The emerging role of the piRNA/PIWI complex in respiratory tract diseases.

PIWI-interacting RNA (piRNA) is a class of recently discovered small non-coding RNA molecules with a length of 18-33 nt that interacts with the PIWI protein to form the piRNA/PIWI complex. The PIWI family is a subfamily of Argonaute (AGO) proteins that also contain the AGO family which bind to microRNA (miRNA). Recently studies indicate that piRNAs are not specific to in the mammalian germline, they are also expressed in a tissue-specific manner in a variety of human tissues and participated in various of diseases, such as cardiovascular, neurological, and urinary tract diseases, and are especially prevalent in malignant tumors in these systems. However, the functions and abnormal expression of piRNAs in respiratory tract diseases and their underlying mechanisms remain incompletely understood. In this review, we discuss current studies summarizing the biogenetic processes, functions, and emerging roles of piRNAs in respiratory tract diseases, providing a reference value for future piRNA research.

Dihydroartemisinin Attenuates Hypoxia-Induced Pulmonary Hypertension Through the ELAVL2/miR-503/PI3K/AKT Axis.

ABSTRACT: Dihydroartemisinin (DHA) is an active form of artemisinin extracted from the traditional Chinese medicine Artemisia annua , which is used to treat malaria. Previous studies have shown that DHA has a therapeutic effect on pulmonary hypertension (PH), but its specific mechanism has not been fully elucidated. In this study, a hypoxia-induced PH mouse model was established and DHA was administered as a therapeutic intervention. We measured hemodynamics and right ventricular hypertrophy and observed hematoxylin and eosin staining of lung tissue sections, proving the therapeutic effect of DHA on PH. Furthermore, cell counting kit-8 and 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay kit were performed to examine cell proliferation of pulmonary artery smooth muscle cells cultured in hypoxia or in normoxia. Transwell migration chamber assay was performed to examine cell migration of the same cell model. Consistent with the therapeutic effect in vivo, DHA inhibited hypoxia-induced cell proliferation and migration. Through high-throughput sequencing of mouse lung tissue, we screened embryonic lethal abnormal vision-like 2 (ELAVL2) as a key RNA binding protein in PH. Mechanistically, DHA inhibited the proliferation and migration of pulmonary artery smooth muscle cells by promoting the expression of ELAVL2 and regulating the miR-503/PI3K/AKT pathway. The binding relationship between ELAVL2 and pre-miR-503 was verified by RNA binding protein immunoprecipitation assay. In conclusion, we first propose that DHA alleviates PH through the ELAVL2/miR-503/PI3K/AKT pathway, which may provide a basis for new therapeutic strategies of PH.

Parthenolide attenuates hypoxia-induced pulmonary hypertension through inhibiting STAT3 signaling.

BACKGROUND: Pulmonary hypertension (PH) is a chronic lung disease characterized by the progressive pulmonary vascular remodeling with increased pulmonary arterial pressure and right ventricular failure. Pulmonary vascular remodeling involves the proliferation, migration, and resistance to apoptosis of pulmonary artery smooth cells (PASMCs). Parthenolide (PTN) is a bioactive compound derived from a traditional medical plant feverfew (Tanacetum parthenium), and it has been studied for treatment of pulmonary fibrosis, lung cancer, and other related ailments. However, the function of PTN in the treatment of PH has not been studied. PURPOSE: This study aimed to evaluate the anti-proliferation and pro-apoptosis effects of PTN on PH and investigate its potential mechanisms. METHODS: An in vivo hypoxia-induced pulmonary hypertension (HPH) model was established by maintaining male rats in a hypoxia chamber (10% O2) for 3 weeks, and PTN was intraperitoneally administered at the dose of 10 or 30 mg/kg. We assessed the impact of PTN on mean pulmonary arterial pressure (mPAP), pulmonary vascular remodeling, and right ventricular hypertrophy. In vitro, we evaluated hypoxia-induced cellular proliferation, migration, and apoptosis of rat PASMCs. Proteins related to the STAT3 signaling axis were analyzed by western blotting and immunofluorescence assays. Recovery experiments were performed using the STAT3 activator, colivelin TFA. RESULTS: PTN significantly alleviated the symptoms of HPH rats by attenuating pulmonary arterial remodeling. It also prevented the proliferation and migration of PASMCs. PTN also induced the apoptosis of PASMCs. PTN could directly interact with STAT3 and markedly inhibited STAT3 phosphorylation and nuclear translocation. In vitro, and in vivo experiments demonstrated that overexpression of STAT3 partially suppressed the effect of PTN. CONCLUSION: Our study indicated that PTN alleviated hypoxia-induced pulmonary hypertension in rats by suppressing STAT3 activity.

Roles of Embryonic Lethal Abnormal Vision-Like RNA Binding Proteins in Cancer and Beyond.

