phenanthrenes and Body-Weight

Dissociated agonists of the glucocorticoid receptor (DAGRs) show similar antiinflammatory effects but improved tolerability compared with standard glucocorticoid receptor (GR) agonists. The prodrug fosdagrocorat (PF-04171327), with active DAGR metabolite PF-00251802 (Metabolite-1), is postulated to show superior efficacy over placebo and prednisone in patients with moderate to severe rheumatoid arthritis (RA). We investigated the population pharmacokinetics of active Metabolite-1 and its active metabolite PF-04015475 (Metabolite-2) in patients with moderate to severe RA enrolled in a 12-week, phase II, randomized, double-blind study (NCT01393639). A simultaneous fit of a two-compartment model for Metabolite-1 and a one-compartment model for Metabolite-2 provided an adequate fit to the data. Significant covariates included weight, with an additional female effect on clearance of Metabolite-1 (∼26%) and Metabolite-2 (∼33%) compared with males. Age influenced clearance of Metabolite-1. In combination, age, weight, and sex predicted >twofold differences in area under the concentration-time curve of Metabolite-1 at the extremes.

Topics: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Area Under Curve; Arthritis, Rheumatoid; Biological Variation, Population; Body Weight; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glucocorticoids; Humans; Male; Middle Aged; Models, Biological; Organophosphates; Phenanthrenes; Prednisone; Prodrugs; Receptors, Glucocorticoid; Severity of Illness Index; Sex Factors; Young Adult

To investigate the population pharmacokinetics of the antimalarial halofantrine (HF) in healthy volunteers and patients with symptomatic falciparum malaria.. Healthy volunteer data were obtained from six volunteers who received three different doses of HF (250, 500 and 1000 mg) after an overnight fast with a washout period of at least 6 weeks between doses. Patient data (n = 188) were obtained from randomised controlled trials conducted on the Thai-Burmese border in the early 1990s. They were either assigned to receive a total HF dose of 24 mg/kg (8 mg/kg every 6 h for 24 h) or 72 mg/kg (8 mg/kg every 6 to 10 h for 3 days). The population pharmacokinetics of HF were evaluated using non-linear mixed effects modelling with a two-compartment model with first-order absorption.. The population estimates of apparent clearance (CL), volume of compartment one (V1), distributional clearance (CLD) and volume of compartment two (V2) of HF in healthy volunteers were 2453 l/day (102 l/h), 2386 l, 716 l/day (29.8 l/h) and 2641 l, respectively. The population estimates of the PK parameters in patients were 429 l/day (17.9 l/h), 729 l, 178 l/day (7.42 l/h) and 1351 l, respectively. All PK parameters were significantly related to body weight and some were related to sex, sampling method, pre-treatment parasite density and whether patients vomited or not. When the two datasets were analysed jointly using a maximum likelihood method, the population estimates in patients were 196 l/day (8.17 l/h), 161 l, 65 l/day (2.71 l/h) and 89 l, respectively, and the parameters were significantly related to body weight and sex. Bayesian analysis of the patient data, with a diffuse prior based on the healthy volunteer data analysis results, yielded the population estimates 354 l/day (14.8 l/h), 728 l, 162 l/day (6.75 l/h) and 1939 l, respectively.. The pharmacokinetic properties of HF in patients with malaria are affected by several demographic variables as well as other relevant covariates. Apparent differences between the healthy volunteer and the patient data analysis results are not entirely due to differences in bioavailability. For the patient data analysis, the Bayesian method was preferred, as the fitting procedure was more stable, allowing random effects to be estimated for all four dispositional parameters.

Topics: Adolescent; Adult; Antimalarials; Bayes Theorem; Biological Availability; Body Weight; Case-Control Studies; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Likelihood Functions; Malaria, Falciparum; Male; Middle Aged; Models, Biological; Myanmar; Nonlinear Dynamics; Phenanthrenes; Thailand; Tissue Distribution; Young Adult

The clinical efficacy and tolerability of halofantrine, a new antimalarial schizontocide, was studied in a multi-centre trial involving 268 patients ranging in age from 6 months to 58 years. The patients were suffering from acute uncomplicated malaria due to either P. vivax or P. falciparum. Patients were treated orally with 3 doses of halofantrine hydrochloride, 500 mg/6-hourly in adults or 8 mg/kg body weight 6-hourly in children. The overall cure rate was 96.9%. The mean fever clearance time for different species was as follows: P. vivax--39.1 hours, P. falciparum--43.2 hours, mixed infection--60.0 hours, and the mean parasitaemia clearance times were 47.7, 55.1 and 72.0 hours, respectively. Recrudescence was reported in 11 (4.1%) patients, although all of them were parasite-free on Day 7 post-treatment. No haematological or biochemical abnormalities were noted. The drug was very well tolerated and no significant side-effects were reported. Halofantrine was found to be highly effective in acute malaria and offers an important alternative to existing medications.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Antimalarials; Body Weight; Child; Child, Preschool; Female; Fever; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Phenanthrenes; Recurrence; Time Factors; Treatment Outcome

Triptolide is a major active ingredient isolated from the traditional Chinese medicine Tripterygium wilfordii, which has anti-inflammatory, anti-cancer, and immunomodulatory effects. However, in clinical studies, triptolide has toxic side effects on the heart, kidney, liver and reproductive organs. With respect to female reproductive toxicity, damaging effects of triptolide on the ovary have been reported, but it has remained unknown whether oocytes are affected by triptolide. Therefore, this study established a concentration gradient of triptolide exposure in mice using 0 (control), 30, 60, and 90 μg triptolide/kg body weight/day administered by gavage. Triptolide administration for 28 d reduced body weight and ovarian weight and affected the developmental potential of oocytes. The triptolide-treated group exhibited meiotic failure of oocytes due to impaired spindle assembly, chromosome alignment, and tubulin stability. Triptolide was also found to induce mitochondrial dysfunction, autophagy and early apoptosis, iron homeostasis, and abnormal histone modifications. These adverse effects could be associated with oxidative stress induced by triptolide. In conclusion, our findings suggest detrimental effects of triptolide on mouse oocytes and, thus, on female reproduction.

Topics: Animals; Apoptosis; Body Weight; Female; Mice; Oocytes; Oxidative Stress; Phenanthrenes

Cryptotanshinone (CRY) has been demonstrated to reverse reproductive disorders. However, whether CRY is effective in the treatment of polycystic ovary syndrome (PCOS) remains unknown. The aim of the present study was to evaluate the therapeutic potential of CRY in PCOS. A rat model of PCOS was established by daily injection of human chorionic gonadotropin and insulin for 22 days. Total body weight and ovarian weight, as well as the levels of luteinizing hormone (LH) and the LH to follicle‑stimulating hormone (FSH) ratio (LH/FSH) significantly increased in rats with PCOS, compared with controls. Moreover, the levels of testosterone (T), tumor necrosis factor (TNF)‑α and high‑mobility group box 1 protein (HMGB1) also increased. However, CRY treatment attenuated the increase in body weight, ovarian weight, LH, LH/FSH ratio, T, TNF‑α and HMGB1 levels, compared with the PCOS group. Treatment with CRY also reduced NF‑κB/p65, HMGB1 and toll‑like receptor (TLR)4 mRNA and protein expression levels in the ovarian tissue and granulosa cells, both in vitro and in vivo. Thus, CRY significantly mitigated the changes in body weight, ovary weight, hormone levels and inflammatory factor levels observed in rats with PCOS. Thus, CRY protects against PCOS‑induced damage of ovarian tissue, possibly through a regulatory pathway involving HMGB1, TLR4 and NF‑κB.

