phenanthrenes and Proteinuria

To observe the clinical efficacy of the Chinese herb, Triptolide, in children with moderately severe Henoch-Schönlein purpura nephritis (HSPN).. From January 2007 to December 2011, 56 HSPN children manifested by nephrotic range proteinuria with normal kidney function and <50% crescents or sclerosing lesions on biopsy were hospitalized in the Children's Hospital of Zhejiang University School of Medicine. They were divided into two groups: the treatment group (n = 42; Triptolide at a dosage of 1 mg/kg · d, combined with prednisone at a dosage of 2 mg/kg · d, within a course of medium-to-long-term therapy of 6 to 9 months) and the control group (n = 14; prednisone alone, with the same procedure).. Short-term remission was observed in 95% of patients from treatment group and in 72% of patients from control group, respectively. There was a significant difference between both groups (χ(2) = 6.222, P = 0.029) for short-term effects. Meanwhile, no significant difference, as proteinuria, hematuria, hypertension, and decreased eGFR, was observed between the two groups in long-term followup (χ(2) = 3.111, P = 0.097). The Kaplan-Meier plot analysis also revealed no significant difference (χ(2) = 2.633, P = 0.105).. Triptolide is effective in relieving short-term symptoms for moderately severe HSPN children, though its long-term effects need to be observed further.

Topics: Biopsy; Child; Child, Preschool; China; Diterpenes; Drugs, Chinese Herbal; Epoxy Compounds; Female; Humans; IgA Vasculitis; Kaplan-Meier Estimate; Male; Nephritis; Phenanthrenes; Proteinuria

Triptolide is a biologically active component of the Chinese antirheumatic herbal remedy Tripterygium wilfordii Hook F, which has been shown to be effective in treating murine lupus. However, its immunological mechanisms are poorly understood. Regulatory T cells (Treg) are pivotal for maintaining peripheral self-tolerance and controlling autoimmunity. This study was undertaken to examine the therapeutic effect of triptolide in lupus mice and the related molecular mechanisms. Our results showed that triptolide treatment ameliorated serum anti-dsDNA, proteinuria and renal histopathologic assessment in MRL/lpr mice, induced the miR-125a-5p expression and enhanced the proportion of Treg in vivo. In vitro, triptolide upregulated the proportion of Treg and the miR-125a-5p expression. Down-regulation of the miR-125a-5p expression reversed the effect of triptolide on Treg. In conclusion, triptolide could induce Treg and the miR-125a-5p expression in vivo and in vitro. Inhibiting the effect of miR-125a-5p could counteract the effect of triptolide on inducing Treg. The study has strong implications for the therapeutic applications of triptolide in systemic lupus erythematosus.

Topics: Animals; Antibodies, Antinuclear; Antirheumatic Agents; Cell Proliferation; Disease Models, Animal; Diterpenes; Epoxy Compounds; Female; Humans; Kidney; Lupus Erythematosus, Systemic; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; MicroRNAs; Phenanthrenes; Proteinuria; T-Lymphocytes, Regulatory; Up-Regulation

The aim of our current study was to investigate the long-term effect and the mechanism of triptolide in an adult nonorthologous rat model of polycystic kidney disease (PKD). Male wild-type (+/+) and Cy/+ cystic Han:SPRD rats were treated with vehicle or triptolide from 4 to 16 wk of age. Rats were killed at 16 wk of age for blood, urine, and organ collection. Human-derived WT9-12 PKD cells were treated with triptolide with or without IL-6 pretreatment. Cell proliferation, apoptosis, and cytotoxicity were determined. Western blotting and immunohistochemistry analysis were performed to evaluate the activation of IL-6-JAK2-STAT3 pathway. Renal function was protected by 12 wk of triptolide treatment in cystic Han:SPRD rats as shown by reduced blood urea nitrogen, serum creatinine, and proteinuria levels. Cyst and kidney growth were also retarded by triptolide treatment in Cy/+ rats. We further found that the proliferation index was reduced by triptolide in cystic rats, which was correlated with the reduced expression of IL-6/IL-6 receptor, decreased phosphorylation of JAK2-STAT3, and increased expression of suppressor of cytokine signaling 3 (SOCS3). The inhibitory effect of triptolide was further studied in WT9-12 cells. Triptolide inhibited cell proliferation and the activation of JAK2-STAT3 pathway in PKD cells, but it increased the expression of SOCS3. Pretreatment with IL-6 attenuated the inhibitory effect of triptolide on STAT3 phosphorylation. Our study revealed a long-term beneficial effect of triptolide in PKD that was probably through inhibition of the JAK2-STAT3 pathway.

