Contractility of all types of invertebrate and vertebrate muscle is dependent upon the actions and interactions of two divalent cations, viz, calcium (Ca2+) and magnesium (Mg2+) ions. The data presented and reviewed herein contrast the actions of several organic Ca2+ channel blockers with the natural, physiologic (inorganic) Ca2+ antagonist, Mg2+, on microvascular and macrovascular smooth muscles. Both direct in vivo studies on microscopic arteriolar and venular smooth muscles and in vitro studies on different types of blood vessels are presented. It is clear from the studies done so far that of all Ca2+ antagonists examined, only Mg2+ has the capability to inhibit myogenic, basal, and hormonal-induced vascular tone in all types of vascular smooth muscle. Data obtained with verapamil, nimopidine, nitrendipine, and nisoldipine on the microvasculature are suggestive of the probability that a heterogeneity of Ca2+ channels, and of Ca2+ binding sites, exists in different microvascular smooth muscles; although some appear to be voltage operated and others, receptor operated, they are probably heterogeneous in composition from one vascular region to another. Mg2+ appears to act on voltage-, receptor-, and leak-operated membrane channels in vascular smooth muscle. The organic Ca2+ channel blockers do not have this uniform capability; they demonstrate a selectivity when compared with Mg2+. Mg2+ appears to be a special kind of Ca2+ channel antagonist in vascular smooth muscle. At vascular membranes it can (i) block Ca2+ entry and exit, (ii) lower peripheral and cerebral vascular resistance, (iii) relieve cerebral, coronary, and peripheral vasospasm, and (iv) lower arterial blood pressure. At micromolar concentrations (i.e., 10-100 microM). Mg2+ can cause significant vasodilatation of intact arterioles and venules in all regional vasculatures so far examined. Although Mg2+ is three to five orders of magnitude less potent than the organic Ca2+ channel blockers, it possesses unique and potentially useful Ca2+ antagonistic properties.

These results suggest that MCP-1 expression and macrophage infiltration is associated with angiogenic promotion in esophageal SCC. MCP-1 expression may be interactively associated with macrophage infiltration in esophageal SCC; MCP-1 may play an important role in tumor angiogenesis through production of angiogenic factors, such as TP, by recruited macrophages in esophageal SCC. Furthermore, CCR-2 expression in vascular endothelial cells may participate partially in angiogenesis. Clinicopathologically, esophageal SCC patients with MCP-1 expression have no favorable prognosis.

miR-122, a liver-specific microRNA, is one of the determinants for liver tropism of hepatitis C virus (HCV) infection. Although miR-122 is required for efficient propagation of HCV, we have previously shown that HCV replicates at a low rate in miR-122-deficient cells, suggesting that HCV-RNA is capable of propagating in an miR-122-independent manner. We herein investigated the roles of miR-122 in both the replication of HCV-RNA and the production of infectious particles by using miR-122-knockout Huh7 (Huh7-122KO) cells. A slight increase of intracellular HCV-RNA levels and infectious titers in the culture supernatants was observed in Huh7-122KO cells upon infection with HCV. Moreover, after serial passages of HCV in miR-122-knockout Huh7.5.1 cells, we obtained an adaptive mutant, HCV 122KO , possessing G28A substitution in the 5'UTR of the HCV genotype 2a JFH1 genome, and this mutant may help to enhance replication complex formation, a possibility supported by polysome analysis. We also found the introduction of adaptive mutation around miR-122 binding site in the genotype 1b/2a chimeric virus, which originally had an adenine at the nucleotide position 29. HCV 122KO exhibited efficient RNA replication in miR-122-knockout cells and non-hepatic cells without exogenous expression of miR-122. Competition assay revealed that the G28A mutant was dominant in the absence of miR-122, but its effects were equivalent to those of the wild type in the presence of miR-122, suggesting that the G28A mutation does not confer an advantage for propagation in miR-122-rich hepatocytes. These observations may explain the clinical finding that the positive rate of G28A mutation was higher in miR-122-deficient PBMCs than in the patient serum, which mainly included the hepatocytederived virus from HCV-genotype-2a patients. These results suggest that the emergence of HCV mutants that can propagate in non-hepatic cells in an miR-122-independent manner may participate in the induction of extrahepatic manifestations in chronic hepatitis C patients. Author summaryA liver-specific microRNA, miR-122, is one of the key determinants of hepatitis C virus (HCV) hepatotropism and is required for efficient propagation of HCV. On the other hand, chronic infection with HCV is often associated with extrahepatic manifestations (EHMs), and a low level of HCV-RNA replication has been detected in some non-hepatic cells. Nonetheless, the detailed mechanisms underlying these phenomena remain unknown. Here, we show that miR-122 is dispensable for low-level replication or infectious particle formation, and a mutant virus adapted to miR-122-knockout cells exhibited efficient but miR-122-independent propagation. The adaptive virus of HCV genotype 2a possessed a G28A substitution in the 5'UTR and facilitated efficient replication complex formation under an miR-122-deficient condition, while it propagated at a level comparable to the wild type HCV in the presence of miR-122. Moreover, various adaptive mutations including C30U were introduced into genotype...

