phenanthrenes and Chronic-Disease

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by cellular infiltration into the joints and cartilage destruction. Neutrophils play a crucial role in the pathogenesis of RA. Triptolide (TP) is a bioactive compound derived from Tripterygium wilfordii Hook F, which has been used in folk medicine as a treatment for a variety of inflammatory disorders, including RA, for many centuries. Previous studies have shown that TP possesses anti-arthritic activity. However, the anti-arthritic mechanism of TP remains to be fully defined. In the present study, we used the adjuvant-induced arthritis (AA) murine model of RA to investigate the impact of TP on RA and neutrophil function. TP alleviated AA by reducing neutrophil recruitment and suppressing the expression of interleukin-6 and tumour necrosis factor-α in vivo. TP also suppressed the expression of pro-inflammatory cytokines in neutrophils, promoted neutrophil apoptosis and inhibited the migration, NETosis and autophagy of neutrophils in vitro. Based on our findings, TP effectively ameliorates RA by down-regulating neutrophil inflammatory functions, indicating that TP represents a potential therapeutic agent for RA.

Topics: Animals; Apoptosis; Arthritis, Experimental; Arthritis, Rheumatoid; Autophagy; Chronic Disease; Cytokines; Diterpenes; Epoxy Compounds; Extracellular Traps; Inflammation; Leukocyte Elastase; Lipopolysaccharides; Male; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils; Peroxidase; Phenanthrenes

Pancreatic cancer is a devastating disease with a survival rate of <5%. Moreover, pancreatic cancer aggressiveness is closely related to high levels of prosurvival mediators, which can ultimately lead to rapid disease progression. One of the mechanisms that enables tumor cells to evade cellular stress and promote unhindered proliferation is the endoplasmic reticulum (ER) stress response. Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response (UPR). The UPR initially compensates for damage, but it eventually triggers cell death if ER dysfunction is severe or prolonged. Triptolide, a diterpene triepoxide, has been shown to be an effective compound against pancreatic cancer. Our results show that triptolide induces the UPR by activating the PKR-like ER kinase-eukaryotic initiation factor 2α axis and the inositol-requiring enzyme 1α-X-box-binding protein 1 axis of the UPR and leads to chronic ER stress in pancreatic cancer. Our results further show that glucose-regulated protein 78 (GRP78), one of the major regulators of ER stress, is downregulated by triptolide, leading to cell death by apoptosis in MIA PaCa-2 cells and autophagy in S2-VP10 cells.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis Regulatory Proteins; Beclin-1; Cell Line, Tumor; Chronic Disease; Diterpenes; DNA-Binding Proteins; Down-Regulation; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Epoxy Compounds; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Gene Silencing; Heat-Shock Proteins; Membrane Proteins; Pancreatic Neoplasms; Phenanthrenes; Regulatory Factor X Transcription Factors; Stress, Physiological; Transcription Factors; Unfolded Protein Response

Topics: Animals; Arthritis, Experimental; Cell Differentiation; Chronic Disease; Colitis; Diterpenes; Epoxy Compounds; Graft Survival; Heart Transplantation; Immunosuppressive Agents; Interleukin-17; Phenanthrenes; T-Lymphocytes, Helper-Inducer

Recent studies have suggested a critical role of TNFR2 signaling associated with NF-kappaB activation in the pathogenesis of Crohn's disease. Triptolide, an extract from Tripterygium wilfordii Hook, has both anti-immune and anti-inflammatory effects. In this study, we evaluated its possible therapeutic effects on colitis in interleukin-10 deficient mice, a murine model of Crohn's disease. Triptolide was administered to IL-10(-/-) mice intraperitoneally every other day for 8 weeks. The severity of colitis in IL-10(-/-) mice was obviously reduced after triptolide treatment, with a reduction in the numbers of CD4+ T cells and macrophages in lamina propria. Triptolide also significantly decreased the production of TNF-alpha and IFN-gamma in colon. Furthermore, triptolide suppressed TNFR2 expression and NF-kappaB activation in colon of IL-10(-/-) mice. These data suggested that triptolide could ameliorate Th1-mediated chronic colitis and disordered immune state in IL-10(-/-) mice. A possible mechanism could be inhibiting TNF-alpha/TNFR2 signal pathway.

Topics: Animals; Chronic Disease; Colitis; Diterpenes; Epoxy Compounds; Immunosuppressive Agents; Interleukin-10; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Phenanthrenes; Receptors, Tumor Necrosis Factor, Type II; Signal Transduction; Tumor Necrosis Factor-alpha

