Marine pharmacology in 2003-4: marine compounds with anthelmintic antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiplatelet, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems, and other miscellaneous mechanisms of action

The current marine pharmacology review that covers the peer-reviewed literature during 2003 and 2004 is a sequel to the authors' 1998-2002 reviews, and highlights the preclinical pharmacology of 166 marine chemicals derived from a diverse group of marine animals, algae, fungi and bacteria. Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal, antituberculosis or antiviral activities were reported for 67 marine chemicals. Additionally 45 marine compounds were shown to have significant effects on the cardiovascular, immune and nervous system as well as possessing anti-inflammatory effects. Finally, 54 marine compounds were reported to act on a variety of molecular targets and thus may potentially contribute to several pharmacological classes. Thus, during 2003-2004, research on the pharmacology of marine natural products which involved investigators from Argentina, Australia, Brazil, Belgium, Canada, China, France, Germany, India, Indonesia, Israel, Italy, Japan, Mexico, Morocco, the Netherlands, New Zealand, Norway, Panama, the Philippines, Portugal, Russia, Slovenia, South Korea, Spain, Thailand, Turkey, United Kingdom, and the United States, contributed numerous chemical leads for the continued global search for novel therapeutic agents with broad spectrum activity.     

Marine Pharmacology in 2000: Marine Compounds with Antibacterial,Anticoagulant, Antifungal,Anti-inflammatory,Antimalarial, Antiplatelet,Antituberculosis, and Antiviral Activities; Affecting the Cardiovascular,Immune, and Nervous Systems and Other Miscellaneous Mechanisms of Action

During 2000 research on the pharmacology of marine chemicals involved investigators from Australia, Brazil, Canada, Egypt, France, Germany, India, Indonesia, Israel, Italy, Japan, the Netherlands, New Zealand, Phillipines, Singapore, Slovenia, South Korea, Spain, Sweden, Switzerland, United Kingdom, and the United States. This current review, a sequel to the authors 1998 and 1999 reviews, classifies 68 peer-reviewed articles on the basis of the reported preclinical pharmacologic properties of marine chemicals derived from a diverse group of marine animals, algae, fungi, and bacteria. Antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antituberculosis, or antiviral activity was reported for 35 marine chemicals. An additional 20 marine compounds were shown to have significant effects on the cardiovascular and nervous system, and to possess anti-inflammatory or immunosuppressant properties. Finally, 23 marine compounds were reported to act on a variety of molecular targets and thus could potentially contribute to several pharmacologic classes. Thus, as in 1998 and 1999, during 2000 pharmacologic research with marine chemicals continued to contribute potentially novel chemical leads to the ongoing global search for therapeutic agents in the treatment of multiple disease categories.     

Marine pharmacology in 1999: compounds with antibacterial,anticoagulant, antifungal,anthelmintic, anti-inflammatory,antiplatelet, antiprotozoal and antiviral activities affecting the cardiovascular,endocrine, immune and nervous systems,and other miscellaneous mechanisms of action

This review, a sequel to the 1998 review, classifies 63 peer-reviewed articles on the basis of the reported preclinical pharmacological properties of marine chemicals derived from a diverse group of marine animals, algae, fungi and bacteria. In all, 21 marine chemicals demonstrated anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antituberculosis or antiviral activities. An additional 23 compounds had significant effects on the cardiovascular, sympathomimetic or the nervous system, as well as possessed anti-inflammatory, immunosuppressant or fibrinolytic effects. Finally, 22 marine compounds were reported to act on a variety of molecular targets, and thus could potentially contribute to several pharmacological classes. Thus, during 1999 pharmacological research with marine chemicals continued to contribute potentially novel chemical leads in the ongoing global search for therapeutic agents for the treatment of multiple disease categories.     

Marine pharmacology in 2005–6: Marine compounds with anthelmintic,antibacterial, anticoagulant,antifungal, anti-inflammatory,antimalarial, antiprotozoal,antituberculosis, and antiviral activities; affecting the cardiovascular,immune and nervous systems,and other miscellaneous mechanisms of action

Background

The review presents the 2005–2006 peer-reviewed marine pharmacology literature, and follows a similar format to the authors' 1998–2004 reviews. The preclinical pharmacology of chemically characterized marine compounds isolated from marine animals, algae, fungi and bacteria is systematically presented.

