Eliminating COVID-19 as the immediate culprit for igniting pancreatitis.

The impact of severe acute respiratory syndrome coronavirus 2 infection on the potential development of pancreatitis is a subject of ongoing debate within academic discourse. Establishing a causal link between COVID-19 and pancreatitis may not be fully supported by relying only on retrospective studies or case reports. This study examined the relationship between COVID-19 phenotypes and pancreatitis by Mendelian randomization (MR) method. The identification of instrumental variables (single nucleotide polymorphisms) that exhibit a robust association with the COVID-19 phenotypes was accomplished through a meticulous process of rigorous screening procedures. We included acute pancreatitis and chronic pancreatitis (CP) as the outcomes in the MR analysis, even though no definitive studies exist between COVID-19 and CP. A direct causal relationship between genetically predicted COVID-19 phenotypes and pancreatitis risk cannot be established. There is an ongoing debate over the designation of COVID-19 as a definitive cause of pancreatitis.

Emodin Ameliorates Severe Acute Pancreatitis-Associated Acute Lung Injury in Rats by Modulating Exosome-Specific miRNA Expression Profiles.

Background: Numerous preclinical investigations have exhibited the beneficial impact of emodin (EMO) on the management of severe acute pancreatitis (SAP)-associated acute lung injury (ALI). However, the potential of EMO to mitigate organ damage through the modulation of exosome (Exo)-specific miRNA expression profiles remains unclear. Methods: The SAP rat model was established by retrograde injection of 5% sodium taurocholate into the pancreatic bile duct. Rats received intragastric administration of EMO at 2 h and 12 h post-modeling. Plasma and bronchoalveolar lavage fluid (BALF)-derived exosomes were isolated and purified from SAP rats treated with EMO. The therapeutic effects of these Exos in SAP rats were assessed using hematoxylin-eosin staining and measurement of inflammatory factor levels. MicroRNA (miRNA) sequencing was conducted on plasma and BALF-derived Exos, and rescue experiments were performed to investigate the function of NOVEL miR-29a-3p in the treatment of SAP using EMO. Results: EMO exhibits ameliorative effects on pancreatic and lung injury and inflammation in rats with SAP. Plasma/BALF-derived Exos from EMO-treated SAP rats also have therapeutic effects on SAP rats. The miRNA expression profile of plasma and BALF-derived Exos in SAP rats underwent significant changes upon exposure to EMO. In particular, 34 differentially expressed miRNAs (DEmiRNAs) were identified when comparing BALF-SAP+EMO-Exo and BALF-SAP-Exo. 39 DEmiRNAs were identified when comparing plasma-SAP+EMO-Exo to plasma-SAP-Exo. We found that SAP rats treated with Exos derived from BALF exhibited a more potent therapeutic response than those treated with Exos derived from plasma. EMO may rely on NOVEL-rno-miR-29a-3p expression to prevent pulmonary injury in SAP rats. Conclusion: The mechanism of action of EMO is observed to have a significant impact on the miRNA expression profile of Exos derived from plasma and BALF in SAP rats. NOVEL-rno-miR-29a-3p, which is specific to Exos, and is derived from BALF, may play a crucial role in the therapeutic efficacy of EMO.

Exosomal MicroRNAs: An Emerging Important Regulator in Acute Lung Injury.

Acute lung injury (ALI) is a clinically life-threatening form of respiratory failure with a mortality of 30%-40%. Acute respiratory distress syndrome is the aggravated form of ALI. Exosomes are extracellular lipid vesicles ubiquitous in human biofluids with a diameter of 30-150 nm. They can serve as carriers to convey their internal cargo, particularly microRNA (miRNA), to the target cells involved in cellular communication. In disease states, the quantities of exosomes and the cargo generated by cells are altered. These exosomes subsequently function as autocrine or paracrine signals to nearby or distant cells, regulating various pathogenic processes. Moreover, exosomal miRNAs from multiple stem cells can provide therapeutic value for ALI by regulating different signaling pathways. In addition, changes in exosomal miRNAs of biofluids can serve as biomarkers for the early diagnosis of ALI. This study aimed to review the role of exosomal miRNAs produced by different sources participating in various pathological processes of ALI and explore their potential significance in the treatment and diagnosis.

Mechanisms of Qingyi Decoction in Severe Acute Pancreatitis-Associated Acute Lung Injury via Gut Microbiota: Targeting the Short-Chain Fatty Acids-Mediated AMPK/NF-κB/NLRP3 Pathway.

