Distinct effects of different doses of kaempferol on D‑GalN/LPS‑induced ALF depend on the autophagy pathway

Mol Med Rep. 2021 Sep;24(3):682. doi: 10.3892/mmr.2021.12321. Epub 2021 Jul 28.

Abstract

Kaempferol, a flavonoid compound, has various biological functions, such as anti‑inflammatory and antitumor activities. Acute liver failure (ALF) is a lethal clinical syndrome that occurs due to severe damage of the liver function. In the present study, the mechanisms underlying the therapeutic effects of kaempferol in ALF were evaluated. An ALF mouse model was established using D‑galactosamine (D‑GalN; 700 mg/kg)/lipopolysaccharide (LPS; 10 µg/kg). A total of 2 h before the administration of D‑GalN/LPS, mice were pretreated with different doses of kaempferol (2.5, 5, 10, 20 and 40 mg/kg), and 6 h after injection of D‑GalN/LPS, mice were euthanized. The survival rate, liver function and levels of inflammatory cytokines were assessed. The results demonstrated that kaempferol pretreatment protected hepatocytes from ALF induced by D‑GalN/LPS via regulation of the autophagy pathway, both in vivo and in vitro. Pretreatment with a high dose of kaempferol significantly decreased the survival rates and increased severe liver damage; however, pretreatment with a low dose of kaempferol had the opposite effect. Furthermore, pretreatment with a high dose of kaempferol enhanced the levels of proinflammatory cytokines [TNF‑α, IL‑6, IL‑12p40, IL‑1β, C‑X‑C motif chemokine ligand (CXCL)‑2, CXCL‑10] and markers of the MAPK signaling pathway [phosphorylated (p)‑JNK, p‑ERK, p‑p38], whereas pretreatment with a low dose of kaempferol had the opposite effect. Pretreatment with a high dose of kaempferol decreased autophagy, whereas pretreatment with a low dose of kaempferol increased autophagy in vivo and in vitro. It was also shown that pretreatment with 3‑methyadenine or autophagy related 7 small interfering RNA, to inhibit autophagy, partially abrogated the hepatoprotective effects of pretreatment with 5 mg/kg kaempferol in the ALF mouse model. These results demonstrate that the effects of different doses of kaempferol on D‑GalN/LPS‑induced ALF varies based on the dose, and that kaempferol exerted its effects via regulation of the autophagy pathway.

Keywords: D‑galactosamine/lipopolysaccharide; acute liver failure; autophagy; kaempferol; liver inflammation.

MeSH terms

  • Animals
  • Autophagy / drug effects*
  • Autophagy-Related Protein 7
  • Cytokines / metabolism
  • Disease Models, Animal
  • Hepatocytes / metabolism
  • Inflammation / pathology
  • Kaempferols / pharmacology*
  • Lipopolysaccharides / adverse effects*
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Liver Failure, Acute / chemically induced
  • Liver Failure, Acute / drug therapy*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Signal Transduction

Substances

  • Atg7 protein, mouse
  • Cytokines
  • Kaempferols
  • Lipopolysaccharides
  • kaempferol
  • Autophagy-Related Protein 7

Grants and funding

This study was supported by the National Natural Science Foundation of China (grant nos. 81770611 and 82002243); the Demonstrating Application and Research of Clinical Diagnosis and Treatment Technology in Beijing (grant nos. Z191100006619096 and Z191100006619097); Key Projects of the Beijing Municipal Education Commission's Science and Technology Plan (grant no. KZ202010025035); Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (grant no. XMLX201830); Key Medical Major of Beijing Sailing Plan (grant no. ZYLX201819); the National Science and Technology Key Project on ‘Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Prevention and Treatment’ (grant nos. 2018ZX10301407-005-002 and 2018ZX10302205-004-004); the Beijing Talents foundation (grant no. 2018000021469G289); Beijing Hospitals Authority Youth Programme (grant no. QML20201702); the Scientific Research Project of Beijing Youan Hospital, Capital Medical University (grant no. YNKTQN20180202); and the Key Public Relations Project of Capital Health Development Scientific Research Project (grant nos. SF2020-1-1151 and SF2021-1G-2181).