肝纤维化的胶原代谢及其相关治疗的研究

肝纤维化是大多数慢性肝病所共有的病理特征 ,其本质是肝内细胞外基质合成大于降解而导致过度沉积。胶原是细胞外基质的主要组成成分 ,因此 ,有效抑制胶原的合成、促进胶原降解是抗肝纤维化的一条重要途径。本文就肝纤维化的胶原代谢和抗肝纤维化治疗作一综述。     

Remodeling of the myocardium and potential targets in the collagen degradation and synthesis pathways

Remodeling of the myocardium is the major mechanism for disability and death in prevalent cardiovascular diseases such as hypertension, heart failure and myocardial infarction (MI). It is a complex process that involves changes in structure, shape and topography at the global level and changes in myocytes and non-myocytes at cellular and subcellular levels that impact negatively on function. Although the myocytes subserve the heart's pump function, the predominant cell type in the heart is the fibroblast (not the myocyte). The fibroblast's major role is deposition of the extracellular matrix (ECM) of which collagen is the principal component. The cardiac extracellular collagen matrix (ECCM) maintains structural and functional integrity, and contributes to coordinated mechanical action with every systole during life. Excessive collagen deposition or pathological fibrosis is an important contributor to left ventricular (LV) dysfunction and poor outcome in hypertension, MI and heart failure. It is also an important problem in the aging heart. Antifibrotic agents that target steps in the collagen synthesis and degradation pathways therefore represent promising strategies for these diseases. Because reparative fibrosis is an essential component of healing of the infarct zone (IZ) after MI, the design of approaches that separately target the IZ and non-infarct zone (NIZ) is challenging. It may be possible in future to target the collagen pathways in the heart or regions of the heart, and not other areas or organs, by delivering drugs or genes locally to specific regions.     

Calcium ethylenediaminetetraacetate (CaEDTA) toxicity—Effect of lysosomal stabilizers and labilizers on CaEDTA-induced collagen degradation in the rat

Degradation of collagen accompanies the progression of CaEDTA toxicity in the rat. After the parenteral administration of CaEDTA (6 m-moles/kg/24 hr, constant i.v. infusion for 48 hr), the urinary excretion of hydroxyproline is markedly increased. Radioisotope studies indicated that the source of this enhanced urinary hydroxyproline is the degradation of both mature and immature collagen. The present study was concerned with the effect of known lysosomal stabilizers and labilizers on CaEDTA-induced collagen breakdown. Massive doses of cortisol (50 mg/kg/8 hr, i.m.), as well as other anti-inflammatory agents believed to stabilize lysosomal membranes, were administered together with CaEDTA to rats. The concurrent administration of cortisol partially antagonized the degradative action of CaEDTA as evidenced by a significant reduction in urinary hydroxyproline excretion. Radioisotope labeling experiments traced this reduction in urinary hydroxyproline to inhibition of CaEDTA-induced degradation of mature (insoluble) collagen. In contrast, the concurrent administration of CaEDTA and vitamin A palmitate (250,000 I.U./kg/12 hr, s.c.), a lysosomal labilizer, produced a synergistic increase in urinary hydroxyproline excretion which was the result of increased breakdown of newly formed (soluble, immature) collagen. These results suggest that lysosomal mechanisms play a role in the degradation of collagen produced by CaEDTA.     

Large artery stiffness and antihypertensive agents

Purpose of Review: Since in hypertensive populations, concentration on peripheral blood pressure only does not achieve 100% of blood pressure-attributable risk reduction, taking into consideration other hemodynamic parameters than peripheral blood pressure could perhaps improve cardiovascular prevention. The main purpose of this review is to analyse the scientific data in favour of considering arterial stiffness parameters as interesting intermediate cardiovascular endpoints in order to optimise risk assessment and risk reduction strategies. Summary: Aortic pulse wave velocity (PWV), a marker of aortic stiffness, has been shown to be a strong independent predictor of cardiovascular morbid events, cardiovascular and all-cause mortality in numerous studies in different populations. Furthermore, it has been shown in a therapeutic trial that the lack of aortic PWV attenuation despite significant drug-induced reduction in mean blood pressure was a significant predictor of cardiovascular death in subjects with end-stage renal disease. In essential hypertension, the Reason Study has shown that, despite a similar decrease in peripheral diastolic blood pressure, different effects on central hemodynamic parameters were observed between blockade of the renin-angiotensin system and atenolol. Novel therapeutic approaches available to reduce the increase of pulse pressure and arterial stiffness with age involve converting enzyme inhibitors in association with diuretic compounds; nitrate derivatives; agents acting on collagen cross-linking; and finally spironolactone and vasopeptidase inhibitors. Conclusion: These results support the hypothesis that measurement of aortic PWV could then help, not only in risk assessment strategies but also in risk reduction strategies by monitoring arterial stiffness under different pharmacological regimens.     

