Desmosine exerts a vital role as a cross-linking molecule integrate into a three-dimensional elastin network. After degradation of mature elastin, desmosine is released and enters into the circulatory system. The purpose was to estimate the association between serum desmosine level and Coronavirus disease 2019 (COVID-19) patients. All 333 COVID-19 patients were enrolled and regarded as the training cohort, and 150 cases were used for completely independent validation cohort. Serum specimens were collected on the day of admission. The level of serum desmosine was determined by enzyme-linked immunosorbent assay (ELISA). Serum desmosine level on the day of admission gradually increased with elevating severity scores among COVID-19 patients. Spearman correlation analysis unveiled the close relationships between serum desmosine level and clinical parameters, such as liver function, renal function, myocardial enzymes, and inflammatory cytokines. The training cohort and external validation cohort revealed that serum desmosine level was positively associated with severity scores by multivariable linear regression analyses. Multivariable logistic regression models found that higher serum desmosine concentration on admission elevated the risks of mechanical ventilation, vasoactive agent use, ICU admission, and death during hospitalization. A receiver operating characteristic (ROC) curve analysis demonstrated the excellent discrimination for the poor prognosis of serum desmosine concentration by the training set and validation set. Baseline serum desmosine level was positively associated with disease severity scores and worse clinical outcomes among COVID-19 patients during hospitalization, substantializing that serum desmosine might serve as a biomarker for discriminating the severity and prognosis in COVID-19 patients.

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), represent a clinical syndrome with high mortality, characterized by excessive pulmonary inflammation and oxidative stress. Despite advancements in conventional supportive care, mortality rates for ALI/ARDS remain persistently high (30

Background1-Nitropyrene (1-NP) is harmful to the respiratory system and can evoke acute lung injury (ALI). Pyroptosis and apoptosis, two important types of programmed cell death, are involved in the pathological process of ALI. However, the roles and mechanisms of pyroptosis and apoptosis on 1-NP-incurred ALI remain unclear.MethodsAll the mice were exposed to a single dose of 1-NP (20 μg/mouse, dissolved in saline) or normal saline via intratracheal instillation. At different times after 1-NP exposure, the mice were sacrificed. Mouse lung epithelial (MLE-12) cells were incubated with 1-NP (5 μM), the indicators of pyroptosis and apoptosis were detected.ResultsPulmonary pathological injury and inflammatory cell infiltration was observed in 1-NP-exposed mice. Additionally, the indicators of apoptosis, Bcl-2 was downregulated, Bad and Caspase-3, and apoptotic cells were increased in 1-NP-exposed mouse lungs and mouse lung epithelial (MLE-12) cells. Meanwhile, the proteins of GSDMD and Pro- and Cleaved Caspase-11 and the mRNAs of Il-1β and Il-18, which are markers of pyroptosis, were increased after 1-NP treatment. Moreover, pretreatment with wedelolactone (WED), an antagonist of Caspase-11, alleviated 1-NP-induced ALI. As expected, pharmacological inhibition or genetic deletion of Caspase-11 abolished 1-NP-induced apoptosis and pyroptosis. Interestingly, 1-NP attenuated Caspase-11 proteasome degradation. Mechanistically, 1-NP downregulated the expression of SYVN1, an E3 ubiquitin ligase of Caspase-11. 1-NP promoted the interaction between SYVN1 and Caspase-11 and inhibited Caspase-11 ubiquitination and subsequent proteasome degradation. Transfection with SYVN1 overexpression plasmids abolished 1-NP-mediated the reduction of Caspase-11 ubiquitination-dependent degradation, apoptosis, and pyroptosis.ConclusionsThese results revealed that acute 1-NP may induce ALI via Caspase-11-mediated apoptosis and pyroptosis by downregulating SYVN1.

