BACKGROUND:Protein lactylation is a novel post-translational modification driven by lactate and has emerged as a critical link between cellular metabolism and epigenetic regulation in inflammatory diseases, including sepsis. However, a systematic profiling of lactylation-related genes (LRGs) and their diagnostic potential in sepsis remains unexplored. METHODS:We conducted an integrative study leveraging transcriptomic data from public repositories (GSE236713 as training set; GSE28750 as validation set). Differential expression analysis identified sepsis-associated genes, which were intersected with LRGs from GeneCards to obtain candidate genes. Functional enrichment was performed. Three machine learning algorithms-LASSO regression, Support Vector Machine (SVM), and Random Forest (RF)-were employed to screen for core biomarkers. Their diagnostic efficacy was validated using ROC curve analysis. Immune infiltration profiles were assessed via CIBERSORT. Key findings were further corroborated in a murine sepsis model induced by cecal ligation and puncture (CLP) using qRT-PCR. RESULTS:We identified 10 candidate LRGs from the initial 3252 differentially expressed genes. Machine learning algorithms narrowed this down to three core biomarkers: SLC4A4, SLC16A4, and CRYAB. These biomarkers demonstrated consistent differential expression patterns (down-regulation of SLC4A4 and up-regulation of SLC16A4 and CRYAB) in both the training and independent validation cohorts. ROC analysis confirmed their robust diagnostic performance, with AUCs all exceeding 0.7. Furthermore, these biomarkers showed significant correlations with specific immune cell subsets, particularly CD8+ T cells and activated mast cells, suggesting a role in immune dysregulation. Validation in the CLP mouse model confirmed the significant dysregulation of these three genes in septic lung tissue. CONCLUSION:This multi-disciplinary study identifies SLC4A4, SLC16A4, and CRYAB as promising lactylation-related diagnostic biomarkers for sepsis. Our findings indicate the intricate interplay between lactate metabolism, epigenetic modification, and immune dysfunction in sepsis, providing new insights for early diagnosis and mechanistic investigation.

Objective:This study aimed to investigate the predictive value of the Systemic-Immune Inflammation Index (SII) and lipoprotein-associated phospholipase A2 (Lp-PLA2) in the early detection of glufosinate ammonium (GA) poisoning-induced neurotoxicity. Methods:A retrospective case-control analysis of patients with acute oral GA poisoning was conducted from January 2021 to August 2024. GA poisoning patients who developed neurotoxicity were identified as the case group. The control group was matched 1:2 with the case group on the year of age interval in GA patients without neurotoxicity. Univariate and multiple logistic regression analyses were performed to explore the independent risk of neurotoxicity induced by GA poisoning. Receiver operator characteristic (ROC) curve and area under the curve (AUC) were performed to evaluate the predictive value of SII, Lp-PLA2, and combination of both in GA poisoning patients associated with neurotoxicity. Results:A cohort of 82 patients experiencing neurotoxicity due to GA poisoning was identified, alongside a control group of 164 individuals who did not exhibit neurotoxic symptoms. The levels of SII and Lp-PLA2 were higher among the case group compared with the control group. After controlling for plasma GA concentration, lactate, neutrophil-to-lymphocyte ratio, and serum ammonia, the results of the multiple logistic regression analysis indicated that the case group was more likely to exhibit elevated levels of the SII (OR = 1.010, 95% CI: 1.004, 1.015, p < 0.001) and Lp-PLA2 (OR = 1.049, 95% CI: 1.032, 1.065, p < 0.001). Furthermore, the areas under the ROC curve of SII, Lp-PLA2, and combination of both were 0.781 (95% CI: 0.717, 0.845, p < 0.001), 0.880 (95% CI: 0.838, 0.923, p < 0.001), and 0.931 (95% CI: 0.901, 0.961, p < 0.001), respectively. Conclusions:The study concluded that SII, Lp-PLA2, and their combination could serve as predictive biomarkers for assessing the neurotoxicity associated with glufosinate ammonium poisoning.

