ascorbic-acid and triptolide

Triptolide (TP) has its unique curative effect in the treatment of rheumatoid arthritis (RA), but its application is limited by the poor water solubility and multi-organ toxicity. We herein developed a novel nanoparticle platform composed of L-ascorbate palmitate (VP, vitamin C derivative) that can deliver TP to synergistically treat arthritis and inhibit the occurrence of oxidative stress. The TP-loaded nanoparticles (termed TP-VP NPs) showed the suitable particle size (about 145 nm) and good physical stability. TP-VP NPs effectively down-regulated IL-1β, IL-6 and TNF-α levels to inhibit the erosion of synovitis and bone tissue, and alleviate the swelling and deformation of CIA mice's feet. Compared to the TP, TP-VP NPs could inhibit effectively the oxidative stress in liver, and alleviate significantly the triptolide-induced toxicity injury in liver, kidney and testicle. The results demonstrated that TP-VP NPs is a promising triptolide delivery system for the treatment of RA, which enhances the water solubility of TP and reduces the toxicity of TP

Topics: Animals; Arthritis, Rheumatoid; Ascorbic Acid; Diterpenes; Epoxy Compounds; Mice; Micelles; Palmitates; Phenanthrenes; Water

Triptolide, a purified diterpenoid from the herb Tripterygium wilfordii Hook.f., was widely used to treat many diseases. However, the hepatotoxicity of triptolide limited its clinical use. Research showed oxidative stress played an important role in triptolide-induced liver injury. To investigate the effect of vitamin C, which was one of the most effective antioxidants, on triptolide-induced hepatotoxicity and its potential mechanism in mice. In the present study, acute liver injury was induced by intraperitoneal injection of triptolide and vitamin C was orally administered. The results showed treatment with vitamin C prevented the triptolide-induced liver injury by reducing the levels of aspartate transaminase from 286.86 to 192.48 U/mL and alanine aminotransferase from 746.75 to 203.36 U/mL. Histopathological changes of liver corresponded to the same trend. Furthermore, vitamin C also protected the liver against triptolide-induced oxidative stress by inhibiting the generation of malondialdehyde (2.22 to 1.49 nmol/mgprot) and hydrogen peroxide (14.74 to 7.19 mmol/gprot) and restoring the level of total superoxide dismutase (24.32 to 42.55 U/mgprot) and glutathione (7.69 to 13.03 μg/mgprot). These results indicated that vitamin C could protect against triptolide-induced liver injury via reducing oxidative stress, and vitamin C may pose a significant health protection in the clinical use of triptolide.

Topics: Alanine Transaminase; Animals; Ascorbic Acid; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Diterpenes; Epoxy Compounds; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Phenanthrenes; Protective Agents

This study investigated the role of reactive oxygen species (ROS) in the pathogenesis of triptolide-induced renal injury in vivo. Rats were randomly divided into 4 groups (n=5 in each): triptolide group in which the rats were intraperitoneally injected with triptolide solution at a dose of 1 mg/kg of body weight on day 8; control group in which the rats received a single intraperitoneal injection of 0.9% physiological saline on day 8; vitamin C group in which the rats were pretreated with vitamin C by gavage at a dose of 250 mg/kg of body weight per day for 7 days before the same treatment as the control group on day 8; triptolide+vitamin C group in which the rats were first subjected to an oral administration of vitamin C at a dose of 250 mg/kg of body weight per day for 7 days, and then to the same treatment as the triptolide group on day 8. All the rats were sacrificed on day 10. Blood samples were collected for detection of plasma creatinine (Pcr) and plasma urea nitrogen (PUN) concentrations. Both kidneys were removed. The histological changes were measured by haematoxylin-eosin (HE) staining. The production of ROS was determined by detecting the fluorescent intensity of the oxidation-sensitive probe rhodamine 123 in renal tissue. Renal malondialdehyde (MDA) content was measured to evaluate lipid peroxidation level in renal tissue. TUNEL staining was performed to assess apoptosis of renal tubular cells. Renal expression of apoptosis-related proteins Bcl-2, Bax, Bid, Bad, Fas and FasL, as well as corresponding encoding genes were assessed by Western Blotting and real-time PCR. The results showed that triptolide treatment promoted the generation of a great amount of ROS, up-regulated the expression of Bax, Bid, Bad, Fas and FasL at both protein and mRNA levels, as well as the ratio of Bax to Bcl-2, and caused the apoptosis of renal tubular cells and renal injury. However, pretreatment with an antioxidant, vitamin C, significantly reduced the generation of ROS and effectively inhibited the triptolide-induced apoptosis of renal tubular cells and renal injury. It was concluded that ROS plays a critical role in triptolide-induced apoptosis of renal tubular cells and renal injury. The protective administration of vitamin C may help alleviate triptolide-induced renal injury and nephrotoxicity.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Ascorbic Acid; Diterpenes; Epoxy Compounds; Kidney Tubules; Male; Phenanthrenes; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

Triptolide (Tri) was isolated from Tripterygium wilfordii Hook f. Tri 0.1-0.2 mg.kg-1 sc or 0.15-0.3 mg.kg-1 ig inhibited markedly the increased vascular permeability induced by ip 0.7% HAc in mice. Tri 0.05-0.1 mg.kg-1 ip or 0.15-0.3 mg.kg-1 ig inhibited hind paws swelling induced by sc 0.15 ml carrageenan and also inhibited the same swelling induced by sc 2.5% formaldehyde 0.1 ml in rats. Tri 0.05-0.1 mg.kg-1 ip inhibited markedly proliferation of granuloma induced by sc implantation of cotton-pellets in rats, but 0.2 mg.kg-1 ip can not inhibit the same swelling induced by sc 0.15 ml carrageenan in adrenalectomized rats. Tri 0.2 mg.kg-1 ip decreased markedly weight of thymus. Tri 0.2 mg.kg-1 ip, but 0.1 mg.kg-1 ip did not reduced the content of ascorbic acid of adrenal gland in rats. Tri 0.2 mg.kg-1 ip did not decrease the pro-staglandin E content in inflammatory tissues. These results indicate that high dose of Tri can stimulate the pituitary-adrenal axis.

Topics: Adrenal Glands; Adrenalectomy; Animals; Anti-Inflammatory Agents, Non-Steroidal; Ascorbic Acid; Capillary Permeability; Carrageenan; Diterpenes; Edema; Epoxy Compounds; Granuloma, Foreign-Body; Male; Mice; Phenanthrenes; Prostaglandins E; Rats