Kaempferol prevents angiogenesis of rat intestinal microvascular endothelial cells induced by LPS and TNF-α via inhibiting VEGF/Akt/p38 signaling pathways and maintaining gut-vascular barrier integrity

Yu, Ruyang; Zhong, Jia; Zhou, Qilyu; Ren, Wei; Liu, Zhongjie; Bian, Yifei

doi:10.1016/j.cbi.2022.110135

Cited by 12 publications

(16 citation statements)

References 48 publications

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“…Among them, quercetin can alleviate renal tubular cell death and inflammation in acute kidney injury by inhibiting ferroptosis [ 32 ]. Kaempferol is considered to have anti-inflammatory and anti-oxidation effects [ 33 ], which can inhibit ferroptosis of hepatocytes by activating Nrf2 pathway [ 34 ]. Isorhamnetin has anti-inflammatory and anti-cancer effects, and can also reduce MDA levels in the prefrontal cortex and hippocampus, thereby preventing oxidation [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

SKP alleviates the ferroptosis in diabetic kidney disease through suppression of HIF-1α/HO-1 pathway based on network pharmacology analysis and experimental validation

Yan,

Yuan,

Chen

et al. 2024

Chin Med

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Background Diabetic kidney disease (DKD) represents a microvascular complication of diabetes mellitus. Shenkang Pills (SKP), a traditional Chinese medicine formula, has been widely used in the treatment of DKD and has obvious antioxidant effect. Ferroptosis, a novel mode of cell death due to iron overload, has been shown to be associated with DKD. Nevertheless, the precise effects and underlying mechanisms of SKP on ferroptosis in diabetic kidney disease remain unclear. Methods The active components of SKP were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Protein–protein interaction (PPI) network and Herb-ingredient-targets gene network were constructed using Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted utilizing the Metascape system database. Additionally, an in vivo model of DKD induced by Streptozotocin (STZ) was established to further investigate and validate the possible mechanisms underlying the effectiveness of SKP. Results We retrieved 56 compounds and identified 223 targets of SKP through the TCMSP database. Key targets were ascertained using PPI network analysis. By constructing a Herb-Ingredient-Targets gene network, we isolated the primary active components in SKP that potentially counteract ferroptosis in diabetic kidney disease. KEGG pathway enrichment analysis suggested that SKP has the potential to alleviate ferroptosis through HIF signaling pathway, thereby mitigating renal injury in DKD. In animal experiments, fasting blood glucose, 24 h urine protein, urea nitrogen and serum creatine were measured. The results showed that SKP could improve DKD. Results from animal experiments were also confirmed the efficacy of SKP in alleviating renal fibrosis, oxidative stress and ferroptosis in DKD mice. These effects were accompanied by the significant reductions in renal tissue expression of HIF-1α and HO-1 proteins. The mRNA and immunohistochemistry results were the same as above. Conclusions SKP potentially mitigating renal injury in DKD by subduing ferroptosis through the intricacies of the HIF-1α/HO-1 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

SKP alleviates the ferroptosis in diabetic kidney disease through suppression of HIF-1α/HO-1 pathway based on network pharmacology analysis and experimental validation

Yan,

Yuan,

Chen

et al. 2024

Chin Med

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“…kaempferol significantly reduced the expression of TNF to suppress the inflammatory response (Palacz-Wrobel et al, 2017). Kaempferol also inhibits angiogenesis by downregulating TNF-a expression (Yu et al, 2022). Inflammation and proliferation of blood vessels are important causes of PDR.…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology and molecular docking to explore Siraitia grosvenorii’s potential mechanism in preventing and treating proliferative diabetic retinopathy

Zhou

Shu²,

Sarsaiya³

et al. 2022

Front. Drug. Discov.