Topics: Animals; Body Weight; Cell Proliferation; Cell Survival; Disease Models, Animal; Female; Gene Expression Regulation; HMGB1 Protein; NF-kappa B; Organ Size; Phenanthrenes; Polycystic Ovary Syndrome; Rats; Signal Transduction; Toll-Like Receptor 4

This study was carried out to investigate the effects of a triptolide (TP) nanosuspension and methotrexate (MTX) nanosuspension on left ventricular remodeling and cardiac function for autoimmune myocarditis (EAM) in rats. The regulating effects on inflammatory cytokines in the peripheral serum and related mechanisms are also discussed.. First, TP and MTX were prepared as a nanosuspension, and the EAM model was successfully established in rats with cardiac myosin. Then, the effect of TP and MTX suspensions was tested in an EAM model.. Results revealed that both TP and MTX suspensions could reduce the degree of myocardial fibrosis and delay the remodeling process of the left ventricle which could further improve cardiac function. Finally, it was found that inflammatory cytokines in the peripheral serum were regulated by the nonspecific immune system and the inhibition of nuclear factor-κB signaling might have partly occurred due to this mechanism.. In summary, this study provided a complete foundation for EAM therapy of profound clinical relevance.

Topics: Animals; Body Weight; Collagen; Cytokines; Diterpenes; Epoxy Compounds; Heart Function Tests; Heart Ventricles; Male; Methotrexate; Myocarditis; Myocardium; Nanoparticles; NF-kappa B; Organ Size; Particle Size; Phenanthrenes; Phosphorylation; Rats, Inbred Lew; Signal Transduction; Suspensions; Ventricular Remodeling

Macrophages infiltrated in adipose tissue play a key role in obesity. Some traditional pharmaceutical compounds may shift the polarization of recruited macrophages to improve metabolic homeostasis. TanshinoneⅡA (TAN2A) is a major active component of Salvia miltiorrhiza, a traditional anti-inflammatory cardiovascular medicine. In our study, we firstly constructed a phenanthroimidazole derivative of TAN2A named TAN20 by chemical synthesis, then identified its structure by chromatography and hydrogen spectroscopy, and finally examined its effects on immunometabolic responses. We found that TAN20 significantly induced the alternatively-activated (M2) rather than the classically-activated macrophages (M1), mainly through releasing the type II cytokines. Such effects were more pronounced than that from TAN2A. Compared to TAN2A, TAN20 substantially reduced body weight, decreased serum free fatty acid and HOMA-IR, and increased insulin sensitivity in obesity-induced diabetic mice. These effects of TAN20 were further validated on diabetic cynomolgus monkeys, which are closer to human physiological conditions. Taken together, our findings explicitly showed that TAN20 significantly polarized the macrophage and improved metabolic homeostasis in obesity-induced diabetic models, suggesting that TAN20 may be a potential drug against diabetes and obesity.

Topics: Abietanes; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Cell Differentiation; Cell Polarity; Cytokines; Diabetes Mellitus, Experimental; Diet, High-Fat; Fatty Acids, Nonesterified; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Macaca fascicularis; Macrophage Activation; Male; Mice; Mice, Inbred C57BL; Obesity; Phenanthrenes; RAW 264.7 Cells

Excess energy intake leads to metabolic dysfunction, accompanied by oxidative stress and poly(ADP-ribose) polymerase (PARP) activation.. To determine the role of PARP activation in the incidence of metabolic dysfunction, PJ34, the PARP inhibitor, was administered to the oleic acid-treated hepatoma cells and high-fat diet-fed mice. The expression of genes was detected by quantitative real-time PCR and western blotting. Lipid droplets in the cells and tissues were stained with Oil Red O.. PJ34 treatment aggravated oleic acid-induced lipid accumulation in hepatoma cells and induced SREBP1 expression by modulating the modification of transcription factor specificity protein 1 (Sp1). The high-fat diet-mice exhibited hyperglycemia, insulin resistance and lipid accumulation after 3 months of feeding. Although the serum level of lipid was not altered after PJ34 treatment, the expression level of lipogenic gene was up-regulated and the lipid accumulation was increased in the liver tissues of high-fat diet + PJ34-treated mice. In the high-fat diet + PJ34-treated mice, the insulin sensitivity was slightly changed and the levels of blood glucose and serum insulin were decreased compared with the mice fed with a high-fat diet alone.. Taken together, PARP inhibition up-regulated the expression level of lipogenic gene and significantly induced lipid accumulation in the liver, which might worsen lipid metabolism disorders. These data will guide future research into the application of PARP inhibitors in the management of metabolic diseases.

Topics: Animals; Blood Glucose; Body Weight; Cell Line, Tumor; Diet, High-Fat; Glucose; Insulin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Oleic Acid; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Promoter Regions, Genetic; Sp1 Transcription Factor; Sterol Regulatory Element Binding Protein 1; Up-Regulation

Cryptotanshinone is one of the compounds extracted from the root of Salvia miltiorrhiza Bunge. Unlike other tanshinones, only a small number of studies have focused on cryptotanshinone for medical treatment. In the present study, the A549 lung cancer cell line and xenograft models of human lung tumors were used to assess the anti-cancer effect of cryptotanshinone. The effect of cryptotanshinone on human lung cancer, including growth inhibition, cell cycle arrest and apoptosis factors, were identified in vitro, and inhibition of tumor formation, improvement of body condition as well as pathological apoptotic effects were detected in vivo. These results suggested that cryptotanshinone is a potential drug for the treatment and prevention of human lung cancer.

Topics: Animals; Apoptosis; Body Weight; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Humans; Lung Neoplasms; Mice; Phenanthrenes; Tumor Burden; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays

Mature and healthy male lesser bandicoot rats, Bandicota bengalensis (n = 40) were fed on bait (mixture of cracked wheat and powdered sugar in 98:2) containing different concentrations of triptolide (0, 0.15, 0.20 and 0.25% w/w) for 15 days in two-choice trials. Results revealed no significant effect of triptolide treatment on weights of vital organs after 30 and 60 days of treatment withdrawal. A significant (P ≤ 0.05) increase in plasma levels of TP, ALP, ACP, ALT and AST in response to stress induced in groups of rats treated with 0.20 and 0.25% triptolide was observed after 30 days of treatment withdrawal. No significant effect of treatment was observed on histomorphology of liver. A significant (P ≤ 0.05) effect of triptolide treatment was, however, observed on testicular function in the form of reduced diameter of seminiferous tubules and number of various spermatogenic cells indicating effect on spermatogenesis and spermiogenesis. The cell stages affected did not recover fully within 60 days period following treatment withdrawal. The present study suggests the potential of triptolide in the reproductive management of B. bengalensis by way of affecting testicular function.