Results

Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis and antiviral activities were reported for 78 marine chemicals. Additionally 47 marine compounds were reported to affect the cardiovascular, immune and nervous system as well as possess anti-inflammatory effects. Finally, 58 marine compounds were shown to bind to a variety of molecular targets, and thus could potentially contribute to several pharmacological classes.

Conclusions

Marine pharmacology research during 2005–2006 was truly global in nature, involving investigators from 32 countries, and the United States, and contributed 183 marine chemical leads to the research pipeline aimed at the discovery of novel therapeutic agents.

General significance

Continued preclinical and clinical research with marine natural products demonstrating a broad spectrum of pharmacological activity will probably result in novel therapeutic agents for the treatment of multiple disease categories.     

Marine pharmacology in 2007–8: Marine compounds with antibacterial,anticoagulant, antifungal,anti-inflammatory,antimalarial, antiprotozoal,antituberculosis, and antiviral activities; affecting the immune and nervous system,and other miscellaneous mechanisms of action

The peer-reviewed marine pharmacology literature in 2007–8 is covered in this review, which follows a similar format to the previous 1998–2006 reviews of this series. The preclinical pharmacology of structurally characterized marine compounds isolated from marine animals, algae, fungi and bacteria is discussed in a comprehensive manner. Antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis and antiviral activities were reported for 74 marine natural products. Additionally, 59 marine compounds were reported to affect the cardiovascular, immune and nervous systems as well as to possess anti-inflammatory effects. Finally, 65 marine metabolites were shown to bind to a variety of receptors and miscellaneous molecular targets, and thus upon further completion of mechanism of action studies, will contribute to several pharmacological classes. Marine pharmacology research during 2007–8 remained a global enterprise, with researchers from 26 countries, and the United States, contributing to the preclinical pharmacology of 197 marine compounds which are part of the preclinical marine pharmaceuticals pipeline. Sustained preclinical research with marine natural products demonstrating novel pharmacological activities, will probably result in the expansion of the current marine pharmaceutical clinical pipeline, which currently consists of 13 marine natural products, analogs or derivatives targeting a limited number of disease categories.     

An Assessment of Toxic Substances Pollution in the Hong Kong Marine Environment

The Environmental Protection Department (EPD) of the Hong Kong Special Administrative Region Government (HKSARG) commissioned a consultancy study in 1999 to better understand the potential sources, fates, and existing pollution state of toxic substances in Hong Kong's marine environment. A desk-top survey and assessment was first performed on a comprehensive initial list of 556 toxic substances. A Preliminary Priority Toxic Substances List (PPTSL) of 135 chemicals was established, consisting of heavy metals, inorganic compounds, organo-metallic compounds, and trace organics. A territory-wide baseline field sampling and laboratory analysis exercise was then undertaken during 2001–2002 to determine the level of these PPTSL chemicals in the potential pollution sources (effluent discharges, stormwater discharges, air deposition) and the receiving marine environment (water, sediment, biota). A draft Priority Toxic Substances List (PTSL) was developed, taking into account chemicals detected in the local marine environment and those listed under the Stockholm Convention, the Rotterdam Convention, and the International Maritime Organization's Harmful Antifouling System Convention. The draft PTSL chemicals were subject to ecological and incremental human health risk assessments. Based on the risk assessment results, 17 Chemicals of Potential Concern (COPC) for Hong Kong's marine environment were identified, most of which were heavy metals in the sediment. The study findings suggest that Hong Kong's marine environment is not widely polluted with chemicals present at concentrations of toxicological concern. Although a number of potentially problematic pollutants (COPC) were identified, they are confined to a few “hot spots” and are unlikely to pose a territory-wide risk. Based on the study recommendations, the EPD initiated in 2004 a toxic substances monitoring program to keep the COPC in the marine environment under close surveillance.     