BACKGROUND AND OBJECTIVE:Ras p21 protein activator 1 (RASA1) is mainly located on cytoplasm and can regulate GTPase activity. The goal of this study was to analyze the association between pulmonary RASA1 expression and chronic obstructive pulmonary disease (COPD) and the potential mechanisms. METHODS:COPD patients and age- and sex-matched control subjects were enrolled. In addition, cigarette smoke (CS) evoked-COPD model in mice and cigarette smoke extract (CSE)-exposed BEAS-2B cells were used. RESULTS:Pulmonary RASA1 expression was reduced compared with control subjects and gradually decreased in parallel with the severity of COPD patients. Correlative analysis found pulmonary RASA1 was positively associated with pulmonary function parameters and inversely correlated with inflammatory cytokines among COPD patients. RASA1 protein expression was downregulated in lung tissues of CS-evoked COPD mice and CSE-exposed BEAS-2B cells. RAS/PI3K/Akt signaling was activated in lung tissues of COPD patients and mice, as well as BEAS-2B cells after CSE treatment. There was a negative correlation between SYVN1 and RASA1 in lung tissues of COPD patients. Mechanistically, CSE exposure enhanced RASA1 proteasome degradation through elevating E3 ubiquitin ligase SYVN1. CS exposure facilitated inflammatory cytokines production via activating RAS/PI3K/Akt signaling. Genetic deletion of SYVN1 alleviated CSE-provoked inflammatory response via inhibiting RAS/PI3K/Akt signaling in BEAS-2B cells. CONCLUSION:These data revealed that E3 ubiquitin ligase SYVN1-provoked RASA1 proteasome degradation involves in inflammatory response through activating RAS/PI3K/Akt signaling in the process of COPD.

Cellular stress is implicated in the progression of lipopolysaccharide (LPS)-evoked acute lung injury (ALI). The goal of this study was to evaluate the effect of oral supplementation with rosiglitazone (RSG), which is an agonist of peroxisome proliferator-activated receptor (PPAR)-γ, on pulmonary inflammatory response, oxidative stress, and endoplasmic reticulum (ER) stress during LPS-evoked ALI in mice. The mice were randomly divided into four groups and orally supplemented with or without RSG (10 mg/kg) once daily for 5 consecutive days before LPS (1 mg/kg) intraperitoneal injection. The mice were sacrificed at 12 h after LPS injection. As expected, LPS-evoked ALI and death were attenuated in mice that were pretreated with RSG. LPS-evoked increase in chemokines (KC, MIP-2, and MCP-1) and proinflammatory cytokines (TNF-α and IL-1β) was inhibited in the mouse lungs by RSG. RSG pretreatment significantly mitigated LPS-evoked nuclear translocation of NF-κB p65 and p50, which regulate inflammatory gene transcription in the lungs. Additionally, LPS-evoked glutathione depletion and lipid peroxidation were alleviated by RSG. The abnormal expression of NADPH oxidases and antioxidant enzymes was restored in the lung tissues by RSG. Further experiments revealed that LPS-evoked upregulation of GRP78, p-IRE1α, and p-EIF2α was blocked by RSG pretreatment. Mechanistically, RSG pretreatment enhanced PPARγ activity in the mouse lungs and bronchial epithelial cells. RSG promoted the interaction between NF-κB p65 and PPARγ in the mouse lungs. Overall, RSG pretreatment protects against LPS-evoked ALI partially through enhancing PPARγ activity and inhibiting the cellular stress response in the mouse lungs.

Runt-related transcription factor 2 (Runx2), a transcription factor of the RUNX family, is involved in various inflammatory diseases. However, the role of Runx2 was unclear in chronic obstructive pulmonary disease (COPD). Pulmonary Runx2 level was compared in COPD patients and control subjects via a case-control study. Runx2 expression was detected in lung tissues of COPD mice and human bronchial epithelial (BEAS-2B) cells simulated with cigarette smoke extracts (CSE). Pulmonary Runx2 expression was upregulated, and inversely associated with pulmonary function and positively correlated with inflammatory cytokines in COPD patients. Mechanistically, Runx2 activation facilitated the transcription of CDK8, a co-regulator of nuclear factor-κB (NF-κB), and inflammatory cytokines production. Luciferase report gene assay confirmed that CDK8 was the downstream target gene of Runx2. Further analysis found that CSE inhibited Runx2 ubiquitination and proteasomal degradation. Besides, CSE elevated nicotinamide adenine dinucleotide (NAD+) consumes and Sirtuin 3 (Sirt3) depletion. Additionally, Runx2 acetylation was increased in CSE-exposed BEAS-2B cells, lungs tissues from COPD mice and patients. Interestingly, Sirt3 overexpression or supplementation with Nicotinamide Riboside (NR), the precursor of NAD+, abolished CSE-induced Runx2 acetylation and Runx2-CDK8 axis activation. In vivo experiment further confirmed NR supplementation evidently mitigated cigarette smoke-induced a COPD-like phenotype in mice. These results indicated that Sirt3 depletion-induced Runx2 acetylation contributes to CDK8 activation and pulmonary inflammation in the progression of COPD.