Topics: Acid Phosphatase; Alanine Transaminase; Alkaline Phosphatase; Animals; Antispermatogenic Agents; Aspartate Aminotransferases; Body Weight; Diterpenes; Epoxy Compounds; Liver; Male; Murinae; Phenanthrenes; Spermatogenesis; Testis

Except its anti-tumour effects, triptolide (TP) also shows multiple pharmacological side activities, such as immune-suppressive and male anti-fertility. To increase the therapeutic index of TP, a novel polymeric micelle system containing TP (TP-PM) has been developed to treat tumour. Our previous studies have demonstrated the good anti-tumour efficacy of TP-PM. This paper investigated the acute toxicity in mice and subacute toxicity in rats of TP-PM and TP. Results demonstrated that the LD50 for TP-PM and TP administered intravenously were 1.06 mg/kg and 0.83 mg/kg in mice, respectively. In subacute toxicity study, TP-PM and TP were administered intravenously at the dose levels of 0.1 mg/kg and 0.3 mg/kg for 14 d. Compared to the control, there was significant decrease in the serum AST activities, the testis ACP activities, thymus index, testis index, and significant increase in spleen index, and obvious histopathological changes in rats treated with TP, however, the toxicities of TP-PM on liver, kidney, testis and spleen are slighter than TP. Compared to TP, TP-PM significantly increased the ACP activity of the testis and decreased the MDA level in serum. So, the polymeric micelles may be a novel drug delivery carrier of TP for reducing the toxicities of TP.

Topics: Administration, Intravenous; Animals; Aspartate Aminotransferases; Body Weight; Diterpenes; Drug Carriers; Drug Delivery Systems; Epoxy Compounds; Female; Kidney; Lethal Dose 50; Liver; Male; Mice; Micelles; Phenanthrenes; Rats; Rats, Wistar; Rodentia; Spleen; Testis; Toxicity Tests, Acute; Toxicity Tests, Subacute

Triptolide is one of the most widely used and one of the most potent Chinese traditional herbal medicines. However, side effects, especially nephrotoxicity, limit the use of triptolide. It has been reported that oxidative stress is involved in drug-induced nephrotoxicity. In the present study, we focused on observing triptolide-induced acute nephrotoxicity in rats and investigating whether or not oxidative stress is involved in the pathogenesis of this process. The results showed that a single large dose peritoneal injection of triptolide caused severe oxidative stress characterized by significant decreases of renal SOD and GSH-Px activities, as well as significant increase of renal MDA content and also led to severe impairment of renal structure and function characterized by injury of renal tubules observed in HE-stained and TUNEL-stained slides and increases of Cre and BUN concentrations in a short time. However, pretreatment with the antioxidant vitamin C significantly ameliorated triptolide-induced depletion in renal SOD and GSH-Px activities, caused marked normalization of renal MDA content and also blunt the impairment of renal tubules and renal function. These results suggest that triptolide induces oxidative stress via impairing the antioxidant system, and oxidative stress contributes, at least in part, to the mechanism of triptolide-induced acute nephrotoxicity.

Topics: Acute Disease; Animals; Antioxidants; Apoptosis; Body Weight; Diterpenes; Drugs, Chinese Herbal; Epoxy Compounds; In Situ Nick-End Labeling; Kidney; Kidney Diseases; Kidney Function Tests; Male; Molecular Structure; Organ Size; Oxidative Stress; Phenanthrenes; Rats; Rats, Sprague-Dawley

Spinal muscular atrophy (SMA) is a progressive neuromuscular disease. Since disease severity is related to the amount of survival motor neuron (SMN) protein, up-regulated functional SMN protein levels from the SMN2 gene are considered a major SMA drug-discovery strategy. In this study, we investigated the possible effects of triptolide, a diterpene triepoxide purified from Tripterygium wilfordii Hook. F., as a new compound for increasing SMN protein.. The effects and mechanisms of triptolide on the production of SMA protein were determined by cell-based assays using the motor neuronal cell line NSC34 and skin fibroblasts from SMA patients. Wild-type (Smn(+/+) SMN2(-/-) , C57BL/6) and SMA-like (Smn(-/-) SMN2) mice were injected with triptolide (0.01 or 0.1 mg·kg(-1) ·day(-1) , i.p.) and their survival rate and level of change in SMN protein in neurons and muscle tissue measured.. In NSC34 cells and human SMA fibroblasts, pM concentrations of triptolide significantly increased SMN protein expression and the levels of SMN complex component (Gemin2 and Gemin3). In human SMA fibroblasts, triptolide increased SMN-containing nuclear gems and the ratio of full-length transcripts (FL-SMN2) to SMN2 transcripts lacking exon 7 (SMN2Δ7). Furthermore, in SMA-like mice, triptolide significantly increased SMN protein levels in the brain, spinal cord and gastrocnemius muscle. Furthermore, triptolide treatment increased survival and reduced weight loss in SMA-like mice.. Triptolide enhanced SMN protein production by promoting SMN2 activation, exon 7 inclusion and increasing nuclear gems, and increased survival in SMA mice, which suggests triptolide might be a potential candidate for SMA therapy.

Topics: Animals; Apoptosis; Blotting, Western; Body Weight; Cell Culture Techniques; Cell Line; Cell Survival; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Epoxy Compounds; Fibroblasts; Gemini of Coiled Bodies; Humans; Kaplan-Meier Estimate; Mice; Mice, Knockout; Molecular Structure; Motor Neurons; Muscular Atrophy, Spinal; Neuroprotective Agents; Phenanthrenes; Real-Time Polymerase Chain Reaction; Survival of Motor Neuron 2 Protein; Transcription, Genetic; Tripterygium; Up-Regulation

This study is designed to investigate the protection of tanshinone IIA (TSIIA) against atherosclerosis in apolipoprotein E deficient (ApoE(-/-)) mice and to explore the mechanisms by focusing on the expressions of scavenger receptors, scavenger receptor-A (SR-A) and CD36. The in vivo study demonstrated that TSIIA (10-90mg/kg) inhibited the atherosclerotic lesions, down-regulated the CD68 protein expression in lesion and decreased the contents of cholesterol in aortas of ApoE(-/-) mice. In addition, TSIIA reduced the serum levels of oxidized LDL (oxLDL) and down-regulated the mRNA expression of CD36, SR-A and peroxisome proliferator-activated receptor gamma (PPARγ) in aortas. The in vitro study showed that TSIIA (0.1-10μM) decreased cholesterol level and DiI-oxLDL uptake in mouse peritoneal macrophages treated with oxLDL (50μg/ml). In addition, TSIIA down-regulated the mRNA and protein expression of CD36 but not that of SR-A in oxLDL treated macrophages. TSIIA also down-regulated the mRNA expression of PPARγ in oxLDL treated macrophages. Furthermore, TSIIA reduced the mRNA expression of CD36 in macrophages treated with PPARγ agonist 15d-PGJ(2) (2μM) or troglitazone (50μM), whereas both 15d-PGJ(2) (0.5-1.5μM) and troglitazone (5-20μM) dose-dependently abolished the down-regulation of CD36 expression by TSIIA in oxLDL treated macrophages. These results suggest that TSIIA attenuates the atherosclerotic lesion in ApoE(-/-) mice, which might be attributed to the properties of both anti-oxidation and down-regulation of scavenger receptors. Furthermore, antagonism of PPARγ might be involved in the down-regulation of CD36 by TSIIA.

