Current Medicinal Chemistry - Volume 20, Issue 8, 2013

The leading Alzheimer's disease (AD) therapeutics to date involves inhibitors of acetylcholinesterase (AChE), which should, in principle, elevate cholinergic signaling and limit inflammation. In spite of the effectiveness in 20%-30% of AD patients, more attention has been paid to find new anti-AChE agents from medicinal plants. Galanthamine, contained in the bulbs and flowers of Galanthus and related genera like Narcissus, represents a good example. The aim of this study is to review the role of possible AChE inhibitors (AChEI) present in plants traditionally used in European medicine for improving memory. Starting from Galanthamine, properties of Melissa species, Salvia officinalis, Arnica chamissonis and Ruta graveolens are discussed to point to the role of these plants as potential sources for the development of therapeutic agents for AD.

Medicinal plants are an essential part of Traditional Chinese Medicine (TCM), an ancient complex therapy considered today as one of the most complete complementary medicine system. Chinese Herbal Medicines (CHM) listings included in Chinese Materia Medica cover more than 1500 plants and a great number of composite preparations. Recently, several TCM herbs have been included into European Pharmacopoeia and many more are on the waiting list. The efficiency of TCM is based on the reinforcing of an organism's natural healing power and the ability to restore the energy homoeostasis. A likely mechanism of at least some of the activities is interacting with redox balance and prevention of oxidative stress. During the past two decades, hundreds of crude herbs, extracts, and isolated compounds have been screened for their antioxidant properties in vitro and in vivo. Consequently, some of traditional Chinese herbs can be regarded as source of very efficient antioxidant compounds, and this activity could explain some of their therapeutic and preventive usefulness. In this review, we outline the recent achievements in the worldwide quest for more efficient antioxidants, with Chinese medicinal and food plants in the central point. Various classes of antioxidant compounds will be mentioned, such as polyphenols or terpenoids that can act either as direct reactive oxygen species scavengers, transition metal reducers and chelators, or as chain breaking antioxidants. Some methodological considerations will be also discussed, with emphasis on the potential importance of the results obtained with antioxidant assays for human health and disease prevention. In this context, several examples of selected, most promising Chinese medicinal plants will be also presented in more detail.

Resveratrol, a star natural product from red wine, has attracted increasing attention around the world. In recent years, resveratrol derivatives (including its oligomers) have shown amazing chemical diversity and biological activities. They have been emerging to be promising new sources of natural antioxidant. This review summarizes recent finding on antioxidant activities of resveratrol derivatives and the structure-activity relationship for the first time. Scientific evidences have highlighted their potential as therapeutic agents for cerebral and cardiovascular diseases. In our opinion, more effort should be devoted to the synthesis of resveratrol oligomers. Based on the structure-activity relationship, screening for resveratrol derivatives with higher antioxidant activity than trans-resveratrol is warranted, and these molecules may have greater therapeutic potential in future investigations.

Platelets are anuclear blood cells originating from bone megakaryocytes. Despite being anuclear, their number is maintained by apoptosis, a process of programmed cell death. The rate of apoptotic death of platelets is accelerated by oxidative and shear stress, ex vivo storage (blood banking conditions) and certain pathophysiological disorders. These factors initiate apoptotic events through the mitochondria- mediated intrinsic pathway. Besides, apoptotic platelets also release phosphatidylserine-positive membrane fractions called microparticles, which cause fibrin deposition and thrombus formation, and are involved in the promulgation of a host of disease conditions including cardiovascular diseases. In this context, several phytochemicals have been reported to be cardioprotective and work by inhibiting platelet aggregation or by dissolving the fibrin clots. Besides, ample reports focus on the positive effects of phytochemicals on normal physiology of platelets, but do not focus on their adverse effects on platelets. Moreover, platelets are reported to be extremely sensitive to therapeutic components in the blood. For example, resveratrol and thymoquinone are hitherto known compounds to possess proapoptotic effects on platelets. In contrast, cinnamtannin B1 and crocin exhibit antiapoptotic effects. Thus, the current review aims to elucidate the underlying mechanisms through which the phytochemicals mediate their effects on platelet apoptosis. Moreover, the need for scrutiny of therapeutic compounds for their effects on platelet functions before including them in treatment regimen is also being emphasized.

