SIRT1/Nrf2/NF-κB Signaling Mediates Anti-Inflammatory and Anti-Apoptotic Activities of Oleanolic Acid in a Mouse Model of Acute Hepatorenal Damage

Abstract

Background and objectives: Oleanolic acid (OA) is a penta-cyclic triterpene with diverse bioactivities such as anticarcinogenic, antiviral, antimicrobial, hepatoprotective, anti-atherosclerotic, hypolipidemic, and gastroprotective. However, its effects on hepatorenal damage remain unclear. The protective activity of OA, separated from Viscum schimperi (Loranthaceae), against TAA (thioacetamide)-produced acute hepatic and renal damage was explored. Materials and Methods: Mice were treated with OA for 7 days before TAA (200 mg/kg, i.p.). Serum indices of hepatorenal injury, pathological lesions, molecular biological indexes, and inflammatory/apoptotic genes were estimated. Results: The tissues of both organs were greatly affected by the TAA injection. That was evident through increased serum markers of hepato-renal injury as well as remarkable histopathological lesions. TAA-induced injury was associated with oxidative and inflammatory responses in both organs as there was an elevation of oxidative stress parameters (4-HNE (4-hydroxy-nonenal), MDA (malondialdehyde), NOx (nitric oxide)), decline of antioxidants (reduced glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (TAC)), and an increase in the gene expression/level of inflammatory mediators (interleukins (1β&6)). The inflammatory response was linked to a significant activation of NF-κB (nuclear-factor kappa-B)/TNF-α (tumor-necrosis factor-alpha) signaling. The inflammatory response in both organs was accompanied by apoptotic changes, including a rise in the gene expression and level of apoptotic parameters (caspase-3 and Bax) along with a decline in Bcl-2 (anti-apoptotic parameter) gene expression and level. These pathogenic events were found to be closely related to the suppression of the antioxidant signaling pathway, Nrf2 (nuclear-factor erythroid 2–related factor-2)/SIRT1 (sirtuin-1)/HO-1 (heme-oxygenase 1). On the other hand, OA significantly ameliorated TAA-induced injury in both organs. On the other hand, OA counterpoised the inflammatory response as it ameliorated NF-κB/TNF-α signaling and cytokine release. OA enhanced Nrf2/SIRT1/HO-1 signaling and counteracted apoptotic damage. Conclusions: OA showed anti-inflammation and antiapoptotic capacities that effectively suppressed TAA-induced acute hepatorenal damage.

Sloanea chocoana and S. pittieriana (Elaeocarpaceae): Chemical and Biological Studies of Ethanolic Extracts and Skincare Properties

“…Alpha-amyrin is a natural product derived from ursane with antibiofilm properties against methicillin-resistant and vancomycin intermediate-resistant Staphylococcus aureus [58]. Oleanolic acid exerts anti-inflammatory, anticarcinogenic, antimicrobial, antiatherosclerotic, hypolipidemic, hepatoprotective, and gastroprotective properties [59]. Glycerol is used in skin care products because acts as an emollient and prevents skin lesions [60], while glyceryl glycoside is used as an emollient in formulations for the treatment of psoriasis [61].…”

Oleanolic acid and its analogues: promising therapeutics for kidney disease

“…T helper cell (Th17) plays an important role in the pathogenesis of lupus nephritis [108]. Research has demonstrated that, in mice with pristane-induced lupus nephritis, treatment with OA reduces dsDNA levels, IL-17A expression and interferon γ (IFN-γ), and alleviate (↑) and (↓) signs show positive and negative effects of oleanolic acid and its analogues on its target molecules, respectively In vivo CP-induced nephrotoxicity in Wistar rats UA (5, 10 mg/kg) GSH↑, SOD↑, CAT↑, MDA↓, IL-1β↓, IL-6↓, TNF-α↓, Caspase-3↓, Caspase-9↓ [141] In vivo STZ-induced DN in SD rats UA (50 mg/kg) TNF-α↓, IL-1β↓, IL-6↓, SOD↑, MDA↓, GSH↑, CAT↑, NO↓, FN↓, E-cad↑, MMP-9↑,TIMP-1↓, α-SMA↓, TGF-β1↓,SMA3↓, SMA7↓, P38↓ [167] In vivo RIRI in SD rats OA (50 mg/kg) PI3K↓, p-AKT↓, PDK1↑, p27↑, TRAP1↑, CypD↓ [168] In vitro HK-2 cells stimulated with OTA OA (2 μM) Bax↓, Bcl-2↑, Cyt-C↓, Caspase-9↓,Caspase-3↓, GRP78↓, CHOP↓ [169] In vivo STZ-induced DN in SD rats OA (50, 100 mg/kg) nephrin↑, CD68↓, COL-IV↓, p-AMPK/ AMPK↑, PGC-1α↑, TLR4↓, NF-κB↓, TGF-β1↓ [103] In vivo STZ-induced DN in SD rats OA (50 mg/kg) Caspase-3↓, Bax↓, CD31, E-cadherin↑, α-SMA↓, Vimentin↓, TGF-β1↓, p-P38↓, FGFR1↑, SIRT3↑, DPP-4↓ [170] In vivo UUO in SD rats UA (40 mg/kg) TGF-β1↓, Keap1↓, Nrf2↑, HO-1↑, 8-oxo-dG↓, Caspase-3↓, Caspase-8↓ [171] In vivo TAA-induced AKI in BALB/c mice OA (45, 90 mg/kg) MDA ↓, NOx ↓, GSH↑, SOD↑, NF-κB↓, TNF-α↓, Bax↓, Bcl2 ↑, Caspase-3↓ Nrf2↑, HO-1↑ [143] In vitro HK-2 cells stimulated with OTA UA (4 μM) Lonp1↑, Sig-1R↑, GRP78↓, p-ERK↓, p-eIF2α↓, CHOP↓, IRE1α↓, Bcl2↑, Bax↓ [142] renal injury by decreasing the deposition of IgG and IgM in the glomeruli [20]. Further studies have revealed that OA inhibits the differentiation of Th17 cells in vitro.…”

“…Treatment of HK-2 cells with ochratoxin A (OTA) enhances the expression of the proapoptotic gene Bax and inhibits the expression of the anti-apoptotic gene Bcl-2, leading to cell apoptosis, however, pretreatment with UA can alleviate this situation [142]. Furthermore, in a mouse model of liver and kidney injury induced by thioacetamide (TAA), OA can reduce the expression of Bax and caspase-3, increase the expression of Bcl-2, and alleviate liver and kidney damage [143]. Thus, the OA-related compounds may thus alleviate kidney injury through the anti-apoptotic pathway.…”

Sirtuins as Players in the Signal Transduction of Citrus Flavonoids

“…This mechanism permits the attachment of ADP-ribose with the acetylic moiety of the substrate, releasing nicotinamide (NAM) and 2′-O-acetyl-adenosine diphosphate-ribose [74]. Several studies reported the involvement of SIRT1 in the pathogenesis, development, and treatment of different illnesses, including inflammation [75], cancer [74], and neurological and metabolic diseases [76][77][78]. The modulation of SIRT1 is one of the multiple mechanisms by which Citrus flavonoids exert their biological properties.…”