Topics: Abietanes; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Aorta, Thoracic; Aortic Valve; Apolipoproteins E; Atherosclerosis; Biological Transport; Body Weight; CD36 Antigens; Cell Survival; Cholesterol; Down-Regulation; Humans; Lipid Metabolism; Lipoproteins, LDL; Liver; Macrophages; Male; Malondialdehyde; Mice; Phenanthrenes; PPAR gamma; RNA, Messenger; Scavenger Receptors, Class A

Triptolide, a diterpenoid triepoxide derived from the Chinese herb Tripterygium wilfordii, exerts an antitumor effect in KB cancer cells through the induction of apoptosis. In this study, we show that triptolide possesses an anticancer effect on drug-sensitive parental KB cells and multidrug-resistant KB-7D and KB-tax cells that overexpress multidrug resistance protein and MDR, respectively. Our data revealed that triptolide decreases the expression of multidrug resistance protein and MDR in both KB-7D and KB-tax cells. It also induces apoptosis in these multidrug-resistant cancer cells by activating caspase-3, and decreasing Mcl-1 and XIAP. Triptolide not only inhibits tumor growth but also induces apoptosis of these drug-resistant cancer cells in xenograft mouse models. Moreover, we also show that triptolide combined with 5-fluorouracil could be an alternative strategy for chemotherapy enhancement. These results indicate the therapeutic value of triptolide on multidrug-resistant cells, and when combined with 5-fluorouracil for the enhancement of cancer therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Body Weight; Caspase 3; Diterpenes; Down-Regulation; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Epoxy Compounds; Fluorouracil; Humans; KB Cells; Myeloid Cell Leukemia Sequence 1 Protein; Phenanthrenes; Proto-Oncogene Proteins c-bcl-2; X-Linked Inhibitor of Apoptosis Protein

Current research on the progression of diabetic nephropathy (DN) suggests many important factors; metabolic disturbance, haemodynamic abnormity, chronic inflammation, oxidative stress, innate immune system activation and podocyte lesion. Triptolide, which is active diterpene purified from the traditional Chinese medicine Tripterygium wilfordii Hook F (TwHF), has anti-inflammatory, anti-oxidative, immunosuppressive and podocyte-protective effects. Herein, we investigated the therapeutic effects of triptolide on DN in db/db diabetic mice and studied the potential mechanisms.. db/db mice with DN were administrated with triptolide or valsartan. After 4, 8 and 12 weeks of treatment, 24-h urine albumin level, blood biochemical parameters and body weight were measured. Glomerulus area, glomerulus volume to Bowman's capsule volume ratio, podocyte changes and inflammatory and oxidative stress markers were quantitatively determined to evaluate renal lesions.. The albuminuria in db/db diabetic mice was markedly attenuated after triptolide treatment, accompanied with alleviated glomerular hypertrophy and podocyte injury. In addition, the inflammation and oxidative stress in the kidneys were also attenuated, accompanied with improved hyperlipidaemia and obesity. The efficacy increased with the prolonging of triptolide treatment, and the efficacy in high-dose triptolide group was superior to that in the low-dose group. The effect of triptolide on glomerular hypertrophy was similar to valsartan, but the effects of triptolide on renal inflammation and oxidative stress were more profound than those of valsartan.. Triptolide can dramatically attenuate albuminuria and renal lesion accompanied with dyslipidaemia and obesity in db/db diabetic mice. It is a new drug that exerts comprehensive protective effects on preventing DN progression.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Body Weight; Chemokine CCL2; Desmin; Diabetic Nephropathies; Diterpenes; Epoxy Compounds; Glomerular Filtration Rate; Immunohistochemistry; Kidney; Lipids; Liver; Mice; Mice, Inbred C57BL; Microscopy, Electron; Phenanthrenes; Podocytes; Reactive Oxygen Species; T-Lymphocytes; Tetrazoles; Valine; Valsartan

Diabetic neuropathy is one of the most common complications in diabetes mellitus. Thus far, effective therapeutic agents for restoring the impaired motor and sensory nerve functions in diabetic neuropathy are still lacking. The antioxidant and neuroprotective properties of tanshinone IIA make it a promising candidate for the treatment of diabetic neuropathy. Therefore, the present study investigated the possible beneficial effect of tanshinone IIA on the impaired nerve functions displayed by a rat diabetic model. Insulin-dependent diabetes in rats was developed by a single dose of streptozotocin (STZ) at 50mg/kg. The diabetic rats were randomly divided into four groups (n=10 in each group), and were intraperitoneally administrated daily for 4 weeks with tanshinone IIA (20mg/kg, 50mg/kg and 100mg/kg), or normal saline from the fourth day after STZ injection, respectively. At the end of tanshinone IIA administration, thermal and mechanical nociceptive threshold were determined by a hot plate test and Von Frey hairs; motor nerve conducting velocity (MNCV) was determined by an electrophysiological method; nerve blood flow (NBF) was detected using a laser Doppler flow meter; Na(+),K(+)ATPase activity, the level of superoxide dismutase (SOD), catalase and malondialdehyde (MDA) in sciatic nerves, and the serum total antioxidant capability were also determined. We found that tanshinone IIA was capable of restoring diabetes-induced deficit in nerve functions (MNCV and NBF), and impairment in thermal and mechanical nociceptive capability. In addition, tanshinone IIA significantly increased the serum total antioxidant capability, improved the activities of Na(+),K(+)ATPase, increased the levels of SOD and catalase, and reduced the MDA level in sciatic nerves in diabetic rats. All the findings indicate the beneficial effect of tanshinone IIA on impaired nerve functions and raise the possibility of developing tanshinone IIA as a therapeutic agent for diabetic neuropathy.

Topics: Animals; Blood Glucose; Body Weight; Catalase; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Drugs, Chinese Herbal; Hyperalgesia; Male; Malondialdehyde; Phenanthrenes; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Sodium-Potassium-Exchanging ATPase; Superoxide Dismutase

Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear receptor that coordinates carbohydrate and lipid metabolism, and is a therapeutic target for type 2 diabetes. Tanshinone IIA (Tan) is a lipophilic diterpene that is widely used to treat cardiovascular diseases in traditional Chinese medicine, and has recently been found to reduce body weight and lower blood lipids. However, its underlying mechanism of antiadipogenic effects remains unknown. Here, we report that Tan inhibits 3T3-L1 preadipocyte differentiation and transcriptional activities of full-length PPARgamma and PPARgamma ligand-binding domains. The effects of Tan are mediated through its property as a natural antagonist of PPARgamma (dissociation constant of an inhibitor value, 2.562 +/- 0.711 microm). Tan treatment reduced adipose mass and body weight, improved glucose tolerance, and lowered the low-density lipoprotein to high-density lipoprotein ratio without changing the food intake in a high-fat diet-induced obese animal model. Our results suggest that the combined properties of Tan in adipogenesis, glucose tolerance, lipogenesis, and cardiovascular protection are beneficial for treating diabetic patients with complex metabolic conditions, in which modulating a single target is often not sufficient to achieve the desired effect.