OBJECTIVES:The C-reactive protein (CRP)-albumin-lymphocyte (CALLY) index is associated with the status of inflammation, immunity, and nutrition in inflammatory diseases. The present research intends to investigate the relationships of the CALLY index with disease severity and clinical prognosis among patients with COVID-19. METHODS:The present study included 1049 COVID-19 subjects from two medical centers. Clinical information was gathered, and the CALLY index was calculated. Associations of CALLY index with severity and prognosis were analyzed among COVID-19 cases. RESULTS:As disease severity scores increased, CALLY index levels on admission gradually decreased. Spearman correlation analyses showed that the CALLY index was closely correlated with many clinical parameters. Linear and logistic regression analyses disclosed that the CALLY index was inversely related to disease severity scores. Simultaneously, the lower CALLY index on admission elevated the risks of mechanical ventilation, vasoactive agent, intensive care unit admission, and death in patients with COVID-19 during hospitalization. Logistic regression analysis further validated that the CALLY index was inversely linked to poor clinical outcomes. Moreover, the severity scores and the CALLY index on admission have a similar predictive capacity for poor prognosis in patients with COVID-19. CONCLUSION:The CALLY index displays a negative relationship with disease severity and poor prognosis, indicating that it can serve as a disease severity indicator and a prognostic tool for patients with COVID-19.

INTRODUCTION:Acute Lung Injury (ALI) is a serious complication of many diseases and can progress to Acute Respiratory Distress Syndrome (ARDS) without intervention. The current study aimed to determine the effect of Maxing Kugan Decoction (MXKGD) on an Oleic Acid (OA)-induced rat model of ALI while also exploring the regulatory effects of MXKGD on the PI3K/AKT signaling pathway and gut microbiota. METHODS:Ultra-Performance Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry (UPLC-QTOF/MS) was employed to determine the chemical ingredients of MXKGD. The therapeutic effects of different doses of MXKGD in treating OA-induced ALI were investigated using histopathology, ELISA assays, and immunofluorescence analysis. Additionally, network pharmacology and 16S rRNA sequencing were utilized to explore the underlying mechanisms of MXKGD in ALI treatment. RESULTS:Through UPLC-QTOF/MS analysis, a total of 104 compounds were identified in MXKGD, including flavonoids, alkaloids, triterpenoids, glycosides, organic acids, and cyclic peptides. Pharmacodynamic results demonstrated that MXKGD could mitigate histomorphological changes in OA-induced ALI, suppress inflammation and oxidative stress, while promoting the proliferation and differentiation of alveolar type II (AT II) cells to repair the alveolar epithelial-microvascular endothelial barrier. Network pharmacology, molecular docking, and subsequent experimental validation revealed that MXKGD upregulates the expression of p-PI3K and p-AKT proteins, thereby activating the PI3K/AKT signaling pathway. Furthermore, MXKGD rebalanced the disturbance of gut microbiota and associated metabolic levels of short-chain fatty acids (SCFAs) to regulate the inflammatory response. DISCUSSION:This study suggests that MXKGD exerts anti-inflammatory effects and protects the alveolar epithelial- microvascular endothelial barrier in ALI models by activating the PI3K/AKT signaling pathway and modulating the abundance of beneficial gut bacteria. However, further metabolomic experiments are required to confirm its precise mechanism of action. CONCLUSION:The data indicate that MXKGD can effectively inhibit the development of ALI by reducing inflammation and regulating the balance of intestinal microbiota. MXKGD may serve as a potential new therapeutic option for treating ALI.