Drug-induced gingival overgrowth--a review

Drug-induced gingival overgrowth is a side effect associated with 3 types of drugs: anticonvulsants (phenytoin), immunosuppressive agents (cyclosporine A), and various calcium channel blockers for cardiovascular diseases. Gingival overgrowth is characterized by the accumulation of extracellular matrix in gingival connective tissues, particularly collagenous components with various degrees of inflammation. Although the mechanisms of these disorders have not been elucidated, recent studies suggest that these disorders seem to be induced by the disruption of homeostasis of collagen synthesis and degradation in gingival connective tissue, predominantly through the inhibition of collagen phagocytosis of gingival fibroblasts. The integrins are a large family of heterodimeric transmembrane receptors for extracellular matrix molecules. alpha2beta1 integrin serves as a specific receptor for type I collagen on fibroblasts, and alpha2 integrin has been shown to play a crucial role in collagen phagocytosis. Actin filaments, which are assembled from monomers and oligomers, are involved in collagen internalization after binding to integrins. Furthermore, the implication of intracellular calcium in the regulation of integrin-mediated binding activity and gelsolin activity, known as a calcium-dependent actin-severing protein, is also described. In this review, we focus on collagen metabolism in drug-induced gingival overgrowth, focusing on the regulation of collagen phagocytosis in fibroblasts.     

The effect of pyridazine compounds on the cardiovascular system

Many natural as well as synthetic heterocylic compounds are known to have different biological activities. The pyridazine moiety is an important structural feature of many biologically active compounds and show diverse pharmacological properties. Pyridazines hold considerable interest relative to the preparation of organic intermediates and physiologically active compounds. However, some compounds bearing pyridazinone rings have been reported to be effective in different cardiovascular diseases. On the basis of the reported literature, we study here on pyridazine compounds to their different biological activities on cardiovascular system. Pyridazinones further draw our focused attention because of their easy fictionalization at various ring positions, which makes them attractive synthetic compounds for designing and development of novel pyridazinone as cardiotonic agents in future.     

Tetracyclines: drugs with huge therapeutic potential

Tetracyclines are an amazing class of chemical agents with multiple therapeutic potential. Structural modification of the original natural tetracyclines led to the synthesis and development of doxycycline and minocycline, compounds with higher lipophilicity, better oral pharmacokinetics and higher potency. Due to diverse pharmacological properties, these drugs are now under extensive investigation for use in the treatment of various disparate diseases. In recent years, several studies have conclusively reported anti-inflammatory, immune-modulating and neuroprotective effects of these compounds. There are currently over 200 ongoing clinical trials on tetracyclines. These studies extend over a wide range of diseases including dermatological diseases, behavior and mental disorders, immune system disorders, cardiovascular diseases, and cancer. In this review we will discuss the chemistry and pharmacology of these agents, and describe how their inhibitory effect on matrix metalloproteinase and on pro-inflammatory cytokines has kindled renewed interest in them. Based on the reports from pre-clinical and clinical trials, the therapeutic potential and application of tetracyclines may well be redefined and extensively extended.     

Active phytochemicals from Chinese herbs as therapeutic agents for the heart

Naturally occurring plant alkaloids, in particular those identified from herbal medicines, are finding therapeutic use. Heart diseases can be well managed with specific formulations of herbal medicines. The combined action of multiple constituents of herbal medicines works with therapeutic benefits in humans. The established formulations of Traditional Chinese medicines show efficacy in treatment of diseases. However, individual herbal principles seldom show pharmacological activity. Nevertheless, some of the active alkaloids and terpenoids from medicinal herbs have been identified. The pharmacological activities of these herbal compounds have been studied. These active constituents of herbal medicine are also used in nutrient supplements, but the modes of action of the active component remain sketchy. The present review describes the recent development of those active principles from herbal medicines as cardiovascular agents. The study will provide insights into herbal medicines for drug development for the treatment of cardiovascular disease.     

