Hepatic circulation: potential for therapeutic intervention

In recent years, knowledge of the physiology and pharmacology of hepatic circulation has grown rapidly. Liver microcirculation has a unique design that allows very efficient exchange processes between plasma and liver cells, even when severe constraints are imposed upon the system, i.e. in stressful situations. Furthermore, it has been recognized recently that sinusoids and their associated cells can no longer be considered only as passive structures ensuring the dispersion of molecules in the liver, but represent a very sophisticated network that protects and regulates parenchymal cells through a variety of mediators. Finally, vascular abnormalities are a prominent feature of a number of liver pathological processes, including cirrhosis and liver cell necrosis whether induced by alcohol, ischemia, endotoxins, virus or chemicals. Although it is not clear whether vascular lesions can be the primary events that lead to hepatocyte injury, the main interest of these findings is that liver microcirculation could represent a potential target for drug action in these conditions.     

Reactive carbonyls and oxidative stress: potential for therapeutic intervention

Reactive aldehydes and ketones are produced as a result of oxidative stress in several disease processes. Considerable evidence is now accumulating that these reactive carbonyl products are also involved in the progression of diseases, including neurodegenerative disorders, diabetes, atherosclerosis, diabetic complications, reperfusion after ischemic injury, hypertension, and inflammation. To counter carbonyl stress, cells possess enzymes that can decrease aldehyde load. These enzymes include aldehyde dehydrogenases (ALDH), aldo-keto reductases (AKR), carbonyl reductase (CBR), and glutathione S-transferases (GST). Some of these enzymes are inducible by chemoprotective compounds via Nrf2/ARE- or AhR/XRE-dependent mechanisms. This review describes the metabolism of reactive carbonyls and discusses the potential for manipulating levels of carbonyl-metabolizing enzymes through chemical intervention.     

Vascular effects of adiponectin: molecular mechanisms and potential therapeutic intervention

Adiponectin is a major adipocyte-secreted adipokine abundantly present in the circulation as three distinct oligomeric complexes. In addition to its role as an insulin sensitizer, mounting evidence suggests that adiponectin is an important player in maintaining vascular homoeostasis. Numerous epidemiological studies based on different ethnic groups have identified adiponectin deficiency (hypoadiponectinaemia) as an independent risk factor for endothelial dysfunction, hypertension, coronary heart disease, myocardial infarction and other cardiovascular complications. Conversely, elevation of circulating adiponectin concentrations by either genetic or pharmacological approaches can alleviate various vascular dysfunctions in animal models. Adiponectin exerts its vasculoprotective effects through its direct actions in the vascular system, such as increasing endothelial NO production, inhibiting endothelial cell activation and endothelium-leucocyte interaction, enhancing phagocytosis, and suppressing macrophage activation, macrophage-to-foam cell transformation and platelet aggregation. In addition, adiponectin reduces neointima formation through an oligomerization-dependent inhibition of smooth muscle proliferation. The present review highlights recent research advances in unveiling the molecular mechanisms that underpin the vascular actions of adiponectin and discusses the potential strategies of using adiponectin or its signalling pathways as therapeutic targets to combat obesity-related metabolic and vascular diseases.     

Dopamine: pharmacologic and therapeutic aspects

Dopamine is a biogenic amine synthesized in the hypothalamus, in the arcuate nucleus, the caudad, and various areas of the central and peripheral nervous system. It has been widely established that dopamine and its agonists play an important role in cardiovascular, renal, hormonal, and central nervous system regulation through stimulation of alpha and beta adrenergic and dopaminergic receptors. There are several agonists of dopamine-2 (DA 2 ) dopaminergic receptors, such as bromocriptine, pergolide, lisuride, quinpirole, and carmoxirole, which inhibit norepinephrine release and produce a decrease in arterial blood pressure; in some cases, bromocriptine and pergolide also reduce heart rate. From a therapeutic point of view, the above-mentioned agonists are used for treating Parkinson's disease, acting over DA 2 dopaminergic receptors of the nigrostriatal system. Bromocriptine and the other dopaminergic agonists mentioned act over DA 2 receptors of the tuberoinfundibular system, inhibiting prolactin release and decreasing hyperprolactinemia and tumor size. Among DA 1 receptor agonists, we can mention fenoldopam, piribedil, ibopamine, SKF 3893, and apomorphine (nonspecific). Activation of these receptors decreases peripheral resistance, inducing lowering of arterial blood pressure and increases in heart rate, sympathetic tone, and activity of the renin aldosterone system. Among DA 2 receptor antagonists, we can mention metoclopramide, domperidone, sulpiride, and haloperidol. From a therapeutic point of view, metoclopramide and domperidone are used in gastric motility disorders, and haloperidol is used in psychotic alterations. Antagonists of DA 1 receptors are SCH23390 and clozapine. Clozapine is used for treating schizophrenia.     

