Background/Aims: To determine whether cerivastatin, a newly developed novel synthetic potent statin, exerts a renoprotective effect, we assessed urinary albumin excretion (UAE) and plasma and urinary endothelin (ET)-1 concentrations in normotensive microalbuminuric type 2 diabetes patients with dyslipidemia. Methods: Sixty normotensive type 2 diabetic patients (38 men and 22 women; mean age 56.5 years) with microalbuminuria (20–200 µg/min) and dyslipidemia (total cholesterol >200 mg/dl, LDL cholesterol >160 mg/dl, HDL cholesterol <35 mg/dl, and triglyceride >150 mg/dl) were enrolled in a double-blind study for 6 months, receiving either cerivastatin (0.15 mg/day) or placebo. Plasma and urinary ET-1 concentrations were measured by radioimmunoassay. Results: Cerivastatin did not affect serum creatinine and HbA_1c levels, and reduced systolic blood pressure slightly, but not significantly. Plasma levels of total cholesterol and LDL cholesterol were significantly reduced (p < 0.01), and plasma triglyceride levels were also reduced significantly (p < 0.05) after 6 months of cerivastatin treatment. A concomitant significant decrease in UAE (p < 0.01), and urinary and plasma ET-1 concentrations (p < 0.01) were found during this period. Conclusion: The use of cerivastatin is associated with decreased microalbuminuria and plasma and urinary ET-1 levels in microalbuminuric patients with type 2 diabetic mellitus and speculate that this may represent an amelioration of renal injury.

Receptor tyrosine kinases (RTKs) play important roles in cellular proliferation, differentiation, and survival. We performed reverse transcriptase-polymerase chain reactions (RT-PCR) from enriched embryonic day 5 (E5) chick motoneurons by panning to identify RTKs involved in the early development of motoneuron. In situ hybridization revealed that Cek8, a member of the eph family, was specifically expressed on motoneurons at the brachial and lumbar segments of the spinal cord which innervate limb muscles, and disappeared after the naturally occurring cell death period (E6-E11). Immunohistochemistry using an anti-Cek8 monoclonal antibody showed the localization of Cek8 protein at the cell bodies and axonal fibers of motoneurons and muscles. The unique expression of Cek8 suggests its involvement in cellular survival or cell-cell interactions for specific subpopulations of developing motoneurons.

Statins such as cerivastatin may be beneficial for restoration of injured podocytes in patients with CGN and hypercholesterolaemia.

Proliferating cell nuclear Ag (PCNA) occurs as a component of multiprotein complexes during cell proliferation. We found the complexes to react with murine anti-PCNA mAbs, but not with anti-PCNA Abs in lupus sera. The complexes were purified from rabbit thymus extract by affinity chromatography using anti-PCNA mAbs (TOB7, TO17, and TO30) and analyzed by ELISA, immunoprecipitation, immunoblotting, and HPLC gel filtration. That PCNA was complexed with other proteins was demonstrated by its copurification with a group of proteins excluded by an HPLC G3000 SW column. Although immunoblot analysis showed the mAbs to react exclusively with the 34-kDa PCNA polypeptide, they nonetheless immunoprecipitated the same group of proteins, confirming the interaction of the isolated PCNA with other proteins. Anti-PCNA sera, including AK, which reacts with biologically functional sites on PCNA, did not react with complexed PCNA, but did react with it once it was dissociated from the complexes. PCNA complexes in turn reacted with murine anti-DNA mAbs, as well as with Abs against p21, replication protein A, DNA helicase II, cyclin-dependent kinases 4 and 5, and topoisomerase I. These findings suggest that the PCNA complexes purified using anti-PCNA mAbs comprise the “protein machinery” for DNA replication and cell cycle regulation. They also suggest that anti-PCNA mAbs are useful tools with which to characterize the protein-protein interactions within PCNA complexes, as well as the autoimmune responses to proteins interacting with PCNA, which may shed light on the mechanisms of autoantibody production in lupus patients.

Cytokine LD78 is a human counterpart of the mouse macrophage inflammatory protein la/hematopoietic stem cell inhibitor. Promoters of the LD78a and LD7813 genes showed similar inducible activities in two leukemic cell lines, K562 and Jurkat, but the induction mechanisms differed between the two cell lines. Further characterization of the LD78a promoter indicated that multiple positive and negative regulatory elements are present, some of which are differentially required for induction and repression of the promoter activity in different cells. One of the negative regulatory elements, ICK-1, functioned in both cell lines in the absence and presence of stimulation and was shown to be a recognition site for positive and negative transcriptional factors. This ICK-1 element contained a direct repeat, and similar repeats were also found in the negative regulatory elements of hematopoietic growth factor interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) gene promoters. Nuclear extracts from K562 and Jurkat cells formed several protein-DNA complexes with the LD78a ICK-1 element, one of which was also observed with the IL-3 and GM-CSF ICK-1 elements. Results from in vivo and in vitro analyses suggested that the protein forming this complex functions as a negative factor. The binding affinity of this protein, ICK-1A, to the LD78Oa ICK-1 element was low and was significantly affected by the incubation temperature and the salt concentration in the binding buffer. ICK-lB, another protein bound specifically by the LD78ai ICK-1 element, was shown to be a positive factor important for induction of the promoter. These results suggested that ICK-IA plays an important role in balanced expression of LD78, IL-3, and GM-CSF during hematopoietic cell growth and differentiation.Human LD78 (48), also known as AT464 (69) or GOS19S (2), is a member of a large superfamily of small secreted cytokines involved in cell growth and inflammation (18,49,54). The mouse counterpart of LD78 is macrophage inflammatory protein la (MIP-la) (8), also known as hematopoietic stem cell inhibitor (19) or L2G25B (30). LD78 shows 74% amino acid sequence identity with MIP-la. By using purified recombinant proteins, both LD78 and MIP-la have been shown to suppress proliferation of hematopoietic stem and immature progenitor cells in vitro (3, 5, 19, 58) and in vivo (11, 32). MIP-lt has also been shown to enhance proliferation of more differentiated progenitor cells in vitro (5). In addition, LD78 has been found to stimulate osteoclast differentiation in a rat bone marrow culture system (29). As well as modulating proliferation and differentiation of hematopoietic cells, MIP-lot affects macrophage function in an autocrine manner (12), and LD78 is chemotactic for T lymphocytes (63).Three distinct LD78 genes, clustered on chromosome 17 (21, 23), have been identified (2,23,43). The LD78ot and LD781 genes both consist of three exons and share 94%

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To determine the efficacy of cyclosporin A (CysA) for the treatment of steroid-resistant interstitial pneumonitis (IP), we enrolled 25 patients with various rheumatic diseases and steroid-resistant IP in a pilot study [4 patients with rheumatoid arthritis (RA), 2 with systemic lupus erythematosus (SLE), 11 with polymyositis/dermatomyositis (PM/DM), 4 with systemic sclerosis (SSc), 1 with mixed connective tissue disease (MCTD), 3 with Sjögren syndrome (SS)]. Twelve patients (48%) showed a persistent response to CysA therapy, and 7 of them had PM/DM, including so-called amyopathic DM. Patients with a persistent response had moderately elevated lactate dehydroxygenase (LDH) levels, whereas patients who died had much higher LDH levels and hypoxia. Even patients with low blood levels of CysA achieved a persistent response. In responding patients, the symptoms, chest X-ray findings, arterial oxygen tension, and LDH level all improved after less than 4 weeks. In conclusion, CysA seem to be useful for treating patients with steroid-resistant IP, whose duration is short and severity is mild.