Lactate exhibits various biological functions, including the mediation of histone and non-histone lactylation to regulate gene transcription, influencing the activity of T lymphocytes, NK cells, and macrophages in immune suppression, activating G protein-coupled receptor 81 for signal transduction, and serving as an energy substrate. The m⁶A modification represents the most prevalent post-transcriptional epigenetic alteration. It is regulated by m⁶A-related regulatory enzymes (including methyltransferases, demethylases, and recognition proteins) that control the transcription, splicing, stability, and translation of downstream target RNAs. Lactate-mediated lactylation at histone H3K18 can modulate downstream target m⁶A modifications by enhancing the transcriptional expression levels of m⁶A-related regulatory enzymes. These enzymes play a crucial role in the progression of diseases such as cancer, fibrosis (in both liver and lung), myocardial ischemia, cerebral hemorrhage, and sepsis. Furthermore, m⁶A-related regulatory enzymes are also subject to lactylation by lactate. In turn, these regulatory enzymes can influence key glycolytic pathway enzymes or modify lactate transporter MCT4 via m⁶A alterations to impact lactate levels and subsequently affect lactylation processes. Graphical abstract 1. Lactate exhibits various biological functions, including the mediation of histone and non-histone lactylation, immune suppression, activating signal transduction, and serving as an energy substrate. 2. Lactate-induced lactylation of histone or non-histone can regulate downstream targets by influencing the transcription and activity of m⁶A-RRE. 3. m⁶A-RRE-mediated modifications can affect key enzymes in the glycolytic pathway or MCT4, impacting lactate levels.

Background: Although thrombosis events have been reported in patients with coronavirus disease 2019 (COVID-19), the association between thrombosis and COVID-19-related critical status or risk of mortality in COVID-19 has been inconsistent.Objective: We conducted a meta-analysis of reports assessing the association between thrombosis and the prognosis of COVID-19.Methods: The EMBASE, Ovid-MEDLINE, and Web of Science databases were searched up to December 9, 2021, and additional studies were retrieved via manual searching. Studies were included if they reported the risk of COVID-19-related critical status or COVID-19-related mortality in relation to thrombosis. The related data were extracted by two authors independently, and a random effects model was conducted to pool the odds ratios (ORs). In addition, stratified analyses were conducted to evaluate the association.Results: Among 6,686 initially identified studies, we included 25 studies published in 2020 and 2021, with a total of 332,915 patients according to predefined inclusion criteria. The associations between thrombosis and COVID-19-related mortality and COVID-19-related critical status were significant, with ORs of 2.61 (95% CI, 1.91–3.55, p < 0.05) and 2.9 (95% CI, 1.6–5.24, p < 0.05), respectively. The results were statistically significant and consistent in stratified analyses.Conclusions: Thrombosis is associated with an increased risk of mortality and critical status induced by COVID-19. Further prospective studies with large sample sizes are required to establish whether these associations are causal by considering more confounders and to clarify their mechanisms.Observational studies cannot prove causality. However, autopsy studies show thrombosis events preceding COVID-19-related deaths. The results of this meta-analysis reported that thrombosis was associated with a 161% increased risk of mortality from COVID-19 and a 190% increased risk of COVID-19-related critical status. The type of thrombosis included in the original studies also seemed to be related to the results.

Background: Sepsis-induced acute lung injury (ALI) is a serious disease constituting a heavy burden on society due to high mortality and morbidity. Inflammation and oxidative stress constitute key pathological mechanisms in ALI caused by sepsis. LL-37 can improve the survival of septic mice. Nevertheless, its function and underlying mechanism in sepsis-evoked ALI is elusive. Methods: The human A549 alveolar epithelial cell line was treated with LL-37 or ZBP1 recombinant vector under LPS exposure. Then, the effects on cell oxidative stress injury, inflammatory response, and autophagy were analyzed. RNA-seq analysis was performed to detect the differentially expressed genes (DEGs) between the LPS and LPS/LL-37 groups. Furthermore, the effects of LL-37 on cecal ligation and the puncture (CLP)-constructed ALI model were explored. Results: LL-37 attenuated LPS-evoked oxidative injury in human alveolar epithelial cells by increasing cell viability and suppressing ROS, malondialdehyde, and lactate dehydrogenase levels and apoptosis. Moreover, LPS-induced releases of pro-inflammatory IL-18, TNF-α, and IL-1β were suppressed by LL-37. Furthermore, LPS’s impairment of autophagy was reversed by LL-37. RNA-seq analysis substantiated 1350 differentially expressed genes between the LPS and LPS/LL-37 groups. Among them was ZBP1, a significantly down-regulated gene with the largest fold change. Moreover, LL-37 suppressed LPS-increased ZBP1 expression. Importantly, ZBP1 elevation restrained LL-37-induced autophagy in LPS-treated cells and abrogated LL-37-mediated protection against LPS-evoked oxidative injury and inflammation. LL-37 ameliorated abnormal histopathological changes, tissue edema, the lung injury score, oxygenation index (PaO2/FiO2), and glycemia contents in the CLP-constructed ALI model, which were offset through ZBP1 elevation via its activator CBL0137. Additionally, LL-37 suppressed inflammation and oxidative stress in lung tissues, concomitant with autophagy elevation and ZBP1 down-regulation. Conclusions: LL-37 may alleviate the progression of sepsis-evoked ALI by attenuating pulmonary epithelial cell oxidative injury and inflammatory response via ZBP1-mediated autophagy activation, indicating a promising approach for the therapy of ALI patients.

Bacteremia represents a significant complication in patients with community-acquired pneumonia (CAP). Nonetheless, there is currently a dearth of systematic research that determines the precise prevalence and risk factors of bacteremia in CAP patients. PubMed, Cochrane Library, Embase, and Web of Science databases were searched for published studies on the prevalence or risk factors for CAP with bacteremia up to April 21, 2024. The NOS scale was utilized to appraise the study quality, and the META process was carried out in R language. 58,342 CAP patients were enrolled in 22 studies. Of these patients, 29,610 underwent blood culture tests, and 2332 patients had positive blood culture results. Meta-analysis pooled results showed that the incidence of bacteremia was 5.1% (95% CI: 3.6-6.8%) in CAP patients. The prevalence of co-bacteremia was 3.1% (95% CI: 1.5-5.1%) in minors and 6.9% (95% CI: 5.2%-8.8%) in adults. The most common pathogens of CAP were Streptococcus pneumoniae, Staphylococcus aureus. In addition, a summary of the original studies found that the risk factors for bacteremia in CAP patients were diverse and varied. The incidence of bacteremia in CAP patients warrants significant attention. There is a pressing need to establish more specific bacterial screening protocols.