Mediators of Inflammation

There is no effective treatment for peripheral nerve injury-induced chronic neuropathic pain (NP), which profoundly impacts the quality of life of those affected. Transmembraneprotein100 (TMEM100) is considered to be a pain regulatory protein and is expressed in the dorsal root ganglion (DRG) of rats. However, the mechanism of pain regulation and the expression of TMEM100 following various peripheral nerve injuries are unclear. In this study, we constructed two pain models of peripheral nerve injury: tibial nerve injury (TNI) and chronic constriction injury (CCI). This study found that the Paw Withdrawal Mechanical Threshold (PWMT) and Paw Withdraw Thermal Latency (PWTL) of the rats in the two pain models decreased significantly, and the expression of TMEM100 in the DRG of two groups also decreased significantly. Furthermore, the decrease in the CCI group was more obvious than in the TNI group. There was no significant statistical significance (). We constructed an adeno-associated virus 6 (AAV6) vector expressing recombinant fluorescent TMEM100 protein and injected it into the sciatic nerve (SN) of two pain models: CCI and TNI. PWMT and PWTL were significantly increased in the two groups, along with the expression of TMEM100 in the spinal cord and DRG. It also significantly inhibited the activation of microglia, astrocytes, and several inflammatory mediators (TNF- α, IL-1 β, and IL-6). In summary, the results of this study suggested that TMEM100 might be a promising molecular strategy for the treatment of NP, and its anti-inflammatory effects might play an important role in pain relief.

Coronary artery disease (CAD) is a caused by atherosclerotic plaque buildup in the coronary arteries that supply blood and oxygen to the heart. Matrix metalloproteinase (MMP) is a family of zinc-dependent endopeptidase that is involved in various stages of atherosclerosis as demonstrated in in vitro and in vivo studies. MMP-2 is associated with both stable and unstable atherosclerotic plaque formation. The current review aimed to identify the role of MMP-2 in atherosclerosis development among CAD patients. Literature search was conducted through four online databases and only studies that were published from 2018 until February 2023 were included. The risk of bias was assessed by using the Newcastle–Ottawa Scale. A total of 10,622 articles were initially identified, and only eight studies that fulfilled the selection criteria were included in this review. The results showed that MMP-2 levels and activity were higher in patients with unstable CAD than those with stable CAD and healthy subjects. There was a significant association between MMP-2 levels and cardiovascular disease with MMP-14 levels, which is a pro-MMP-2 activator. In addition, two single nucleotide polymorphisms of the MMP-2 gene (rs243865 and rs243866) were significantly associated with the development of atherosclerosis. In conclusion, MMP-2 plays a crucial role in the development of atherosclerosis among patients with CAD and could be a potential target for CAD therapy.

Most patients diagnosed with chronic obstructive pulmonary disease (COPD) present with hallmark features of airway mucus hypersecretion, including cough and expectoration. Airway mucus function as a native immune system of the lung that severs to trap particulate matter and pathogens and allows them to clear from the lung via cough and ciliary transport. Chronic mucus hypersecretion (CMH) is the main factor contributing to the increased risk of morbidity and mortality in specific subsets of COPD patients. It is, therefore, primarily important to develop medications that suppress mucus hypersecretions in these patients. Although there have been some advances in COPD treatment, more work remains to be done to better understand the mechanism underlying airway mucus hypersecretion and seek more effective treatments. This review article discusses the structure and significance of mucus in the lungs focusing on gel-forming mucins and the impacts of CMH in the lungs. Furthermore, we summarize the article with pharmacological and nonpharmacological treatments as well as novel and interventional procedures to control CMH in COPD patients.

Introduction. Bronchiolitis obliterans (BO) is a chronic lung disease, which occurs after an insult to the lower airways, in particular after airway infections or after stem cell transplantation, and which results in persistent inflammation. N–3 and n–6 polyunsaturated fatty acids (PUFA) have been shown to influence the inflammatory processes in chronic inflammatory conditions. Since BO is maintained by persistent pulmonary inflammation, a disbalanced n–6/n–3 fatty acid profile could support the inflammatory process in patients with BO and therefore, could become an approach to new therapeutic options. Methods. Twenty-five patients with BO (age: 13; 7–39) and 26 healthy controls (age: 19; 7–31) participated in the study. Lung function (forced viral capacity (FVC), forced expiratory volume 1 (FEV1), residual volume (RV)), and lung clearance index (LCI) were measured. Induced sputum was analyzed for cytology and cytokine levels (IL-1ß, IL-6, IL-8, TNF-α) using cytometric bead array (CBA). The PUFA profile was determined in the serum and induced sputum by gas chromatography. Results. Patients presented with significantly lower FVC and FEV1 as well as higher RV and LCI measurements compared to the control group. Apart from a massive airway inflammation indicated by elevated numbers of total cells and neutrophils, the CBA analysis showed significantly increased levels of IL-1β, IL-6, and IL-8. The analysis of PUFA in sputum and serum revealed a significant difference in the ratio between the n–6 PUFA arachidonic acid (AA) and the n–3 PUFA docosahexaenoic acid (DHA) (AA : DHA). Furthermore, the AA : DHA ratio significantly correlated with the inflammatory cytokines in induced sputum. Conclusion. Lung function in BO is significantly impaired and associated with uncontrolled neutrophil-dominated airway inflammation. Furthermore, the imbalance in the AA/DHA ratio in favor of n–6 PUFA demonstrates a pro-inflammatory microenvironment in the cell membrane, which correlates with the inflammatory cytokines in induced sputum and might be an option for an anti-inflammatory therapy in BO.