The pivotal roles of gut microbiota in severe acute pancreatitis-associated acute lung injury (SAP-ALI) are increasingly revealed, and recent discoveries in the gut-lung axis have provided potential approaches for treating SAP-ALI. Qingyi decoction (QYD), a traditional Chinese medicine (TCM), is commonly used in clinical to treat SAP-ALI. However, the underlying mechanisms remain to be fully elucidated. Herein, by using a caerulein plus lipopolysaccharide (LPS)-induced SAP-ALI mice model and antibiotics (Abx) cocktail-induced pseudogermfree mice model, we tried to uncover the roles of the gut microbiota by administration of QYD and explored its possible mechanisms. Immunohistochemical results showed that the severity of SAP-ALI and intestinal barrier functions could be affected by the relative depletion of intestinal bacteria. The composition of gut microbiota was partially recovered after QYD treatment with decreased Firmicutes/Bacteroidetes ratio and increased relative abundance in short-chain fatty acids (SCFAs)-producing bacteria. Correspondingly increased levels of SCFAs (especially propionate and butyrate) in feces, gut, serum, and lungs were observed, generally consistent with changes in microbes. Western-blot analysis and RT-qPCR results indicated that the AMPK/NF-κB/NLRP3 signaling pathway was activated after oral administration of QYD, which was found to be possibly related to the regulatory effects on SCFAs in the intestine and lungs. In conclusion, our study provides new insights into treating SAP-ALI through modulating the gut microbiota and has prospective practical value for clinical use in the future. IMPORTANCE Gut microbiota affects the severity of SAP-ALI and intestinal barrier function. During SAP, a significant increase in the relative abundance of gut pathogens (Escherichia, Enterococcus, Enterobacter, Peptostreptococcus, Helicobacter) was observed. At the same time, QYD treatment decreased pathogenic bacteria and increased the relative abundance of SCFAs-producing bacteria (Bacteroides, Roseburia, Parabacteroides, Prevotella, Akkermansia). In addition, The AMPK/NF-κB/NLRP3 pathway mediated by SCFAs along the gut-lung axis may play an essential role in preventing the pathogenesis of SAP-ALI, which allows for reduced systemic inflammation and restoration of the intestinal barrier.

Exosome-derived CIRP: An amplifier of inflammatory diseases.

Cold-inducible RNA-binding protein (CIRP) is an intracellular stress-response protein and a type of damage-associated molecular pattern (DAMP) that responds to various stress stimulus by altering its expression and mRNA stability. Upon exposure to ultraviolet (UV) light or low temperature, CIRP get translocated from the nucleus to the cytoplasm through methylation modification and stored in stress granules (SG). During exosome biogenesis, which involves formation of endosomes from the cell membrane through endocytosis, CIRP also gets packaged within the endosomes along with DNA, and RNA and other proteins. Subsequently, intraluminal vesicles (ILVs) are formed following the inward budding of the endosomal membrane, turning the endosomes into multi-vesicle bodies (MVBs). Finally, the MVBs fuse with the cell membrane to form exosomes. As a result, CIRP can also be secreted out of cells through the lysosomal pathway as Extracellular CIRP (eCIRP). Extracellular CIRP (eCIRP) is implicated in various conditions, including sepsis, ischemia-reperfusion damage, lung injury, and neuroinflammation, through the release of exosomes. In addition, CIRP interacts with TLR4, TREM-1, and IL-6R, and therefore are involved in triggering immune and inflammatory responses. Accordingly, eCIRP has been studied as potential novel targets for disease therapy. C23 and M3, polypeptides that oppose eCIRP binding to its receptors, are beneficial in numerous inflammatory illnesses. Some natural molecules such as Luteolin and Emodin can also antagonize CIRP, which play roles similar to C23 in inflammatory responses and inhibit macrophage-mediated inflammation. This review aims to provide a better understanding on CIRP translocation and secretion from the nucleus to the extracellular space and the mechanisms and inhibitory roles of eCIRP in diverse inflammatory illnesses.

Ferroptosis in Rat Lung Tissue during Severe Acute Pancreatitis-Associated Acute Lung Injury: Protection of Qingyi Decoction.

Qingyi decoction (QYD) has anti-inflammatory pharmacological properties and substantial therapeutic benefits on severe acute pancreatitis (SAP) in clinical practice. However, its protective mechanism against SAP-associated acute lung injury (ALI) remains unclear. In this study, we screened the active ingredients of QYD from the perspective of network pharmacology to identify its core targets and signaling pathways against SAP-associated ALI. Rescue experiments were used to determine the relationship between QYD and ferroptosis. Then, metabolomics and 16s rDNA sequencing were used to identify differential metabolites and microbes in lung tissue. Correlation analysis was utilized to explore the relationship between core targets, signaling pathways, metabolic phenotypes, and microbial flora, sorting out the potential molecular network of QYD against SAP-associated lung ALI. Inflammatory damage was caused by SAP in the rat lung. QYD could effectively alleviate lung injury, improve respiratory function, and significantly reduce serum inflammatory factor levels in SAP rats. Network pharmacology and molecular docking identified three key targets: ALDH2, AnxA1, and ICAM-1. Mechanistically, QYD may inhibit ferroptosis by promoting the ALDH2 expression and suppress neutrophil infiltration by blocking the cleavage of intact AnxA1 and downregulating ICAM-1 expression. Ferroptosis activator counteracts the pulmonary protective effect of QYD in SAP rats. In addition, seven significant differential metabolites were identified in lung tissues. QYD relatively improved the lung microbiome's abundance in SAP rats. Further correlation analysis determined the correlation between ferroptosis, differential metabolites, and differential microbes. In this work, the network pharmacology, metabolomics, and 16s rDNA sequencing were integrated to uncover the mechanism of QYD against SAP-associated ALI. This novel integrated method may play an important role in future research on traditional Chinese medicine.