Chronic pains management costs billions of dollars in medical exchequer to the world population. Additionally, 77% of people with chronic pains also have a degree of medically treatable depression. Opioids have a narrower safety index due to their side effects associated with its tolerance, hyperalgesia and subsequent dependence. Likewise, non steroidal anti-inflammatory drugs and anticonvulsants, also have limited safety and tolerability profile in the management of chronic pains. Bacopa monnieri, a renowned ayurvedic medicine has a strong antidepressant effect and significant antinociceptive effect, which is comparable to the effect of morphine via adenosinergic, opioidergic, and adrenergic mechanisms. BM has been also reported to be effective in neuropathic pains. Additionally, it has a strong anti-inflammatory effect mediated via COX-2 inhibitory mechanism. Apart from its effect of augmenting morphine analgesia, BM also inhibits opioid-withdrawal induced hyperalgesia, and acquisition and expression of morphine tolerance. BM is reported to have a strong protective effect against toxic effects of opiates on major organs like brain, kidneys and heart. BM is well documented to be safe and well tolerated herbal therapy in multiple clinical trials including various age groups. This minireview evaluated the preclinical data that highlights potential of BM as a future candidate for clinical management of chronic pains.

Plants and plant cells have been used to produce many diverse and valuable recombinant proteins, including subunit vaccines, antibodies and antibody fragments, hormones, blood products, cytokines and enzymes. Different plant species and platforms have been explored as production hosts, each with unique properties in terms of production timescales, environmental containment, scalability, downstream processing strategy and overall costs. Whole plants are suitable for the economical and safe production of recombinant proteins on a large scale, providing unique advantages for pharmaceutical proteins that are required in large amounts and normally too expensive for conventional manufacturing processes. Seed-based systems have additional advantages because they exploit the natural storage properties of seeds to facilitate batch processing and distribution. The stabilizing effect of seeds after harvest allows recombinant subunit vaccines and antibodies to be delivered via the mucosal route as they are better able to withstand the harsh microenvironment when protected by the plant matrix. Although the differences between plant and human N-glycans were initially thought to limit the therapeutic potential of plant-derived glycoproteins, several such products have now been tested in the clinic and in some cases the presence of plant glycans has been turned into an advantage because they improve the performance of the protein or confer unique characteristics. In this review we discuss recent case studies of recombinant pharmaceuticals produced in plants to demonstrate the versatility and unique advantages of molecular farming and the bottlenecks that remain to be addressed.

Plant cells cultured in liquid medium in bioreactors are now being used commercially to produce biopharmaceutical proteins. The emergence of in vitro plant cell culture as a production vehicle reflects the importance of key biosafety and biocontainment concerns affecting the competitiveness of alternative systems such as mammalian cell culture and agriculture. Food plant species are particularly attractive as hosts for in vitro protein production: the risk of transgene escape and food chain contamination is eliminated using containment facilities, while regulatory approval for oral delivery of drugs may be easier than if non-edible species were used. As in whole plants, proteolysis in cultured plant cells can lead to significant degradation of foreign proteins after synthesis; however, substantial progress has been made to counter the destructive effects of proteases in plant systems. Although protein secretion into the culture medium is advantageous for product recovery and purification, measures are often required to minimise extracellular protease activity and product losses due to irreversible surface adsorption. Disposable plastic bioreactors, which are being used increasingly in mammalian cell bioprocessing, are also being adopted for plant cell culture to allow rapid scale-up and generation of saleable product. This review examines a range of technical and regulatory issues affecting the choice of industrial production platform for foreign proteins, and assesses progress in the development of in vitro plant systems for biopharmaceutical production.

Metabolomics is playing an increasingly important role in plant science. It aims at the comprehensive analysis of the plant metabolome which consists both of primary and secondary metabolites. The goal of metabolomics is ultimately to identify and quantify this wide array of small molecules in biological samples. This new science is included in several systems biology approaches and is based primarily on the unbiased acquisition of mass spectrometric (MS) or nuclear magnetic resonance (NMR) data from carefully selected samples. This approach provides the most ‘‘functional’’ information of the ‘omics’ technologies of a given organism since metabolites are the end products of the cellular regulatory processes. The application of state-of-the-art data mining, that includes various untargeted and targeted multivariate data analysis methods, to the vast amount of data generated by this data-driven approach leads to sample classification and the identification of relevant biomarkers. The biological areas that have been successfully studied by this holistic approach include global metabolite composition assessment, mutant and phenotype characterisation, taxonomy, developmental processes, stress response, interaction with the environment, quality control assessment, lead finding and mode of action of botanicals. This review summarises the main MS- and NMR-based approaches that are used to perform these studies and discusses the potential and current limitations of the various methods. The intent is not to provide an exhaustive overview of the field, which has grown considerably over the past decade, but to summarise the main strategies that are used and to discuss the potential and limitations of the different approaches as well as future trends.