Topics: 3T3 Cells; Abietanes; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; DNA, Complementary; Female; Flow Cytometry; Genes, Reporter; Glucose Tolerance Test; Lipids; Mice; Mice, Inbred C57BL; Obesity; Phenanthrenes; Polymerase Chain Reaction; PPAR gamma; RNA; Transfection

Diabetic neuropathy is manifested either by loss of nociception (painless syndrome) or by mechanical hyperalgesia and tactile allodynia (pain in response to nonpainful stimuli). While therapies with vasodilators or neurotrophins reverse some functional and metabolic abnormalities in diabetic nerves, they only partially ameliorate neuropathic pain. The reported link between nociception and targets of the anti-inflammatory drug sulfasalazine prompted us to investigate its effect on neuropathic pain in diabetes.. We examined the effects of sulfasalazine, salicylates, and the poly(ADP-ribose) polymerase-1 inhibitor PJ34 on altered nociception in streptozotocin-induced diabetic rats. We also evaluated the levels of sulfasalazine targets in sciatic nerves and dorsal root ganglia (DRG) of treated animals. Finally, we analyzed the development of tactile allodynia in diabetic mice lacking expression of the sulfasalazine target nuclear factor-kappaB (NF-kappaB) p50.. Sulfasalazine completely blocked the development of tactile allodynia in diabetic rats, whereas relatively minor effects were observed with other salicylates and PJ34. Along with the behavioral findings, sciatic nerves and DRG from sulfasalazine-treated diabetic rats displayed a decrease in NF-kappaB p50 expression compared with untreated diabetic animals. Importantly, the absence of tactile allodynia in diabetic NF-kappaB p50(-/-) mice supported a role for NF-kappaB in diabetic neuropathy. Sulfasalazine treatment also increased inosine levels in sciatic nerves of diabetic rats.. The complete inhibition of tactile allodynia in experimental diabetes by sulfasalazine may stem from its ability to regulate both NF-kappaB and inosine. Sulfasalazine might be useful in the treatment of nociceptive alterations in diabetic patients.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Body Weight; Chromatography, High Pressure Liquid; Diabetes Mellitus, Experimental; Ganglia, Spinal; Immunoblotting; Inosine; NF-kappa B p50 Subunit; Pain; Pain Measurement; Phenanthrenes; Rats; Salicylates; Sciatic Nerve; Sulfasalazine; Tandem Mass Spectrometry

As the unique quality control standard of Tabellae Glucosidorum Tripterygii Totorum, triptolide (CAS 38748-32-2) has a narrow therapeutic window. A significant side-effect of triptolide is its male reproductive toxicity the mechanism of which is still unknown. Therefore, in the present study the male reproductive toxicity and toxicokinetics of triptolide were investigated. Male Sprague-Dawley (SD) rats were treated with triptolide by oral administration (gastric infusion; 0, 100, 200, 400 microg/kg) once daily for 8 weeks. At the end of the treatment, the concentrations of triptolide in blood and testis samples were analyzed with liquid chromatography/mass spectrometry (LC/MS) to obtain the toxicokinetic parameters. Triptolide showed a non-linear kinetics profile and was rapidly absorbed but relatively slowly eliminated in the rats. Specifically, an accumulation of triptolide was seen in the testis. In the hematological study, mean corpuscular hemoglobin concentration (MCHC) had a marginal decrease in all triptolide treated groups. Alkaline phosphatase (ALP) in serum increased significantly only in the 400 microg/kg group during clinical chemistry assays although no histopathological change was found in the hematopoietic system or liver. In the male reproductive toxicity studies, the testis and epididymis weights of all triptolide treatment groups decreased significantly. The cauda epididymis sperm content and motility even decreased to zero. Evident changes were observed in the seminiferous tubules and the epididymides of triptolide treated rats (e.g., intraepithelial vacuoles of varying sizes; increased germ cells de generation, exfoliation and tubular atrophy). These findings provide valuable information to estimate the reproductive risk of triptolide in humans.

Topics: Animals; Area Under Curve; Blood Cell Count; Body Weight; Chromatography, High Pressure Liquid; Diterpenes; Epididymis; Epoxy Compounds; Half-Life; Immunosuppressive Agents; Infertility, Male; Male; Mass Spectrometry; Organ Size; Phenanthrenes; Rats; Rats, Sprague-Dawley; Sperm Count; Sperm Motility; Testis

Our goal was to identify the role of poly(ADP-ribose) polymerase (PARP) in cerebrovascular dysfunction in Type 1 diabetes mellitus (T1D). In a first series of studies, rats were assigned to nondiabetic and diabetic (streptozotocin; 50 mg/kg IP) groups. Two to three months after injection of streptozotocin, we examine in vivo responses of pial arterioles to nitric oxide synthase (NOS)-dependent (adenosine diphosphate (ADP), acetylcholine and histamine) and -independent (nitroglycerin) agonists. After the initial examination of reactivity to the agonists, we treated pial arterioles acutely with an inhibitor of PARP (PJ-34; 1 microM), and then we again examined responses to the agonists. In a second series of studies, we examine superoxide production (lucigenin chemiluminescence) by parietal cortex tissue in nondiabetic and diabetic rats. We found that dilation of pial arterioles in response to ADP, acetylcholine and histamine, but not to nitroglycerin, was impaired in diabetic compared to nondiabetic rats. In addition, although PJ-34 did not alter responses in nondiabetic rats, PJ-34 alleviated T1D-induced impairment of NOS-dependent vasodilation. We also found that basal production of superoxide was increased in diabetic compared to nondiabetic rats and that PJ-34 decreased this basal production of superoxide. Our findings suggest that T1D impairs NOS-dependent reactivity of cerebral arterioles by a mechanism that appears to be related to the formation of superoxide via activation of PARP.

Topics: Acetylcholine; Adenosine Diphosphate; Animals; Arterioles; Blood Glucose; Blood Pressure; Body Weight; Cerebrovascular Circulation; Cerebrovascular Disorders; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Enzyme Inhibitors; Histamine; Male; Models, Biological; Nitroglycerin; Parietal Lobe; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Rats; Rats, Sprague-Dawley; Superoxides; Vasodilation

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants present in air and food. Among PAHs, benzo(a)pyrene(BaP), phenanthrene (PH) and pyrene (PY) are considered to be important for their toxicity or abundance. To investigate the changes of biomarkers after PAH exposure, rats were treated with BaP (150 microg/kg) alone or with PH (4,300 microg/kg) and PY (2,700 microg/kg) (BPP group) by oral gavage once per day for 30 days. 7-ethoxyresorufin-O-deethylase activity in liver microsomal fraction was increased in only BaP groups. The highest concentration (34.5 ng/g) of BaP, was found in muscle of rats treated with BaP alone at 20 days of treatment; it was 23.6 ng/g in BPP treated rats at 30 days of treatment. The highest PH concentration was 47.1 ng/g in muscle and 118.8 ng/g in fat, and for PY it was 29.7 ng/g in muscle and 219.9 ng/g in fat, in BPP groups. In urine, 114-161 ng/ml 3-OH-PH was found, while PH was 41-69 ng/ml during treatment. 201-263 ng/ml 1-OH-PY was found, while PH was 9-17 ng/ml in urine. The level of PY, PH and their metabolites in urine was rapidly decreased after withdrawal of treatment. This study suggest that 1-OH-PY in urine is a sensitive biomarker for PAHs; it was the most highly detected marker among the three PAHs and their metabolites evaluated during the exposure period and for 14 days after withdrawal.