[Research progress on molecular mechanism of transcription factor C/EBPß in lung diseases].

CCAAT enhancer binding protein ß (C/EBPß), as a nuclear transcription factor necessary for the development of liver, airway epithelium, and adipose tissue, plays a vital role in physiological processes related to cell proliferation, apoptosis, and differentiation. However, the up-regulation of C/EBPß activates signal pathways related to inflammatory response, epithelial-mesenchymal transition, cell proliferation and invasion, immune response, and angiogenesis by regulating a series of downstream genes transcription promotes the development of lung diseases. Therefore, targeting C/EBPß may be a potential treatment strategy for lung diseases. This paper summarizes the regulatory effects of C/EBPß and related signaling pathways in lung infection, asthma, chronic obstructive pulmonary disease, lung injury, pulmonary fibrosis, and lung cancer to provide a theoretical basis for the precision medicine of lung diseases.

C/EBPß Promotes LPS-Induced IL-1ß Transcription and Secretion in Alveolar Macrophages via NOD2 Signaling.

Objective: C/EBPß, a crucial transcription factor, regulates innate immunity and inflammatory responses. However, the role played by C/EBPß in alveolar macrophage (AM) inflammatory responses remains unknown. This study aimed to investigate the role and mechanism of C/EBPß in alveolar macrophages (AMs) from the transcriptional level and to search for natural compounds targeting C/EBPß. Methods: Rat AMs were infected with Lv-sh-C/EBPß and treated with LPS, and the expression levels of iNOS, TNF-α, IL-6, and IL-1ß were measured by RT-qPCR, Western blotting, and ELISA. Mechanistically, transcriptome sequencing (RNA-seq) revealed changes in gene expression patterns in AMs after LPS stimulation and C/EBPß knockdown. Functional enrichment analyses and rescue experiments identified and validated inflammation-associated cell signaling pathways regulated by C/EBPß. Furthermore, virtual screening was used to search for natural compounds that inhibit C/EBPß with the structure of helenalin as a reference. Results: Following stimulation with LPS, AMs exhibited an increased expression of C/EBPß. C/EBPß knockdown significantly decreased the expression levels of inflammatory mediators. A total of 374 differentially expressed genes (DEGs) were identified between LPS-stimulated C/EBPß knockdown and negative control cells. The NOD-like receptor signaling may be a key target for C/EBPß, according to functional enrichment analyses of the DEGs. Further experiments showed that the muramyl dipeptide (MDP, NOD2 agonist) reversed the downregulation of inflammatory mediators and the NF-κB pathway caused by the C/EBPß knockdown. The virtual screening revealed that N-caffeoyltryptophan, orilotimod, and petasiphenone have comparable pharmacological properties to helenalin (a known C/EBPß inhibitor) and demonstrate a great binding capacity to C/EBPß. Conclusion: Ablation of C/EBPß may attenuate LPS-induced inflammatory damage in AMs by inhibiting the NOD2 receptor signaling pathway. Three natural compounds, N-caffeoyltryptophan, orilotimod, and petasiphenone, may be potential C/EBPß inhibitors.

The gut-lung axis in severe acute Pancreatitis-associated lung injury: The protection by the gut microbiota through short-chain fatty acids.

The role of gut microbiota in regulating the intestinal homeostasis, as well as the pathogenesis of severe acute pancreatitis-associated lung injury (PALI) is widely recognized. The bioactive functions of metabolites with small molecule weight and the detail molecular mechanisms of PALI mediated by "gut-lung axis" have gradually raised the attentions of researchers. Several studies have proved that short-chain fatty acids (SCFAs) produced by gut microbiome play crucial roles and varied activities in the process of PALI. However, relevant reviews reporting SCFAs in the involvement of PALI is lacking. In this review, we firstly introduced the synthetic and metabolic pathways of SCFAs, as well as the transport and signal transduction routes in brief. Afterwards, we focused on the possible mechanisms and clues of SCFAs to participate in the fight against PALI which referred to the inhibition of pathogen proliferation, anti-inflammatory effects, enhancement of intestinal barrier functions, and the maintenance and regulation of immune homeostasis via pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). In addition, the latest reported pathological and physiological mechanisms of the gut-lung axis involved in PALI were reviewed. Finally, we summarized the potential therapeutic interventions of PALI by targeting SCFAs, including dietary fiber supplementation, direct supplementation of SCFAs/prebiotics/probiotics, and drugs administration, which is expected to provide new sights for clinical use in the future.