Reamberin for pathogenetic therapy of acute and chronic viral diseases of the liver

The study including 427 patients with acute and chronic viral hepatitis was designed to assess results of clinical and laboratory diagnostics of hepatic problems and the state of thiosulfide antioxidative system. It was shown that infusion of succinate-containing preparation reamberin (400 ml/day for 10 days) took less time to eliminate clinical manifestation of the disease (dispeptic and asthenovegetative syndromes) than conventional therapy. Simultaneously the levels of biochemical markers of hepatic cytolysis and cholestasis significantly decreased while serum antioxidative potential recovered. The normal size of the liver was achieved 3.4 times more frequently than in control. No side effects or adverse reactions other than listed in the instruction for use of reamberin occurred. The preparation had to be withdrawn only in one patient.     

Persistent episomal transgene expression in liver following delivery of a scaffold/matrix attachment region containing non-viral vector

An ideal gene therapy vector should enable persistent transgene expression without limitations of safety and reproducibility. Here we report the development of a non-viral episomal plasmid DNA (pDNA) vector that appears to fulfil these criteria. This pDNA vector combines a scaffold/matrix attachment region (S/MAR) with a human liver-specific promoter (alpha1-antitrypsin (AAT)) in such a way that long-term expression is enabled in murine liver following hydrodynamic injection. Long-term expression is demonstrated by monitoring the longitudinal luciferase expression profile for up to 6 months by means of in situ bioluminescent imaging. All relevant control pDNA constructs expressing luciferase are unable to sustain significant transgene expression beyond 1 week post-administration. We establish that this shutdown of expression is due to promoter methylation. In contrast, the S/MAR element appears to inhibit methylation of the AAT promoter thereby preventing transgene silencing. Although this vector appears to be maintained as an episome throughout, we have no evidence for its establishment as a replicating entity. We conclude that the combination of a mammalian, tissue-specific promoter with the S/MAR element is sufficient to drive long-term episomal pDNA expression of genes in vivo.     

Immunocorrective therapy of patients with chronic active liver diseases of a viral nature

A study of the effect of immunocorrective drugs on the clinicobiochemical and immunological indices of patients with chronic active liver diseases of viral nature made it possible to work out criteria for administration of levamisole (the absence of the cytolytic syndrome, the presence of immunodeficiency in the system of cellular immunity and disturbance of immunoregulation), prednisolone, the combination of prednisolone and azathioprine, and d-Penicillamine (severe hepatocellular insufficiency, the presence of autoimmune reactions and disturbance of immunoregulation). The treatment of patients with chronic active diseases with immunocorrective drugs required a strict individual approach taking account of clinicobiochemical, immunological and morphological indices.     

Eicosanoids in chronic liver diseases

Serum levels of eicosanoids in patients suffering from chronic hepatic diseases were analysed in correlation with morphological characteristics of the hepatic lesion, body reactivity, manifestations of the alternative and immune phases of the inflammation. The results could be contributing to diagnosing and treating chronic inflammation in the liver.     

周期性张应力与软骨细胞基质金属蛋白酶的表达**☆

背景：课题组前期研究证实,在关节软骨缺损及骨性关节炎的动物模型中,软骨细胞可过度表达基质金属蛋白酶,各种异常刺激均可能打破基质金属蛋白酶与金属蛋白酶组织抑制因子间平衡,从而导致关节软骨细胞外基质退变,软骨细胞功能下降和失调。目的：观察兔关节软骨缺损修复过程中周期性张应力对软骨细胞基质金属蛋白酶表达的影响。方法：建立兔单侧膝关节软骨缺损模型,术后10周分离软骨细胞体外培养,非手术侧软骨细胞为正常组,术侧软骨细胞随机分为高应力组、低应力组及对照组,加载幅度为 sin10%,0.1,1.0,0 Hz 的周期性张应力,于24 h、48 h、1周、2周和4周后 RT-PCR 测定各组基质金属蛋白酶2,3,9,13的表达。结果与结论：加载周期性张应力24 h 后,正常组及对照组间的基质金属蛋白酶2,3,9,13的表达差异有显著性意义(P <0.05);加载周期性张应力1周、2周及4周后高应力组和低压力组间差异有显著性意义(P <0.05);同时发现,低应力组中基质金属蛋白酶2,3,9,13的表达持续下降,加载周期性张应力24 h 与4周之间的差异有显著性意义(P <0.05)。可见力学载荷可影响兔关节软骨缺损修复过程中基质金属蛋白酶的表达,在细胞分子水平上,关节软骨缺损病理的发生发展与应力相互影响。     