Objective. To elucidate the mechanism by which LINC00174 promotes colon cancer progression by targeting the microRNA-2467-3p (miR-2467-3p)/enolase 3 (ENO3) axis to regulate inflammation and glycolysis. Methods. The expression of LINC00174 and ENO3 in colon cancer tissues, its relationship with survival rate, and correlation were analyzed using bioinformatic analysis. The effects of LINC00174 overexpression and silencing on the biological behavior of and inflammation in colon cancer cells were analyzed via transfection experiments. The target relationships between miR-2467-3p or LINC00174 and ENO3 were verified using sequence prediction and the dual-luciferase reporter assay, respectively. Furthermore, LINC00174- and/or miR-2467-3p-overexpressing cells were prepared to determine the effects on ENO3 protein levels and glycolysis. Finally, the effects of LINC00174 and/or miR-2467-3p overexpression on colon cancer, ENO3 protein levels, and inflammation were analyzed using a tumor-bearing mice model. Results. LINC00174 and ENO3 were overexpressed and associated with a lower survival rate. LINC00174 was positively correlated with ENO3 in colon cancer tissues. Furthermore, the overexpression of LINC00174 in colon cancer cell lines promoted the proliferation, migration, and invasion of colon cancer cells and inflammation but inhibited apoptosis. The overexpression of miR-2467-3p inhibited ENO3 protein levels, which was attenuated via LINC00174 overexpression. Furthermore, it inhibited the biological behavior of and inflammation and glycolysis in colon cancer cells and blocked their LINC00174-induced promotion. Moreover, using animal experiments, the regulatory effects of LINC00174 on tumor growth, ENO3 protein levels, and inflammation via miR-2467-3p were confirmed. Conclusion. LINC00174 promotes the glycolysis, inflammation, proliferation, migration, and invasion of colon cancer cells and inhibits apoptosis. The cancer-promoting mechanism of LINC00174 is related to targeting miR-2467-3p to promote ENO3 protein levels.

Background/Aims. The underlying mechanisms of differential responsiveness to IFN remain poorly understood. The elongation factor Tu GTP binding domain-containing protein 2 (EFTUD2), involved in RNA splicing and pre-mRNA processing, was recognized as a novel innate immune regulator of the IFN antihepatitis C virus (HCV) effect. The aim of this study is to elucidate the mechanisms underlying EFTUD2’s involvement in IFN-mediated anti-HBV responses. Methods. Using a CRISPR/Cas9 gene-editing system, EFTUD2 single allele knockout HepG2.2.15 cells were constructed. Subsequently, the HBV biomarkers in EFTUD2^+/– HepG2.2.15 cells and wild-type (WT) cells with or without IFN-α treatment were detected. And the EFTUD2-regulated genes were then identified using mRNA sequence. Selected gene mRNA variants and their proteins were examined by qRT-PCR and Western blotting. To confirm the effects of EFTUD2 on HBV replication and IFN-stimulated gene (ISG) expression, a rescue experiment in EFTUD2^+/– HepG2.2.15 cells was performed by EFTUD2 overexpression. Results. IFN-induced anti-HBV activity was found to be restricted in EFTUD2^+/– HepG2.2.15 cells. The mRNA sequence showed that EFTUD2 could regulate classical IFN and virus response genes. Mechanistically, EFTUD2 single allele knockout decreased the expression of ISG-encoded proteins, comprising Mx1, OAS1, and PKR (EIF2AK2), through mediated gene splicing. However, EFTUD2 did not affect the expression of Jak-STAT pathway genes. Furthermore, EFTUD2 overexpression could restore the attenuation of IFN anti-HBV activity and the reduction of ISG resulting from EFTUD2 single allele knockout. Conclusion. EFTUD2, the spliceosome factor, is not IFN-inducible but is an IFN effector gene. EFTUD2 mediates IFN anti-HBV effect through regulation of gene splicing for certain ISGs, including Mx1, OAS1, and PKR. EFTUD2 does not affect IFN receptors or canonical signal transduction components. Therefore, it can be concluded that EFTUD2 regulates ISGs using a novel, nonclassical mechanism.