for lung cancer. The present study aimed to explore the pathogenesis between these two diseases through a comprehensive analysis. Differentially expressed genes (DEGs) screened in the asthma‑related GSE165934 dataset were analyzed to find relevant inflammatory pathways. Overlapping genes regulated by inflammatory pathways and lung cancer‑DEGs from The Cancer Genome Atlas (TCGA) were obtained and subjected to survival and gene‑wide mutation analyses, and nomogram construction to determine the hub gene. The hub gene was further analyzed through expression validation, immunoassays and functional experiments to investigate its role and mechanism in lung cancer. Functional enrichment analysis showed that 1,275 DEGs from GSE165934 were closely associated with the Toll‑like receptor signaling pathway, and 8 overlapping genes were identified from 12 genes regulated by the Toll‑like receptor signaling pathway and 3,134 TCGA‑DEGs. After a series of bioinformatics analyses, it was found that triggering receptor expressed on myeloid cells 1 (TREM1) was the hub gene involved in the mechanism of asthma and lung cancer. TREM1 was also found to be a suppressor gene in lung cancer correlated with immune cells, immune checkpoint‑related genes and tumor mutational burden score. Additionally, the results of Cell Counting Kit‑8 and Transwell experiments demonstrated that overexpression of TREM1 could significantly inhibit the invasion, proliferation and migration of lung cancer cells. Reverse transcription‑quantitative PCR and western blotting demonstrated that the overexpression of TREM1 could also significantly reduce the level of Toll‑like receptor signaling pathway proteins. The present findings suggest that TREM1 is associated with the mechanism of asthma and lung cancer through its regulation of the Toll‑like receptor signaling pathway. Furthermore, TREM1 may serve as a potential treatment target and prognostic indicator for patients with lung cancer.