These results suggest that AFP-producing gastric cancers have high malignant potential (high proliferative activity, weak apoptosis, and rich neovascularization) compared with that of AFP-negative gastric cancers. These biological characteristics of AFP-producing gastric cancer reflect the aggressive behavior and the poor prognosis of patients with this type of cancer.

These results suggest that mutant p53 expression is associated with angiogenesis and distant metastasis in esophageal SCC, and that the coexpression of p53 and VEGF may play an important role in angiogenesis, and have important clinical significance.

These results suggest that AFP-producing gastric cancers have high malignant potential (high proliferative activity, weak apoptosis, and rich neovascularization) compared with that of AFP-negative gastric cancers. These biological characteristics of AFP-producing gastric cancer reflect the aggressive behavior and the poor prognosis of patients with this type of cancer.

1 The aim of the present study was to characterize the subtypes of bradykinin (BK) receptors that evoke the relaxation and contraction induced by BK and to identify the main contracting and relaxing factors in isolated porcine basilar artery by measuring changes in isometric tension and a thromboxane (TX) metabolite. 2 Endothelial denudation completely abolished both responses. [Thi 5,8 , ]-BK (a B 2 -receptor antagonist) inhibited the BK-induced relaxation and contraction, whereas des-Arg 9 , [Leu 8 ]-BK (a B 1 -receptor antagonist) had no e ect. 3 L-nitro-arginine (L-NA, a nitric oxide synthase inhibitor) completely inhibited BK-induced relaxation. Indomethacin (a cyclo-oxygenase inhibitor) completely and ONO-3708 (a TXA 2 / prostaglandin H 2 receptor antagonist) partially inhibited BK-induced contraction, whereas OKY-046 (a TXA 2 synthase inhibitor) and nordihydroguaiaretic acid (a lipoxygenase inhibitor) did not. 4 In the presence of L-NA, the contractile response to BK was inhibited by indomethacin or ONO-3708 and was competitively antagonized by [Thi 5,8 , D-Phe 7 ]-BK (pA 2 =7.50). In the presence of indomethacin, the relaxant response to BK was inhibited by L-NA and was competitively antagonized by [Thi 5,8 , ]-BK (pA 2 =7.59). 5 TXA 2 release was not induced by BK-stimulation. 6 These results suggest that the endothelium-dependent relaxation and contraction to BK in the porcine basilar artery is mediated via activation of endothelial B 2 -receptors. The main relaxing factor may be NO and the main contracting factor may be prostaglandin H 2 .

In patients with liver cirrhosis, treatment with diuretics can increase zinc excretion by suppressing the reabsorption of zinc through renal tubules, which might lead to zinc deficiency.