Approach to nigericin derivatives and their therapeutic potential

A new nigericin analogue that has been chemically modified was synthesized through a fluorination process from the parent nigericin, produced from a novel Streptomyces strain DASNCL-29. Fermentation strategies were designed for the optimised production of nigericin molecule and subjected for purification and structural analysis. The fermentation process resulted in the highest yield of nigericin (33% (w/w)). Initially, nigericin produced from the strain DASNCL-29 demonstrated polymorphism in its crystal structure, i.e., monoclinic and orthorhombic crystal lattices when crystallised with methanol and hexane, respectively. Furthermore, nigericin produced has been subjected to chemical modification by fluorination to enhance its efficacy. Two fluorinated analogues revealed that they possess a very potent antibacterial activity against Gram positive and Gram negative bacteria. To date, the nigericin molecule has not been reported for any reaction against Gram-negative bacteria, which are increasingly becoming resistant to antibiotics. For the first time, fluorinated analogues of nigericin have shown promising activity. In vitro cytotoxicity analysis of fluorinated analogues demonstrated tenfold lesser toxicity than the parent nigericin. This is the first type of study where the fluorinated analogues of nigericin showed very encouraging activity against Gram-negative organisms; moreover, they can be used as a candidate for treating many serious infections.

A new nigericin analogue that has been chemically modified was synthesized through a fluorination process from the parent nigericin, produced from a novel Streptomyces strain DASNCL-29.     

Artificial neural network technologies to identify biomarkers for therapeutic intervention

High-throughput technologies such as DNA/RNA microarrays, mass spectrometry and protein chips are creating unprecedented opportunities to accelerate towards the understanding of living systems and the identification of target genes and pathways for drug development and therapeutic intervention. However, the increasing volumes of data generated by molecular profiling experiments pose formidable challenges to investigate an overwhelming mass of information and turn it into predictive, deployable markers. Advanced biostatistics and machine learning methods from computer science have been applied to analyze and correlate numerical values of profiling intensities to physiological states. This article reviews the application of artificial neural networks, an information-processing tool, to the identification of sets of diagnostic/prognostic biomarkers from high-throughput profiling data.     

The therapeutic potential of NO-NSAIDs

NSAIDs, including those that are selective for cyclooxygenase-2, are among the most widely used drugs. However, these drugs produce significant side effects in the gastrointestinal and cardiorenal systems, which greatly limit their utility. In recent years, a new type of anti-inflammatory agent has been developed that appears to offer significant advantages over conventional and Cox-2-selective NSAIDs. No-NSAIDs are derivatives of conventional NSAIDs, which are able to release nitric oxide over prolonged periods of time. The combination of balanced inhibition of the two main isoforms of COX with controlled release of nitric oxide yields a series of drugs that exert anti-inflammatory and analgesic activities in a wide range of settings, and have markedly reduced gastrointestinal and cardiorenal toxicity. Recent clinical trials of NO-NSAIDs have provided a 'proof of concept' that is completely consistent with pre-clinical characterization of these compounds.     