Topics: Adipose Tissue; Animals; Benzo(a)pyrene; Biomarkers; Blood Chemical Analysis; Body Weight; Cytochrome P-450 CYP1A1; Environmental Pollutants; Female; Liver; Lymphocytes; Muscle, Skeletal; Organ Size; Phenanthrenes; Pyrenes; Rats; Rats, Sprague-Dawley; Time Factors

The lysosomal system occupies a central and crucial role in cellular food degradation (intracellular digestion), toxic responses and internal turnover (autophagy) of the hepatopancreatic digestive cell of the blue mussel Mytilus edulis. Understanding the dynamic response of this system requires factors affecting performance, conceived as a function of the throughput, degradative efficiency and lysosomal membrane stability, to be defined and quantified. A previous carbon/nitrogen flux model has been augmented by separately identifying lysosomal 'target' material (autophagocytosed or endocytosed proteins, carbohydrates and lipids) and 'internal' material (digestive enzymes and lipid membrane components). Additionally, the whole cell's energetic costs for maintaining lysosomal pH and production of these internal components have been incorporated, as has the potentially harmful effect of generation of lipofuscin on the transitory and semi-permanent lysosomal constituents. Inclusion of the three classes of nutrient organic compounds at the whole cell level allows for greater range in the simulated response, including deamination of amino acids to provide molecules as a source of energy, as well as controlling nitrogen and carbon concentrations in the cytosol. Coupled with a more functional framework of pollutant driven reactive oxygen species (ROS) production and antioxidant defence, the separate and combined effects of three stressors (nutritional quality, nutrient quantity and a polycyclic aromatic hydrocarbon [PAH-phenanthrene]) on the digestive cell are simulated and compare favourably with real data.

Topics: Animal Nutritional Physiological Phenomena; Animals; Autophagy; Body Weight; Computer Simulation; Endocytosis; Energy Metabolism; Hepatopancreas; Lysosomes; Models, Biological; Mytilus edulis; Phenanthrenes; Seasons; Starvation; Time Factors

The activation of the poly(ADP-ribose) polymerase (PARP) plays an important role in the pathophysiology of various diseases associated with oxidative stress. We found increased amounts of poly(ADP) ribosylated proteins in diabetic kidneys of Lepr(db/db) (BKsJ) mice, suggesting increased PARP activity. Therefore, we examined the effects of two structurally unrelated PARP inhibitors (INO-1001 and PJ-34) on the development of diabetic nephropathy of Lepr(db/db) (BKsJ) mice, an experimental model of type 2 diabetes. INO-1001 and PJ-34 were administered in the drinking water to Lepr(db/db) mice. Both INO-1001 and PJ-34 treatment ameliorated diabetes-induced albumin excretion and mesangial expansion, which are hallmarks of diabetic nephropathy. PARP inhibitors decreased diabetes-induced podocyte depletion in vivo and blocked hyperglycemia-induced podocyte apoptosis in vitro. High glucose treatment of podocytes in vitro led to an early increase of poly(ADP) ribosylated modified protein levels. Reactive oxygen species (ROS) generation appears to be a downstream target of hyperglycemia-induced PARP activation, as PARP inhibitors blocked the hyperglycemia-induced ROS generation in podocytes. INO-1001 and PJ-34 also normalized the hyperglycemia-induced mitochondrial depolarization. PARP blockade by INO-1001 and PJ-34 prevented hyperglycemia-induced nuclear factor-kappaB (NFkappaB) activation of podocytes, and it was made evident by the inhibitor of kappaBalpha phosphorylation and NFkappaB p50 nuclear translocation. Our results indicate that hyperglycemia-induced PARP activation plays an important role in the pathogenesis of glomerulopathy associated with type 2 diabetes and could serve as a novel therapeutic target.

Topics: Animals; Apoptosis; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enzyme Activation; Indoles; Kidney; Mice; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Reactive Oxygen Species; Receptors, Cell Surface; Receptors, Leptin

The putative selective estrogen receptor modulator (+)-Z-bisdehydrodoisynolic acid (Z-BDDA) has been found to improve cardiovascular risk in rodents. The objective of this study was to investigate the effectiveness of (+)-Z-BDDA compared with the antidiabetic drug, rosiglitazone, in treating obesity and risk factors associated with the metabolic syndrome.. Female Zucker Diabetic Fatty rats were randomly assigned to three treatment groups for 29 weeks: control (C), 1.8 mg (+)-Z-BDDA/kg diet [control diet + (+)-Z-BDDA (CB)], or 100 mg rosiglitazone/kg diet [control diet + rosiglitazone (CR)]. At sacrifice, physiological, biochemical, and molecular parameters were examined.. CB animals gained less weight and exhibited a decrease in total body lipids (p < 0.05) as compared with C or CR rats. Body weight and total body lipids were the highest in CR rats (p < 0.05). Liver weights in CB and CR rats were lower (p < 0.05) than in C rats, whereas kidney weights were lower in CB (p < 0.05) than in C and CR animals. Fasting plasma glucose was lower (p < 0.05) in the CB and CR animals when compared with C animals. C rats exhibited the highest concentration of total plasma cholesterol, and CR-treated rats exhibited the lowest concentration. Plasma triglycerides followed the same pattern as plasma cholesterol. Histomorphometry of heart vasculature revealed that CB and CR treatments produced a significant shift from small to large venules and arterioles compared with C (p < 0.05). Liver expression profiles of peroxisome proliferator-activated receptor (PPAR) alpha, PPARgamma, and PPAR-regulated genes revealed encouraging CB-induced effects.. These results suggest that (+)-Z-BDDA may have applications in treating obesity and complications associated with the metabolic syndrome.

Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Coronary Vessels; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Gene Expression; Hypoglycemic Agents; Kidney; Liver; Metabolic Syndrome; Obesity; Organ Size; Phenanthrenes; PPAR alpha; PPAR gamma; Random Allocation; Rats; Rats, Zucker; Risk Factors; Rosiglitazone; Selective Estrogen Receptor Modulators; Thiazolidinediones; Triglycerides

To investigate the skeletal effects of total tanshinone in ovariectomized rats by analyzing cancellous bone histomorphometry of fourth lumbar vertebrae (LV4) and proximal tibial metaphyses (PTM).. Four-month-old Sprague-Dawley female rats were sham-operated and treated with vehicle or ovariectomized and treated with either vehicle, total tanshinone (200 mg x kg(-1) x d(-1), equivalent to 35 microg x kg(-1) x d(-1) of tanshinone II A and 16 microg x kg(-1) x d(-1) of cryptotanshinone), or 17alpha-ethynylestradiol (30 microg x kg(-1) x d(-1) as positive treatment group) starting one day post-surgery for 10 weeks. Double in vivo fluorochrome labeling was administered to all rats. The undecalcified longitudinal LV4 and PTM sections were cut and stained with Goldner's Trichrome (4-microm thickness) or unstained (8-microm thickness) for the bone histomorphometric analysis.. A significant decrease in trabecular bone volume (BV/TV) and trabecular number (Tb.N) and a significant increase in osteoclast surface (OCS/BS) and mineralizing surface (MS/BS) were found in both LV and PTM of vehicle-treated OVX rats compared with sham controls. Tanshinone completely prevented the decreases in BV/TV and Tb.N and the increase in OCS/BS in the LV4, and partially prevented the decreases in BV/TV and Tb.N in the PTM of OVX rats. In addition, tanshinone increased trabecular thickness (Tb.Th) whereas it did not alter MS/BS. Moreover, tanshinone had no effect on uterine weight and body weight of OVX rats. Estrogen treatment increased BV/TV and Tb.N and decreased OCS/BS, but, also markedly decreased MS/BS and increased uterine weight in OVX rats.. The current study demonstrated that the adequate supply of tanshinone prevented OVX-induced cancellous bone loss in rats through inhibition of elevated bone resorption.