INTRODUCTION:Acute respiratory distress syndrome (ARDS) is a severe and life-threatening complication of COVID-19, for which no specific antiviral treatment currently exists. Shenfu Injection (SFI), a traditional Chinese medicine formulation, has shown clinical promise in improving respiratory function and reducing mortality in ARDS patients. However, its underlying molecular mechanisms remain poorly understood. METHODS:A combined network pharmacology and bioinformatics approach was used to elucidate the potential mechanisms of SFI against COVID-19-induced ARDS. SFI-related targets were identified through multiple public databases, followed by Gene Ontology (GO) and KEGG pathway enrichment analyses. Gene expression data from GEO datasets (GSE171110 and GSE273149) were used to identify differentially expressed genes in COVID-19-induced ARDS, which were then intersected with SFI targets. Molecular docking was performed to evaluate the binding affinities between major active compounds in SFI and core viral proteins, including 3CLpro, RdRp, and ACE2. RESULTS:A total of 398 SFI-associated targets were identified, with key targets including SRC, MAPK1, MAPK3, PIK3R1, and STAT3. Active compounds such as Gomisin B, Deoxyharringtonine, Ginsenoside-Rh4_qt, Suchilactone, and Celabenzine were highlighted. Enrichment analyses identified 2,883 GO terms and 219 KEGG pathways (p < 0.05), primarily involving the PI3K-Akt, MAPK, TNF, NF-κB, and apoptosis signaling pathways. GEO data analysis confirmed the involvement of these pathways in COVID-19-induced ARDS. Molecular docking showed strong binding affinities, particularly between Ginsenoside-Rh4_qt and 3CLpro/ACE2, and Celabenzine with RdRp. DISCUSSION:The findings suggest that SFI exerts therapeutic effects through modulation of key inflammatory and immune pathways and by direct interaction with SARS-CoV-2 viral proteins. This multi-target mechanism aligns with the pharmacological characteristics of traditional Chinese medicine. However, further experimental validation is required to confirm these computational predictions and assess clinical relevance. CONCLUSION:This study provides mechanistic insights into how SFI may alleviate COVID-19-induced ARDS via modulation of critical signaling pathways and interaction with viral targets, offering a theoretical foundation for its clinical application in the management of severe COVID-19 cases.

INTRODUCTION:This study clarified the multitarget mechanisms of TCM formulas for treating ACS with CCHV pattern, providing a scientific basis for climate-adaptive prevention and treatment strategies for cardiovascular diseases. METHODS:Literature mining screened clinically effective TCM formulas. Meridian tropism was analyzed via TCMICS; active compounds were retrieved from TCMSP. GEO transcriptomic data and disease targets from GeneCards, OMIM, and PharmGKB were integrated to construct herbcompound- target and PPI networks, followed by GO and KEGG enrichment analyses. Molecular docking, 100-ns MD simulations, and ADME analysis verified the pharmacokinetics of drug formulations, supplemented by cell experiment validation of key interactions. RESULTS:A core formula consisting of Fuzi, Ganjiang, Wutou, Shujiao, Renshen, and Gancao was identified. Key bioactive compounds (e.g., quercetin, kaempferol) targeted TP53, AKT1, and MAPK1, modulating glycolipid metabolism, inflammation, and oxidative stress. They exhibited strong binding to AKT1 (binding free energies -16.89 and -21.26 kcal·mol⁻¹), forming stable complexes. They also possessed favorable pharmacological properties, inhibited cold - induced cardiomyocyte apoptosis, and showed a correlation with AKT1 and TP53 in WB experiments. DISCUSSION:Core TCM drugs demonstrate that they target AKT1 and TP53 via quercetin and kaempferol, regulating metabolism, inflammation, and oxidative stress. CONCLUSION:This provides a multitarget mechanism basis for treating ACS with CCHV patterns.

Sini Decoction (SND), particularly its components Zingiber officinale Roscoe and Glycyrrhiza uralensis Fisch, is traditionally used to mitigate the cardiotoxicity induced by Aconitum carmichaelii Debeaux, but the underlying mechanism remains incompletely understood. This study employed an integrative strategy combining network pharmacology to identify core targets, molecular docking to evaluate compound-target interactions, and in vitro experiments using H9c2 cardiomyocytes for functional validation. Network analysis identified 301 potential targets associated with aconitine-induced cardiotoxicity, with TNF, IL6, and AKT1 as core targets. Z. officinale Roscoe and G. uralensis Fisch shared 35 cardioprotective targets with aconitine toxicity, including STAT3, AKT1, and IL6. Molecular docking demonstrated strong binding affinities of 6-gingerol, a key bioactive compound of Z. officinale Roscoe, to core targets such as SRC and MAPK3. In vitro, 6-gingerol significantly alleviated aconitine-induced cytotoxicity, reduced lactate dehydrogenase release, and restored AKT and MAPK phosphorylation. In addition, it modulated the inflammatory cytokines TNF and IL6 and the apoptosis-related genes Bcl2 and Bax. These findings indicate that 6-gingerol exerts protective effects against aconitine-induced cardiotoxicity by regulating the AKT/MAPK signaling pathway and suppressing inflammation and apoptosis, providing mechanistic evidence for the detoxifying property of Sini Decoction.

