Cannabis as a Source of Approved Drugs: A New Look at an Old Problem.

Cannabis plants have been used in medicine since ancient times. They are well known for their anti-diabetic, anti-inflammatory, neuroprotective, anti-cancer, anti-oxidative, anti-microbial, anti-viral, and anti-fungal activities. A growing body of evidence indicates that targeting the endocannabinoid system and various other receptors with cannabinoid compounds holds great promise for addressing multiple medical conditions. There are two distinct avenues in the development of cannabinoid-based drugs. The first involves creating treatments directly based on the components of the cannabis plant. The second involves a singular molecule strategy, in which specific phytocannabinoids or newly discovered cannabinoids with therapeutic promise are pinpointed and synthesized for future pharmaceutical development and validation. Although the therapeutic potential of cannabis is enormous, few cannabis-related approved drugs exist, and this avenue warrants further investigation. With this in mind, we review here the medicinal properties of cannabis, its phytochemicals, approved drugs of natural and synthetic origin, pitfalls on the way to the widespread clinical use of cannabis, and additional applications of cannabis-related products.

A multidimensional systems biology analysis of cellular senescence in aging and disease.

BACKGROUND: Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of aging and has been linked to aging-related diseases. Many genes play a role in cellular senescence, yet a comprehensive understanding of its pathways is still lacking. RESULTS: We develop CellAge (http://genomics.senescence.info/cells), a manually curated database of 279 human genes driving cellular senescence, and perform various integrative analyses. Genes inducing cellular senescence tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes, while genes inhibiting cellular senescence overlap with pro-longevity and oncogenes. Furthermore, cellular senescence genes are strongly conserved in mammals but not in invertebrates. We also build cellular senescence protein-protein interaction and co-expression networks. Clusters in the networks are enriched for cell cycle and immunological processes. Network topological parameters also reveal novel potential cellular senescence regulators. Using siRNAs, we observe that all 26 candidates tested induce at least one marker of senescence with 13 genes (C9orf40, CDC25A, CDCA4, CKAP2, GTF3C4, HAUS4, IMMT, MCM7, MTHFD2, MYBL2, NEK2, NIPA2, and TCEB3) decreasing cell number, activating p16/p21, and undergoing morphological changes that resemble cellular senescence. CONCLUSIONS: Overall, our work provides a benchmark resource for researchers to study cellular senescence, and our systems biology analyses reveal new insights and gene regulators of cellular senescence.

Recent Updates on the Phytochemistry and Pharmacological Properties of Phlomis viscosa Poiret.

Crude ethanolic extracts from Phlomis viscosa Poiret leaves from the Judea region (Israel) are renowned for their remarkable geroprotective properties: anti-inflammatory, anti-diabetic, and anti-cancer. A phytochemical investigation carried out in this study revealed that the tested plant might belong to a particular distinct chemotype because its phytochemicals are different from compounds that were mentioned in the literature. Among the compounds identified by us was diosmin, the synthetic derivatives of which were further obtained and investigated. In particular, activities of the isolated compounds and synthesized diosmin derivatives were assessed. Our results revealed that the following compounds significantly lessened secretion of some pro-inflammatory cytokines: diosmin, himachala-2-diene, and 5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl) chromen-4-one. In addition, diosmin, synthesized diosmin derivatives, and some identified terpenes were found to have anti-diabetic activities. A significant anti-cancer effect of the whole extract on U-87 (human glioblastoma carcinoma cells line) and MCF7 (human breast carcinoma cell line) was also demonstrated, and it was better than that of DOX (doxorubicin). Collectively, the results obtained in the in vitro models suggest a wide spectrum of beneficial bioactivities of the extract and its active compounds.

Wound healing and longevity: lessons from long-lived αMUPA mice.