Triptolide, the principal active ingredient in the extract of Chinese herb Tripterygium wilfordii Hook , has both anti-inflammatory and immunomodulatory activities. However, the potential therapeutic role of triptolide in IBD was still unknown. Interleukin-10 deficient mice, a well characterized experimental model of inflammatory bowel disease, spontaneously developed a Th1 T cell-mediated colitis with many similarities to Crohn's disease. This study was designed to investigate the therapeutic effect of triptolide on the chronic colitis in IL-10-/- mice.. Triptolide was intraperitoneally administrated every another day for 8 weeks to IL-10-/- mice. The gross and histological appearances of the colon, the level of inflammatory mediators and transcription factor activation in the colon were evaluated and compared with the control group.. The 8-week administration of triptolide resulted in a significant decrease in the severity of colitis, together with lower production of TNF-alpha ,IFN-gamma and IL-4 in colon. The level of serum amyloid A was decreased in triptolide-treated mice. Gene expressions of IL-12 and IL-23 in colon were also downregulated after treatment. Furthermore, administration of triptolide markedly reduced NF-small ka, CyrillicB activation in colon mucosa of IL-10-/- mice.. The efficacy of tritpolide treatment for the reduction of intestinal inflammation in IL-10-/- mice is a result of both anti-inflammatory and immunosuppressive activity. Triptolide holds significant potential for clinical applications for CD treatment.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Colitis; Colon; Disease Models, Animal; Diterpenes; Epoxy Compounds; Immunosuppressive Agents; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-23; Interleukin-4; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappaB-Inducing Kinase; Phenanthrenes; Protein Serine-Threonine Kinases; Serum Amyloid A Protein; Tumor Necrosis Factor-alpha

To study chronic renal interstitial fibrosis induced by aristolochic acid (AA) in animal models.. Female Wistar rats were divided into two groups: AA group (n = 42) peritoneally injected with AA (5 mg.kg-1.d-1) for 16 weeks and control group (n = 5) peritoneally injected with normal saline (2 ml/d) for 16 weeks. The body weight of rats was taken. At week 8, 12, 16, and 24 six rats were killed in the AA group. The five rats in the control group were killed at week 24. Specimens of lood and urine were taken before the animals were killed. Specimens of renal tissue were taken after the animals were killed. Twenty-four hour urine protein, urine beta 2 microglobulin (beta 2-MG), and renal function were tested regularly. Pathological examination, including tubulo-interstitial area calculation, was made to the renal specimens.. The body weight of rats in AA group became significantly lower than that of the control rats after 16 weeks' AA injection (P < 0.01). The blood urea nitrogen (BUN) and serum creatinine (Scr) in AA group increased significantly than those of the control group at the 16th, 20th, and 24th weeks (P < 0.05). Optical microscopy showed tubular-interstitial damage in AA group in 16 weeks. Renal tubular atrophy and multifocal renal interstitial fibrosis were shown in 24 weeks. The area of renal tubule increased and the area of the lumen remarkably decreased at week 16 compared with those in the control group. The area of renal tubule decreased remarkably and the area of renal interstitial greatly in the AA group at week 24. Electrical microscopy showed increase of primary and secondary lysosomes and diasappearence of part of brush border of tubular endothelial cells at week 16, and accumulation of secondary lysosome in cytoplasm at weeks 20 and 24 in the AA group. Histoimmunofluorescence showed that IgG, IgA, IgM, C3, and C1q were negative in the renal tissue of experimental animals.. Animal models with chronic renal tubuloointerstitial nephropathy induced by aristolochic acid were successfully established. Aristolochic acid may have chronic toxicity to renal tissues, and cause chronic renal interstitial fibrosis in rats.

Topics: Animals; Aristolochic Acids; Blood Urea Nitrogen; Body Weight; Carcinogens; Chronic Disease; Creatine; Disease Models, Animal; Female; Fibrosis; Kidney Tubules, Proximal; Nephritis, Interstitial; Phenanthrenes; Rats; Rats, Wistar

To realize and classify the aristolochic acid nephropathy (AAN) according to its clinical and pathological manifestations.. Fifty eight cases in our Division during October 1998 to August 2001 were reviewed, and their clinical, laboratory and pathological manifestations as well as the response of therapy were analyzed. The aristolochic acid (AA) component in some Chinese traditional drugs taken by our patients was detected with thin-layer chromatography (TLC) scan.. AAN might be divided the following three types: (1) acute AAN (n = 4): acute tubular necrosis and acute renal failure were its pathological and clinical characters, respectively. (2) tubular dysfunctional AAN (n = 7): tubular degradation with atrophy, and renal tubular acidosis and/or Fanconi syndrome were its main pathological and clinical manifestations, respectively. (3) chronic AAN (n = 47): renal interstitial fibrosis with few infiltrated mononuclear cells, and chronically progressive renal failure were its dominant pathological and clinical findings, respectively. Steroid therapy was tried to treat some patients with AAN, and a few patients in the first two types obtained some good effects. AA component was demonstrated by the TLC scan in the drugs taken by our patients.. Chinese traditional drugs containing AA are able to cause a special tubulointerstitial nephropathy which may be classified three types with different outcome. To definite effects of steroid on AAN still need to be proved by further studies.

Topics: Adult; Aristolochic Acids; Carcinogens; Chronic Disease; Drugs, Chinese Herbal; Female; Humans; Kidney Tubular Necrosis, Acute; Male; Middle Aged; Nephritis, Interstitial; Phenanthrenes

Topics: Chronic Disease; Humans; Immunity, Active; Otorhinolaryngologic Diseases; Phenanthrenes

Topics: Anti-Bacterial Agents; Chronic Disease; Drug Resistance, Microbial; Humans; Phagocytosis; Phenanthrenes; Suppuration