Baicalin alleviates acute lung injury in vivo and in vitro.

The aim of the present study was to evaluate the effects and mechanisms of Baicalin (BA) on acute lung injury (ALI). ALI model was established by lipopolysaccharide (LPS) and proteomics, immunoprecipitation and F-box/WD repeat containing protein 7 （FBXW7） knockout (KO) mice and FBXW7 silence mouse lung epithelial (MLE-12) cells were used to investigate the mechanisms of BA on acute lung injury ALI. The results showed that 218 differentially expressed proteins were identified in the lung tissue of ALI mice and FBXW7 was one of the changed most proteins and was significantly decreased in in the lung tissue of ALI mice. It was also found that FBXW7 had protective effects on ALI via inhibition of Absent in Melanoma 2 （AIM2） inflammasomes also found that BA mitigated ALI via FBXW7/AIM2 signal pathway. In conclusion, FBXW7 as a key marker was identified in ALI and has a protective effect on ALI and BA regulated FBXW7/AIM2 signal pathway to alleviate ALI. This study provided a new method for treating ALI.

Activation of the AMPK/Nrf2 pathway ameliorates LPS-induced acute lung injury by inhibiting oxidative stress and reducing inflammation.

BACKGROUND: Numerous diseases-related acute lung injury (ALI) contributed to high mortality. Currently, the therapeutic effect of ALI was still poor. The detailed mechanism of ALI remained elusive and this study aimed to elucidate the mechanism of ALI. METHOD: This study was performed to expose the molecular mechanisms of AMPK/Nrf2 pathway regulating oxidative stress in LPS-induced AMI mice. The mouse ALI model was established via intraperitoneal injection of LPS, then the lung tissue and blood samples were obtained, followed by injection with Dimethyl fumarate (DMF). Finally, Western blot, HE staining, injury score, lung wet/dry ratio, reactive oxygen species (ROS) and ELISA were used to elucidate the mechanism of AMPK/Nrf2 pathway in LPS -induced acute lung injury by mediating oxidative stress. RESULTS: The lung tissue injury score was evaluated, showing higher scores in the model group compared to the AMPK activator and control groups. DCFH-DA indicated that LPS increased ROS production, while AMPK activator DMF reduced it, with the model group exhibiting higher ROS levels than the control and AMPK activator groups. The lung wet/dry ratio was also higher in the model group. Western blot analysis revealed LPS reduced AMPK and Nrf2 protein levels, but DMF reversed this effect. ELISA results showed elevated IL-6 and IL-1ß levels in the model group compared to the AMPK activator and control groups. CONCLUSION: CONCLUSION: Activating the AMPK/Nrf2 pathway can improve LPS-induced acute lung injury by down-regulation of the oxidative stress and corresponding inflammatory factor level.

Dexmedetomidine attenuates sepsis-associated acute lung injury by regulating macrophage efferocytosis through the ROS/ADAM10/AXL pathway.

BACKGROUND: The lungs are highly susceptible to damage during sepsis, with severe lung injury potentially progressing to acute respiratory distress syndrome and even fatal sepsis. Effective efferocytosis of apoptotic cells is crucial in alleviating inflammation and tissue injury. METHODS: We established a septic lung injury mouse model via intraperitoneal injection of lipopolysaccharide. Lung injury was assessed by histology, immunofluorescence, neutrophil immunohistochemistry staining, and cytokine detection. We extracted alveolar macrophages by bronchoalveolar lavage and primary macrophages from mouse bone marrow to investigate the regulatory effects of Dexmedetomidine (DEX) on efferocytosis. We further validated the molecular mechanisms underlying the regulation of macrophage efferocytosis by DEX through knockdown of AXL expression. Additionally, we examined the efferocytic ability of monocytes isolated from patients. RESULTS: We discovered that DEX treatment effectively alleviated pulmonary injury and inflammation. Lipopolysaccharide reduced macrophage efferocytosis and AXL expression which were reversed by DEX. We also found DEX inhibited the increased activation of A Disintegrin And Metalloproteinase 10 (ADAM10) and the production of soluble AXL. Moreover, our findings demonstrated that DEX decreased the elevated ROS production linked to higher ADAM10 activation. Blocking AXL negated DEX's benefits on efferocytosis and lung protection. Efferocytosis in monocytes from septic lung injury patients was notably lower than in healthy individuals. CONCLUSION: Our findings demonstrated that DEX treatment effectively reduces septic lung injury by promoting macrophage efferocytosis through ROS/ADAM10/AXL signaling pathwway.