Does the longevity phenotype offer an advantage in wound healing (WH)? In an attempt to answer this question, we explored skin wound healing in the long-lived transgenic αMUPA mice, a unique model of genetically extended life span. These mice spontaneously eat less, preserve their body mass, are more resistant to spontaneous and induced tumorigenesis and live longer, thus greatly mimicking the effects of caloric restriction (CR). We found that αMUPA mice showed a much slower age-related decline in the rate of WH than their wild-type counterparts (FVB/N). After full closure of the wound, gene expression in the skin of old αMUPA mice returned close to basal levels. In contrast, old FVB/N mice still exhibited significant upregulation of genes associated with growth-promoting pathways, apoptosis and cell-cell/cell-extra cellular matrix interaction, indicating an ongoing tissue remodeling or an inability to properly shut down the repair process. It appears that the CR-like longevity phenotype is associated with more balanced and efficient WH mechanisms in old age, which could ensure a long-term survival advantage.

ShcC proteins: brain aging and beyond.

To date, most studies of Shc family of signaling adaptor proteins have been focused on the near-ubiquitously expressed ShcA, indicating its relevance to age-related diseases and longevity. Although the role of the neuronal ShcC protein is much less investigated, accumulated evidence suggests its importance for neuroprotection against such aging-associated conditions as brain ischemia and oxidative stress. Here, we summarize more than decade of studies on the ShcC expression and function in normal brain, age-related brain pathologies and immune disorders with a focus on the interactions of ShcC with signaling proteins/pathways, and the possible implications of these interactions for changes associated with aging.

Uncovering the geroprotective potential of medicinal plants from the Judea region of Israel.

Plants growing in the Judea region are widely used in traditional medicine. This phytogeographic zone stands out in its climatic conditions and biodiversity. Consequently, both endemic and widely distributed Mediterranean plants growing in the area have unique chemotypes characterized by accumulation of relatively high levels of phytosteroids. Our comprehensive analysis revealed that many of the plants growing in the Judea region may hold a geroprotective potential. With this in mind, we undertook a wide screen of dozens of candidate herbal extracts for their cell protective, wound-healing, anti-inflammatory, and anti-cancer activities. The results obtained thus far have clearly shown that the extracts tested (1) protect normal human fibroblasts from genotoxic stress (prevent DNA double-strand beaks, increase cell survival and reduce the number of cells undergoing cellular senescence), (2) decrease secretion of pro-inflammatory cytokines, (3) promote wound healing, and (4) exert more pronounced cytotoxicity toward cancer cells.

The role of DNA damage and repair in aging through the prism of Koch-like criteria.

Since the first publication on Somatic Mutation Theory of Aging (Szilárd, 1959), a great volume of knowledge in the field has been accumulated. Here we attempted to organize the evidence "for" and "against" the hypothesized causal role of DNA damage and mutation accumulation in aging in light of four Koch-like criteria. They are based on the assumption that some quantitative relationship between the levels of DNA damage/mutations and aging rate should exist, so that (i) the longer-lived individuals or species would have a lower rate of damage than the shorter-lived, and (ii) the interventions that modulate the level of DNA damage and repair capacity should also modulate the rate of aging and longevity and vice versa. The analysis of how the existing data meets the proposed criteria showed that many gaps should still be filled in order to reach a clear-cut conclusion. As a perspective, it seems that the main emphasis in future studies should be put on the role of DNA damage in stem cell aging.

Gadd45 proteins: relevance to aging, longevity and age-related pathologies.

The Gadd45 proteins have been intensively studied, in view of their important role in key cellular processes. Indeed, the Gadd45 proteins stand at the crossroad of the cell fates by controlling the balance between cell (DNA) repair, eliminating (apoptosis) or preventing the expansion of potentially dangerous cells (cell cycle arrest, cellular senescence), and maintaining the stem cell pool. However, the biogerontological aspects have not thus far received sufficient attention. Here we analyzed the pathways and modes of action by which Gadd45 members are involved in aging, longevity and age-related diseases. Because of their pleiotropic action, a decreased inducibility of Gadd45 members may have far-reaching consequences including genome instability, accumulation of DNA damage, and disorders in cellular homeostasis - all of which may eventually contribute to the aging process and age-related disorders (promotion of tumorigenesis, immune disorders, insulin resistance and reduced responsiveness to stress). Most recently, the dGadd45 gene has been identified as a longevity regulator in Drosophila. Although further wide-scale research is warranted, it is becoming increasingly clear that Gadd45s are highly relevant to aging, age-related diseases (ARDs) and to the control of life span, suggesting them as potential therapeutic targets in ARDs and pro-longevity interventions.