Calpain is one of the intracellular calcium-activated cysteine proteases and exerts pivotal functions in many diseases. The aim was to explore the relationship of serum calpain-5 concentration and Coronavirus disease 2019 (COVID-19) via a cohort study. The whole 338 COVID-19 patients were selected. Clinical features and demographic information were collected. The concentration of serum calpain-5 was measured via enzyme-linked immunosorbent assay (ELISA). Serum calpain-5 concentration was upregulated with increased severity scores, including SMART-COP, 4 C-Mortality, CURXO, A-DROP, DTPNCP, COVID-GRAM, PSI, and CURB-65 in COVID-19 patients. Spearman correlation analyses suggested there were tight correlations between serum calpain-5 level and numbers of clinical features. Additionally, multivariate linear and logistic regression models showed that serum calpain-5 level was positively associated with severity scores. Moreover, the frequencies of mechanical ventilation, vasoactive agent usage, ICU admission, and death during hospitalization within 30 days were grown with elevated serum calpain-5 concentration on admission. Logistic regression analyses demonstrated that serum higher calpain-5 on admission elevated the risk of adverse prognosis during hospitalization within 30 days. The concentration of serum calpain-5 is positively correlated with disease severity and adverse prognosis, implying calpain-5 may be involved in the progression of COVID-19. Serum calpain-5 level may served as a useful biomarker for guiding clinicians in managing and monitoring disease outcome in COVID-19 patients. Clinical trial number: Not applicable.

Idiopathic pulmonary fibrosis (IPF) has a higher morbidity and poor prognosis. Gui-Zhi-Fu-Ling-Wan (GFW) is a traditional Chinese herbal formula which exerts anti-inflammatory and anti-oxidative effects. The goal was to determine the protective effect of GFW on bleomycin (BLM)-induced pulmonary fibrosis. One hundred and twenty-four mice were randomly divided into eight groups, and orally supplemented with GFW (1 g/kg) in 1 week ago and continuing to 1 week later of single BLM intratracheal injection (5.0 mg/kg). Lung tissues were collected in 7 days and 21 days after BLM injection. BEAS-2B cells were pretreated with GFW (100 μg/mL) for three consecutive days before BLM (10 μg/mL) exposure. Cells were harvested in 12 or 24 h after BLM co-culture. GFW supplementation alleviated BLM-induced alveolar structure destruction and inflammatory cell infiltration in mice lungs. BLM-incurred collagen deposition was attenuated by GFW. In addition, GFW pretreatment repressed BLM-evoked downregulation of E-cadherin, and elevation of N-cadherin and Vimentin in mouse lungs. Besides, BLM-excited GPX4 reduction, ferritin increases, lipid peroxidation, and free iron overload were significantly relieved by GFW pretreatment in mouse lungs and BEAS-2B cells. Notably, BLM-provoked mitochondrial reactive oxygen species (mtROS) excessive production, elevation of mitochondrial stress markers, such as HSP70 and CLPP, and mitochondrial injury, were all abolished in mouse lungs and BEAS-2B cells by GFW pretreatment. GFW supplementation attenuated BLM-evoked lung injury and pulmonary fibrosis partially through repressing EMT and mtROS-mediated ferroptosis in pulmonary epithelial cells.

Benzo[a]pyrene (BaP) and the end-product BaP-7,8-diol-9,10-epoxide (BPDE) are representative environmental contaminants. In the present study, chronic BPDE exposure decreased pulmonary function and evoked chronic obstructive pulmonary disease (COPD)-like lung lesions. In addition, the expression of p53, p21, and p16, β-galactosidase-positive cells, and the mRNA levels of senescence-associated secretory phenotype (SASP) were all elevated in mouse lungs and mouse lung epithelial type II (MLE-12) cells after chronic BPDE. Moreover, BPDE elevated (lactate dehydrogenase B) LDHB expression and lactate production. Additionally, the pharmacological inhibition or knockdown of LDHB alleviated BPDE-evoked cellular senescence and COPD. Mechanistically, BPDE induced histone H4K12 lactylation (H4K12la) at the promoter of the p53 gene, which facilitated cellular senescence and COPD. In addition, BPDE activated the aryl hydrocarbon receptor (AhR) in pulmonary epithelial cells. A dual-luciferase reporter assay revealed that AhR is a direct transcription factor of LDHB. AhR antagonists or knockdown attenuated BPDE-induced LDHB transcription and H4K12la. A casecontrol study confirmed that the BaP concentration was elevated in COPD patients. Furthermore, the number of AhR-positive nuclei was positively correlated with H4K12la and cellular senescence in the lung tissues of COPD patients. Collectively, these findings reveal that BaP exposure contributes to COPD by inducing pulmonary epithelial cell senescence via AhR-mediated histone H4K12 lactylation.