Topics: Animals; Apoptosis; Blood Urea Nitrogen; Cell Line; Cell Proliferation; Creatinine; Disease Models, Animal; Disease Progression; Diterpenes; Epoxy Compounds; Humans; Interleukin-6; Janus Kinase 2; Kidney; Male; Phenanthrenes; Phosphorylation; Polycystic Kidney Diseases; Proteinuria; Rats, Transgenic; Receptors, Interleukin-6; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein

Podocyte injury is a primary contributor to proteinuria. Triptolide is a major active component of Tripterygium wilfordii Hook F that exhibits potent antiproteinuric effects. We used our previously developed in vivo zebrafish model of inducible podocyte-target injury and found that triptolide treatment effectively alleviated oedema, proteinuria and foot process effacement. Triptolide also inhibited podocyte apoptosis in our zebrafish model and in vitro. We also examined the mechanism of triptolide protection of podocyte. Whole-genome expression profiles of cultured podocytes demonstrated that triptolide treatment downregulated apoptosis pathway-related GADD45B expression. Specific overexpression of gadd45b in zebrafish podocytes abolished the protective effects of triptolide. GADD45B is a mediator of podocyte apoptosis that contains typical NF-κB binding sites in the promoter region, and NF-κB p65 primarily transactivates this gene. Triptolide inhibited NF-κB signalling activation and binding of NF-κB to the GADD45B promoter. Taken together, our findings demonstrated that triptolide attenuated proteinuria and podocyte apoptosis via inhibition of NF-κB/GADD45B signalling, which provides a new understanding of the antiproteinuric effects of triptolide in glomerular diseases.

Topics: Animals; Animals, Genetically Modified; Anti-Infective Agents; Antigens, Differentiation; Apoptosis; Cells, Cultured; Diterpenes; Epoxy Compounds; Humans; Immunosuppressive Agents; Metronidazole; NF-kappa B; Phenanthrenes; Podocytes; Proteinuria; Zebrafish; Zebrafish Proteins

Topics: Adult; Diterpenes; Epoxy Compounds; Female; Humans; Male; Medicine, East Asian Traditional; Middle Aged; Phenanthrenes; Phytotherapy; Polycystic Kidney, Autosomal Dominant; Proteinuria; Treatment Outcome; Tripterygium

Henoch-Schönlein purpura (HSP) is one of the most common causes of systemic vasculitis in children. The incidence of HSP nephritis (HSPN) among HSP patients has been reported to be 15-62%. Even so, what constitutes severe HSPN is controversial. In the study reported here, we retrospectively reviewed the clinical features and prognosis of 101 children with HSPN, ISKDC grade IIIa/IIIb, from January 1992 to November 2008. Patients with isolated hematuria and/or proteinuria <50 mg/kg/day received triptolide alone, and those with nephrotic range proteinuria received a combination therapy of prednisone and triptolide. Nephrotic syndrome was the most common clinical manifestation (45.5%). There were no significant differences in the clinical features (χ(2) = 2.756, P = 0.252), the side effects related to treatment (χ(2) = 2.259, P = 0.894), prognosis between IIIa and IIIb (χ(2) = 3.013, P = 0.222), or prognosis in grade IIIa patients receiving triptolide alone or triptolide and prednisone (χ(2) = 1.207, P = 0.272) and grade IIIb patients (χ(2) = 1.158, P = 0.282). No significant difference in clinical manifestations and long-term prognosis of our HSPN patients with grade IIIa or grade IIIb were found, implying that our patients with International Study and Kidney Disease in Children (ISKDC) grade IIIb were not the most severe cases of HSPN. Our results may also suggest that treatment with steroid may not alter the clinical outcome of such grade IIIa or IIIb patients.

Topics: Adolescent; Biopsy; Chi-Square Distribution; Child; Child, Preschool; China; Diterpenes; Drug Therapy, Combination; Epoxy Compounds; Female; Hematuria; Humans; IgA Vasculitis; Immunosuppressive Agents; Male; Nephritis; Nephrotic Syndrome; Phenanthrenes; Prednisone; Proteinuria; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome

