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Trimetazidine Alleviates Bleomycin-Induced Pulmonary Fibrosis by Targeting the Long Noncoding RNA CBR3-AS1-Mediated miRNA-29 and Resistin-Like Molecule alpha 1: Deciphering a Novel Trifecta Role of LncRNA CBR3-AS1/miRNA-29/FIZZ1 Axis in Lung Fibrosis.
Alzahrani, Abdullah R; Mohamed, Doaa I; Abo Nahas, Hebatallah H; Alaa El-Din Aly El-Waseef, Dalia; Altamimi, Abdulmalik S; Youssef, Ibrahim H; Ibrahim, Ibrahim Abdel Aziz; Mohamed, Soha M Y; Sabry, Yasmine Gamal; Falemban, Alaa H; Elhawary, Nasser Attia; Bamagous, Ghazi A; Jaremko, Mariusz; Saied, Essa M.
Afiliação
  • Alzahrani AR; Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
  • Mohamed DI; Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
  • Abo Nahas HH; Zoology Department, Faculty of Science, Port Said University, Port Said, Egypt.
  • Alaa El-Din Aly El-Waseef D; Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
  • Altamimi AS; Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
  • Youssef IH; Department of Chest Diseases, Faculty of Medicine, Al-Azhar University, Cairo, Egypt.
  • Ibrahim IAA; Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
  • Mohamed SMY; Physiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
  • Sabry YG; Physiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
  • Falemban AH; Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
  • Elhawary NA; Department of Medical Genetics, College of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia.
  • Bamagous GA; Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
  • Jaremko M; Smart-Health Initiative and Red Sea Research Center, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
  • Saied EM; Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt.
Drug Des Devel Ther ; 18: 3959-3986, 2024.
Article em En | MEDLINE | ID: mdl-39252766
ABSTRACT

Introduction:

Pulmonary fibrosis (PF) and tissue remodeling can greatly impair pulmonary function and often lead to fatal outcomes.

Methodology:

In the present study, we explored a novel molecular interplay of long noncoding (Lnc) RNA CBR3-AS1/ miRNA-29/ FIZZ1 axis in moderating the inflammatory processes, immunological responses, and oxidative stress pathways in bleomycin (BLM)-induced lung fibrosis. Furthermore, we investigated the pharmacological potential of Trimetazidine (TMZ) in ameliorating lung fibrosis.

Results:

Our results revealed that the BLM-treated group exhibited a significant upregulation in the expression of epigenetic regulators, lncRNA CBR3-AS1 and FIZZ1, compared to the control group (P<0.0001), along with the downregulation of miRNA-29 expression. Furthermore, Correlation analysis showed a significant positive association between lnc CBR3-AS1 and FIZZ1 (R=0.7723, p<0.05) and a significant negative association between miRNA-29 and FIZZ1 (R=-0.7535, p<0.05), suggesting lnc CBR3-AS1 as an epigenetic regulator of FIZZ1 in lung fibrosis. BLM treatment significantly increased the expression of Notch, Jagged1, Smad3, TGFB1, and hydroxyproline. Interestingly, the administration of TMZ demonstrated the ability to attenuate the deterioration effects caused by BLM treatment, as indicated by biochemical and histological analyses. Our investigations revealed that the therapeutic potential of TMZ as an antifibrotic drug could be ascribed to its ability to directly target the epigenetic regulators lncRNA CBR3-AS1/ miRNA-29/ FIZZ1, which in turn resulted in the mitigation of lung fibrosis. Histological and immunohistochemical analyses further validated the potential antifibrotic effects of TMZ by mitigating the structural damage associated with fibrosis.

Discussion:

Taken together, our study showed for the first time the interplay between epigenetic lncRNAs CBR3-AS1 and miRNA-29 in lung fibrosis and demonstrated that FIZZ1 could be a downregulatory gene for lncRNA CBR3-AS1 and miRNA-29. Our key findings demonstrate that TMZ significantly reduces the expression of fibrotic, oxidative stress, immunomodulatory, and inflammatory markers, along with epigenetic regulators associated with lung fibrosis. This validates its potential as an effective antifibrotic agent by targeting the CBR3-AS1/miRNA-29/FIZZ1 axis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fibrose Pulmonar / Trimetazidina / Bleomicina / MicroRNAs / RNA Longo não Codificante Limite: Animals Idioma: En Revista: Drug Des Devel Ther Assunto da revista: FARMACOLOGIA / TERAPIA POR MEDICAMENTOS Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Arábia Saudita País de publicação: Nova Zelândia
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fibrose Pulmonar / Trimetazidina / Bleomicina / MicroRNAs / RNA Longo não Codificante Limite: Animals Idioma: En Revista: Drug Des Devel Ther Assunto da revista: FARMACOLOGIA / TERAPIA POR MEDICAMENTOS Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Arábia Saudita País de publicação: Nova Zelândia