Our previous study revealed that mice exposed to 1-nitropyrene (1-NP) develop pulmonary fibrosis and senescent alveolar cells. However, the impacts of chronic 1-NP on chronic obstructive pulmonary disease (COPD) and the underlying mechanism are unclear. Our research suggested that chronic 1-NP evoked alveolar structure damage, inflammatory cell infiltration, and pulmonary function decline in mice. Moreover, 1-NP increased p53 and p21 expression, the number of β-galactosidase-positive cells, and cell cycle arrest in mouse lungs and MLE-12 cells. Moreover, 1-NP promoted glycolysis and upregulated lactic dehydrogenase A (LDHA) and lactate production in mouse lungs and MLE-12 cells. Elevated glycolysis provoked histone lactylation, but not histone acetylation in pulmonary epithelial cells. Mechanistically, histone H3 lysine 14 lactylation (H3K14la) was upregulated in pulmonary epithelial cells. P53 knockdown mitigated 1-NP-induced cell cycle arrest and senescence in MLE-12 cells. CUT&Tag and ChIP-qPCR experiments confirmed that increased H3K14la directly upregulated p53 transcription in pulmonary epithelial cells. As expected, LDHA knockdown alleviated 1-NP-triggered cell cycle arrest and senescence in MLE-12 cells. In addition, supplementation with oxamate, an inhibitor of LDH, attenuated 1-NP-incurred premature senescence and the COPD-like phenotype in mice. These data revealed for the first time that histone lactylation-induced the increase in p53 transcription contributes to pulmonary epithelial cell senescence during 1-NP-induced COPD progression. Our results provide a basis for repressing lactate production as a promising therapeutic strategy for COPD.

Osteopontin, a phosphorylated glycoprotein, is highly expressed in lung tissues and is elevated in inflammatory diseases. However, its role in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) remains unclear. A total of 281 AECOPD patients, 89 stable COPD (SCOPD) cases, and 89 healthy volunteers were enrolled in this prospective cohort according to the inclusion and exclusion criteria. Demographic information and clinical features were obtained from electronic medical records systems. Fasting venous blood was collected on the day of admission, and baseline serum osteopontin was measured using an enzyme-linked immunosorbent assay. The primary endpoints—death, frequency of acute exacerbations, and hospital length of stay—were evaluated through a follow-up study. Baseline serum osteopontin levels were higher in AECOPD patients compared to SCOPD patients and healthy volunteers. Linear regression analysis revealed positive associations between serum osteopontin and severity scores in AECOPD patients, and an inverse correlation of serum osteopontin and pulmonary function in SCOPD patients. In addition, baseline serum osteopontin levels were elevated in AECOPD patients with poorer prognosis. Logistic regression analysis indicated that serum osteopontin was positively correlated with the risks of death and acute exacerbations in the first year. Receiver operating characteristic (ROC) curve analysis suggested that the predictive ability of serum osteopontin for poor prognosis was comparable to that of the COPD Assessment Test (CAT) score and superior to the modified Medical Research Council (mMRC) score among AECOPD patients. Our findings indicate that baseline serum osteopontin is positively associated with severity scores and adverse clinical outcomes, highlighting its potential value as a surrogate prognostic biomarker in AECOPD patients.

INTRODUCTION:Syndecan-1 is one of cell surface proteoglycans that mediates the connection between cytoskeleton and interstitial matrix. The previous studies have demonstrated that syndecan-1 exerts an essential role in several pulmonary diseases. However, there are few researches about the relation of serum syndecan-1 with corona virus disease 2019 (COVID-19). METHODS:All 235 COVID-19 patients were summoned. Serum samples and demographic characteristics were collected. Serum syndecan-1 level was determined by ELISA. The relationships of serum syndecan-1 with severity and prognosis were evaluated in COVID-19 patients through a prospective cohort study. RESULTS:On admission, serum syndecan-1 level was raised in pace with COVID-19 severity scores. After treatment, serum syndecan-1 was decreased. Multivariate linear and logistic regression analyses revealed that higher age, coronary heart diseases, other chronic heart diseases, and SpO2 decrease were the risks of syndecan-1 elevation among COVID-19 patients. Moreover, Pearson or Spearman correlative analyses confirmed the positive links between serum syndecan-1 and many characteristics in COVID-19 patients. In addition, mixed linear and logistic regression models found that serum syndecan-1 level was positively correlated to COVID-19 severity scores. Additionally, patients with higher serum syndecan-1 levels on admission had a higher risk of mechanical ventilation, ICU admission, death, and longer hospital stay during hospitalization. CONCLUSION:The serum syndecan-1 concentration is positively correlated with the severity and poor prognosis in COVID-19 patients. Syndecan-1 is a potential biomarker for the diagnosis and prognosis of COVID-19 in the future.