Embryonic lethal abnormal vision-like (ELAVL) proteins are RNA binding proteins that were originally discovered as indispensable regulators of the development and functioning of the nervous system. Subsequent studies have shown that ELAVL proteins not only exist in the nervous system, but also have regulatory effects in other tissues. ELAVL proteins have attracted attention as potential therapeutic targets because they stabilize multiple mRNAs by binding within the 3'-untranslated region and thus promote the development of tumors, including hepatocellular carcinoma, pancreatic cancer, ovarian cancer, breast cancer, colorectal carcinoma and lung cancer. Previous studies have focused on these important relationships with downstream mRNAs, but emerging studies suggest that ELAVL proteins also interact with non-coding RNAs. In this review, we will summarize the relationship of the ELAVL protein family with mRNA and non-coding RNA and the roles of ELAVL protein family members in a variety of physiological and pathological processes.

Necroptosis-related lncRNAs: Combination of bulk and single-cell sequencing reveals immune landscape alteration and a novel prognosis stratification approach in lung adenocarcinoma.

Necroptosis, which is recently recognized as a form of programmed cell death, plays a critical role in cancer biology, including tumorigenesis and cancer immunology. It was recognized not only to defend against tumor progression by suppressing adaptive immune responses but also to promote tumorigenesis and cancer metastasis after recruiting inflammatory responses. Thus the crucial role of necrosis in tumorigenesis has attracted increasing attention. Due to the heterogeneity of the tumor immune microenvironment (TIME) in lung adenocarcinoma (LUAD), the prognosis and the response to immunotherapy vary distinctly across patients, underscoring the need for a stratification algorithm for clinical practice. Although previous studies have formulated the crucial role of lncRNAs in tumorigenicity, the relationship between necroptosis-related lncRNAs, TIME, and the prognosis of patients with LUAD was still elusive. In the current study, a robust and novel prognostic stratification model based on Necroptosis-related LncRNA Risk Scoring (NecroLRS) and clinicopathological parameters was constructed and systemically validated in both internal and external validation cohorts. The expression profile of four key lncRNAs was further validated by qRT-PCR in 4 human LUAD cell lines. And a novel immune landscape alteration was observed between NecroLRS-High and -Low patients. To further elucidate the mechanism of necroptosis in the prognosis of LUAD from a single-cell perspective, a novel stratification algorithm based on K-means clustering was introduced to extract both malignant and NecroLRS-High subsets from epithelial cells. And the necroptosis-related immune infiltration landscape and developmental trajectory were investigated respectively. Critically, NecroLRS was found to be positively correlated with neutrophil enrichment, inflammatory immune response, and malignant phenotypes of LUAD. In addition, novel ligand-receptor pairs between NecroLRS-High cells and other immunocytes were investigated and optimal therapeutic compounds were screened to provide potential targets for future studies. Taken together, our findings reveal emerging mechanisms of necroptosis-induced immune microenvironment alteration on the deteriorative prognosis and may contribute to improved prognosis and individualized precision therapy for patients with LUAD.

Dihydroartemisinin Attenuates Hypoxic Pulmonary Hypertension via the Downregulation of miR-335 Targeting Vangl2.

Dihydroartemisinin (DHA) is a traditional antimalarial drug. DHA plays a crucial role in preventing pulmonary hypertension (PH); however, its regulatory function on microRNAs (miRNAs) in PH remains unclear. This study aimed to investigate whether DHA exerts its protective functions by regulating miR-335 in PH. Hypoxia-induced PH models were induced both in vitro and in vivo. Mice were treated with various concentrations of DHA, and pulmonary arterial smooth muscle cells (PASMCs) were treated with DHA, miR-335 inhibitor, miR-335 mimic, or Van Gogh-like 2 (Vangl2) plasmid. The expression of miR-335 and Vangl2, pulmonary arterial remodeling index; right ventricular hypertrophy index; and proliferation and migration indexes were measured. DHA improved pulmonary vascular remodeling and alleviated PH in vivo. miRNA sequencing and real-time PCR results further show that the increase in hypoxia-induced miR-335 was avoided by DHA administration, and miR-335 increased the hypoxia-induced PASMC proliferation and migration. MiRNA databases and dual-luciferase reporter assay show that miR-335 directly targets Vangl2, and Vangl2 decreased the hypoxia-induced PASMC proliferation and migration. The miR-335 inhibitor failed to inhibit hypoxia-induced proliferation and migration upregulation in Vangl2 knockdown PASMCs, and the effect of DHA can be blocked by miR-335 upregulation. In hypoxic PH, MiR-335 is increased, whereas Vangl2 is decreased. MiR-335 can significantly promote the hypoxia-induced proliferation and migration of PASMCs by targeting the Vangl2 gene. DHA effectively reverses the hypoxia-induced upregulation of miR-335 expression, avoiding the miR-335-mediated downregulation of Vangl2 and thereby promoting the expression of Vangl2 to prevent PH.