The pathogenetic mechanism of post-Covid-19 pulmonary fibrosis is currently a topic of intense research interest, but still largely unexplored. The aim of this work was to carry out a systematic exploratory search of the literature (Scoping review) to identify and systematize the main pathogenetic mechanisms that are believed to be involved in this phenomenon, in order to highlight the same molecular aspect of the lung. These aims could be essential in the future for therapeutic management. We identified all primary studies involving in post COVID19 syndrome with pulmonary fibrosis as a primary endpoint by performing data searches in various systematic review databases. Two reviewers independently reviewed all abstracts (398) and full text data. The quality of study has been assess through SANRA protocol. A total of 32 studies involving were included, included the possible involvement of inflammatory cytokines, concerned the renin-angiotensin system, the potential role of galectin-3, epithelial injuries in fibrosis, alveolar type 2 involvement, Neutrophil extracellular traps (NETs) and the others implied other specific aspects (relationship with clinical and mechanical factors, epithelial transition mesenchymal, TGF-β signaling pathway, midkine, caspase and macrophages, genetics). In most cases, these were narrative reviews or letters to the editor, except for 10 articles, which presented original data, albeit sometimes in experimental models. From the development of these researches, progress in the knowledge of the phenomenon and hopefully in its prevention and therapy may originate.
Purpose: To unravel the oncogenic role of CDCA4 in different cancers from the perspective of tumor immunity.
Methods: Raw data on CDCA4 expression in tumor samples and paracancerous samples were obtained from TCGA and GTEX databases. In addition, we investigated pathological stages and the survival analysis of CDCA4 in pan-cancer across Gene Expression Profiling Interactive Analysis (GEPIA) database. Cox Proportional Hazards Model shows that high CDCA4 levels are associated with several vital indicators in oncology. On the one hand, we explored the correlation between CADA4 expression and tumor immune infiltration by the TIMER tool; On the other hand, we utilized the methods of CIBERSORT and ESTIMATE computational to evaluate the proportion of tumor infiltrating immune cells (TIIC) and the amounts of stromal and immune components based on TCGA database. The use of antineoplastic drugs and the expression of CDCA4 also showed a high correlation via linear regression. Protein–Protein Interaction analysis was performed in the GeneMANIA database, and enrichment analysis was performed and predicted signaling pathways were identified by using Gene Ontology and Kyoto Encyclopedia of Genes. The correlation between CDCA4 expression with Copy number variations (CNV) and methylation is detailed, respectively. Molecular biology experiments including Western blotting, flow cytometry, EDU staining, Transwell and Wound Healing assay to validate the cancer promoting role of CDCA4 in hepatocellular carcinoma (HCC).
Results: Most tumors highly expressed CDCA4. Elevated CDCA4 expression was associated with poor OS and DFS. There was a significant correlation between CDCA4 expression and TITCs. Moreover, markers of TIICs exhibited distinct patterns of CDCA4 associated immune infiltration. In addition, we pay attention to the association between the expression of CDCA4 and the use of the anti-tumor drugs. CDCA4 is related to biological progress (BP), cellular component (CC) and molecular function (MF). Dopaminergic Synapse, AMPK, Sphingolipid, Chagas Disease, mRNA Surveillance were significantly enriched pathways in positive and negative correlation genes with CDCA4. CNV is thought to be a positive correlation with CDCA4 expression. Conversely, methylation is negative correlation with CDCA4 expression. Molecular biology experiments confirm a cancer promoting role for CDCA4 in HCC
Conclusion: CDCA4 may serve as a biomarker for cancer immunologic infiltration and poor prognosis, providing a new way of thinking for cancer treatment.
Liver fibrosis is the pathological process of excessive extracellular matrix deposition after liver injury and is a precursor to cirrhosis, hepatocellular carcinoma (HCC). It is essentially a wound healing response to liver tissue damage. Numerous studies have shown that hepatic stellate cells play a critical role in this process, with various cells, cytokines, and signaling pathways engaged. Currently, the treatment targeting etiology is considered the most effective measure to prevent and treat liver fibrosis, but reversal fibrosis by elimination of the causative agent often occurs too slowly or too rarely to avoid life-threatening complications, especially in advanced fibrosis. Liver transplantation is the only treatment option in the end-stage, leaving us with an urgent need for new therapies. An in-depth understanding of the mechanisms of liver fibrosis could identify new targets for the treatment. Most of the drugs targeting critical cells and cytokines in the pathogenesis of liver fibrosis are still in pre-clinical trials and there are hardly any definitive anti-fibrotic chemical or biological drugs available for clinical use. In this review, we will summarize the pathogenesis of liver fibrosis, focusing on the role of key cells, associated mechanisms, and signaling pathways, and summarize various therapeutic measures or drugs that have been trialed in clinical practice or are in the research stage.
Pulmonary fibrosis is a pathologic process associated with scarring of the lung interstitium. Interstitial lung diseases (ILDs) encompass a large and heterogenous group of disorders, a number of which are characterized by progressive pulmonary fibrosis that leads to respiratory failure and death. Idiopathic pulmonary fibrosis (IPF) has been described as an archetype of progressive fibrosing ILD, and the development of pirfenidone and nintedanib has been a major breakthrough in the treatment of patients with this deadly disease. Both drugs principally target scar-forming fibroblasts and have been shown to significantly slow down the accelerated decline of lung function by approximately 50%. In addition, nintedanib has been approved for patients with other progressive fibrosing ILDs and systemic sclerosis-associated ILD. However, there is still no cure for pulmonary fibrosis and no meaningful improvement of symptoms or quality of life has been shown. Advancement in research, such as the advent of single cell sequencing technology, has identified additional pathologic cell populations beyond the fibroblast which could be targeted for therapeutic purposes. The preclinical and clinical development of novel drug candidates is hampered by profound challenges such as a lack of sensitive clinical outcomes or suitable biomarkers that would provide an early indication of patient benefit. With the availability of these anti-fibrotic treatments, it has become even more difficult to demonstrate added efficacy, in particular in short-term clinical studies. Patient heterogeneity and the paucity of biomarkers of disease activity further complicate clinical development. It is conceivable that future treatment of pulmonary fibrosis will need to embrace more precision in treating the right patient at the right time, explore novel measures of efficacy, and likely combine treatment options.
Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by an abnormal reepithelialisation, an excessive tissue remodelling and a progressive fibrosis within the alveolar wall that are not due to infection or cancer. Oxidative stress has been proposed as a key molecular process in pulmonary fibrosis development and different components of the redox system are altered in the cellular actors participating in lung fibrosis. To this respect, several activators of the antioxidant machinery and inhibitors of the oxidant species and pathways have been assayed in preclinical in vitro and in vivo models and in different clinical trials. This review discusses the role of oxidative stress in the development and progression of IPF and its underlying mechanisms as well as the evidence of oxidative stress in human IPF. Finally, we analyze the mechanism of action, the efficacy and the current status of different drugs developed to inhibit the oxidative stress as anti-fibrotic therapy in IPF.