Rituximab Induced Rare Cystic Lesion in Lungs in a Nephrotic Child: A Case Report.

Rituximab has been extensively used for managing B-cell lymphomas due to its anti-CD20 monoclonal antibody activity. Over the last decade, its application has been extended to manage frequent relapsing or steroid-dependent nephrotic syndrome. Its use has been comparatively safe, but few cases of adverse effects on the lung have been reported in the adult population. These lung injury presentations are rarely reported in a pediatric group with only four cases in the literature. Below is a rare case of rituximab-induced lung injury in a 9-year-old boy with frequent relapse of nephrotic syndrome, which developed after four days of rituximab infusion. Suspecting infection and sepsis, several antibiotics were started, but with no improvement in respiratory complaints, even antifungal and antituberculosis treatments were initiated. Finally, setting up a casual relation with the time of infusion to the development of complaints, association with rituximab was suspected. The patient responded to steroid therapy with complete resolution of respiratory complaints. To our knowledge, this is the first reported case of rituximab-induced cystic lesion in lungs from India.

Metabolome classification of Tongkat Ali (Eurycoma longifolia Jack) and its Commercial Products via UHPLC-QTOF-MS-MS and its protective effect against 5-Flurouracil-Induced Testicular Toxicity in Male rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongkat Ali (Eurycoma longifolia Jack) is a chief herbal medicine that is well recognized for its aphrodisiac properties, available in various commercial products worldwide. AIM OF THE STUDY: The aim of this work is to identify the different classes of secondary metabolites present in Tongkat Ali commercial products versus authenticated root, and to assess its root extract mitigative effect against 5-flurouracil (5FU)-induced testicular toxicity. MATERIALS AND METHODS: High-resolution UHPLC-QTOF-MS/MS metabolites analysis was utilized on the ethanolic Tongkat Ali extract (TAE) parallel to three Mlayasian commercial products, followed by a multivariate data analysis to understand the variability among UHPLC-MS metabolites datasets. Adult male rats were treated with 5-Fluorouracil (5FU) +/- Tongkat Ali extract. Semen parameters, serum testosterone, LH, and FSH, and testicular oxidative stress biomarkers like malondialdehyde (MDA) levels, Nuclear factor kappa B (NF-κB) and erythroid 2-related factor 2 (Nrf2) were analyzed. RESULTS: The main categories of secondary metabolites identified through UHPLC-MS/MS profiling were quassinoids, alkaloids, fatty acids, lignans and coumarins. Long Jack Plus® ELP-2 clustered alongside authentic roots ELR on the negative side, while Naturelle® ELP-1 and Nu-Prep-LEAKI® ELP-3 were positioned on the opposite side. The OPLS-DA model was used to identify markers for preparations from authentic roots, with commercial products enriching in ailanthone epoxide. In vivo results showed that 5FU reduced sperm parameters by 42%, while TAE improved sperm quality by 35-43% and 58-74% at dose of 400 and 800 mg/kg, respectively. Testosterone, reduced by 74% with 5FU, increased 2.3- to 3.2-fold with TAE. TAE also reduced MDA by 31-62%, NF-κB by 32-55% and increased Nrf2 by 1-2 folds. CONCLUSION: The manuscript presents a comparative metabolomics study and in vivo investigation into the potential of Tongkat Ali root to improve testicular function in male rats intoxicated with 5FU, an area not previously explored. Further research is required to understand the mechanisms.

The critical roles of caveolin-1 in lung diseases.

Caveolin-1 (Cav-1), a structural and functional component in the caveolae, plays a critical role in transcytosis, endocytosis, and signal transduction. Cav-1 has been implicated in the mediation of cellular processes by interacting with a variety of signaling molecules. Cav-1 is widely expressed in the endothelial cells, smooth muscle cells, and fibroblasts in the various organs, including the lungs. The Cav-1-mediated internalization and regulation of signaling molecules participate in the physiological and pathological processes. Particularly, the MAPK, NF-κB, TGFß/Smad, and eNOS/NO signaling pathways have been involved in the regulatory effects of Cav-1 in lung diseases. The important effects of Cav-1 on the lungs indicate that Cav-1 can be a potential target for the treatment of lung diseases. A Cav-1 scaffolding domain peptide CSP7 targeting Cav-1 has been developed. In this article, we mainly discuss the structure of Cav-1 and its critical roles in lung diseases, such as pneumonia, acute lung injury (ALI), asthma, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, pulmonary fibrosis, and lung cancer.

