TLR4/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity

Abstract

Background: Cisplatin (Cp) is an antineoplastic agent with a dose-limiting nephrotoxicity. Cp-induced nephrotoxicity is characterized by the interplay of oxidative stress, inflammation, and apoptosis. Toll-4 receptors (TLR4) and NLPR3 inflammasome are pattern-recognition receptors responsible for activating inflammatory responses and are assigned to play a significant role with gasdermin (GSDMD) in acute kidney injuries. N-acetylcysteine (NAC) and chlorogenic acid (CGA) have documented nephroprotective effects by suppressing oxidative and inflammatory pathways. Therefore, the current study aimed to investigate the contribution of the upregulation of TLR4/inflammasomes/gasdermin signaling to Cp-induced nephrotoxicity and their modulation by NAC or CGA. Methods: A single injection of Cp (7 mg/kg, i.p.) was given to Wistar rats. Rats received either NAC (250 mg/kg, p.o.) and/or CGA (20 mg/kg, p.o.) one week before and after the Cp injection. Results: Cp-induced acute nephrotoxicity was evident by the increased blood urea nitrogen and serum creatinine and histopathological insults. Additionally, nephrotoxicity was associated with increased lipid peroxidation, reduced antioxidants, and elevated levels of inflammatory markers (NF-κB and TNF-α) in the kidney tissues. Moreover, Cp upregulated both TLR4/NLPR3/interleukin-1beta (IL-1β) and caspase-1/GSDMD-signaling pathways, accompanied by an increased Bax/BCL-2 ratio, indicating an inflammatory-mediated apoptosis. Both NAC and/or CGA significantly corrected these changes. Conclusions: This study emphasizes that inhibition of TLR4/NLPR3/IL-1β/GSDMD might be a novel mechanism of the nephroprotective effects of NAC or CGA against Cp-induced nephrotoxicity in rats.

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.…”

“…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.…”

Alcohol-induced liver injury in signalling pathways and curcumin's therapeutic potential

“…In traditional Asian medicinal practices, curcumin has been an extensively employed therapeutic agent attributed to its multifaceted health-promoting characteristics, such as antioxidative, anti-inflammatory, antimutagenic, antimicrobial, and anticancer activities [45] . Being a polyphenol, curcumin exhibits broad biological activity, as it can interact with several cellular signalling pathways, thereby substantiating its extensive health benefits [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] .…”

Protective effects of N-acetyl-l-cysteine against penconazole-triggered hepatorenal toxicity in adult rats

“…The cysteine derivative serves as a donor of L-cysteine, which is the building block and the limiting substrate for de novo synthesis of GSH ( 22 ). A large body of evidence has shown that NAC is potentially useful in treatment of various liver and kidney injuries ( 2 , 7 , 13 , 17 , 20 , 35 ).…”