Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a "screening hit" through a "drug lead" to a "marketed drug" is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

An alternate route for metastatic cells: Metastatic tumor cells are thought to reach distant organs by traveling through the blood circulation or the lymphatic system. Two studies of mouse models now suggest a hybrid route for tumor cell dissemination. Pereiraet al.and Brownet al.used distinct methodologies to monitor the fate of tumor cells in lymph nodes. They found that tumor cells could invade local blood vessels within a node, exit the node by entering the blood circulation, then go on to colonize the lung. Whether this dissemination route occurs in cancer patients is unknown; the answer could potentially change the way that affected lymph nodes are treated in cancer.Science, this issue p.1403, p.1408

Resveratrol, the phenolic substance isolated initially from Veratrum grandiflorum and richly present in grapes, wine, peanuts, soy, and berries, has been attracting attention of scientists and medical doctors for many decades. Herein, we review its effects on the vascular system. Studies utilizing cell cultures and pre-clinical models showed that resveratrol alleviates oxidative stress and inflammation. Furthermore, resveratrol suppresses vascular smooth muscle cell proliferation, promotes autophagy, and has been investigated in the context of vascular senescence. Pre-clinical models unambiguously demonstrated numerous vasculoprotective effects of resveratrol. In clinical trials, resveratrol moderately diminished systolic blood pressure in hypertensive patients, as well as blood glucose in patients with diabetes mellitus. Yet, open questions remain, as exemplified by a recent report which states that the intake of resveratrol might blunt certain positive effects of exercise in older persons, and further research addressing the framework for long-term use of resveratrol as a food supplement, will stay in demand.

During embryonic development, lymph sacs form from the cardinal vein, and sprout centrifugally to form mature lymphatic networks. Separation of the lymphatic from the blood circulation by a hitherto unknown mechanism is essential for the homeostatic function of the lymphatic system. O-glycans on the lymphatic endothelium have recently been suggested to be required for establishment and maintenance of distinct blood and lymphatic systems, primarily by mediating proper function of podoplanin. Here, we show that this separation process critically involves platelet activation by podoplanin. We found that platelet aggregates build up in wild-type embryos at the separation zone of podoplanin+ lymph sacs and cardinal veins, but not in podoplanin−/− embryos. Thus, podoplanin−/− mice develop a “nonseparation” phenotype, characterized by a blood-filled lymphatic network after approximately embryonic day 13.5, which, however, partially resolves in postnatal mice. The same embryonic phenotype is also induced by treatment of pregnant mice with acetyl salicylic acid, podoplanin-blocking antibodies, or by inactivation of the kindlin-3 gene required for platelet aggregation. Therefore, interaction of endothelial podoplanin of the developing lymph sac with circulating platelets from the cardinal vein is critical for separating the lymphatic from the blood vascular system.

Cellular senescence is characterized by a permanent cell-cycle arrest and a pro-inflammatory secretory phenotype, and can be induced by a variety of stimuli, including ionizing radiation, oxidative stress, and inflammation. In endothelial cells, this phenomenon might contribute to vascular disease. Plasma levels of the inflammatory cytokine tumor necrosis factor alpha (TNFα) are increased in age-related and chronic conditions such as atherosclerosis, rheumatoid arthritis, psoriasis, and Crohn’s disease. Although TNFα is a known activator of the central inflammatory mediator NF-κB, and can induce the intracellular generation of reactive oxygen species (ROS), the question whether TNFα can induce senescence has not been answered conclusively. Here, we investigated the effect of prolonged TNFα exposure on the fate of endothelial cells and found that such treatment induced premature senescence. Induction of endothelial senescence was prevented by the anti-oxidant N-acetyl cysteine, as well as by plumericin and PHA-408, inhibitors of the NF-κB pathway. Our results indicated that prolonged TNFα exposure could have detrimental consequences to endothelial cells by causing senescence and, therefore, chronically increased TNFα levels might possibly contribute to the pathology of chronic inflammatory diseases by driving premature endothelial senescence.

Pomegranate (Punica granatum L.), one of the oldest known edible fruits, is nowadays broadly consumed throughout the world. Its fruits and seeds as well as other anatomical compartments (e.g., flowers and leaves) are rich in numerous bioactive compounds and therefore, the scientific interest in this plant has been constantly growing in recent years. It has been shown that pomegranate and its extracts exhibit potent antioxidative, antimicrobial, and anticarcinogenic properties. The present review summarizes some recent studies on pomegranate, highlighting mainly its vasculoprotective role attributed to the presence of hydrolyzable tannins ellagitannins and ellagic acid, as well as other compounds (e.g., anthocyanins and flavonoids). These in vitro and in vivo studies showed that substances derived from pomegranate reduce oxidative stress and platelet aggregation, diminish lipid uptake by macrophages, positively influence endothelial cell function, and are involved in blood pressure regulation. Clinical studies demonstrated that daily intake of pomegranate juice lessens hypertension and attenuates atherosclerosis in humans. Altogether, the reviewed studies point out the potential benefits of a broader use of pomegranate and its constituents as dietary supplements or as adjuvants in therapy of vascular diseases, such as hypertension, coronary artery disease, and peripheral artery disease.