Imidazo[2,1-b]thiazole system: a scaffold endowing dihydropyridines with selective cardiodepressant activity

The synthesis, characterization, and functional in vitro assays in cardiac tissues and smooth muscle (vascular and nonvascular) of a number of 4-imidazo[2,1- b]thiazole-1,4-dihydropyridines are reported. The binding properties for the novel compounds have been investigated and the interaction with the binding site common to other aryl-dihydropyridines has been demonstrated. Interestingly, the novel 4-aryl-dihydropyridines are L-type calcium channel blockers with a peculiar pharmacological behavior. Indeed, the imidazo[2,1- b]thiazole system is found to confer to the dihydropyridine scaffold an inotropic and/or chronotropic cardiovascular activity with a high selectivity toward the nonvascular tissue. Finally, molecular modeling studies were undertaken for the most representative compounds with the aim of describing the binding properties of the new ligands at molecular level and to rationalize the found structure-activity relationship data. Due to the observed pharmacological behavior of our compounds, they might be promising agents for the treatment of specific cardiovascular pathologies such as cardiac hypertrophy and ischemia.     

Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K

We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.     

Dexamethasone inhibits collagen degradation induced by the combination of interleukin-1 and plasminogen in cartilage explant culture.

Glucocorticoids ameliorate erosion in animal osteoarthritis (OA) models and suppress synthesis of matrix metalloproteinases (MMP). However, in in vitro studies, their inhibitory effects on matrix degradation of cartilage have not been well documented by monitoring aggrecan. Collagen was monitored in this study to examine the effects of dexamethasone in cartilage explant culture. Dexamethasone clearly blocked collagen degradation induced by the combination of interleukin-1 (IL-1) and plasminogen at the concentration of 10(-9) M, which is much lower than the concentrations reportedly required to inhibit matrix synthesis. In addition, MMP-1 and MMP-3 were suppressed by dexamethasone treatment in a similar range of concentrations. The conversion of plasminogen to plasmin, however, was not blocked by treatment with dexamethasone. These results suggest that the inhibitory effect of dexamethasone on collagen degradation may be due to suppression of MMP production rather than suppression of fibrinolytic cascade. Thus, the ability of glucocorticoids to inhibit matrix degradation in vitro, which could be clearly shown by monitoring collagen degradation, may endorse their efficacy in animal OA models and suggest potential therapeutic effectiveness.     

Biologically active phospholipids as potential cardiovascular drugs

Both useful and undesirable cardiovascular properties have been associated with naturally occurring and synthetically derived phospholipids. Certain phospholipids may function physiologically (or pathophysiologically) in such processes as blood pressure regulation, cardiac rhythm, and platelet aggregation. Drugs that can modify the synthesis or degradation of endogenous phospholipid mediators or selectively mimic or block their effects may be of interest as potentially useful cardiovascular agents. This article reviews the current literature in this area and defines in chemical, biochemical, and biological terms the potential of the phospholipid-type compounds in the development of useful cardiovascular drugs.     

丹酚酸对缺血性心脏病的作用及作用机制研究进展

丹酚酸为唇形科植物丹参的最主要的水溶性活性成分,具有多种药理作用,被广泛应用于防治心血管疾病。本文通过查阅国内外最新研究文献,对丹酚酸防治缺血性心脏病的作用及作用机制进行综述,并介绍了丹酚酸A和丹酚酸B等丹参的主要水溶性成分通过保护血管内皮、舒张冠状动脉、促进血管再生、抗血小板聚集、抑制炎性反应、抗细胞凋亡和清除自由基等多角度防治缺血性心脏病的作用机制,为进一步研究丹酚酸对缺血性心脏病的作用及药物研发提供理论依据。     

Pharmacological prevention of cardiovascular aging--targeting the Maillard reaction

The development of myocardial and large vessel stiffness with aging underlies the development of diastolic heart failure and isolated systolic hypertension. Nonenzymatic reaction between glucose and proteins (Maillard reaction) leading to collagen crosslinking in the myocardium and arterial wall has been implicated in age-related increase in cardiovascular stiffness. In the present issue, Chang et al. show that aminoguanidine, an inhibitor of protein crosslinking, retards age-related decline in the elastic properties of the left ventricle and arteries. The significance of these findings is discussed in this commentary.     

Green tea attenuates diabetes induced Maillard-type fluorescence and collagen cross-linking in the heart of streptozotocin diabetic rats.

