The clinical impact of the fibrate and thiazolidinedione drugs on dyslipidemia and diabetes is driven mainly through activation of two transcription factors, peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ. However, substantial differences exist in the therapeutic and side-effect profiles of specific drugs. This has been attributed primarily to the complexity of drug-target complexes that involve many coregulatory proteins in the context of specific target gene promoters. Recent data have revealed that some PPAR ligands interact with other non-PPAR targets. Here we review concepts used to develop new agents that preferentially modulate transcriptional complex assembly, target more than one PPAR receptor simultaneously, or act as partial agonists. We highlight newly described on-target mechanisms of PPAR regulation including phosphorylation and nongenomic regulation. We briefly describe the recently discovered non-PPAR protein targets of thiazolidinediones, mitoNEET, and mTOT. Finally, we summarize the contributions of on- and off-target actions to select therapeutic and side effects of PPAR ligands including insulin sensitivity, cardiovascular actions, inflammation, and carcinogenicity.
Immunization of mice with myelin components results in experimental autoimmune encephalomyelitis (EAE), which is mediated by myelin-specific CD4+ T cells and anti-myelin antibodies. Tumor necrosis factor α (TNF-α) and lymphotoxin α (LT-α) are thought to be involved in the events leading to inflammatory demyelination in the central nervous system. To ascertain this hypothesis 129 × C57BL/6 mice with an inactivation of the tnf and lta genes (129 × C57BL/6−/−) and SJL/J mice derived from backcrosses of the above mentioned mutant mice (SJL−/−) were immunized with mouse spinal cord homogenate (MSCH) or proteolipid protein. Both 129 × C57BL/6−/− mice and SJL−/− mice developed EAE. In SJL−/− mice immunized with MSCH, a very severe form of EAE with weight loss, paralysis of all four limbs, and lethal outcome was observed. The histologic hallmark was an intense perivascular and parenchymal infiltration with predominantly CD4+ T cells and some CD8+ T cells associated with demyelination in both brain and spinal cord. These results indicate that TNF-α and LT-α are not essential for the development of EAE.
Recent evidence suggests that macrophages and/or other nonparenchymal cells may release important mediators contributing to the hepatic necrosis induced by high doses of acetaminophen (APAP). The nature and causative role of these mediators has remained elusive, however. To investigate the role of the proinflammatory cytokine, tumor necrosis factor (TNF) in the initiation and early propagation of APAP-induced liver injury, we have used mice deficient in both TNF and the closely related lymphotoxin-␣ (LT-␣). Male TNF/LT-␣ knockout mice and C57BL/6 wild-type mice were treated with a hepatotoxic dose of APAP (400 mg/kg, intraperitoneally), and the development of liver injury was monitored over 8 hours. Both genotypes exhibited similar basal activities of hepatic cytochrome P450 2E1 and 1A2. After APAP administration, both the rate of glutathione consumption and the extent of subsequent selective protein binding did not differ significantly in the knockout and wild-type mice. The TNF/LT-␣-deficient mice developed severe centrilobular necrosis and exhibited highly increased levels of serum alanine aminotransferase and aspartate aminotransferase, the extent of which was not significantly different from that in wild-type mice. In C57BL/6 mice exposed to APAP, no increases in hepatic transcripts of TNF or LT-␣ were found by reverse transcription-polymerase chain reaction, nor was immunoreactive serum TNF detected by enzyme-linked immunosorbent assay over 8 hours posttreatment. These data indicate that, in the absence of the genes encoding for TNF and LT-␣, APAP bioactivation was not altered and mice still developed severe hepatic necrosis. Thus, TNF is unlikely to be a key mediator in the early pathogenesis of APAP-induced hepatotoxicity. (HEPATOLOGY 1998;27:1021-1029.)
Signaling via TNF receptor type 1 (TNFR1) was shown to be crucial in host defense against the intracellular pathogens L. monocytogenes, M. tuberculosis and M. bovis. Toinvestigate the function of TNF and LTα in host defense against M. bovis, mice double deficient for TNF and LTα (TNF / LTα – / –), TNF / LTα – / – mice complemented with a murine LTα transgene (TNF– / –) and LTα – / – mice were infected with BCG and the ensuing pathology was investigated. Control mice showed a normal host defense with early clearance of bacteria. The granulomatous reaction in the liver was accompanied by recruitment of activated macrophages characterized by their acid phosphatase positivity and differentiation into epithelioid cells as well as a coordinated expression of proinflammatory transcripts. In contrast, TNF / LTα – / – mice showed no comparable recruitment of activated macrophages in the liver. Furthermore, these mice showed extensive necrotic pulmonary lesions with massive growth of acid fast bacilli. Reintroduction of LTα as a transgene into TNF / LTα – / – mice prolonged survival but did not restore resistance to BCG. This, at least partially protective role of LTα was further supported by data demonstrating that LTα ‐deficient mice as well were susceptible to BCG infection. In contrast to the deleterious effect of TNF / LTα deficiency in BCG infection, BCG‐infected TNF / LTα – / – mice were tolerant to LPS‐induced shock. These results demonstrate that TNF as well as LTα are involved in murine host defense against BCG and that absence of TNF / LTα protects BCG‐infected mice from LPS mediated shock.