Background sepsis-induced cardiomyopathy (SIC) is a critical complication of sepsis, contributing significantly to high mortality rates. The underlying molecular mechanisms remain poorly understood, and effective therapeutic strategies are urgently needed. Xuebijing (XBJ), a traditional Chinese medicine formulation, has shown potential in treating sepsis due to its anti-inflammatory and antioxidant properties. However, its specific role in regulating SIC and the key molecular targets involved have not been fully elucidated. Methods Differentially expressed genes (DEGs) between septic patients and healthy controls were identified using the GEO dataset (Series accession: GSE95233). Weighted gene co-expression network analysis (WGCNA) was employed to determine sepsis-related gene modules. Machine learning algorithms (LASSO regression, SVM-RFE, and Random Forest) were used to screen key therapeutic targets of XBJ. Functional enrichment (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene set enrichment analysis) were performed to explore biological pathways. The relative abundance of immune cell types in normal and disease samples was estimated using the CIBERSORT algorithm. Molecular docking validated the binding affinity between XBJ components and key targets. In vitro, H9C2 cells were treated with lipopolysaccharide (LPS) to simulate sepsis-induced cardiac injury, and the effects of XBJ and PADI4 overexpression on inflammation and oxidative stress were assessed by enzyme-linked immunosorbent assays, colorimetric assays, and fluorometric assay. In vivo, a cecal ligation and puncture (CLP) rat model was used to evaluate XBJ’s therapeutic efficacy. Results WGCNA identified the “MEblue” module as the most clinically significant in sepsis (r = -0.81, P = 2e-29). By intersecting XBJ component targets, DEGs, and module genes, 20 candidate genes were identified. Machine learning algorithms further narrowed these to three key genes: N-ribosyldihydronicotinamide:quinone dehydrogenase 2 (NQO2), peptidyl arginine deiminase 4 (PADI4), and protein kinase C eta (PRKCH). PADI4 showed the most significant differential expression in sepsis and strong binding affinity with XBJ components (binding energy < −6 kcal/mol). Immune infiltration analysis revealed significant alterations in immune cell populations in sepsis (P < 0.05), with PADI4 expression correlating with neutrophil degranulation and T-cell differentiation pathways. In vitro, XBJ attenuated LPS-induced inflammation and oxidative stress in H9C2 cells (P < 0.05), but these effects were reversed by PADI4 overexpression (P < 0.05). In vivo, XBJ improved cardiac function (elevated ejection fraction and fractional shortening) and reduced inflammation and oxidative stress in CLP-induced sepsis rats (P < 0.05). Conclusion XBJ ameliorated sepsis-induced cardiomyopathy by inhibiting PADI4 to suppress inflammation and oxidative stress. These findings highlight PADI4 as a potential biomarker and therapeutic target for SIC.

Sepsis-induced acute lung injury is a significant clinical challenge with high morbidity and mortality rates. Currently, no effective therapeutic interventions are available. The aim of this study was to elucidate the role and underlying mechanisms of Caveolin-2 in sepsis-induced acute lung injury. To this end, a Caveolin-2 knockdown model was utilized both in vivo and in vitro, facilitating a comprehensive evaluation of several parameters, including lung tissue injury, inflammatory responses, oxidative stress markers, changes in apoptotic protein expression, and indicators of macrophage polarization. Additionally, the study investigated alterations in proteins associated with the Hippo signaling pathway and assessed the effects of Hippo pathway inhibitors on apoptosis and polarization. Our results indicate that the knockdown of Caveolin-2 facilitates the polarization of macrophages towards the protective M2 macrophage polarization and mitigates macrophage apoptosis. This process is associated with a reduction in oxidative stress and inflammatory responses, culminating in the activation of the Hippo signaling pathway. Conversely, the overexpression of Caveolin-2 intensifies inflammation and oxidative damage, while promoting apoptosis and M1 macrophage polarization. Our findings provide novel insights into the role of Caveolin-2 and Hippo signal pathway in sepsis-induced acute lung injury and establish a foundation for future research and the development of potential therapeutic strategies.