The Thyroid Hormone Analog GC-1 Mitigates Acute Lung Injury by Inhibiting M1 Macrophage Polarization.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening condition with a high mortality rate of ≈40%. Thyroid hormones (THs) play crucial roles in maintaining homeostasis of the cellular microenvironment under stress. The previous studies confirmed that the clinical-stage TH analog GC-1 significantly alleviates pulmonary fibrosis by improving the function of mitochondria in epithelial cells. However, the effects of GC-1 on macrophages in lung injury and the related mechanisms remain unclear. This study evaluated the therapeutic effects of GC-1 in two murine models of lipopolysaccharide (LPS)- or hydrochloric acid (HCl)-induced ALI. Additionally, mouse alveolar macrophages (AMs) and human THP-1-derived macrophages are utilized to investigate the impact of GC-1 on macrophage polarization. GC-1 effectively reduces the inflammatory response and lung injury in ALI mice, as evidenced by neutrophil infiltration, cytokine levels, alveolar fluid clearance, and pulmonary pathology. Notably, GC-1 selectively inhibits M1 macrophage polarization, which may be achieved by impeding NF-κB signaling activation through the DNMT3b-PPARγ-NF-κB pathway in a TH receptor ß1 (TRß1)-dependent manner, consequently suppressing the polarization of macrophages toward the M1 phenotype and overproduction of inflammatory cytokines. Overall, these findings highlight the immunomodulatory property of GC-1 as an anti-inflammatory strategy for ALI/ARDS and inflammation-related diseases.

Apocynin alleviates thioacetamide-induced acute liver injury: Role of NOX1/NOX4/NF-κB/NLRP3 pathways.

The liver has a distinctive capacity to regenerate, yet severe acute injury can be life-threatening if not treated appropriately. Inflammation and oxidative stress are central processes implicated in the pathophysiology of acute livery injury. NOX isoforms are important enzymes for ROS generation, NF-κB and NLRP3 activation, its inhibition could be vital in alleviating acute liver injury (ALI). Here in our study, we used apocynin, a natural occurring potent NOX inhibitor, to exploreits potential protective effect against thioacetamide (TAA)-induced ALI through modulating crucial oxidative and inflammatory pathways. Rats were injected once with TAA (500 mg/kg/i.p) and treated with apocynin (10 mg/kg/i.p) twice before TAA challenge. Sera and hepatic tissues were collected for biochemical, mRNA expression, western blot analysis and histopathological assessments. Pretreatment with apocynin improved liver dysfunction evidenced by decreased levels of aminotransferases, ALP, GGT and bilirubin. Apocynin reduced mRNA expression of NOX1 and NOX4 which in turn alleviated oxidative stress, as shown by reduction in MDA and NOx levels, and elevation in GSH levels andcatalase and SOD activities. Moreover, apocynin significantly reduced MPO gene expression. We also demonstrate that apocynin ameliorated inflammation through activating IκBα and suppressing IKKα, IKKß, NF-κBp65 and p-NF-κBp65, IL-6 andTNF-α. Additionally, apocynin potentiated the gene expression of anti-inflammatory IL-10 and reduced levels of hepatic NLRP3, Caspase-1 and IL-1ß. These results suggest that apocynin protects against ALI in association with the inhibition of NOX1 and NOX4 and regulating oxidative and inflammatory pathways.

Discovery of a potent, Highly selective, and In vivo anti-inflammatory Efficacious, P2Y6R antagonist with a novel quinoline-pyrazole scaffold.

