Regulation of macrophage activation by lactylation in lung disease.

Lactylation is a process where lactate, a cellular metabolism byproduct, is added to proteins, altering their functions. In the realm of macrophage activation, lactylation impacts inflammatory response and immune regulation. Understanding the effects of lactylation on macrophage activation is vital in lung diseases, as abnormal activation and function are pivotal in conditions like pneumonia, pulmonary fibrosis, COPD, and lung cancer. This review explores the concept of lactylation, its regulation of macrophage activation, and recent research progress in lung diseases. It offers new insights into lung disease pathogenesis and potential therapeutic targets.

Role of ADAM and ADAMTS proteases in pathological tissue remodeling.

Pathological tissue remodeling is closely associated with the occurrence and aggravation of various diseases. A Disintegrin And Metalloproteinases (ADAM), as well as A Disintegrin And Metalloproteinase with ThromboSpondin motifs (ADAMTS), belong to zinc-dependent metalloproteinase superfamily, are involved in a range of pathological states, including cancer metastasis, inflammatory disorders, respiratory diseases and cardiovascular diseases. Mounting studies suggest that ADAM and ADAMTS proteases contribute to the development of tissue remodeling in various diseases, mainly through the regulation of cell proliferation, apoptosis, migration and extracellular matrix remodeling. This review focuses on the roles of ADAM and ADAMTS proteinases in diseases with pathological tissue remodeling, with particular emphasis on the molecular mechanisms through which ADAM and ADAMTS proteins mediate tissue remodeling. Some of these reported proteinases have defined protective or contributing roles in indicated diseases, while their underlying regulation is obscure. Future studies are warranted to better understand the catalytic and non-catalytic functions of ADAM and ADAMTS proteins, as well as to evaluate the efficacy of targeting these proteases in pathological tissue remodeling.

Structural Variability of Lipoarabinomannan Modulates Innate Immune Responses within Infected Alveolar Epithelial Cells.

Mycobacterium tuberculosis (M. tb) is an intracellular pathogen persisting in phagosomes that has the ability to escape host immune surveillance causing tuberculosis (TB). Lipoarabinomannan (LAM), as a glycolipid, is one of the complex outermost components of the mycobacterial cell envelope and plays a critical role in modulating host responses during M. tb infection. Different species within the Mycobacterium genus exhibit distinct LAM structures and elicit diverse innate immune responses. However, little is known about the mechanisms. In this study, we first constructed a LAM-truncated mutant with fewer arabinofuranose (Araf) residues named M. sm-ΔM_6387 (Mycobacterium smegmatis arabinosyltransferase EmbC gene knockout strain). It exhibited some prominent cell wall defects, including tardiness of mycobacterial migration, loss of acid-fast staining, and increased cell wall permeability. Within alveolar epithelial cells (A549) infected by M. sm-ΔM_6387, the uptake rate was lower, phagosomes with bacterial degradation appeared, and microtubule-associated protein light chain 3 (LC3) recruitment was enhanced compared to wild type Mycobacteriumsmegmatis (M. smegmatis). We further confirmed that the variability in the removal capability of M. sm-ΔM_6387 resulted from host cell responses rather than the changes in the mycobacterial cell envelope. Moreover, we found that M. sm-ΔM_6387 or its glycolipid extracts significantly induced expression changes in some genes related to innate immune responses, including Toll-like receptor 2 (TLR2), class A scavenger receptor (SR-A), Rubicon, LC3, tumor necrosis factor alpha (TNF-α), Bcl-2, and Bax. Therefore, our studies suggest that nonpathogenic M. smegmatis can deposit LC3 on phagosomal membranes, and the decrease in the quantity of Araf residues for LAM molecules not only impacts mycobacterial cell wall integrity but also enhances host defense responses against the intracellular pathogens and decreases phagocytosis of host cells.

Smartphone-Based Electrochemical Biosensors for Directly Detecting Serum-Derived Exosomes and Monitoring Their Secretion.

Exosomes are potential biomarkers, which play an important role in early diagnosis and prognosis prediction of cancer-related diseases. Nevertheless, direct quantification of exosomes in biological fluid, especially in point-of-care tests (POCTs), remains extremely challenging. Herein, we developed a sensitive and portable electrochemical biosensor in combination with smartphones for quantitative analysis of exosomes. The improved double-antibody sandwich method-based poly-enzyme signal amplification was adopted to detect exosomes. We could detect as low as 7.23 ng of CD63-positive exosomes in 5 µL of serum within 2 h. Importantly, we demonstrated that the biosensor worked well with microliter-level serum and cell culture supernatant. The biosensor holds great potential for the detection of CD-63-expressing exosomes in early diagnosis of prostate disease because CD63-positive exosomes were less detected from the prostate patient serum. Also, the biosensor was used to monitor the secretion of exosomes with the drug therapy, showing a close relationship between the secretion of exosomes and the concentration of cisplatin. The biosensing platform provides a novel way toward POCT for the diagnosis and prognosis prediction of prostate disease and other diseases via biomarker expression levels of exosomes.