Membranous nephropathy is a major cause of nephrotic syndrome in adults where podocyte injuries were found to mediate the development of proteinuria. Triptolide, a major active component of Tripterygium wilfordii Hook F, has potent immunosuppressive, anti-inflammatory and antiproteinuric effects. To study its antiproteinuric properties, we established an experimental rat model of passive Heymann nephritis and a C5b-9 injury model of podocytes in vitro. Treatment or pretreatment with triptolide markedly reduced established proteinuria as well as the titer of circulating rat anti-rabbit IgG antibodies in these nephritic rats, accompanied by a reduction in glomerular C5b-9 deposits. Expression of desmin, a marker of podocyte injury, diminished after triptolide treatment, whereas quantitative analysis of mean foot process width showed that effacement of foot processes was substantially reversed. In in vitro studies we found that triptolide deactivated NADPH oxidase, suppressed reactive oxygen species generation and p38 mitogen-activated protein kinase, and restored RhoA signaling activity. Triptolide did not interfere with the formation of C5b-9 on the membrane of podocytes. Thus, triptolide reduces established heavy proteinuria and podocyte injuries in rats with passive Heymann nephritis, and protects podocytes from C5b-9-mediated injury.

Topics: Administration, Oral; Animals; Cell Line; Complement Membrane Attack Complex; Cytoprotection; Desmin; Disease Models, Animal; Diterpenes; Epoxy Compounds; Female; Glomerulonephritis, Membranous; Heymann Nephritis Antigenic Complex; Immunoglobulin G; Immunosuppressive Agents; Mice; NADPH Oxidases; p38 Mitogen-Activated Protein Kinases; Phenanthrenes; Podocytes; Proteinuria; Rabbits; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; rho GTP-Binding Proteins; rhoA GTP-Binding Protein; Signal Transduction; Tacrolimus; Time Factors

Chronic kidney disease (CKD) is a common cause of end-stage renal disease. Antihypertensive agents are used clinically to inhibit the progression of CKD, but cannot prevent eventual renal failure. This study investigated the effect of Tanshinone IIA, an active component of Salvia miltiorrhiza, in rats suffering from CKD induced by 5/6 nephrectomy. After development of renal insufficiency, the rats were treated with Tanshinone IIA (10 mg/kg) for 8 weeks. Serum creatinine, angiotensin II (Ang II), transforming growth factor β1 (TGF-β1) and collagen IV levels were significantly reduced in Tanshinone IIA treated rats compared with a control group. In addition, Tanshinone IIA suppressed increases in urinary protein excretion in CKD rats. These findings suggest that chronic oral administration of Tanshinone IIA can improve renal dysfunction associated with CKD.

Topics: Abietanes; Administration, Oral; Angiotensin II; Animals; Collagen Type IV; Creatinine; Disease Models, Animal; Drugs, Chinese Herbal; Kidney; Male; Phenanthrenes; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Salvia miltiorrhiza; Transforming Growth Factor beta1

Diabetic nephropathy (DN) has become the leading cause of end stage renal failure, and prevention or retardation of DN has become a major goal in biomedical research. In this study, Tanshinone IIA, a component extracted from Salvia miltiorrhiza, was studied in experimental rats in which DN was induced by streptozotocin (STZ) treatment. The DN rats were treated with 10 mg/kg of Tanshinone IIA for 12 weeks to analyze its reno-protective effect with different parameters. Renal hypertrophy and 24-h urinary protein excretion were ameliorated by Tanshinone IIA. Moreover, advanced glycation end-products (AGEs), angiotensin II (Ang II), transforming growth factor beta(1) (TGF-beta(1)), collagen IV, and monocyte/macrophage (ED-1) either in the serum or kidney were significantly reduced. These results suggest that Tanshinone IIA might have protective effects on several pharmacological targets during the progression of DN, and could be a potential drug for the prevention of DN.

Topics: Abietanes; Angiotensin II; Animals; Blood Glucose; Collagen Type IV; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme-Linked Immunosorbent Assay; Glycation End Products, Advanced; Immunohistochemistry; Kidney; Macrophages; Monocytes; Neutrophil Infiltration; Phenanthrenes; Protective Agents; Proteinuria; Rats; Transforming Growth Factor beta1

Extracts of Tripterygium wilfordii Hook F have been used to treat glomerulonephritis for more than 30 years in China with dramatic antiproteinuric effects. Triptolide, a diterpene triepoxide, is one of the major active components of these extracts. To clarify its antiproteinuric effects we induced podocyte injury by puromycin aminonucleoside. Triptolide effectively reduced the proteinuria induced by puromycin in nephrotic rats without reducing the glomerular filtration rate. The antiproteinuric effect was associated with improvement in the foot process effacement, a decrease in the podocyte injury marker desmin as well as the restoration of nephrin and podocin expression and distribution. In cultured mouse podocytes triptolide pretreatment prevented the puromycin-induced disruption of the actin cytoskeleton and microfilament-associated synaptopodin while protecting nephrin and podocin expression. Triptolide suppressed reactive oxygen species generation and p38 mitogen-activated protein kinase activation while restoring RhoA signaling activity. These results show that triptolide ameliorates puromycin aminonucleoside-mediated podocyte injury in vivo and in vitro.

