Protocatechuic acid ameliorates lipopolysaccharide‐induced kidney damage in mice via downregulation of TLR‐4‐mediated IKBKB/NF‐κB and MAPK/Erk signaling pathways

Abstract

Acute kidney injury (AKI) is a very critical cause of death in the whole world. Lipopolysaccharide (LPS) induces kidney damage by activating various deleterious inflammatory and oxidative pathways. Protocatechuic acid, a natural phenolic compound, has shown to exert beneficial effects against oxidative and inflammatory responses.The study aimed to clarify the nephroprotective activity of protocatechuic acid in LPS-induced acute kidney damage in mice. Forty male Swiss mice were allocated in four groups as follows: normal control group; LPS (250 μg/kg, ip)-induced kidney injury group; LPS-injected mice treated with protocatechuic acid (15 mg/kg, po), and LPS-injected mice treated with protocatechuic acid (30 mg/kg, po). Significant tolllike receptor 4 (TLR-4)-mediated activation of IKBKB/NF-κB and MAPK/Erk/COX-2 inflammatory pathways has been observed in kidneys of mice treated with LPS. Oxidative stress was revealed by inhibition of total antioxidant capacity, catalase, nuclear factor erythroid 2-related factor 2 (Nrf2), and NAD(P)H quinone oxidoreductase (NQO1) enzyme along with increased nitric oxide level. In parallel, focal inflammatory effects were shown in between the tubules and glomeruli as well as in the perivascular dilated blood vessels at the cortex affecting the normal morphology of the kidney tissues of LPS-treated mice. However, treatment with protocatechuic acid reduced LPS-induced changes in the aforementioned parameters and restored normal histological features of the affected tissues. In conclusion, our study uncovered that protocatechuic acid has nephroprotective effects in mice with AKI through opposing different inflammatory and oxidative cascades.

Study on network pharmacology of Ginkgo biloba extract against ischaemic stroke mechanism and establishment of UPLC‐MS/MS methods for simultaneous determination of 19 main active components

“…The benefits of G. biloba and its preparations in the prevention and treatment of cardiovascular diseases mainly derive from the effective chemical components such as flavonoids and terpenoid lactones. In this study, through data mining and network pharmacology analysis of relevant literature, we found that the organic acid components (protocatechuic acid, caffeic acid, chlorogenic acid, and gallic acid), flavonoid components (quercetin‐3‐O‐glucoside, quercetin‐3‐O‐rutinoside, kaempferol‐3‐O‐rutinoside, kaempferol‐3‐O‐glucoside, isorhamnetin‐3‐O‐rutinoside, isorhamnetin‐3‐O‐glucoside, apigenin‐7‐O‐glucoside, and apigenin), and terpenoid lactones (bilobalide, ginkgolide A, ginkgolide B, ginkgolide C, and ginkgolide J) had different effects such as anti‐inflammatory and anti‐oxidative activities, protecting the nervous system, changing blood rheology, and so on 22–50 . These components may be the potential active substance basis of its anti‐IS effect, so they were included in the scope of analysis and investigation of the active components of GBE against IS.…”

“…Some studies have shown that ingredients such as caffeic acid, protocatechuic acid, gallic acid, bilobalide, and ginkgolide A can inhibit the TLR4/NF-κB signalling pathway, reduce the expression level of MAPK, and achieve anti-inflammatory effects. 23,25,29,31,33 Bilobalide, ginkgolide A, and so on can play an antiinflammatory role by regulating inflammation-related pathways and inhibiting the release of inflammatory factors. Quercetin-3-O-rutinoside, kaempferol-3-O-rutinoside, kaempferol-3-O-glucoside, and isorhamnetin-3-O-rutinoside can inhibit the PI3K-Akt, NF-κB, and other signalling pathways and reduce cardiovascular and cerebrovascular injuries.…”

“…From the C‐T‐P network analysis, it can be seen that among the 19 potential active ingredients that were initially were screened, caffeic acid, protocatechuic acid, gallic acid, bilobalide, ginkgolide A, quercetin‐3‐O‐rutinoside, kaempferol‐3‐O‐rutinoside, kaempferol‐3‐O‐glucoside, isorhamnetin‐3‐O‐rutinoside, and so on are the main active ingredients of GBE that contribute to its anti‐IS effect. Some studies have shown that ingredients such as caffeic acid, protocatechuic acid, gallic acid, bilobalide, and ginkgolide A can inhibit the TLR4/NF‐κB signalling pathway, reduce the expression level of MAPK, and achieve anti‐inflammatory effects 23,25,29,31,33 . Bilobalide, ginkgolide A, and so on can play an anti‐inflammatory role by regulating inflammation‐related pathways and inhibiting the release of inflammatory factors.…”

“…Quercetin‐3‐O‐rutinoside, kaempferol‐3‐O‐rutinoside, kaempferol‐3‐O‐glucoside, and isorhamnetin‐3‐O‐rutinoside can inhibit the PI3K‐Akt, NF‐κB, and other signalling pathways and reduce cardiovascular and cerebrovascular injuries 37–44 . The ingredients such as caffeic acid, protocatechuic acid, gallic acid, bilobalide, ginkgolide A, quercetin‐3‐O‐rutinoside, kaempferol‐3‐O‐rutinoside, kaempferol‐3‐O‐glucoside, and isorhamnetin‐3‐O‐rutinoside also have anti‐oxidative, free radical‐scavenging, and anti‐apoptotic effects 22–50 . Consequently, it was deduced that anti‐inflammatory, anti‐oxidative, anti‐apoptotic, and other activities are the main anti‐IS effects of GBE.…”

“…Based on literature data mining, flavonoid‐glycosides and terpenes in G. biloba are the main components of its pharmacological activities such as anti‐inflammatory, antioxidant, blood circulation‐improving, and platelet anti‐aggregatory activities 22–51 . Therefore, the above ingredients were selected for the study of the active ingredients of GBE against IS, as shown in Table 1.…”