4-Hydroxynonenal (4-HNE), a product of lipid peroxidation, is recognized as a biomarker of oxidative stress. However, its relationship with the severity and prognosis of acute exacerbation in chronic obstructive pulmonary disease (AECOPD) remains unclear. This prospective cohort study aimed to investigate the associations between plasma 4-HNE levels and disease severity and prognosis in AECOPD patients. A total of 150 AECOPD patients, 80 stable COPD (SCOPD) patients, and healthy volunteers were enrolled. Plasma 4-HNE and inflammatory cytokines were measured using enzyme-linked immunosorbent assay (ELISA). Compared to healthy individuals, plasma 4-HNE levels were significantly elevated in both SCOPD and AECOPD patients, with progressively increasing alongside worsening pulmonary function and higher mMRC, CAT, and CCQ scores. In AECOPD patients, plasma 4-HNE was positively correlated with inflammatory cytokines, and linear regression analysis revealed that elevated plasma 4-HNE was associated with increased disease severity. Furthermore, higher plasma 4-HNE levels at admission were linked to prolonging hospital stays and AECOPD, indicating a poorer prognosis. Compared with several conventional biomarkers, plasma 4-HNE demonstrated superior predictive value for AECOPD and clinical outcomes. These findings suggest that plasma 4-HNE may be a useful biomarker for assessing severity and prognosis in AECOPD patients, potentially playing a role in the underlying pathophysiology of the disease.

To explore the factors affecting patient outcomes in pulmonary artery thromboendarterectomy (PTE) under deep hypothermic circulatory arrest (DHCA) and cardiopulmonary bypass (CPB) support and to provide a reference for further improving the effect of PTE. Eighty-five patients with chronic thromboembolic pulmonary hypertension (CTEPH) who underwent PTE under DHCA and CPB support at Beijing Anzhen Hospital from January 2015 to October 2023 were enrolled, including 56 males (65.88

Mesencephalic astrocyte-derived neurotrophic factor (MANF), a novel endoplasmic reticulum stress-induced neurotrophic factor, exerts a protective role in both nervous and non-nervous systems. However, the relationship between serum MANF content and community-acquired pneumonia (CAP) patients remains unclear. A total of 319 adult patients diagnosed with CAP were enrolled. Serum MANF level was quantified using enzyme-linked immunosorbent assay (ELISA). A prospective cohort study was conducted to investigate the association of serum MANF levels with severity and prognosis. Compared with healthy volunteers, serum MANF content was evidently upregulated in CAP patients. The level of serum MANF was dramatically increased in parallel with the scores of CURB-65, PSI, APACHE II, and SMART-COP in CAP cases. Additionally, multivariate linear and logistic regression analyses revealed that serum MANF level was positively associated with scoring criteria among CAP patients. Besides, serum MANF level on admission was significantly elevated in CAP patients who required mechanical ventilation, ICU admission, and died within 30 days. Moreover, the higher serum MANF level on admission evidently increased the risk of poor prognosis during hospitalization. There was a better predictive power of serum MANF for poorly prognostic outcomes in CAP patients. The expression of serum MANF exhibits the positive correlations with the severity and poor prognosis among CAP patients. Serum MANF may have considerable clinical value and be regarded as a diagnostic and prognostic biomarker for CAP.

High-dose methotrexate (HDMTX) is the cornerstone of the treatment for primary central nervous system lymphoma (PCNSL). The prevention of drug-induced toxicities is critical. This study aims to identify key factors associated with HDMTX-induced toxicities (hematotoxicity, hepatotoxicity and nephrotoxicit) in 713 Chinese PCNSL patients undergoing 3021 HDMTX treatment courses. Demographic data, administration information, laboratory tests, area under the curve, co-medications, and 30 single nucleotide polymorphisms were collected to analyze the association of HDMTX-related toxicities using PLINK and SPSS. Higher ALB level, female, ABCB1 rs1045642, MTHFR rs1801131, and MTHFD1 rs2236225 were associated with lower risk of anemia, while the combination of furosemide, torasemide, bumetanide, and levetiracetam associating with higher risk. Co-use of torasemide had higher incidence of neutropenia. Higher level of ALB was correlated with less leukopenia; torasemide and rs2236225 were related to more leukopenia. Female, furosemide, rs1801133, ABCG2 rs2231142, ABCC2 rs717620 were related to more thrombocytopenia, while rs1045642 and high ALB were related to less. Rs1801131 and female were correlated with more hepatotoxicity, whereas furosemide was correlated with less. In nephrotoxicity, female and rs1801394 were correlated with less, MTHFR rs1801131 and rs1801133 were correlated with more. In conclusion, higher ALB levels had a lower risk of HDMTX toxicities; loop diuretics and levetiracetam generally accelerated the occurrence of toxicities. Rs1801133 GG, rs1128503 GG + AG, rs2231142 AA+ AC, rs717620 TT + GT were associated with increased risk of toxicity; rs1045642 TT and rs1801394 GG + AG were less likely to develop toxicity.

