Protective effects of heterophyllin B against bleomycin-induced pulmonary fibrosis in mice via AMPK activation

Shi, Wen; Hao, Jiatong; Wu, Yanliang; Liu, Chang; Shimizu, Kuniyoshi; Li, Renshi; Zhang, Chaofeng

doi:10.1016/j.ejphar.2022.174825

Cited by 13 publications

(9 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…EMT plays a prominent role in pulmonary fibrosis and AMPK was involved in EMT (Hwang et al, 2021; Shi et al, 2022). Hence, we further studied the effect of nitazoxanide and tizoxanide on EMT in MLE‐12 cells.…”

Section: Resultsmentioning

confidence: 99%

Anthelmintic nitazoxanide protects against experimental pulmonary fibrosis

Chen

Dong

et al. 2023

British J Pharmacology

View full text Add to dashboard Cite

Background and PurposeNitazoxanide is a therapeutic anthelmintic drug. Our previous studies found that nitazoxanide and its metabolite tizoxanide activated adenosine 5′‐monophosphate‐activated protein kinase (AMPK) and inhibited signal transducer and activator of transcription 3 (STAT3) signals. As AMPK activation and/or STAT3 inhibition are targets for treating pulmonary fibrosis, we hypothesized that nitazoxanide would be effective in experimental pulmonary fibrosis.Experimental ApproachThe mitochondrial oxygen consumption rate of cells was measured by using the high‐resolution respirometry system Oxygraph‐2K. The mitochondrial membrane potential of cells was evaluated by tetramethyl rhodamine methyl ester (TMRM) staining. The target protein levels were measured by using western blotting. The mice pulmonary fibrosis model was established through intratracheal instillation of bleomycin. The examination of the lung tissues changes were carried out using haematoxylin and eosin (H&E), and Masson staining.Key ResultsNitazoxanide and tizoxanide activated AMPK and inhibited STAT3 signalling in human lung fibroblast cells (MRC‐5 cells). Nitazoxanide and tizoxanide inhibited transforming growth factor‐β1 (TGF‐β1)‐induced proliferation and migration of MRC‐5 cells, collagen‐I and α‐smooth muscle cell actin (α‐SMA) expression, and collagen‐I secretion from MRC‐5 cells. Nitazoxanide and tizoxanide inhibited epithelial–mesenchymal transition (EMT) and inhibited TGF‐β1‐induced Smad2/3 activation in mouse lung epithelial cells (MLE‐12 cells). Oral administration of nitazoxanide reduced the bleomycin‐induced mice pulmonary fibrosis and, in the established bleomycin‐induced mice, pulmonary fibrosis. Delayed nitazoxanide treatment attenuated the fibrosis progression.Conclusions and ImplicationsNitazoxanide improves the bleomycin‐induced pulmonary fibrosis in mice, suggesting a potential application of nitazoxanide for pulmonary fibrosis treatment in the clinic.

show abstract

Section: Resultsmentioning

confidence: 99%

Anthelmintic nitazoxanide protects against experimental pulmonary fibrosis

Chen

Dong

et al. 2023

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…The role of CC as an activator or inhibitor of PI3K-AKT-mTOR-NFκB pathways is contextual not only disease-specific but are also model system-specific with substantial technical variabilities in the studies reporting such role [ 65 , 72 , 73 , 74 ]. Furthermore, known chemical modifications and/or homologs of CC were designed to enhance its effects on BMP/BMP receptors as an anti-fibrotic agent in pulmonary fibrosis and diabetic nephropathy [ 75 , 76 , 77 ].…”