Molecular links between cellular senescence, longevity and age-related diseases - a systems biology perspective.

The role of cellular senescence (CS) in age-related diseases (ARDs) is a quickly emerging topic in aging research. Our comprehensive data mining revealed over 250 genes tightly associated with CS. Using systems biology tools, we found that CS is closely interconnected with aging, longevity and ARDs, either by sharing common genes and regulators or by protein-protein interactions and eventually by common signaling pathways. The most enriched pathways across CS, ARDs and aging-associated conditions (oxidative stress and chronic inflammation) are growth-promoting pathways and the pathways responsible for cell-extracellular matrix interactions and stress response. Of note, the patterns of evolutionary conservation of CS and cancer genes showed a high degree of similarity, suggesting the co-evolution of these two phenomena. Moreover, cancer genes and microRNAs seem to stand at the crossroad between CS and ARDs. Our analysis also provides the basis for new predictions: the genes common to both cancer and other ARD(s) are highly likely candidates to be involved in CS and vice versa. Altogether, this study shows that there are multiple links between CS, aging, longevity and ARDs, suggesting a common molecular basis for all these conditions. Modulating CS may represent a potential pro-longevity and anti-ARDs therapeutic strategy.

Is rate of skin wound healing associated with aging or longevity phenotype?

Wound healing (WH) is a fundamental biological process. Is it associated with a longevity or aging phenotype? In an attempt to answer this question, we compared the established mouse models with genetically modified life span and also an altered rate of WH in the skin. Our analysis showed that the rate of skin WH in advanced ages (but not in the young animals) may be used as a marker for biological age, i.e., to be indicative of the longevity or aging phenotype. The ability to preserve the rate of skin WH up to an old age appears to be associated with a longevity phenotype, whereas a decline in WH-with an aging phenotype. In the young, this relationship is more complex and might even be inversed. While the aging process is likely to cause wounds to heal slowly, an altered WH rate in younger animals could indicate a different cellular proliferation and/or migration capacity, which is likely to affect other major processes such as the onset and progression of cancer. As a point for future studies on WH and longevity, using only young animals might yield confusing or misleading results, and therefore including older animals in the analysis is encouraged.

Common gene signature of cancer and longevity.

An association between aging/longevity and cancer has long been suggested, yet the evolutionary and molecular links between these complicated traits remain elusive. Here, we analyze the relationship between longevity- and cancer-associated genes/proteins (LAGs/LAPs and CAGs/CAPs, respectively). Specifically, we address the following questions: (1) to what extent the CAGs and LAGs are evolutionary conserved and how they (or their orthologs) are related to each other in diverse species? (2) Could they act in cooperative manner at a protein level via protein-protein interactions (PPIs) and, if so, by forming a PPI network? We found that (i) the common genes (both LAGs and CAGs) show the same remarkable trend from yeast to humans: tumor suppressors are associated with lifespan extension, whereas the oncogenes are associated with reduced lifespan; (ii) LAPs and CAPs have a significantly higher average connectivity than other proteins in the human interactome; and (iii) LAPs and CAPs may act in cooperative manner via numerous direct and indirect PPIs between themselves and eventually by forming a PPI network. Altogether, the results of this study provide strong evidence for the existence of evolutionary and molecular links between longevity and cancer.

From disease-oriented to aging/longevity-oriented studies.

Aging should be considered a major risk factor for life-threatening degenerative pathologies including atherosclerosis, cancer, neurodegeneration, diabetes type II, osteoporosis, and sarcopenia. Although an apparent paradox, it appears that the most effective way to delay or even to avert age-related diseases is to live longer. Common changes in the epigenetic control of gene expression may be one of the central mechanisms behind both aging and age-associated pathologies. If so, epigenetic interventions may serve in a twofold manner: (a) to extend the lifespan and (b) cure age-related degenerative diseases. Currently predominant disease-oriented paradigm should be reconsidered toward aging/longevity oriented.