DNAzymes as potential therapeutic molecules

Numerous DNA-based biopharmaceuticals are able to control disease progression by induction and/or inhibition of genes. These potent therapeutics include plasmids containing transgenes, antisense oligonucleotides, aptamers, ribozymes, DNAzymes and short interfering RNAs. DNAzymes, which cleave RNA substrates in a sequence-specific manner, have been studied as potential therapeutics to target pathogenic mRNAs, and may yield drugs that are safer than those currently available. This reviewo discusses the structural design of DNAzymes and their modification for stability. Their therapeutic application and use as biomarkers is also discussed.     

Preconditioning: evolution of basic mechanisms to potential therapeutic strategies

Preconditioning describes the phenomenon by which a traumatic or stressful stimulus confers protection against subsequent injury. Originally recognized in dog heart subjected to ischemic challenges, preconditioning has been demonstrated in multiple species, can be induced by various stimuli, and is applicable in different organ systems. Tremendous progress has been made elucidating the signal transduction cascade of preconditioning. Preconditioning represents a potent tissue-protective condition, and mechanistic understanding may allow safe clinical application. This review recalls the history of preconditioning and how it relates to the history of the investigation of endogenous adaptation; summarizes the current mechanistic understanding of acute preconditioning; outlines the signal transduction cascade leading to the development of delayed preconditioning; discusses preconditioning in noncardiac tissue; and explores the potential of using preconditioning clinically.     

糖尿病心肌病及潜在的干预

糖尿病心肌病是严重的心血管并发症之一,氧化应激与糖尿病心肌病的发病密切相关,因此,抗氧化治疗一直是糖尿病心肌病治疗领域的热点。金属硫蛋白（MT）作为内源性高效的非特异性的抗氧化剂,Nrf2作为抗氧化基因的重要调控因子,都在抗氧化过程中都发挥了重要作用。如何应用安全有效的MT和Nrf2诱导剂来清除多种活性自由基有效地预防糖尿病性心肌病,在防治糖尿病心血管并发症方面将有广阔的应用前景。     

HPV proteins as targets for therapeutic intervention

Human papillomaviruses (HPV) are the aetiological agents of several types of anogenital tumours, particularly cervical carcinoma. Recent evidence also suggests a role for HPV in the development of squamous cell carcinomas of the skin, especially in immunocompromised individuals. HPV infection also produces a number of non-malignant, but nonetheless cosmetically unpleasant lesions. Therefore, any effective therapeutic treatment for HPV-induced diseases would be extremely beneficial both on humanitarian grounds as well as being economically very attractive. In this review, we will discuss the functions of the viral proteins that appear to be the most appropriate for the development of therapeutics aimed at the treatment of viral infection and virus-induced cancers.     

Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria

Phenylketonuria (PKU) is an inborn error of metabolism caused by mutations in phenylalanine hydroxylase (PAH). Over 500 disease-causing mutations have been identified in humans, most of which result in PAH protein misfolding and increased turnover in vivo. The use of pharmacological chaperones to stabilize or promote correct folding of mutant proteins represents a promising new direction in the treatment of misfolding diseases. We performed a high-throughput ligand screen of over 1,000 pharmacological agents and identified 4 compounds (I-IV) that enhanced the thermal stability of PAH and did not show substantial inhibition of PAH activity. In further studies, compounds III (3-amino-2-benzyl-7-nitro-4-(2-quinolyl)-1,2-dihydroisoquinolin-1-one) and IV (5,6-dimethyl-3-(4-methyl-2-pyridinyl)-2-thioxo-2,3-dihydrothieno[2,3- d]pyrimidin-4(1H)-one) stabilized the functional tetrameric conformation of recombinant WT-PAH and PKU mutants. These compounds also significantly increased activity and steady-state PAH protein levels in cells transiently transfected with either WT-PAH or PKU mutants. Furthermore, PAH activity in mouse liver increased after a 12-day oral administration of low doses of compounds III and IV. Thus, we have identified 2 small molecules that may represent promising alternatives in the treatment of PKU.     

Thyroidectomy: understanding the potential for complications.

Thyroidectomy is a relatively common procedure. Complications may result from the surgery itself or from secondary metabolic disturbances. Medical-surgical nurses must act quickly and efficiently to detect and treat postoperative complications.