Topics: Abietanes; Animals; Body Weight; Bone Density; Bone Resorption; Drugs, Chinese Herbal; Ethinyl Estradiol; Female; Lumbar Vertebrae; Organ Size; Osteoclasts; Ovariectomy; Phenanthrenes; Rats; Rats, Sprague-Dawley; Tibia; Uterus

Poly(ADP-ribose) polymerase activation depletes NAD+ and high-energy phosphates, activates protein kinase C, and affects gene expression in various tissues. This study was designed to characterise the effects of the potent, orally active poly(ADP-ribose) polymerase inhibitor PJ34 in the Wistar rat model of early diabetic neuropathy.. Control and streptozotocin-diabetic rats were maintained with or without PJ34 treatment (30 mg x kg(-1) x day(-1)) for two weeks, after two weeks without treatment. Endoneurial blood flow was assessed by hydrogen clearance; metabolites and high-energy phosphates were assayed by enzymatic spectrofluorometric methods; and poly(ADP-ribose) was detected by immunohistochemistry.. Blood glucose concentrations were increased to a similar extent in untreated and PJ34-treated diabetic rats compared with controls. Intense poly(ADP-ribose) immunostaining was observed in the sciatic nerve of diabetic rats, but not in other groups. Final sciatic motor nerve conduction velocity and digital sensory nerve conduction velocity were reduced by 24% and 22% respectively in diabetic rats compared with controls (p<0.01 for both), and both were 98% corrected by PJ34 (p<0.01 vs diabetic group for both). In contrast, with PJ34 treatment, nerve blood flow showed a modest (17%) increase, and vascular conductance showed a tendency to increase. Free mitochondrial and cytosolic NAD+:NADH ratios, assessed from the glutamate and lactate dehydrogenase systems, phosphocreatine concentrations, and phosphocreatine:creatine ratios were decreased in diabetic rats and essentially normalised by PJ34. In both untreated and PJ34-treated diabetic rats, nerve glucose, sorbitol and fructose were increased to a similar extent. PJ34 did not affect any variables in control rats.. Short-term poly(ADP-ribose) polymerase inhibitor treatment reverses functional and metabolic abnormalities of early diabetic neuropathy. Complete normalisation of nerve blood flow is not required for correction of motor or sensory nerve conduction velocities, provided that a therapeutic agent can restore nerve energy state via direct action on Schwann cells.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Diuretics; Enzyme Inhibitors; Male; Motor Neurons; NAD; Neural Conduction; Neurons, Afferent; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Wistar; Sciatic Neuropathy; Sorbitol

Two fluorimetric HPLC methods are described for the quantification of naphthols, phenanthrols and 1-hydroxypyrene (1-OHP) in urine specimens obtained from male Wistar rats exposed to naphthalene, phenanthrene and pyrene. The polycyclic aromatic hydrocarbons (PAHs) were given intraperitoneally, either alone (1.0 mmol/kg body weight) or as an equimolar mixture (0.33 mmol/kg), using the same dosages for repeated treatments on week 1 and week 2. Between these treatments, PAH-metabolizing activities encoded by aryl hydrocarbon (Ah) receptor-controlled genes were induced in the rats with beta-naphthoflavone (betaNF). Chromatographic separation of five phenanthrols (1-, 2-, 3-, 4-, and 9-isomers) was accomplished using two different RP C-18 columns. Despite selective detection (programmable wavelengths), the quantification limits in the urine ranged widely: 1-OHP (0.18 microg/l)

Topics: Administration, Oral; Animals; beta-Naphthoflavone; Biomarkers; Body Weight; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP1A1; Drug Therapy, Combination; Environmental Monitoring; Enzyme Induction; Genetic Variation; Injections, Intraperitoneal; Liver; Male; Naphthols; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Pyrenes; Rats; Rats, Wistar; Reproducibility of Results

Four truck drivers involved in a humanitarian mission across the Sahara towards Mali fell ill 15 days after their return. Plasmodium falciparum malaria (thankfully, non pernicious) was diagnosed with 3 to 4 days delay. The four drivers had been treated with chloroquine and proguanil but the dosage may have been insufficient with regard to their body weight (average weight = 110 kg). These 4 travelers had all slept outside (in Tintane, near Kiffa in Mauritania), without any anti-vectorial protection, whereas their other 8 companions (none of whom caught malaria) had slept in their vehicles. The evolution of the 4 cases was favourable despite the difficulties involved in urgently obtaining sufficient amounts of quinine for treatment. How can these cases be explained in relation to prophylactic treatment of associated chloroquine and proguanil? One explanation might be resistance of the P. falciparum strain. We were unable to study this possibility. The high incidence and similitude of cases points towards a hypothesis of resistance both to proguanil and chloroquine. Resistance to chloroquine, as has been formally ascertained in Mauritania, reinforces such a conviction. And yet prophylaxis does not prevent pernicious malaria. This clinical form of the disease, with P. falciparum primo-invasion occurring under rigorous chemoprophylaxis is characteristic of a partially resistant strain. The most reasonable explanation besides "chance" is that we are dealing here with a partially resistant strain of Plasmodium falciparum which is thus also partially sensitive to--in this case highly effective--therapeutic treatment. Indeed, chloroquino-resistant strains are more sensitive to mefloquine and halofantrine. Another explanation might be under-dosage of Savarine with relation to the body weight of these 4 patients. We should be aware of adapting more rigorously the posology of prescribed prophylaxis. But above all, this outbreak should remind us that we should recommend to travelers and drivers planning a trip to Sub-Saharan Africa to take with them anti-vectorial protective gear. Finally, the observation of these cases indicates once more the difficulty in France of establishing a proper diagnosis in face of malaria. Health personnel must systematically call to mind malaria in face of thrombopenia or fever following a sojourn in an endemic area even when chemoprophylaxis has been correctly followed.

Topics: Adult; Altruism; Animals; Antimalarials; Body Weight; Chemoprevention; Chloroquine; Drug Resistance; Humans; Malaria, Falciparum; Male; Mali; Mauritania; Middle Aged; Morocco; Phenanthrenes; Plasmodium falciparum; Proguanil; Quinine; Travel

Chinese-herb nephropathy (CHN) is a rapidly progressive renal fibrosis associated with the intake of a Chinese herb (Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acids (AA). This study attempted to reproduce the main features of human CHN (renal failure, tubular atrophy, and interstitial fibrosis) in a rat model similar to that of cyclosporin-induced nephropathy. Salt-depleted male Wistar rats received daily subcutaneous injections of either 1 mg/kg body wt AA (low-dose AA group), 10 mg/kg body wt AA (high-dose AA group), or vehicle (control group) for 35 d. On days 10 and 35, assessment of renal function, measurements of urinary excretion of glucose, protein, and leucine aminopeptidase, and histologic analyses were performed (six rats euthanized/group). High-dose AA induced glucosuria, proteinuria, and elevated serum creatinine levels and reduced leucine aminopeptidase enzymuria on days 10 and 35, whereas low-dose AA had no significant effect. Tubular necrosis associated with lymphocytic infiltrates (day 10) and tubular atrophy surrounded by interstitial fibrosis (day 35) were the histologic findings for the high-dose AA-treated rats. In both AA groups, urothelial dysplasia was also observed, as well as fibrohistiocytic sarcoma at the injection site. A short-term model of AA-induced renal fibrosis was established in salt-depleted Wistar rats. These results support the role of AA in human CHN and provide a useful model for examination of the pathophysiologic pathways of renal fibrosis.