Limb ischemia-reperfusion (I/R) injury is a life-threatening complication of acute limb ischemia that can result in severe skeletal muscle damage and limb loss, yet effective pharmacological therapies remain limited. Kaempferol (KAE), a naturally occurring dietary flavonoid with well-documented anti-inflammatory, antioxidant, and anti-apoptotic properties, has been shown to confer protection in myocardial and cerebral I/R models. Nevertheless, its therapeutic potential and molecular mechanisms in limb I/R injury have not yet been elucidated. In this study, we systematically investigated the protective effects and underlying mechanisms of KAE in a mouse hindlimb I/R model. A network pharmacology approach was initially applied to provide a global overview of potential biological processes associated with KAE treatment. The therapeutic efficacy and molecular mechanisms of KAE were subsequently evaluated using in vivo experiments combined with transcriptomic profiling. Mice subjected to 4 h of hindlimb ischemia followed by 24 h of reperfusion received KAE (50 or 100 mg/kg, intraperitoneally) for 7 consecutive days prior to I/R induction. KAE markedly improved hindlimb microcirculation, alleviated tissue edema and infarction, preserved muscle histological integrity, and attenuated elevations of circulating muscle injury biomarkers. In parallel, KAE significantly suppressed I/R-induced oxidative stress, inflammatory infiltration, and apoptotic cell death, as evidenced by reduced ROS accumulation, decreased pro-inflammatory cytokine expression, and favorable modulation of apoptosis-related proteins. Transcriptomic analysis revealed pronounced activation of inflammatory pathways and suppression of the PPAR signaling pathway following limb I/R injury, whereas KAE treatment selectively restored PPAR pathway activity while inhibiting NF-κB signaling. qRT-PCR and Western blot analyses further demonstrated that KAE predominantly upregulated PPARα expression and reduced NF-κB p65 phosphorylation in reperfused skeletal muscle. Collectively, these findings provide comprehensive evidence that KAE protects against hindlimb I/R injury, with activation of PPARα signaling and concomitant suppression of NF-κB-driven inflammation representing a proposed mechanism, thereby supporting KAE as a promising pharmacological candidate for limb I/R injury.

Background: Sepsis-related acute respiratory distress syndrome (ARDS) is a fatal disease without effective therapy. Kaempferol is a flavonoid compound extracted from natural plant products; it exerts numerous pharmacological effects. Kaempferol attenuates sepsis-related ARDS; however, the underlying protective mechanism has not been elucidated completely. Objective: This study aimed to use network pharmacology and experimental verification to investigate the mechanisms by which kaempferol attenuates sepsis-related ARDS. Methods: We screened the targets of kaempferol by PharMapper, Swiss Target Prediction, and CTD database. We identified the targets of sepsis-related ARDS by GeneCards, DisGeNet, OMIM, and TTD. The Weishengxin platform was used to map the targets of both kaempferol and sepsis-related ARDS. We created a Venn diagram to identify the intersection targets. We constructed the "component-intersection targets-disease" network diagram using Cytoscape 3.9.1 software. The intersection targets were imported into the STRING database for developing the protein-protein interaction network. Metascape was used for the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. We selected the leading 20 KEGG pathways to establish the KEGG relationship network. Finally, we performed experimental verification to confirm our prediction results. Results: Through database screening, we obtained 502, 360, and 78 kaempferol targets, disease targets of sepsis-related ARDS, and intersection targets, respectively. The core targets consisted of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, albumin (ALB), IL-1β, and AKT serine/ threonine kinase (AKT)1. GO enrichment analysis identified 426 items, which were principally involved in response to lipopolysaccharide, regulation of inflammatory response, inflammatory response, positive regulation of cell migration, positive regulation of cell adhesion, positive regulation of protein phosphorylation, response to hormone, regulation of reactive oxygen species (ROS) metabolic process, negative regulation of apoptotic signaling pathway, and response to decreased oxygen levels. KEGG enrichment analysis identified 151 pathways. After eliminating the disease and generalized pathways, we obtained the hypoxia-inducible factor 1 (HIF-1), nuclear factor κB (NF-κB), and phosphoinositide 3-kinase (PI3K)-Akt signaling pathways. Our experimental verification confirmed that kaempferol blocked the HIF-1, NF-κB, and PI3K-Akt signaling pathways, diminished TNF-α, IL-1β, and IL-6 expressions, suppressed ROS production, and inhibited apoptosis in lipopolysaccharide (LPS)-induced murine alveolar macrophage (MH-S) cells. Conclusion: Kaempferol can reduce inflammatory response, ROS production, and cell apoptosis by acting on the HIF-1, NF-κB, and PI3K-Akt signaling pathways, thereby alleviating sepsis- related ARDS.

