Paeonol protects endotoxin-induced acute kidney injury: potential mechanism of inhibiting TLR4-NF-κB signal pathway.

STUDY DESIGN AND METHODS: In order to determine the therapeutic effect and mechanism of paeonol on acute kidney injury induced by endotoxin, an acute kidney injury model was established by intraperitoneal administration of lipopolysaccharide in mice in vivo and on LPS-induced dendritic cells in vitro. Renal tissues were used for histologic examination. Concentrations of blood urea nitrogen and serum creatinine were detected, inflammatory cytokines were determined by ELISA. The relative proteins' expression of TLR4-NF-κB signal pathway was assessed by Western blot, the localization and expression of phospho-NF-κB p65 in kidney was monitored by immunohistochemistry. RESULTS: Treatment of paeonol successfully cuts histopathological scores and dilutes the concentrations of blood urea nitrogen and serum creatinine as index of renal injury severity. In addition, paeonol reduces pro-inflammatory cytokines and increases anti-inflammatory cytokines stimulated by LPS in a dose-dependent manner. Paeonol also inhibits the expression of phosphorylated NF-κB p65, IκBα and IKKß, and restrains NF-κB p65 DNA-binding activity. Paeonol treatment also attenuates the effects of LPS on dendritic cells, with significant inhibition of pro-inflammatory cytokines release, then TLR4 expression and NF-κB signal pathway have been suppressed. CONCLUSIONS: These results indicated that paeonol has protective effects on endotoxin-induced kidney injury. The mechanisms underlying such effects are associated with its successfully attenuate inflammatory and suppresses TLR4 and NF-κB signal pathway. Therefore, paeonol has great potential to be a novel and natural product agent for treating AKI or septic-AKI.

Salvianolic acid A as a multifunctional agent ameliorates doxorubicin-induced nephropathy in rats.

Nephrotic syndrome (NS) is still a therapeutic challenge. To date there is no ideal treatment. Evidence suggest that multidrug therapy has more effect than monotherapy in amelioration of renal injury. Salvianolic acid A (SAA) is the major active component of Salviae Miltiorrhizae Bunge. Previous studies have demonstrated that SAA is a multi-target agent and has various pharmacological activities. The pleiotropic properties of SAA predict its potential in the treatment of NS. The study investigated the effect of SAA on doxorubicin-induced nephropathy. The kidney function related-biochemical changes, hemorheological parameters and oxidative stress status were determined, and histological examination using light and transmission electron microcopies and western blot analysis were also performed. Results revealed that treatment with SAA alleviated histological damages, relieved proteinuria, hypoalbuminemia and hyperlipidemia, reduced oxidative stress, as well as improving hemorheology. Furthermore, SAA restored podocin expression, down-regulated the expression of NF-κB p65 and p-IκBα while up-regulating IκBα protein expression. Overall, as a multifunctional agent, SAA has a favorable renoprotection in doxorubicin-induced nephropathy. The anti-inflammation, antioxidant, amelioration of podocyte injury, improvement of hemorheology and hypolipidemic properties may constituent an important part of its therapeutic effects. All these indicate that SAA is likely to be a promising agent for NS.

Therapeutic effect of a hydroxynaphthoquinone fraction on dextran sulfate sodium-induced ulcerative colitis.

AIM: To evaluate the therapeutic effect of hydroxynaphthoquinone mixture (HM) on dextran sulfate sodium (DSS)-induced colitis and explore the underlying mechanisms. METHODS: BALB/c mice received 3.5% DSS for 6 d to induce ulcerative colitis. Groups of mice were orally administered HM 3.5, 7 and 14 mg/kg and mesalazine 200 mg/kg per day for 7 d. During the experiment, clinical signs and body weight, stool consistency and visible fecal blood were monitored and recorded daily. A disease activity index score was calculated for each animal. At the conclusion of the experiment, the colonic histopathological lesions were evaluated. Myeloperoxidase (MPO) activity and tumor necrosis factor-α (TNF-α) levels were determined. Protein expression levels of TNF-α, nuclear factor-κB (NF-κB) p65, inhibitor of κB (IκB) and phosphorylation of IκB (p-IκB) were analyzed by Western blot analysis. RESULTS: Administration of 3.5% DSS for 6 d successfully induced acute colitis associated with soft stool, diarrhea, rectal bleeding, and colon shortening, as well as a loss of body weight. Administration of HM effectively attenuated the severity of colonic mucosa injury. For histopathological analysis, HM treatment improved histological alterations and lowered pathological scores compared with the DSS only group. This manifested as a reduction in the extent of colon injury and inflammatory cell infiltration, as well as the degree of mucosal destruction. In addition, HM at doses of 7 and 14 mg/kg significantly decreased MPO activity in colonic tissue (0.98 ± 0.22 U/g vs 1.32 ± 0.24 U/g, 0.89 ± 0.37 U/g vs 1.32 ± 0.24 U/g tissue, P < 0.05) and serum TNF-α levels (68.78 ± 7.34 ng/L vs 88.98 ± 17.79 ng/L, 64.13 ± 14.13 ng/L vs 88.98 ± 17.79 ng/L, P < 0.05). Furthermore, HM down-regulated the expression of TNF-α, NF-κB p65 and p-IκBα in colonic tissue while up-regulating IκBα protein expression. These results suggest that the significant anti-inflammatory effect of HM may be attributable to its inhibition of TNF-α production and NF-κB activation. CONCLUSION: HM had a favorable therapeutic effect on DSS-induced ulcerative colitis, supporting its further development and clinical application in inflammatory bowel disease.