Topics: Animals; Aristolochic Acids; Body Weight; Carcinoma, Transitional Cell; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Fibrosis; Injections, Subcutaneous; Kidney; Kidney Failure, Chronic; Kidney Tubules; Male; Pelvic Neoplasms; Phenanthrenes; Rats; Rats, Wistar; Reference Values; Sarcoma; Sodium Chloride; Survival Analysis

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 further evaluate the antifertility effects of tripchlorolide, a derivative of triptolide produced at the extraction procedure of Tripterygium wilfordii Hook. f., in male rats and to investigate its sites and possible mechanisms of action.. In male rats, tripchlorolide was given by oral garage at a dose of 50 micrograms.kg-1.d-1 for 5 weeks, fertility was assessed by mating tests, and biochemical indices and light microscopic observation of the epididymides and testes were also performed.. Administration of tripchlorolide at 50 micrograms.kg-1.d-1 for 3 weeks did not influence the fertility of male rats, but 5-week treatment rendered the rats infertile. The density and motility of spermatozoa collected from cauda epididymides were reduced significantly. The epididymal weights, as well as the L-carnitine concentration and alpha-glucosidase content in the epididymal fluid were decreased. There were no significant differences in alpha-glucosidase and acid phosphatase (ACP) in caput epididymal homogenates between the control and the experimental rats. Obvious morphological changes were observed in the epididymal spermatozoa, mainly including head and tail separation or acrosome curving. Sloughed spermatids were found in the seminifeous and epididymal tubules. In testicular homogenates, tripchlorolide had no influence on the lactate dehydrogenase-C4 (LDH-C4) and hyaluronidase activities. No apparent lesions were observed in the seminiferous and epididymal epithelium.. At the dose level employed, tripchlorolide has a significant effect on the fertility in male rats and the primary sites of action may be spermatids and testicular and epididymal spermatozoa.

Topics: Animals; Body Weight; Contraceptive Agents, Male; Diterpenes; Epididymis; Fertility; Male; Organ Size; Phenanthrenes; Rats; Rats, Sprague-Dawley; Sperm Motility; Testis

Doisynolic acids are non-steroidal estrogenic compounds originally obtained from alkali fusion of estrone and equilenin. Z-bisdehydrodoisynolic acids (Z-BDDA) exhibit a low binding affinity accompanied by a disproportionately high biologic activity. Two experiments were designed to investigate the chronic effects of (+)-, (-)- and (+/-)-Z-BDDA and (+)-17beta-estradiol (E2) in male and female rats. The (+)-, (-)- and (+/-)-forms Z-BDDA were prepared and injected, daily for four to six weeks into male and female rats and changes in body weight, food intake, metabolic parameters, and reproductive parameters were investigated. Results from both experiments demonstrate that in male and female rats, (+)- and (+/-)-Z-BDDA had similar estrogenic effects on reproductive organ weight. Surprisingly, (-)-Z-BDDA did not induce the increase in uterine weight observed with (+)- and (+/-)-Z-BDDA and E2, demonstrating selective estrogen receptor modulation (SERM). Beneficial metabolic effects, although compound- and gender-specific, included a significant weight repression, reduction in cholesterol, reduction in blood glucose, and positive alterations in body fat distribution. Future research defining the optimal dosages of (-)-Z-BDDA that will maximize beneficial effects and minimize undesirable effects on reproductive tissues will lead to more efficacious treatment options for endocrine-responsive conditions in males and females.

Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Eating; Estradiol; Female; Male; Organ Size; Phenanthrenes; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Reproduction; Stereoisomerism; Testis; Testosterone; Uterus

The effects of dietary intake and intraperitoneal (i.p.) administration of an extract of the spice rosemary and of the rosemary constituent carnosol on the liver activities of glutathione-S-transferase (GST) and NAD(P)H-quinone reductase (QR) in the female rat were evaluated. Rosemary extract at concentrations from 0.25 to 1.0% (by wt.) in the diet resulted in a significant 3.5- to 4.5-fold increase in liver GST and a 3.3- to 4.0-fold increase in liver QR activities compared to controls. Carnosol supplemented in the diet at levels from 0.01 to 1.0% did not enhance GST activity. When rosemary extract and carnosol were administered i.p. there was a significant increase in liver GST and QR activities. The injection of rosemary extract (200 mg/kg) was associated with 1.5-fold and 3.2-fold increases in GST and QR activities, respectively, compared to controls. The injection of carnosol at doses from 100 to 400 mg/kg was associated with 1.6- to 1.9-fold increases in GST activity and 3.1- to 4.8-fold increases in QR activity, compared to controls. These data indicate that rosemary extract in the diet or injected i.p. and carnosol administered i.p. are effective enhancers of the in vivo activity of liver GST and QR in the female rat.

Topics: Abietanes; Animals; Anticarcinogenic Agents; Antioxidants; Body Weight; Female; Glutathione Transferase; Liver; Phenanthrenes; Plant Extracts; Quinone Reductases; Rats; Rats, Sprague-Dawley; Spices; Stimulation, Chemical

The nephrotoxic action of aristolochic acid (AA) was investigated in female Wistar rats given single doses of 10, 50 or 100 mg/kg by gastric tube. Renal lesions developed within 3 days, the effect being dose-dependent. Histologically, there was evidence of necrosis of the epithelium of the renal tubules, and functionally, there were rises in plasma creatinine and urea together with increases in urinary glucose, protein, N-acetyl-beta-glucosaminidase, gammaglutamyl transferase and malate dehydrogenase. Taking AA as an example, the aim of the present study was to consider the suitability of this model, based on a combination of histology and laboratory investigations, as a short-term test for the detection of nephrotoxic agents.

Topics: Animals; Aristolochic Acids; Body Weight; Carcinogens; Creatinine; Dose-Response Relationship, Drug; Female; Kidney; Kidney Diseases; Kidney Function Tests; Organ Size; Phenanthrenes; Rats; Rats, Wistar; Urea

Topics: Adult; Aged; Body Weight; Glycyrrhiza; Humans; Hypotension, Orthostatic; Middle Aged; Phenanthrenes; Plants, Medicinal; Potassium; Retinal Artery; Tranquilizing Agents

Topics: Androgens; Antimetabolites; Body Weight; Female; Humans; Male; Organ Size; Ovary; Pharmacology; Phenanthrenes; Progestins; Prostate; Research; Seminal Vesicles; Testis; Uterus

Topics: Animals; Body Weight; Body Weights and Measures; Nutritional Sciences; Phenanthrenes; Rats; Steroids; Weight Gain