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Although Siraitia grosvenorii (abbreviated as S.g.) is frequently used to prevent and cure diabetes problems, the precise mechanism underlying its ability to do so remains unknown. Through network pharmacology and molecular docking techniques, we studied the early molecular mechanisms of S.g in the treating of proliferative diabetic retinopathy (PDR) in this study. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen the active compounds and related targets of S.g. Oral bioavailability (OB) 30% and drug likeness (DL) 0.18 were used as screening criteria. The active compounds without knowledge of a probable target were excluded. The Uniprot database included converted symbols for the associated targets. GEO2R was used to explore several genes related to PDR. Using jvenn web service to intersect targets of S.g and PDR. The Xiantao Academic Online website was used to examine the expression patterns of intersect targets in PDR samples. The STRING database was used to create a protein-protein interaction (PPI) network of intersecting targets. Cytoscape software was used to show the PPI network, MCODE software was used to evaluate the network’s core proteins, and CytoHubba software was used to extract the important networks of the top three targets. Omicshare platform carried a functional analysis using the Gene Ontology (GO) and pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Pymol, AutoDock Vina software, Schrödinger Software were used to conduct molecular docking experiments or pockets search on the top three targets. The results showed that 85 targets were matched to six active compounds of S.g. 18 intersect targets were found. Seven DEGs were up-regulated and eleven genes were down-regulated when these targets were divided into two groups. TNF, PTGS2, and CASP3 were the main targets, according to the PPI network. The intersect targets were mostly related to angiogenesis, cell proliferation, oxidative stress, inflammatory response, and metabolism. It was discovered that the core targets TNF, PTGS2, and CASP3 had various levels of affinity for their respective compounds. Interestingly, multiple good drug-forming pockets for CASP3 and PTGS2 targets were identified through Schrödinger software. In particular, six compounds bind to the top three core targets to inhibit IL-17 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, Pathways in cancer and 14 other signaling pathways to inhibit inflammation, apoptosis, oxidative stress, arachidonic acid metabolism, and angiogenesis to prevent and treat PDR. The study’s findings, which served as a guide for the widespread use of S.g in PDR clinical practise, included multi-substances and targets of S.g to prevent and cure PDR.

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“…As for the mechanism of action, the administration of kaempferol inhibited several pathways, such as the decreased protein levels of TLR4, p-NF-κB p65/NF-κB p65, p-I-κB/I-κB, p-STAT/STAT in the cells [ 40 ]. In another study, it was found that treating rat intestinal microvascular endothelial cells with a concentration of 100 μmol/L kaempferol for 24 h resulted in a reduction of cell inflammation when exposed to LPS and TNF-α co-challenge [ 41 ]. This treatment led to decreased levels of IL-6 in the culture supernatant, as well as down-regulation of the protein level of p-p65/p65, and the mRNA levels of IL-6 and RELA/p65 .…”

Section: Regulation Of Intestinal Health By Kaempferolmentioning

confidence: 99%

“…This treatment led to decreased levels of IL-6 in the culture supernatant, as well as down-regulation of the protein level of p-p65/p65, and the mRNA levels of IL-6 and RELA/p65 . The treatment also led to an increase in the levels of IL-10 in the culture supernatant [ 41 ]. More interestingly, according to the findings of a previous study, the exposure of Caco-2 cells to kaempferol at a concentration of 20 μmol/L for a duration of 24 h resulted in the suppression of immunoglobulin E-mediated allergic inflammation.…”

Section: Regulation Of Intestinal Health By Kaempferolmentioning

confidence: 99%

“…The impairment of the intestinal barrier function has been documented in diquat [ 32 ], indomethacin [ 31 ], LPS [ 49 ], LPS and TNF-α [ 41 ], and deoxynivalenol [ 50 , 51 ]-induced models of intestinal cells. It has been reported that kaempferol exhibits the ability to alleviate the intestinal barrier dysfunction caused by these stimuli.…”

Section: Regulation Of Intestinal Health By Kaempferolmentioning

confidence: 99%

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A Critical Review of Kaempferol in Intestinal Health and Diseases

Chen,

Zhong,

Huang

et al. 2023

Antioxidants

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Kaempferol, a secondary metabolite found in plants, is a naturally occurring flavonoid displaying significant potential in various biological activities. The chemical structure of kaempferol is distinguished by the presence of phenyl rings and four hydroxyl substituents, which make it an exceptional radical scavenger. Most recently, an increasing number of studies have demonstrated the significance of kaempferol in the regulation of intestinal function and the mitigation of intestinal inflammation. The focus of the review will primarily be on its impact in terms of antioxidant properties, inflammation, maintenance of intestinal barrier function, and its potential in the treatment of colorectal cancer and obesity. Future research endeavors should additionally give priority to investigating the specific dosage and duration of kaempferol administration for different pathological conditions, while simultaneously conducting deeper investigations into the comprehensible mechanisms of action related to the regulation of aryl hydrocarbon receptor (AhR). This review intends to present novel evidence supporting the utilization of kaempferol in the regulation of gut health and the management of associated diseases.

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Kaempferol prevents angiogenesis of rat intestinal microvascular endothelial cells induced by LPS and TNF-α via inhibiting VEGF/Akt/p38 signaling pathways and maintaining gut-vascular barrier integrity

Cited by 12 publications

References 48 publications

SKP alleviates the ferroptosis in diabetic kidney disease through suppression of HIF-1α/HO-1 pathway based on network pharmacology analysis and experimental validation

SKP alleviates the ferroptosis in diabetic kidney disease through suppression of HIF-1α/HO-1 pathway based on network pharmacology analysis and experimental validation

Network pharmacology and molecular docking to explore Siraitia grosvenorii’s potential mechanism in preventing and treating proliferative diabetic retinopathy

A Critical Review of Kaempferol in Intestinal Health and Diseases

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