Topics: Animals; Cells, Cultured; Cholesterol; Cytoskeleton; Desmin; Diterpenes; Epoxy Compounds; Glomerular Filtration Rate; Intracellular Signaling Peptides and Proteins; MAP Kinase Signaling System; Membrane Proteins; Mice; Nephrosis; Phenanthrenes; Podocytes; Proteinuria; Puromycin Aminonucleoside; Rats; Reactive Oxygen Species; Serum Albumin; Triglycerides

Investigations on reducing the toxicity of triptolide through poly(D, L-lactic acid) nanoparticles as a drug carrier by oral administration to Wistar rats.. Triptolide-loaded poly (D, L-lactic acid) nanoparticles (TP-PLA-NPs) were prepared by modified spontaneous emulsification solvent diffusion (modified-SESD). The shape of nanoparticles was observed by transmission electron microscope (TEM). The size distribution and mean diameter were measured by laser light scattering technique. The entrapment efficiency and contents of drug loading were determined by RP-HPLC. The physical state of drug loaded in nanopartiles were primarily investigated by X-ray powder diffractometry. TP-PLA-NPs release behavior in vitro was carried out. After oral administration of the nanoparticles to Wistar rats in 15d, the toxicity for liver and kidney were studied by determining aspartate transaminase (AST), alanine transaminase (ALT) and blood urea nitrogen in serum and concentration of protein in urine.. The preparation process adapted to the formulation was as follows: the volume ratio of the aqueous and organic phases was 40/15; the surfactant concentration was 1%; the drug concentration was 0.3%; triptolide-PLA was 1:15 (w/w). The mean diameter was 149.7 nm and the polydispersity index was 0. 088 for the nanoparticles prepared by above conditions. The entrapment efficiency and content of drug loading were 74.27% and 1.36%, respectively. The release behavior of drug in vitro showed an initial burst effect, subsequently a slower rate stage. The results indicated that the liver toxicity (P < 0.01) and kidney toxicity (P < 0.05) caused by triptolide could be decreased significantly by nanoparticles carrier.. PLA-NPs might be used as a new oral carrier for triptolide.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Urea Nitrogen; Delayed-Action Preparations; Diterpenes; Drug Carriers; Drug Delivery Systems; Epoxy Compounds; Lactic Acid; Male; Nanotechnology; Particle Size; Phenanthrenes; Polyesters; Polymers; Proteinuria; Rats; Rats, Wistar; Tripterygium

Quinine was compared with a 9-phenanthrene methanol (WR33063) and a 4-quinoline methanol (WR30090) for the treatment of 207 patients with falciparum malaria in Southeast Thailand. Quinine eradicated parasitaemia (average 70 hours) more rapidly than either WR30090 (72 hours) or WR33063 (77 hours). But WR33063 had a higher cure rate (92%) than WR30090 (86%) or quinine (85%). The mean duration of fever and of parasitaemia were combined with the failure rate to form an arbitrary efficacy index. Using this concept WR33063 was the most effective drug. The recrudescence rate correlated with the degree and duration of parasitaemia and with the duration of fever. WR33063 was the least toxic drug. Side effects associated with WR30090 appeared to be headache, backache and urticaria. Quinine was the most toxic drug. All 3 drugs were inconvenient in having to be administered every 8 hours for 6 days. One patient did not respond to oral quinine but did respond to an intravenous quinine infusion (IVQ). A "Medication Ward Round" was perfected during the study and comprised sequential history, drug administration, physical examination, dose notation and patient observation. Falciparum nephrosis was diagnosed in one patient.

Topics: Adolescent; Drug Administration Schedule; Drug Evaluation; Drug Hypersensitivity; Drug Resistance, Microbial; Humans; Malaria; Male; Phenanthrenes; Plasmodium falciparum; Proteinuria; Quinine; Quinolines; Thailand; Urticaria

Topics: Animals; Basement Membrane; Glycosides; Glycosuria; Guinea Pigs; Heart; In Vitro Techniques; Ketone Bodies; Kidney; Kidney Function Tests; Kidney Glomerulus; Kidney Tubular Necrosis, Acute; Kidney Tubules; Kidney Tubules, Proximal; Lethal Dose 50; Liver; Liver Function Tests; Natriuresis; Nephrosis; Oxidative Phosphorylation; Phenanthrenes; Potassium; Proteinuria; Rabbits; Rats; Time Factors