The P2Y6 receptor (P2Y6R), as a crucial member of the purine family, is a potential therapeutic target for the treatment of intestinal inflammation, tracheal inflammation and diabetes. We first discovered the hit compound (5a, IC50 = 168.5 nM against P2Y6R) through our in-house library screening. Then, further medicinal chemistry efforts were made to optimize compound 5a, and a potent P2Y6R antagonist (5 ab) with better antagonistic activity (IC50 = 19.6 nM) was obtained. The molecular docking, CETSA, SPR and pull-down results indicated that compound 5 ab displayed strong binding to P2Y6R. Also, compound 5 ab possessed high selectivity and satisfying oral bioactivity and pharmacokinetic profiles. In experiments with LPS-induced acute lung injury in mice, after treatment with compound 5 ab, the level of inflammatory factors IL-6, TNF-α and IL-ß were considerably decreased, the infiltration of immune cells was decreased. Further exploration revealed that 5 ab inhibited the expression and release of chemokines in lung tissue, suppressing the activation of the NLRP3 inflammasome. Compound 5 ab had certain anti-inflammatory abilities in vivo and in vitro. These results demonstrate that compound 5 ab is a potential P2Y6R antagonist and is worthy of further study.

Acacetin protects against acute lung injury by upregulating SIRT1/ NF-κB pathway.

Acacetin is one of the natural flavone components found in many plants and possesses diverse pharmacological activities. The anti-inflammatory properties and definite mechanism of acacetin remains incompletely illuminated. Here, we evaluated the efficacy of acacetin on lipopolysaccharide (LPS)-induced acute lung injury in vivo and TNF-α-stimulated cellular injury in vitro. As indicated by survival experiments, acacetin reduced mortality and improved survival time of LPS-induced acute lung injury in mice. 50 mg/kg of acacetin obtained higher survival (about 60 %), and 20 mg/kg of acacetin was about 46.7 %. In addition, 20 mg/kg of acacetin rescued lung histopathologic damage in LPS treated mice, lowered lung-to-body weight and lung wet-to-dry ratios, suppressed myeloperoxidase activity in lung tissue, the contents of protein, the numbers of total cells and neutrophils in bronchoalveolar lavage fluid (BALF), and the contents of inflammatory cytokines such as TNF-α, IL-6, IL-17 and IL-1ß in BALF. Acacetin also increased the activity and expression of SIRT1, thereby suppressing acetylation-dependent activation NF-κB. Similarly, in vitro, acacetin increased cell viability, reduced levels of TNF-α, IL-6, IL-17, and IL-1ß, increased NAD+ levels as well as NAD/NADH ratio, and then up-regulated the activity and expression of SIRT1, and restrained acetylation-dependent activation NF-κB in TNF-α-stimulated A549 cells, which could be abolished by SIRT1 siRNA. Collectively, the current study showed that acacetin exerts a protective effiect on acute lung injury by improving the activity and expression SIRT1, thereby suppressing the acetylation-dependent activation of NF-κB-p65 and the release of downstream inflammatory cytokines.

Forsythiaside A alleviates acute lung injury via the RNF99/TRAF6/NF-κB signaling pathway.

The aim of this study was to investigated the effects of forsythiaside A (FA) on acute lung injury (ALI). The lung tissue pathological was detected by hematoxylin-eosin staining (HE) staining. Wet weight/dry weight (w/d) of the lung in mice was measured. Cytokine such as interleukin 1ß (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α) were also detected. Compared with the vector group, the protein expression levels of TRAF6 and TAK1 the RNF99 group were significantly reduced. Ubiquitinated TRAF6 protein was increased after knockdown of RNF99. Finally, it was found that FA significantly ameliorated ALI via regulation of RNF99/TRAF6/NF-κB signal pathway. In conclusion, RNF99 was an important biomarker in ALI and FA alleviated ALI via RNF99/ TRAF6/NF-κB signal pathway.

Human umbilical cord mesenchymal stem cells-derived exosomes attenuate burn-induced acute lung injury via inhibiting ferroptosis.

Our previous study has shown that exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs-exo) alleviated burn-induced acute lung injury (ALI). In this study, we explored a novel mechanism by which hUCMSCs-exo contributed to the inhibition of burn-induced ALI. The ALI rat model with severe burn was established for the in vivo experiments, and rats PMVECs were stimulated with the serum from burn-induced ALI rats for the in vitro experiments. The pathological changes of lung tissues were evaluated by HE staining; the cell viability was measured using CCK-8; the iron level and Fe2+ concentration were assessed using Iron Assay Kit and Fe2+ fluorescence detection probe; the mRNA expression of SLC7A11 and GPX4 were measured by qRT-PCR; the protein levels of SLC7A11, GPX4, Nrf2 and HO-1 were detected by western blot. Both the in vivo and in vitro experiments revealed that ferroptosis was significantly induced in burn-induced ALI, which as verified by increased iron level and Fe2+ concentration, and decreased SLC7A11 and GPX4 mRNA and protein levels. Furthermore, both hUCMSCs-exo and Fer-1 (the inhibitor of ferroptosis) alleviated lung inflammation and up-regulated protein levels of Nrf2 and HO-1 in the lung tissues of burn-induced ALI rats. These results suggested that hUCMSCs-exo exhibited a protective role against burn-induced ALI by inhibiting ferroptosis, partly owing to the activation of Nrf2/HO-1 pathway, thus providing a novel therapeutic strategy for burn-induced ALI.

