Journal of Cardiothoracic-Renal Research最新文献

Gene expression profiling has the potential to improve individualized etiology diagnosis. A statistical approach based on a multidimensional scaling (MDS) vector model is introduced to construct patient-specific rules for individualized diagnosis based on gene expression profiles. The method has a dual function of discovering new disease classes/subclasses as well as constructing patient-specific diagnostic rules without prior knowledge of class distinction. The diagnostic rule consists of two components: (1) diagnostic gene expression pattern that suggests a critical etiological condition associated with a disease category, and (2) patient-specific correlations to the diagnostic pattern. The method is applied to construct the diagnostic rule for heart failure by which the heart failure etiology has been successfully discerned with gene expression profiles. The diagnostic rule for two potential heart failure sub-classes has been constructed to further classify heart failure patients and exploit related molecular pathogenesis. Furthermore, the diagnostic gene expression patterns reveal molecular mechanisms relevant to heart failure, and facilitate biomarker identification. The method provides an approach to exploring feasibility of gene expression profiling in individualized etiology diagnosis for therapeutic decision-making.

It has been speculated that a reduction in nitric oxide (NO) bioavailability as a result of decreased NO synthase (NOS) cofactor tetrahydrobiopterin (BH₄) plays an essential role in cardiovascular pathologies including dilated cardiomyopathy, ischemia–reperfusion injury, endothelial dysfunction, atherosclerosis, hypertension and diabetes. Treatment remedies towards BH₄ or its rate-limiting enzyme GTP cyclohydrolase I (GTPCH I) have shown some unusual therapeutic promises against cardiovascular diseases. To the contrary, blockade of BH₄ synthesis antagonizes cerebral infarction via inhibition of inducible NOS and ONOO⁻. In addition, GTPCH I may be stimulated by cytokines including interferon-γ, tumor necrosis factor-α and inflammatory mediators, suggesting a possible role of double-edge sword for BH₄ in cardiovascular medicine. Accumulation of free radicals and oxidative stress has been indicated to oxidize BH₄, although the precise role of BH₄ deficiency in cardiovascular pathophysiology remains largely elusive. Recent pharmacological, gene transfer and transgenic studies have provided new insight towards the ultimate understanding of BH₄ in the pathogenesis and therapy of cardiovascular diseases. However, whether BH₄ should be considered as a panacea for NO deficiency is debatable. This review intends to update the picture of pathophysiology of BH₄ deficiency, pros and cons in therapeutics using BH₄ and its rate limiting enzyme GTP cyclohydrolase I (GTPCH I) against NO deficiency.

Background

High cyclosporine (CsA) levels might lead to nephrotoxicity due to increasing angiotensin II (AII) and transforming growth factor-beta (TGF-β) production. We hypothesized that a chronic reduction in CsA levels would decrease local renal AII and TGF-β expression and result in improvement of renal function and renal pathological changes in renal transplant recipients.

Methods

We determined the AII and TGF-β expression by immunohistochemical staining (IHCS) in sequential human renal biopsy specimens in patients with chronic allograft nephropathies (time between biopsies: 15.9 ± 0.8 months) after they had their CsA levels reduced by 50%. Pathological evaluation included percentage expression (%) of interstitial fibrosis and tubular atrophy (FIB), vascular sclerosis (VS), transplant glomerulopathy (TG), and vascular hyalinosis (VH). Serum creatinine (CR, mg/dl) and BUN (mg/dl) levels were also investigated.

Results

Renal pathological score significantly improved with chronic reduction in CsA blood levels (FIB: from 52 to 26%, p < 0.05; VS: from 22 to 5%, p < 0.05; TG: from 40 to 13%, p < 0.05; VH: from 17 to 1.8%, p < 0.05, respectively). Renal function also significantly improved with chronic reduction of CsA blood level (BUN: from 84 ± 14 to 40 ± 3 mg/dl, p < 0.05; CR: from 3.4 ± 0.4 to 2.2 ± 0.1 mg/dl, p < 0.05, respectively). AII and TGF-β IHCS score (0–4) and positive staining area (%) were significantly decreased in patients with chronic reduction in CsA levels.

Conclusion

These data indicate that chronic reduction in CsA diminishes production of renal tissue AII and AT1 receptor expression, and results in decreased fibrosis and improvement of renal function in patients with chronic allograft nephropathy.

Background: 6-(1-Proproxyiminomethyl)-5,8-dimethoxy-1,4-naphthoquinone S-53 (DMNQ S-53) was synthesized to develop a novel anti-tumor agent against lung cancer. Methods: Cytotoxicity assay, DNA fragmentation assay, cell cycle analysis, mitochondrial potential measurement and Western blotting were employed in vitro and also Lewis lung carcinoma (LLC) animal model was used for evaluating the anti-tumor of DMNQ S53 in vivo. Results and conclusions: DMNQ S-53 exerted cytotoxicity against LLC cells with IC₅₀ of ∼5 μM. DMNQ S-53 also increased the sub G1 cell population stained by propidium iodide (PI) as well as ladder-like DNA fragmentation in a concentration dependent manner. Western blot analysis revealed that DMNQ S-53 induced apoptosis was associated with the activation of caspase-9 and -3, cleavage of poly (ADP-ribose) polymerase (PARP) and the increased ratio of Bax to Bcl-2 expression in LLC cells in a concentration dependent manner. In addition, DMNQ S-53 reduced mitochondrial potential suggesting the involvement of the mitochondrial intrinsic pathway. Furthermore, intraperitoneally injection of DMNQ S-53 resulted in the inhibition of the tumor volume/weight of LLC cells inoculated on the flank of C57BL6 mice up to ∼50%. Taken together, these results strongly indicate that DMNQ S-53 may inhibit LLC tumor growth in vitro and in vivo via apoptosis induction through the mitochondria-mediated caspase activation pathway.