Chung HS, et al. J Korean Med Sci. 2020 Mar;35(19):e189. https://doi.org/10.3346/jkms.2020.35.e189

Septic acute kidney injury (AKI) is an important medical problem worldwide, but current treatments are limited. During sepsis, lipopolysaccharide (LPS) activates various signaling pathways involved in multiorgan failure. Carnosic acid is a natural phenolic diterpene and has multiple bioactivities, such as anti-tumor, anti-inflammatory, and anti-oxidative effects. However, the effect of carnosic acid on septic AKI has not been explored. Therefore, this study aimed to determine whether carnosic acid has a therapeutic effect on LPS-induced kidney injury. Administration of carnosic acid after LPS injection ameliorated histological abnormalities and renal dysfunction. Cytokine production, immune cell infiltration, and nuclear factor-κB activation after LPS injection were also alleviated by carnosic acid. The compound suppressed oxidative stress with the modulation of pro-oxidant and antioxidant enzymes. Tubular cell apoptosis and caspase-3 activation were also inhibited by carnosic acid. These data suggest that carnosic acid ameliorates LPS-induced AKI via inhibition of inflammation, oxidative stress, and apoptosis and could serve as a useful treatment agent for septic AKI.

Hepatocyte apoptosis and inflammation play important roles in cholestatic liver diseases. Bee venom-derived secretory phospholipase A2 (bvPLA2) has been shown to ameliorate various inflammatory diseases. However, whether bvPLA2 has a therapeutic effect against cholestatic liver disease has not been evaluated. Therefore, we investigated the effects of bvPLA2 on cholestatic liver injury and fibrosis in a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding. The administration of bvPLA2 ameliorated liver damage, cholestasis, and fibrosis in DDC diet-fed mice, as assessed by serum biochemical tests and histological examinations. In addition, bvPLA2 reduced myofibroblast accumulation, concomitant with suppression of transforming growth factor-β signaling cascade. The administration of bvPLA2 inhibited hepatocyte apoptosis in DDC diet-fed mice as represented by a reduction in the number of cells stained with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and suppression of caspase-3 activation. Moreover, bvPLA2 reduced cytokine production along with the inhibition of the nuclear factor kappa-B pathway. The number of regulatory T-cells was increased by bvPLA2, while the number of other immune cells, including neutrophils, macrophages, and CD8⁺ T-cells, was decreased. Our data indicate that the administration of bvPLA2 ameliorates cholestatic liver injury and fibrosis by inhibiting hepatocyte apoptosis and inflammation.

Acetaminophen (APAP) can cause acute liver failure, but treatment options are still limited. Kahweol is the main diterpene compound of coffee and possesses antioxidant and anti‐inflammatory properties. Emerging evidence suggests that this natural diterpene exerts favorable effects on several inflammatory diseases. However, the action of kahweol on APAP toxicity has not been addressed. The purpose of this study was to explore whether kahweol has a protective activity against APAP‐induced hepatotoxicity and to investigate the mechanism. Administration of kahweol reduced serum levels of liver injury indicators and ameliorated histological abnormalities in APAP‐treated mice. Kahweol inhibited lipid peroxidation and nucleic acid oxidation with restoration of glutathione content and stimulation of nuclear factor erythroid‐2‐related factor 2‐dependent cellular defense system. Hepatocyte death was also decreased by kahweol, which was associated with inhibition of endoplasmic reticulum (ER) stress. Moreover, kahweol reduced hepatic levels of inflammatory mediators, inhibited nuclear factor‐κB activation, and attenuated infiltration of neutrophils and macrophages. These findings suggest that kahweol has a protective activity against APAP‐induced liver injury and this effect is related to the suppression of oxidative stress, hepatocyte death, ER stress, and inflammation.

Acetaminophen (APAP) overdose can cause severe liver damage, but therapeutic options are limited. Apamin is a natural peptide present in bee venom and has antioxidant and anti-inflammatory properties. Accumulating evidence suggests that apamin has favorable actions in rodent models of inflammatory disorders. Here, we examined the effect of apamin on APAP-evoked hepatotoxicity. Intraperitoneal administration of apamin (0.1 mg/kg) alleviated histological abnormalities and reduced serum levels of liver enzymes in mice injected with APAP. Apamin inhibited oxidative stress through an increase in the amount of glutathione and activation of the antioxidant system. Apamin also attenuated apoptosis with inhibition of caspase-3 activation. Moreover, apamin reduced serum and hepatic levels of cytokines in APAP-injected mice. These effects were accompanied by suppression of NF-κB activation. Furthermore, apamin inhibited chemokine expression and inflammatory cell infiltration. Our results suggest that apamin dampens APAP-evoked hepatotoxicity through inhibiting oxidative stress, apoptosis, and inflammation.

Acute kidney injury (AKI) is a common complication of sepsis. Eupatilin (EUP) is a natural flavone with multiple biological activities and has beneficial effects against various inflammatory disorders. However, whether EUP has a favorable effect on septic AKI remains unknown. Here, we examined the effect of EUP on lipopolysaccharide (LPS)-evoked AKI in mice. LPS-evoked renal dysfunction was attenuated by EUP, as reflected by reductions in serum creatinine and blood urea nitrogen levels. LPS injection also induced structural damage such as tubular cell detachment, tubular dilatation, brush border loss of proximal tubules, and upregulation of tubular injury markers. However, EUP significantly ameliorated this structural damage. EUP decreased serum and renal cytokine levels, prevented macrophage infiltration, and inhibited mitogen-activated protein kinase and NF-κB signaling cascades. Lipid peroxidation and DNA oxidation were increased after LPS treatment. However, EUP mitigated LPS-evoked oxidative stress through downregulation of NPDPH oxidase 4 and upregulation of antioxidant enzymes. EUP also inhibited p53-mediated apoptosis in LPS-treated mice. Therefore, these results suggest that EUP ameliorates LPS-evoked AKI through inhibiting inflammation, oxidative stress, and apoptosis.