Ciliary Motility Decreased by a CO2/HCO3--Free Solution in Ciliated Human Nasal Epithelial Cells Having a pH Elevated by Carbonic Anhydrase IV.

An application of CO2/HCO3--free solution (Zero-CO2) did not increase intracellular pH (pHi) in ciliated human nasal epithelial cells (c-hNECs), leading to no increase in frequency (CBF) or amplitude (CBA) of the ciliary beating. This study demonstrated that the pHi of c-hNECs expressing carbonic anhydrase IV (CAIV) is high (7.64), while the pHi of ciliated human bronchial epithelial cells (c-hBECs) expressing no CAIV is low (7.10). An extremely high pHi of c-hNECs caused pHi, CBF and CBA to decrease upon Zero-CO2 application, while a low pHi of c-hBECs caused them to increase. An extremely high pHi was generated by a high rate of HCO3- influx via interactions between CAIV and Na+/HCO3- cotransport (NBC) in c-hNECs. An NBC inhibitor (S0859) decreased pHi, CBF and CBA and increased CBF and CBA in c-hNECs upon Zero-CO2 application. In conclusion, the interactions of CAIV and NBC maximize HCO3- influx to increase pHi in c-hNECs. This novel mechanism causes pHi to decrease, leading to no increase in CBF and CBA in c-hNECs upon Zero-CO2 application, and appears to play a crucial role in maintaining pHi, CBF and CBA in c-hNECs periodically exposed to air (0.04% CO2) with respiration.

Tetramethylpyrazine ameliorates LPS-induced acute lung injury via the miR-369-3p/DSTN axis.

Acute lung injury (ALI) is a severe clinical respiratory condition characterized by high rates of mortality and morbidity, for which effective treatments are currently lacking. In this study, lipopolysaccharide (LPS) was used to induce ALI mice, demonstrating the efficacy of tetramethylpyrazine (TMP) in ameliorating ALI. Subsequent we perfored high-throughput sequencing analysis and used Targetscan 8.0 and miRWalk 3.0 databases to predict the interaction between microRNAs and destrin (DSTN), ultimately identifying miR-369-3p as the focus of the investigation. The adenovirus carrying miR-369-3p was administered one week prior to LPS-induced in order to assess its potential efficacy in ameliorating ALI in mice. The findings indicated that the overexpression of miR-369-3p resulted in enhanced lung function, reduced pulmonary edema, inflammation, and permeability in LPS-induced ALI mice, while the suppression of miR-369-3p exacerbated the damage in these mice. Furthermore, the beneficial effects of TMP on LPS-induced ALI were negated by the downregulation of miR-369-3p. The results of our study demonstrate that TMP mitigates LPS-induced ALI through upregulation of miR-369-3p. Consequently, the findings of this study advocate for the clinical utilization of TMP in ALI treatment, with miR-369-3p emerging as a promising target for future ALI interventions.

The therapeutic potential of gelsolin in attenuating cytokine storm, ARDS, and ALI in severe COVID-19.

Severe COVID-19 cases often progress to life-threatening conditions such as acute respiratory distress syndrome (ARDS), sepsis, and multiple organ dysfunction syndrome (MODS). Gelsolin (GSN), an actin-binding protein with anti-inflammatory and immunomodulatory properties, is a promising therapeutic target for severe COVID-19. Plasma GSN levels are significantly decreased in critical illnesses, including COVID-19, correlating with dysregulated immune responses and poor outcomes. GSN supplementation may mitigate acute lung injury, ARDS, and sepsis, which share pathophysiological features with severe COVID-19, by scavenging actin, modulating cytokine production, enhancing macrophage phagocytosis, and stabilizing the alveolar-capillary barrier. Preliminary data indicate that recombinant human plasma GSN improves oxygenation and lung function in severe COVID-19 patients with ARDS. Although further research is needed to optimize GSN therapy, current evidence supports its potential to mitigate severe consequences of COVID-19 and improve patient outcomes. This review provides a comprehensive analysis of the biological characteristics, mechanisms, and therapeutic value of GSN in severe COVID-19.