This study aimed to investigate whether enema is associated with nervous system injury caused by diquat poisoning using a population-based case-control analysis. Medical records of patients with acute diquat poisoning admitted to the hospital from January 2018 to January 2024 were retrospectively collected. Central nervous system injury symptoms following diquat poisoning defined the case group, while the control group were matched 1:2 on population-based without nervous system injury in diquat poisoning patients. Conditional logistic regression models were used for analysis. We identified 101 diquat poisoning patients with nervous system injury and selected 202 diquat poisoning patients without nervous system injury. Diquat poisoning patients performed 2 and ≧ 3 enemas had ORs of nervous system injury of 3.084 (95% CI 1.230, 7.734) and 4.693 (95% CI 1.408, 15.645) compared with diquat poisoning patients with no enema, respectively. Further analyses were performed in various age subgroups. The ORs of conducting 2 and ≧ 3 enemas were dramatically higher among case group than control group in subgroup aged ≧ 60 years old (OR  10.184, 14.982 respectively). We concluded that enema may be associated with an increased risk of nervous system injury caused by DQ poisoning, particularly among the elderly.

Correction of Discovery Medicine 2023, 35 (179) https://www.discovmed.com/EN/10.24976/Discov.Med.202335179.90 The authors wish to make the following correction to this paper [1]: The authors would like to correct the name of their affiliated institution, the corrected author's affiliation is provided below: 1Department of Emergency Medicine, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, 210002 Nanjing, Jiangsu, China.

To identify the underlying mechanism by which quercetin (Que) alleviates sepsis-related acute respiratory distress syndrome (ARDS). In vivo, C57BL/6 mice were assigned to sham, cecal ligation and puncture (CLP), and CLP+Que (50 mg/kg) groups (n=15 per group) by using a random number table. The sepsisrelated ARDS mouse model was established using the CLP method. In vitro, the murine alveolar macrophages (MH-S) cells were classified into control, lipopolysaccharide (LPS), LPS+Que (10 μmol/L), and LPS+Que+acetylcysteine (NAC, 5 mmol/L) groups. The effect of Que on oxidative stress, inflammation, and apoptosis in mice lungs and MH-S cells was determined, and the mechanism with reactive oxygen species (ROS)/p38 mitogen-activated protein kinase (MAPK) pathway was also explored both in vivo and in vitro. Que alleviated lung injury in mice, as reflected by a reversal of pulmonary histopathologic changes as well as a reduction in lung wet/dry weight ratio and neutrophil infiltration (P<0.05 or P<0.01). Additionally, Que improved the survival rate and relieved gas exchange impairment in mice (P<0.01). Que treatment also remarkedly reduced malondialdehyde formation, superoxide dismutase and catalase depletion, and cell apoptosis both in vivo and in vitro (P<0.05 or P<0.01). Moreover, Que treatment diminished the release of inflammatory factors interleukin (IL)-1β, tumor necrosis factor-α, and IL-6 both in vivo and in vitro (P<0.05 or P<0.01). Mechanistic investigation clarifified that Que administration led to a decline in the phosphorylation of p38 MAPK in addition to the suppression of ROS expression (P<0.01). Furthermore, in LPS-induced MH-S cells, ROS inhibitor NAC further inhibited ROS/p38 MAPK pathway, as well as oxidative stress, inflammation, and cell apoptosis on the basis of Que treatment (P<0.05 or P<0.01). Que was found to exert anti-oxidative, anti-inflammatory, and anti-apoptotic effects by suppressing the ROS/p38 MAPK pathway, thereby conferring protection for mice against sepsis-related ARDS.