DNA Framework-Supported Electrochemical Analysis of DNA Methylation for Prostate Cancers.

Epigenetic alterations hold great promise as biomarkers for early stage cancer diagnosis. Nevertheless, direct identification of rare methylated DNA in the genome remains challenging. Here, we report an ultrasensitive framework nucleic acid-based electrochemical sensor for quantitative and highly selective analysis of DNA methylation. Notably, we can detect 160 fg of methylated DNA in million-fold unmethylated DNA samples using this electrochemical methylation-specific polymerase chain reaction (E-MSP) method. The high sensitivity of E-MSP enables one-step detection of low-abundance methylation at two different genes in patient serum samples. By using a combination test with two methylation alterations, we achieve high accuracy and sensitivity for reliable differentiation of prostate cancer and benign prostate hypertrophy (BPH). This new method sheds new light on translational use in early cancer diagnosis and in monitoring patients' responses to therapeutic agents.

Risk factors and mortality for patients with Bloodstream infections of Klebsiella pneumoniae during 2014-2018: Clinical impact of carbapenem resistance in a large tertiary hospital of China.

BACKGROUND: Bloodstream infection (BSI) caused by Klebsiella pneumoniae (KP), especially carbapenem-resistant KP (CRKP), results in high morbidity and mortality. AIMS: We aim to identify risk factors that associated with the mortality of patients with KP BSI, as well as predictors of developing CRKP BSI. RESULTS: In this retrospective cohort study, we examined 285 inpatients with BSI caused by KP in a tertiary hospital in China between 2014 and 2018, and 46 patients were infected with CRKP. We identified that hematological tumor (odds ratio (OR): 8.359, [95% CI: 2.162-33.721], P=0.002), CRKP isolation (OR: 7.766, [95% CI: 2.796-21.576], P=0.001), chronic lung disease (OR: 5.020, [95% CI: 1.275-19.768], P=0.020), and septic shock (OR: 4.591, [95% CI: 1.686-12.496], P=0.003) were independent risk factors for the death of KP BSI. A 28-day mortality of KP BSI score ranging from 0 to 22 was developed based on the above 4 independent variables. Our scoring system revealed that the 28-day mortality were 9.14%, 35.29%, 38.10 %, 75% and 100% for carriers with a score of 0, 5, 6-10, 11-13 and ≥14, respectively. Additionally, CRKP infection were independently associated with intensive care unit stay (OR: 5.506, [95% CI: 2.258-13.424], P=0.001), exposure to antifungals (OR: 4.679, [95% CI: 2.065-10.063], P=0.001), exposure to fluoroquinolones (OR: 2.892, [95% CI: 1.151-7.267], P=0.020), and the number of isolated bacterial species from the patient ≥ 3 (OR: 2.414, [95% CI: 1.306-4.463], P=0.005). CONCLUSION: Our study may be useful for the reduction of the mortality of patients with KP BSI and the prevention of developing CRKP BSI in hospitals.

High-Sensitivity and High-Efficiency Detection of DNA Hydroxymethylation in Genomic DNA by Multiplexing Electrochemical Biosensing.

DNA hydroxymethylation (5-hmC) is a kind of new epigenetic modification, which plays key roles in DNA demethylation, genomic reprogramming, and the gene expression in mammals. For further exploring the functions of 5-hmC, it is necessary to develop sensitive and selective methods for detecting 5-hmC. Herein, we developed a novel multiplexing electrochemical (MEC) biosensor for 5-hmC detection based on the glycosylation modification of 5-hmC and enzymatic signal amplification. The 5-hmC was first glycosylated by T4 ß-glucosyltransferase and then oxidated by sodium periodate. The resulting glucosyl-modified 5-hmC (5-ghmC) was incubated with ARP-biotin and was bound to avidin-HRP. The 5-hmC can be detected at the subnanogram level. Finally, we performed 5-hmC detection for mouse tissue samples and cancer cell lines. The limit of detection of the MEC biosensor is 20 times lower than that of commercial kits based on optical meaurement. Also, the biosensor presented high detection specificity because the chemical reaction for 5-hmC modification can not happen at any other unhydroxymethylated nucleic acid bases. Importantly, benefited by its multiplexing capacity, the developed MEC biosensor showed excellent high efficiency, which was time-saving and cost less.