Rosuvastatin ameliorates chemically induced acute lung injury in rats by targeting ferroptosis, heat shock protein B1, and inflammation.

Acute lung injury (ALI) is a life-threatening condition characterized by respiratory failure. Rosuvastatin (RSV) is an antihypercholesterolemic agent with antioxidant properties. The current study aimed to investigate RSV novel therapeutic impact on ALI with emphasis on oxidative stress, inflammation, and heat shock protein B1 (HSPB1). Male albino rats (N = 30) were divided into five groups. Normal control (NC) group: rats received normal saline 2 mL/kg P.O daily. Lipopolysaccharides (LPS) group: rats received LPS (3 mg/kg intraperitoneally once). RSV group: rats received RSV (2 mg/kg P.O daily). LPS + RSV group: rats received RSV as in group 3 and on the 7th day rats received LPS as group 2. LPS + Dexamethasone (DX): rats received DX (2 mg/kg P.O, daily for one week) and on the 7th day rats received LPS as group 2. At the end of experiment (one week), lung tissue was used to determine HSPB1, high mobility group box 1 (HMGB1) using ELISA. IL-6, nuclear factor-2 (Nrf2), haem Oxygenase-1 (HO-1) protein levels were assessed using immunohistochemistry. GSH, catalase, MDA, NO, albumin and urea are assessed by colorimetry. The results revealed that RSV treatment resolved histopathological changes in lung tissue induced by LPS. Compared to LPS group, LPS + RSV group showed significant decrease in urea, NO, MDA, HMGB1, IL-6 and HO-1 level compared to LPS-treated rats. Conversely, RSV treatment significantly increased HSPB1, Nrf2, albumin, GSH, and CAT levels compared to LPS rats. RSV is effective for amelioration of ALI and thus can be used as adjuvant therapy for ALI.

Enhanced In Vitro Recapitulation of In Vivo Liver Regeneration by Co-Culturing Hepatocyte Organoids with Adipose-Derived Mesenchymal Stem Cells, Alleviating Steatosis and Apoptosis in Acute Alcoholic Liver Injury.

Hepatocyte organoids (HOs) have superior hepatic functions to cholangiocyte-derived organoids but suffer from shorter lifespans. To counteract this, we co-cultured pig HOs with adipose-derived mesenchymal stem cells (A-MSCs) and performed transcriptome analysis. The results revealed that A-MSCs enhanced the collagen synthesis pathways, which are crucial for maintaining the three-dimensional structure and extracellular matrix synthesis of the organoids. A-MSCs also increased the expression of liver progenitor cell markers (KRT7, SPP1, LGR5+, and TERT). To explore HOs as a liver disease model, we exposed them to alcohol to create an alcoholic liver injury (ALI) model. The co-culture of HOs with A-MSCs inhibited the apoptosis of hepatocytes and reduced lipid accumulation of HOs. Furthermore, varying ethanol concentrations (0-400 mM) and single-versus-daily exposure to HOs showed that daily exposure significantly increased the level of PLIN2, a lipid storage marker, while decreasing CYP2E1 and increasing CYP1A2 levels, suggesting that CYP1A2 may play a critical role in alcohol detoxification during short-term exposure. Moreover, daily alcohol exposure led to excessive lipid accumulation and nuclear fragmentation in HOs cultured alone. These findings indicate that HOs mimic in vivo liver regeneration, establishing them as a valuable model for studying liver diseases, such as ALI.

Protective Effect of Hibifolin on Lipopolysaccharide-Induced Acute Lung Injury Through Akt Phosphorylation and NFκB Pathway.