INTRODUCTION:Diquat poisoning is common in Asia and the optimal enhanced elimination strategy is unknown. This study aimed to evaluate the clinical value of plasma diquat concentrations in guiding personalized extracorporeal treatment regimens for patients with acute diquat poisoning. METHODS:This multi-center retrospective cohort study included 163 patients with acute diquat poisoning admitted between February 2022 and July 2023. Patients were divided into three groups based on plasma diquat concentrations measured upon presentation to the emergency department: low (<100 μg/L), medium (100-1,000 μg/L), and high (≥1,000 μg/L). The evaluated extracorporeal treatment regimens included hemoperfusion alone and a combination of hemoperfusion with continuous veno-venous hemodiafiltration. Kaplan-Meier survival curves were used to estimate cumulative survival probabilities, with survival probabilities compared using log-rank tests. RESULTS:All 66 patients survived in the low concentration group, regardless of the extracorporeal treatment used. In the medium and high concentration groups, five patients who refused extracorporeal treatment died, whereas 92 patients who received extracorporeal treatment had a case fatality rate of 48.9%. In the high concentration group, patients receiving hemoperfusion combined with continuous veno-venous hemodiafiltration had a case fatality rate of 76.7% and better survival probabilities, compared to hemoperfusion-only patients, which had no survivors. Additionally, among those treated with a combination of hemoperfusion and continuous veno-venous hemodiafiltration, the time interval from the end of hemoperfusion session to the initiation of continuous veno-venous hemodiafiltration was, on average, shorter for survivors than deaths (3.7 h versus 4.7 h). DISCUSSION:This retrospective observational study of diquat poisoned patients highlights the potential for personalized extracorporeal treatment regimens using an initial plasma diquat concentration. Future randomized trials are warranted to evaluate the optimal use of extracorporeal treatments. CONCLUSION:Obtaining plasma diquat concentrations may be of great value for guiding extracorporeal treatment regimens to improve prognosis in patients with acute diquat poisoning.

STUDY OBJECTIVE:To enable emergency physicians to make well-informed triage and treatment decisions, accurate tools to evaluate the severity of diquat poisoning are needed. This study establishes severity indices for diquat poisoning (SIDPs) in assessing the risk of death for patients with acute diquat poisoning for triage purposes and 28-day mortality. METHODS:This multicenter cohort study involved 204 patients. Predictors identified by the Burota algorithm and stepwise Cox regression were incorporated into Cox proportional hazards models to develop SIDPs, one for triage and one for prognosis (SIDP-T and SIDP-P, respectively). SIDP-T predictors were based on self-reported information at emergency department (ED) presentation, and SIDP-P predictors included additional biomarkers obtained in the ED. Models were developed using data from one hospital (n=106), followed by internal validation using bootstrapping and external validation using a data set (n=98) from 35 different hospitals. RESULTS:SIDP-T found age, estimated diquat amount, heart rate, and Glasgow Coma Scale score to be the key predictors, achieving a C-index of 0.79 (0.70, 0.88), positive predictive value of 0.86 (0.49, 0.99) and negative predictive value of 0.76 (0.66, 0.83) in external validation. SIDP-P included age, initial plasma diquat concentration, white blood cell count, and aspartate aminotransferase, with C-index of 0.82 (0.74, 0.90), positive predictive value of 1 (0.51, 1) and negative predictive value of 0.74 (0.65, 0.82) on the external validation set. CONCLUSION:Our derived severity indices can provide rapid mortality prediction. SIDP-T uses self-reported information and basic vital signs at ED admission, and SIDP-P adds biomarkers and accurately predicts 28-day outcome.

Background: Acute Respiratory Distress Syndrome (ARDS) is an acute life-threatening disease, and luteolin has the potential to become a therapeutic agent for ARDS. However, its mechanism of action has not yet been clarified. Objective: The present study explored the potential effects and mechanisms of luteolin in the treatment of ARDS through network pharmacology analysis and verified them through biological experiments. Methods: The potential targets of luteolin and ARDS were obtained from online databases. Functional enrichment and protein-protein interaction (PPI) analyses were performed to explore the underlying molecular mechanisms and to identify hub targets. Molecular docking was used to verify the relationship between luteolin and target proteins. Finally, the effects of luteolin on key signaling pathways and biological processes were verified by in vitro and in vivo experiments. Results: A total of 146 luteolin- and 496 ARDS-related targets were extracted from public databases. The network pharmacological analysis suggested that luteolin could inhibit ARDS through the following potential therapeutic targets: AKT1, RELA, and NFKBIA. Inflammatory and oxidative stress responses were the main biological processes involved, with the AKT/NF-κB signaling pathway being the key signaling pathway targeted by luteolin for the treatment of ARDS. Molecular docking analysis indicated that luteolin had a good binding affinity to AKT1, RELA, and NFKBIA. The in vitro and in vivo experiments revealed that luteolin could regulate the inflammatory response and oxidative stress in the treatment of ARDS by inhibiting the AKT/NF- κB signaling pathway. Conclusion: Luteolin could reduce the production of reactive oxygen species and inflammatory factors by inhibiting the AKT/NF-κB signaling pathway, thus reducing apoptosis and attenuating ARDS.