Section: Discussionmentioning

confidence: 99%

Compound C Inhibits Ovarian Cancer Progression via PI3K-AKT-mTOR-NFκB Pathway

Ghoneum

Gonzalez

Afify

et al. 2022

Cancers

View full text Add to dashboard Cite

Epithelial Ovarian cancer (OvCa) is the leading cause of death from gynecologic malignancies in the United States, with most patients diagnosed at late stages. High-grade serous cancer (HGSC) is the most common and lethal subtype. Despite aggressive surgical debulking and chemotherapy, recurrence of chemo-resistant disease occurs in ~80% of patients. Thus, developing therapeutics that not only targets OvCa cell survival, but also target their interactions within their unique peritoneal tumor microenvironment (TME) is warranted. Herein, we report therapeutic efficacy of compound C (also known as dorsomorphin) with a novel mechanism of action in OvCa. We found that CC not only inhibited OvCa growth and invasiveness, but also blunted their reciprocal crosstalk with macrophages, and mesothelial cells. Mechanistic studies indicated that compound C exerts its effects on OvCa cells through inhibition of PI3K-AKT-NFκB pathways, whereas in macrophages and mesothelial cells, CC inhibited cancer-cell-induced canonical NFκB activation. We further validated the specificity of the PI3K-AKT-NFκB as targets of compound C by overexpression of constitutively active subunits as well as computational modeling. In addition, real-time monitoring of OvCa cellular bioenergetics revealed that compound C inhibits ATP production, mitochondrial respiration, and non-mitochondrial oxygen consumption. Importantly, compound C significantly decreased tumor burden of OvCa xenografts in nude mice and increased their sensitivity to cisplatin-treatment. Moreover, compound C re-sensitized patient-derived resistant cells to cisplatin. Together, our findings highlight compound C as a potent multi-faceted therapeutic in OvCa.

show abstract

“…215 AMPK activation was also involved in the Heterophyllin B (a natural product)-mediated inhibition of TGF-β1-induced EMT in MLE-12 cells, inhibition of TGF-β1-induced fibroblasts activation and ECM accumulation in primary mouse lung fibroblasts, and inhibition of bleomycin-induced PF and abnormal energy metabolism in mice. 216…”

Section: The Activation Of Ampk Can Inhibit Nox4 Smad2/3 and Lox2 Pat...mentioning

confidence: 99%

“…In bleomycin‐induced PF mice, Wedelolactone attenuated the PF by activation of the AMPK, inhibited pro‐inflammatory cytokines (IL‐1β, TNF‐α, and TGF‐β1) release, and decreased the p‐Smad2/3 level and protein levels of pro‐fibrotic factors (a‐SMA and collagen I) in lung tissues 215 . AMPK activation was also involved in the Heterophyllin B (a natural product)‐mediated inhibition of TGF‐β1‐induced EMT in MLE‐12 cells, inhibition of TGF‐β1‐induced fibroblasts activation and ECM accumulation in primary mouse lung fibroblasts, and inhibition of bleomycin‐induced PF and abnormal energy metabolism in mice 216 …”

Section: Targeting Ampk Pathways In Pfmentioning

confidence: 99%

Preclinical evidence using synthetic compounds and natural products indicates that AMPK represents a potential pharmacological target for the therapy of pulmonary diseases

Yang,

Rubin,

et al. 2024

Medicinal Research Reviews

View full text Add to dashboard Cite

Adenosine 5′‐monophosphate (AMP)‐activated protein kinase (AMPK) is a highly conserved eukaryotic enzyme discovered as a key regulator of cellular energy homeostasis, with anti‐inflammation, antioxidative stress, anticancer, and antifibrosis beneficial effects. AMPK is dysregulated in human pulmonary diseases such as acute lung injury, nonsmall cell lung cancer, pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma. This review provides an overview of the beneficial role of natural, synthetic, and Chinese traditional medicines AMPK modulators in pulmonary diseases, and highlights the role of the AMPK signaling pathway in the lung, emphasizing the importance of finding lead compounds and drugs that can target and modulate AMPK to treat the lung diseases.

show abstract

Protective effects of heterophyllin B against bleomycin-induced pulmonary fibrosis in mice via AMPK activation

Cited by 13 publications

References 35 publications

Anthelmintic nitazoxanide protects against experimental pulmonary fibrosis

Anthelmintic nitazoxanide protects against experimental pulmonary fibrosis

Compound C Inhibits Ovarian Cancer Progression via PI3K-AKT-mTOR-NFκB Pathway

Preclinical evidence using synthetic compounds and natural products indicates that AMPK represents a potential pharmacological target for the therapy of pulmonary diseases

Contact Info

Product

Resources

About