Acute lung injury (ALI) is a difficult condition to manage, especially when it is complicated by bacterial sepsis. Hibifolin, a flavonoid glycoside, has anti-inflammatory properties that make it a potential treatment for ALI. However, more research is needed to determine its effectiveness in LPS-induced ALI. In this study, male ICR mice were treated with hibifolin before LPS-induced ALI. Protein content and neutrophil count in bronchoalveolar lavage (BAL) fluid were measured by BCA assay and Giemsa staining method, respectively. The levels of proinflammatory cytokines and adhesive molecules were detected by ELISA assay. The expression of NFκB p65 phosphorylation, IκB degradation, and Akt phosphorylation was assessed by western blot assay. Hibifolin pre-treatment significantly reduced pulmonary vascular barrier dysfunction and neutrophil infiltration into the BAL fluid in LPS-induced ALI mice. In addition, LPS-induced expression of proinflammatory cytokines (IL-1ß, IL-6, TNF-α) and adhesive molecules (ICAM-1, VCAM-1) within the BAL fluid were markedly reduced by hibifolin in LPS-induced ALI mice. More, hibifolin inhibited LPS-induced phosphorylation of NFκB p65, degradation of IκB, and phosphorylation of Akt in lungs with ALI mice. In conclusion, hibifolin shows promise in improving the pathophysiological features and proinflammatory responses of LPS-induced ALI in mice through the NFκB pathway and its upstream factor, Akt phosphorylation.

Endothelial Cell-Derived Extracellular Vesicles Promote Aberrant Neutrophil Trafficking and Subsequent Remote Lung Injury.

The development of acute respiratory distress syndrome (ARDS) in sepsis is associated with substantial morbidity and mortality. However, the molecular pathogenesis underlying sepsis-induced ARDS remains elusive. Neutrophil heterogeneity and dysfunction contribute to uncontrolled inflammation in patients with ARDS. A specific subset of neutrophils undergoing reverse transendothelial migration (rTEM), which is characterized by an activated phenotype, is implicated in the systemic dissemination of inflammation. Using single-cell RNA sequencing (scRNA-seq), it identified functionally activated neutrophils exhibiting the rTEM phenotype in the lung of a sepsis mouse model using cecal ligation and puncture. The prevalence of neutrophils with the rTEM phenotype is elevated in the blood of patients with sepsis-associated ARDS and is positively correlated with disease severity. Mechanically, scRNA-seq and proteomic analys revealed that inflamed endothelial cell (EC) released extracellular vesicles (EVs) enriched in karyopherin subunit beta-1 (KPNB1), promoting abluminal-to-luminal neutrophil rTEM. Additionally, EC-derived EVs are elevated and positively correlated with the proportion of rTEM neutrophils in clinical sepsis. Collectively, EC-derived EV is identified as a critical regulator of neutrophil rTEM, providing insights into the contribution of rTEM neutrophils to sepsis-associated lung injury.

Predictive Efficacy of the Advanced Lung Cancer Inflammation Index in Hepatocellular Carcinoma After Hepatectomy.

Background: Hepatocellular carcinoma (HCC) presents a significant global health challenge due to its poor prognosis and high recurrence rates post-surgery. This study examines the predictive efficacy of the Advanced Lung Cancer Inflammation Index (ALI) in assessing the post-hepatectomy prognosis of patients with HCC. Methods: A cohort comprising 1654 HCC patients who underwent hepatectomy at Guangxi Medical University Cancer Hospital from 2013 to 2019 was enrolled. Patients were stratified into two groups according to the median ALI level, and then subjected to propensity score matching (PSM) in a 1:1 ratio. Kaplan-Meier survival curves, the traditional Cox proportional hazards (CPH) model, and machine learning (ML) models were employed to analyze and evaluate ALI's prognostic significance. Furthermore, ALI's prognostic value in digestive system tumors was validated via analysis of the National Health and Nutrition Examination Survey (NHANES) database. Results: After applying PSM, a final cohort of 1284 patients, categorized into high and low ALI groups, revealed a significantly reduced survival time in the low ALI cohort. Univariate and multivariate Cox analyses identified ALI, BCLC stage, CK19, Hepatitis B virus (HBV) DNA, lymph node metastasis, and microvascular invasion (MVI) as independent predictors of prognosis. Both traditional CPH and ML models incorporating ALI demonstrated excellent predictive accuracy, validated through calibration curves, time-dependent ROC curves, and decision curve analysis. Furthermore, the prognostic value of ALI in digestive tumors was confirmed in the NHANES database. Conclusion: The ALI exhibits potential as a prognostic predictor in patients with HCC following hepatectomy, providing valuable insights into postoperative survival.