Fluorofenidone protects against renal fibrosis by inhibiting STAT3 tyrosine phosphorylation.

Signaling through the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, especially JAK2/STAT3, is involved in renal fibrosis. Fluorofenidone (FD), a novel pyridone agent, exerts anti-fibrotic effects in vitro and in vivo. Herein, we sought to investigate whether FD demonstrates its inhibitory function through preventing JAK2/STAT3 pathway. In this study, we examined the effect of FD on activation of rat renal interstitial fibroblasts, glomerular mesangial cells (GMC), and expression of JAK2/STAT3. Moreover, we explored the histological protection effects of FD in UUO rats, db/db mice, and phosphorylation of JAK2/STAT3 cascade. Our studies found that pretreatment with FD resulted in blockade of activation of fibroblast and GMC manifested by fibronectin (FN) and α-smooth muscle actin (α-SMA) protein expression and decline of STAT3 tyrosine phosphorylation induced by IL-6 or high glucose. In unilateral ureteral obstruction rats and a murine model of spontaneous type 2 diabetes (db/db mice), treatment with FD blocked the expression of FN and α-SMA, prevented renal fibrosis progression, and attenuated STAT3 activation. However, FD administration did not interfere with JAK2 activation both in vivo and in vitro. In summary, the molecular mechanism by which FD exhibits renoprotective effects appears to involve the inhibition of STAT3 phosphorylation.

Fluorofenidone attenuates oxidative stress and renal fibrosis in obstructive nephropathy via blocking NOX2 (gp91phox) expression and inhibiting ERK/MAPK signaling pathway.

BACKGROUND/AIMS: We evaluated the therapeutic effects of fluorofenidone (AKF-PD), a novel pyridone agent, targeting oxidative stress and fibrosis in obstructive nephropathy. METHODS: AKF-PD was used to treat renal interstitial fibrosis in unilateral ureteral obstruction (UUO) obstructive nephropathy in rats. The expression of NOX2 (gp91phox), fibronectin and extracellular signal regulated kinase (ERK) were detected by western blot. A level of Malondialdehyde (MDA), an oxidative stress marker, was measured by ELISA. In addition, ROS and the expressions of NOX2, collagen I (a1), fibronectin and p-ERK were measured in angiotensin (Ang) II-stimulated rat proximal tubular epithelial cells (NRK-52E) in culture. RESULTS: In NRK-52E cells, AKF-PD reduced AngII induced expressions of ROS, NOX2, fibronectin, collagen I (a1) and p-ERK. In UUO kidney cortex, AKF-PD attenuated the degree of renal interstitial fibrosis, which was associated with reduced the expressions of collagen I (a1) and fibronectin. Furthermore, AKF-PD downregulated the expressions of NOX2, MDA and p-ERK. CONCLUSION: AKF-PD treatment inhibits the progression of renal interstitial fibrosis by suppressing oxidative stress and ERK/MAPK signaling pathway.

Fluorofenidone inhibits nicotinamide adeninedinucleotide phosphate oxidase via PI3K/Akt pathway in the pathogenesis of renal interstitial fibrosis.

AIM: Oxidative stress plays an important role in the progression of renal interstitial fibrosis. The nicotinamide adeninedinucleotide phosphate (NADPH) oxidase (Nox) family is considered one of the major sources of reactive oxygen species (ROS). In the present study, we investigated the inhibitory effects of a novel anti-fibrotic agent, Fluorofenidone (AKF-PD), upon Nox-mediated oxidative stress and deposition of extracellular matrix (ECM) in the development of renalinterstitial fibrosis. METHODS: AKF-PD was used to treat renal fibrosis in unilateral ureteral obstruction (UUO) obstructive nephropathy in rats. The expression of Nox homologues, p-Akt, collagen I and III were detected by immunoblotting or immunohistochemistry. Levels of 8-iso prostaglandin F2alpha (8-Iso PGF2a) was measured by enzyme linked immunosorbent assay. In addition, ROS and the expression of collagen I (1a), Nox subunits and p-Akt was measured in angiotensin (Ang) II-stimulated rat proximal tubular epithelial (NRK-52E) cells in culture. RESULTS: AKF-PD treatment significantly attenuated tubulo-interstitial injury, ECM deposition and oxidative stress in fibrotic rat kidneys. In addition, AKF-PD inhibited the expression of ROS, Collagen I (1a), Nox2, p-Akt in Ang II-stimulated NRK-52E cells. CONCLUSION: AKF-PD attenuates the progression of renal interstitial fibrosis partly by suppressing NADPH oxidase and ECM deposition via the PI3K/Akt signalling pathway, suggesting AKF-PD is a potential novel therapeutic agent against renal fibrosis.

Oviposition preference and adult performance of the whitefly predator Serangium japonicum (Coleoptera: Coccinellidae): effect of leaf microstructure associated with ladybeetle attachment ability.

BACKGROUND: The leaf surface microstructure can greatly influence predator feeding behavior. However, its effects on predator oviposition preference, which is crucial for arthropod fitness at the population level, are largely unknown. This study aimed to test leaf discs and plants of five common host plant species of Bemisia tabaci, including Chinese kale, cotton, cucumber, eggplant, and sweetpotato, to determine the oviposition preference and offspring and adult performance of the whitefly predator Serangium japonicum. Cannibalism risk, attachment force, microstructure of the abaxial leaf surface (ALS), and ladybeetle tarsal morphology were examined. RESULTS: Ladybeetle's oviposition preference had no correlation with offspring performance but positively correlated with fecundity. Further, oviposition preference to leaf discs and fecundity positively correlated with attachment force. The cannibalism risk was not significantly different between plant species. The ALS of Chinese kale and eggplant supported the smallest and the largest attachment forces, respectively. The first one had epicuticular wax crystals, whereas the latter had stellate trichomes. The ALS of cotton and sweetpotato did not bear wax crystals or long trichomes. Cucumber leaves were covered with tapered trichomes. Tenant setae on the distal second tarsomere and a pair of curved, tapered claws on the distal fourth tarsomere were the attachment structures of S. japonicum, which interacted with the plant surface structures and generated the attachment force. CONCLUSION: Plant morphological traits, associated with ladybeetle attachment force and adult performance might be key factors in ladybeetle oviposition preference, and are expected to occur in other host plant herbivore-predator systems.