Rationale: Paraquat, a highly toxic bipyridyl herbicide lacking a specific antidote, poses severe risks upon ingestion. However, the diagnosis of paraquat poisoning is complicated by its nonspecific initial symptoms, particularly when a detailed exposure history is not provided. Patient’s Concern: A 33-year-old man inadvertently ingested an unknown liquid and presented to medical services a day later with complaints of ongoing nausea, vomiting, and diarrhea. The assessment revealed elevated serum creatinine, signaling acute kidney injury, initially thought due to gastroenteritis and dehydration. Diagnosis: Acute renal insufficiency due to paraquat poisoning. Interventions: The treatment involved fluid resuscitation and antibiotics, but his decline led to intensive care unit transfer. Subsequent chest computed tomography scans indicated lung changes indicative of paraquat poisoning. A detailed history review and comprehensive blood and urine toxicology screens confirmed the diagnosis. Subsequently, aggressive interventions such as hemoperfusion and continuous renal replacement therapy were initiated, yet there was a further decline in respiratory function, necessitating mechanical ventilation. The prognosis was poor, and ultimately, the family chose to withdraw care. Outcomes: The patient succumbed to his illness. Lessons: This case underscores the importance of promptly and accurately diagnosing paraquat poisoning, as its vague early signs can lead to diagnostic delays, crucial due to the condition’s rapid progression. Alertness to paraquat poisoning is essential in patients with sudden gastrointestinal and renal symptoms post-exposure. Additionally, it underscores the necessity for public health measures to avert paraquat ingestion and advance therapeutic approaches.

To explore the potential effects and mechanisms of Liang-Ge-San (LGS) for the treatment of acute respiratory distress syndrome (ARDS) through network pharmacology analysis and to verify LGS activity through biological experiments. The key ingredients of LGS and related targets were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. ARDS-related targets were selected from GeneCards and DisGeNET databases. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed using the Metascape Database. Molecular docking analysis was used to confirm the binding affinity of the core compounds with key therapeutic targets. Finally, the effects of LGS on key signaling pathways and biological processes were determined by in vitro and in vivo experiments. A total of LGS-related targets and 496 ARDS-related targets were obtained from the databases. Network pharmacological analysis suggested that LGS could treat ARDS based on the following information: LGS ingredients luteolin, wogonin, and baicalein may be potential candidate agents. Mitogen-activated protein kinase 14 (MAPK14), recombinant V-Rel reticuloendotheliosis viral oncogene homolog A (RELA), and tumor necrosis factor alpha (TNF-α) may be potential therapeutic targets. Reactive oxygen species metabolic process and the apoptotic signaling pathway were the main biological processes. The p38MAPK/NF-κ B signaling pathway might be the key signaling pathway activated by LGS against ARDS. Moreover, molecular docking demonstrated that luteolin, wogonin, and baicalein had a good binding affinity with MAPK14, RELA, and TNF α. In vitro experiments, LGS inhibited the expression and entry of p38 and p65 into the nucleation in human bronchial epithelial cells (HBE) cells induced by LPS, inhibited the inflammatory response and oxidative stress response, and inhibited HBE cell apoptosis (P<0.05 or P<0.01). In vivo experiments, LGS improved lung injury caused by ligation and puncture, reduced inflammatory responses, and inhibited the activation of p38MAPK and p65 (P<0.05 or P<0.01). LGS could reduce reactive oxygen species and inflammatory cytokine production by inhibiting p38MAPK/NF-κ B signaling pathway, thus reducing apoptosis and attenuating ARDS.