The enhanced myocardial collagen content, collagen glycation and the resulting advanced glycation end products (AGE) which exhibit the characteristics of increased cross-linking are proposed for the stiffness of myocardium in diabetes. To explore the cardioprotective effect of green tea in diabetes, we study the effect of green tea extract on myocardial collagen characteristics in streptozotocin diabetic rats. The effect of green tea on marker enzymes in serum and cardiac tissues were also assayed to understand the extent of protection. Six weeks after the diabetes induction, diabetic rats were treated with green tea extract [300 mg (kg body weight)(-1)day(-1)] for 4 weeks. AGE were determined by fluorescence assay and cross-linking of collagen by solubility measurement while collagen content was measured by biochemical assay. The activities of aspartate transaminase (AST), lactate dehydrogenase (LDH) and creatine kinase (CPK) were measured by biochemical assay. The increase in blood glucose, glycated hemoglobin and systolic blood pressure in diabetic rats were reduced upon green tea treatment. The activities of AST, LDH and CPK were significantly increased in serum whereas decreased in cardiac tissues in diabetic rats representing the cardiac damage. Administration of green tea to diabetic rats significantly ameliorates these enzyme activities. There was no significant difference in the myocardial collagen content among the experimental rats. A significant (P<0.05) increase in collagen linked Maillard-type fluorescence and decrease in collagen solubility in the myocardium of diabetic rats as compared to control rats (0.955+/-0.02 versus 0.683+/-0.04 and 30+/-1.41 versus 45.17+/-1.17, respectively) indicates the increase in advanced glycation end products formation and degree of collagen cross-linking. Green tea administration to diabetic rats significantly (P<0.05) decreased the fluorescence (0.73+/-0.02) whereas increased the solubility of collagen (41.5+/-1.04) indicating the reduction in advanced glycation end products and collagen cross-linking. The present study reveals that green tea by ameliorating myocardial collagen characteristics may provide a therapeutic option in the treatment of cardiovascular complications of diabetes.     

Pharmacological effects of xanthones as cardiovascular protective agents

Many epidemiological studies indicate that consumption of dietary polyphenolic compounds is beneficial in the prevention of cardiovascular diseases. Xanthones are a class of polyphenolic compounds that commonly occur in plants and have been shown to have extensive biological and pharmacological activities. Recently, the pharmacological properties of xanthones in the cardiovascular system have attracted great interest. Xanthones and xanthone derivatives have been shown to have beneficial effects on some cardiovascular diseases, including ischemic heart disease, atherosclerosis, hypertension and thrombosis. The protective effects of xanthones in the cardiovascular system may be due to their antioxidant, antiinflammatory, platelet aggregation inhibitory, antithrombotic and/or vasorelaxant activities. In particular, the antagonism of endogenous nitric oxide synthase inhibitors by xanthones may represent the basis for improved endothelial function and for reduction of events associated with atherosclerosis.     

Myocardial glycogen dynamics: New perspectives on disease mechanisms

Cardiac glycogen regulation involves a complex interplay between multiple signalling pathways, allosteric activation of enzymes, and sequestration for autophagic degradation. Signalling pathways appear to converge on glycogen regulatory enzymes via insulin (glycogen synthase kinase 3β, protein phosphatase 1, allosteric action of glucose‐6‐phosphate), β–adrenergic (phosphorylase kinase protein phosphatase 1 inhibitor), and 5′ adenosine monophosphate‐activated protein kinase (allosteric action of glucose‐6‐phosphate, direct glycogen binding, insulin receptor). While cytosolic glycogen synthesis and breakdown are relatively well understood, recent findings relating to phagic glycogen degradation highlight a new area of investigation in the heart. It has been recently demonstrated that a specific glycophagy pathway is operational in the myocardium. Proteins involved in recruiting glycogen to the forming phagosome have been identified. Starch–binding domain‐containing protein 1 is involved in binding glycogen and mediating membrane anchorage via interaction with a homologue of the phagosomal protein light‐chain 3. Specifically, it has been shown that starch–binding domain‐containing protein 1 and light‐chain 3 have discrete phagosomal immunolocalization patterns in cardiomyocytes, indicating that autophagic trafficking of glycogen and protein cargo in cardiomyocytes can occur via distinct pathways. There is strong evidence from glycogen storage diseases that phagic/lysosomal glycogen breakdown is important for maintaining normal cardiac glycogen levels and does not simply constitute a redundant ‘alternative’ breakdown route for glycogen. Advancing understanding of glycogen handling in the heart is an important priority with relevance not only to genetic glycogen storage diseases but also to cardiac metabolic stress disorders such as diabetes and ischaemia.