Collagen matrix scaffolds: Future perspectives for the management of chronic liver diseases

Approximately 1.5 billion chronic liver disease(CLD) cases have been estimated worldwide, encompassing a wide range of liver damage severities. Moreover, liver disease causes approximately 1.75 million deaths per year. CLD is typically characterized by the silent and progressive deterioration of liver parenchyma due to an incessant inflammatory process, cell death, over deposition of extracellular matrix proteins, and dysregulated regeneration. Overall, these processes impair the correct functio...     

基质金属蛋白酶与肝癌侵袭和转移的研究进展

近年来研究发现细胞外基质 (ECM )在肿瘤的侵袭和转移过程中起着重要作用 ,金属蛋白酶 (MMPs)通过对ECM的降解而促进肿瘤的转移。现就金属蛋白酶的结构、功能及其与肝癌侵袭、转移的研究进展作一综述     

MMP-2、MMP-9、TIMP-1和TIMP-2在乳腺癌中的表达及临床意义

目的 研究MMP—2、MMP—9、TIMP—1和TIMP—2在乳腺癌中的表达及与临床病理特征的关系。方法 免疫组化SP法检测历例原发性乳腺癌、13例乳腺纤维腺瘤和15例乳腺纤维腺病中的蛋白表达。结果 ①乳腺癌中MMP—2、MMP—9的阳性表达显著高于乳腺纤维腺瘤和纤维腺病(P＜0．05)；②MMP—9的阳性表达与乳腺癌肿瘤大小、临床分期呈正相关(P＜0．05)，伴腋窝淋巴结转移的乳腺癌中MMP—9、MMP—2呈高表达，但TIMP—1显著低表达；乳腺癌中MMP—9与TIMP—1的表达呈负相关(P＜0.05)；③MMP—2、MMP—9表达的乳腺癌患者预后差。结论 乳腺癌中MMP—2、MMP—9表达显著高于乳腺良性病变；可作为判断乳腺癌预后的标记。     

Cell-cell contact activation of fibroblasts increases the expression of matrix metalloproteinases

BACKGROUND: We recently found that direct homotypic cell-cell contacts between human dermal fibroblasts induce a novel form of cell activation leading to non-apoptotic programmed cell death. As the major features of this process we identified massive induction of cyclo-oxygenase-2 and production of inflammatory prostaglandins. On the surface of the decomposing spheroids, activation of the major extracellular proteolytic cascade, plasminogen activation, associated with surface exposure of alpha-enolase, took place. AIM: To further characterize pericellular proteolysis by cell-cell contact-activated fibroblasts we studied the role of the other major extracellular proteolytic system, matrix metalloproteinases (MMPs). METHODS: MMP expression in fibroblast clusters and monolayers was compared using mRNA microarrays and immunoblot analyses. The activities of MMPs were confirmed using MMP inhibitors and caseinolysis. RESULTS: In microarrays MMP-1, -10, and -14 (MT1-MMP) were induced 5.8-, 106-, and 5.6-fold, respectively. These findings were confirmed by immunoblotting. Radial caseinolysis showed low level of proteolytic activity in spheroid-conditioned media; ilomastat, a general inhibitor of MMPs, suppressed 50% of the proteolytic activity thus confirming it to be at least in part due to MMPs. A cocktail of tetracycline-derived MMP inhibitors suppressed lactate dehydrogenase (LDH) release only 11%, and if combined with aprotinin 28%. CONCLUSIONS: Cell-cell contact activation of fibroblasts induced MMP-1, -10, and MT1-MMP expression, suggesting similar signaling to that in inflammation and cancer.