The finding that rosiglitazone may increase risk for cardiovascular events has led to regulatory guidelines requiring demonstration of cardiovascular safety in appropriate outcome trials for new type 2 diabetes mellitus drugs. The emerging data on the possibly increased risk of bladder cancer with pioglitazone may prompt the need for post-approval safety studies for new drugs. Since PPAR-α and -γ affect key cardiometabolic risk factors (diabetic dyslipidemia, insulin resistance, hyperglycemia, and inflammation) in a complementary fashion, combining their benefits has emerged as a particularly attractive option. New PPAR-targeted therapies that balance the relative potency and/or activity toward PPAR-α and -γ have shown promise in retaining efficacy while reducing potential side effects.
The constellation of changes known as the acute phase response (APR) is a cytokine-driven process initiated by tissue inflammation. The proinflammatory cytokines, TNF, IL-1 and IL-6, are considered to be the primary mediators of the APR. IL-6 and IL-1beta gene-deleted mice (Fattori et al., J. Exp. Med. 1994. 180: 1243-1250; Kopf et al., Nature 1994. 368: 339-342; Fantuzzi et al., J. Immunol. 1996. 157: 291-296, respectively), exhibit impaired APR to turpentine injection but only a slight reduction in plasma acute phase protein levels in response to lipopolysaccharide (LPS). This infers an important role for TNF in the LPS-induced APR, however, in the present study, normal APR to both turpentine and LPS were observed in TNF/LTalpha-deficient mice. A striking absence of elevated major acute phase proteins, SAP and SAA, was observed in mice deficient in TNF/LTalpha and IL-6, suggesting that TNF-alpha or LTalpha do indeed exert important nonredundant synergism in the IL-1/IL-6 primary response. The regulation of other parameters typically altered in an APR, body weight, blood glucose and haptoglobin, was normal in LPS-dosed TNF/LTalpha-deficient and wild-type mice. The observed transcriptional response for SAA and SAP in these TNF/LTalpha/IL-6-deficient mice, in lieu of elevated plasma levels, suggests that SAA and SAP expression is possibly posttranscriptionally regulated.
The constellation of changes known as the acute phase response (APR) is a cytokine-driven process initiated by tissue inflammation. The proinflammatory cytokines, TNF, IL-1 and IL-6, are considered to be the primary mediators of the APR. IL-6 and IL-1beta gene-deleted mice (Fattori et al., J. Exp. Med. 1994. 180: 1243-1250; Kopf et al., Nature 1994. 368: 339-342; Fantuzzi et al., J. Immunol. 1996. 157: 291-296, respectively), exhibit impaired APR to turpentine injection but only a slight reduction in plasma acute phase protein levels in response to lipopolysaccharide (LPS). This infers an important role for TNF in the LPS-induced APR, however, in the present study, normal APR to both turpentine and LPS were observed in TNF/LTalpha-deficient mice. A striking absence of elevated major acute phase proteins, SAP and SAA, was observed in mice deficient in TNF/LTalpha and IL-6, suggesting that TNF-alpha or LTalpha do indeed exert important nonredundant synergism in the IL-1/IL-6 primary response. The regulation of other parameters typically altered in an APR, body weight, blood glucose and haptoglobin, was normal in LPS-dosed TNF/LTalpha-deficient and wild-type mice. The observed transcriptional response for SAA and SAP in these TNF/LTalpha/IL-6-deficient mice, in lieu of elevated plasma levels, suggests that SAA and SAP expression is possibly posttranscriptionally regulated.
In the early 1900s, the abnormal toxicity test (ATT) was developed as an auxiliary means to ensure safe and consistent antiserum production. Today, the ATT is utilized as a quality control (QC) release test according to pharmacopoeial or other regulatory requirements. The study design has not been changed since around 1940. The evidence of abnormal toxicity testing as a prediction for harmful batches is highly questionable and lacks a scientific rationale. Numerous reviews of historical ATT results have revealed that no reliable conclusions can be drawn from this QC measure. Modern pharmaceutical manufacturers have thorough control of the manufacturing process and comply with good manufacturing practice rules. Contaminants are appropriately controlled by complying with the validated manufacturing processes and strict QC batch release confirming batch-to-batch consistency. Recognizing that product safety, efficacy, and stability can be ensured with strict QC measures, nowadays most regulatory authorities do not require the ATT for most product classes. In line with the replacement, reduction, and refinement (3Rs) initiative, the test requirement has been deleted from approximately 80 monographs of the European Pharmacopoeia and for the majority of product classes in the United States. For these reasons, it is recommended that the ATT should be consistently omitted world-wide and be removed from pharmacopoeias and other regulatory requirements.
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