Background:Circulating lactate is associated with poor prognosis in sepsis-induced acute lung injury (S-ALI). However, it remains unclear whether microvascular dysfunction, a hallmark of S-ALI, is related to circulating lactate levels and what the underlying mechanisms are. The aim of this study was to investigate the role and mechanisms of lactate in pulmonary microvascular dysfunction in S-ALI. Methods:The effects of lactate on pulmonary microvascular function were assessed in a septic mouse model. Primary mouse pulmonary microvascular endothelial cells (MPMVECs) were isolated to evaluate the impact of lactate on MPMVEC permeability. Transcriptomic sequencing was employed to investigate the involvement of lactate in regulating MPMVEC ferroptosis, and the results were validated by in vivo and in vitro experiments. Histone lactylation was identified as a regulator of lipid peroxidation and iron homeostasis dysregulation in lactate-induced ferroptosis in MPMVECs. Gain- and loss-of-function approaches were used to assess the role of histone lactylation in regulating ferroptosis and pulmonary microvascular dysfunction. Correlations between serum lactate and ferroptosis levels and their associations with patient prognosis were investigated in patients with sepsis-associated acute respiratory distress syndrome (S-ARDS). Results:The mouse serum lactate level reached a peak at 18 h after caecal ligation and puncture surgery. Elevated lactate levels during sepsis promoted ferroptosis in PMVECs, leading to increased pulmonary vascular permeability and exacerbation of ALI. Mechanistically, lactate increased the lactylation of histone H3 at K18 (H3K18la), which promoted ACSL4 transcription in MPMVECs, resulting in excessive lipid peroxidation. Additionally, elevated H3K18la promoted LC3 transcription and indirectly upregulated NCOA4 expression through the transcription factor GATA2, facilitating ferritinophagy. Serum lactate levels were significantly correlated with ferroptosis levels in S-ARDS patients, and both were associated with poor patient prognosis. Conclusions:This study revealed a critical role for high lactate-derived histone lactylation in PMVEC ferroptosis and the progression of ALI during sepsis, providing new insights and potential therapeutic mechanisms.

Cytokeratin (CK)18 is present in the bronchi and alveolar epithelium of the lung, and its cleavage product, CK-18M30, serves as a biological marker of apoptosis. However, the specific roles of CK-18 and CK-18M30 in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) remain unclear. This study enrolled 289 patients with AECOPD who met the inclusion criteria. Demographic information and clinical characteristics of the patients were documented. A 3-year follow-up period was implemented to evaluate acute exacerbations and mortality. Serum CK-18 and CK-18M30 concentrations were measured using enzyme-linked immunosorbent assays. Serum concentrations of CK-18/CK-18M30 at admission in patients with AECOPD were higher than those in the control group. As severity increased, serum CK-18/CK-18M30 levels increased progressively in AECOPD patients. Pearson’s correlation analysis revealed that serum CK-18/CK-18M30 concentrations were positively correlated with several clinical parameters. Linear and logistic regression models demonstrated positive correlations between serum CK-18 and CK-18M30 levels at admission and severity scores. Furthermore, higher serum CK-18/CK-18M30 levels at admission were associated with increased frequency of death and acute exacerbation in patients with AECOPD within 3 years. Serum CK-18/CK-18M30 levels at admission were positively correlated with severity and poor prognosis in patients with AECOPD within 3 years. Therefore, serum CK-18 and CK-18M30 concentrations may serve as novel diagnostic and prognostic biomarkers for patients with AECOPD.