BACKGROUND:Sepsis-related acute respiratory distress syndrome (ARDS) has a high mortality rate, and no effective treatment is available currently. Quercetin is a natural plant product with many pharmacological activities, such as antioxidative, anti-apoptotic, and anti-inflammatory effects. This study aimed to elucidate the protective mechanism of quercetin against sepsis-related ARDS.METHODS:In this study, network pharmacology and in vitro experiments were used to investigate the underlying mechanisms of quercetin against sepsis-related ARDS. Core targets and signaling pathways of quercetin against sepsis-related ARDS were screened and were verified by in vitro experiments.RESULTS:A total of 4,230 targets of quercetin, 360 disease targets of sepsis-related ARDS, and 211 intersection targets were obtained via database screening. Among the 211 intersection targets, interleukin-6 (IL-6), tumor necrosis factor (TNF), albumin (ALB), AKT serine/threonine kinase 1 (AKT1), and interleukin-1β (IL-1β) were identified as the core targets. A Gene Ontology (GO) enrichment analysis revealed 894 genes involved in the inflammatory response, apoptosis regulation, and response to hypoxia. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis identified 106 pathways. After eliminating and generalizing, the hypoxia-inducible factor-1 (HIF-1), TNF, nuclear factor-κB (NF-κB), and nucleotide-binding and oligomerization domain (NOD)-like receptor signaling pathways were identified. Molecular docking revealed that quercetin had good binding activity with the core targets. Moreover, quercetin blocked the HIF-1, TNF, NF-κB, and NOD-like receptor signaling pathways in lipopolysaccharide (LPS)-induced murine alveolar macrophage (MH-S) cells. It also suppressed the inflammatory response, oxidative reactions, and cell apoptosis.CONCLUSION:Quercetin ameliorates sepsis-related ARDS by binding to its core targets and blocking the HIF-1, TNF, NF-κB, and NOD-like receptor signaling pathways to reduce inflammation, cell apoptosis, and oxidative stress.

BackgroundSepsis is a life-threatening organ dysfunction caused by an exaggerated response to infection. In the lungs, one of the most susceptible organs, this can manifest as acute respiratory distress syndrome (ARDS). Shenfu (SF) injection is a prominent traditional Chinese medicine used to treat sepsis. However, the exact mechanism of its action has rarely been reported in the literature.PurposeIn the present study, we detected the protective effect of SF injection on sepsis-induced ARDS and explored its underlying mechanism.MethodsWe investigated the potential targets and regulatory mechanisms of SF injections using a combination of network pharmacology and RNA sequencing. This study was conducted both in vivo and in vitro using a mouse model of ARDS and lipopolysaccharide (LPS)-stimulated MLE-12 cells, respectively.ResultsThe results showed that SF injection could effectively inhibit inflammation, oxidative stress, and apoptosis to alleviate LPS-induced ARDS. SF inhibited the PI3K-AKT pathway, which controls autophagy and apoptosis. Subsequently, MLE-12 cells were treated with 3-methyladenine to assess its effects on autophagy and apoptosis. Additional experiments were conducted by adding rapamycin, an mTOR antagonist, or SC79, an AKT agonist, to investigate the effects of SF injection on autophagy, apoptosis, and the PI3K-AKT pathway.ConclusionOverall, we found that SF administration could enhance autophagic activity, reduce apoptosis, suppress inflammatory responses and oxidative stress, and inhibit the PI3K-AKT pathway, thus ameliorating sepsis-induced ARDS.

Objective：The objective of this study was to investigated whether enema is associated with nervous system injury caused by diquat poisoning using a population-based case-control analysis. Methods: The medical records of patients with acute diquat(DQ) poisoning admitted to the hospital from January 2018 to January 2024 were retrospectively collected. A series of symptoms of central nervous system injury occurred after DQ poisoning were defined as DQ nervous system injury, which identified as the case group in our study. The controls group were matched 1:2 on population-based without nervous system injury in DQ poisoning patients. Conditional logistic regression models were performed. Results: We identified 101 DQ poisoning patients with nervous system injury and selected 202 DQ patients without nervous system injury. DQ poisoning patients performed 2 and ≧3 enemas had ORs of nervous system injury of 3.084(95%CI 1.230, 7.734) and 4.693(95%CI 1.408, 15.645) compared with DQ poisoning patients with no enema, respectively. Further analyses were performed in various age subgroups. The ORs of conducting 2 and ≧3 enemas were dramatically higher among cases group than controls group in subgroup aged ≧60 years old (OR=10.184, 14.982 respectively). Conclusions: We concluded that enemas increased the risk of with nervous system injury caused by DQ, particularly among the elderly.