Anaemia, hypothyroidism and immune suppression associated with polychlorinated biphenyl exposure in bottlenose dolphins (Tursiops truncatus)

Polychlorinated biphenyls (PCBs), persistent chemicals widely used for industrial purposes, have been banned in most parts of the world for decades. Owing to their bioaccumulative nature, PCBs are still found in high concentrations in marine mammals, particularly those that occupy upper trophic positions. While PCB-related health effects have been well-documented in some mammals, studies among dolphins and whales are limited. We conducted health evaluations of bottlenose dolphins (Tursiops truncatus) near a site on the Georgia, United States coast heavily contaminated by Aroclor 1268, an uncommon PCB mixture primarily comprised of octa- through deca-chlorobiphenyl congeners. A high proportion (26%) of sampled dolphins suffered anaemia, a finding previously reported from primate laboratory studies using high doses of a more common PCB mixture, Aroclor 1254. In addition, the dolphins showed reduced thyroid hormone levels and total thyroxine, free thyroxine and triiodothyronine negatively correlated with PCB concentration measured in blubber (p = 0.039, < 0.001, 0.009, respectively). Similarly, T-lymphocyte proliferation and indices of innate immunity decreased with blubber PCB concentration, suggesting an increased susceptibility to infectious disease. Other persistent contaminants such as DDT which could potentially confound results were similar in the Georgia dolphins when compared with previously sampled reference sites, and therefore probably did not contribute to the observed correlations. Our results clearly demonstrate that dolphins are vulnerable to PCB-related toxic effects, at least partially mediated through the endocrine system. The severity of the effects suggests that the PCB mixture to which the Georgia dolphins were exposed has substantial toxic potential and further studies are warranted to elucidate mechanisms and potential impacts on other top-level predators, including humans, who regularly consume fish from the same marine waters.     

A bitter plant with a sweet future? A comprehensive review of an oriental medicinal plant: Andrographis paniculata

Andrographis paniculata (Burm.f) Nees is one of the most popular and important medicinal plant of the Orient, and South East Asia. It finds mention in various forms in Indian, Chinese, Malay, Thai, Unani, and Japanese systems of medicine. The plant exhibits anti-cancer, anti-inflammatory, anti-diabetic, anti-hypertensive, anti-venom, cholestatic, hepatoprotective, anti-thrombotic, anti-retroviral, anti-microbial, anti-pyretic, anti-malarial, anti-oxidant, immunomodulatory, and cardioprotective effects. The major active principles contributing to biological activity are diterpene lactones, but flavonoids, xanthones and caffeic acid derivatives also contribute to anti-oxidant, anti-proliferative, anti-atherosclerotic, and anti-malarial effects. As a result of its wide spectrum of pharmacological activity, almost impeccable safety profile, being a widely cultivated medicinal plant, we have collected and compiled various facets of this plant. Extensive datamining of the phytochemistry and pharmacology of Andrographis paniculata revealed more than 50 diterpene lactones, 30 flavonoids, 8 quinic acid derivatives, and 4 xanthones. This review contains information on around 80 isolated compounds, out of which more than half of the compounds have no reported pharmacological activity. Though there are some good reviews available on Andrographis paniculata, the authors of the earlier reviews focused on one or two aspects of the plant and none have attempted to integrate the available information on this plant. This provided us the much needed impetus, warranting a full-fledged and complete review on Andrographis paniculata, one of the most popular and important Oriental medicinal plant.     

Variation in ice conditions has strong effects on the breeding of marine birds at Prince Leopold Island, Nunavut

The maximum extent of sea ice in the northern hemisphere has been contracting for several decades, with implications for all ice-associated biota. To determine how variation in ice conditions affects reproduction in marine birds, we studied the effects of ice conditions on breeding of four species of seabirds over four years at Prince Leopold Island, Nunavut, a colony close to the limits of ice conditions where breeding is feasible. In 2000 and 2003, open water was present close to the colony in June, when the birds began to lay eggs. In 2001 and 2002, the ice edge in June was >200 km to the east of the colony, forcing birds to commute long distances to open water to feed. Egg-laying by thick-billed murres, black-legged kittiwakes and glaucous gulls was delayed and eggs and clutches were smaller in 2001 and 2002. However, northern fulmars laid at the same time in all years, although their incubation shifts were longer in 2001 and 2002 than in 2003. Open water was present close to the colony by the time of hatching in all years. Despite this, nestling survival of northern fulmars, body condition and nestling growth of thick-billed murres and body condition and nestling survival of black-legged kittiwakes were lower in 2001 and 2002 than in –2000 and 2003. All these indicators suggest that feeding conditions in the years of late ice break-up continued to be worse than usual even after open water was available at the colony. Our study suggests that current trends towards earlier ice break-up in the Arctic may be beneficial for marine birds at Prince Leopold Island, at least in the short-term.     

Immunopharmacology: a new frontier

Immunopharmacology is a hybrid science which has been founded upon the principles, theory, and technical developments of both immunology and pharmacology, but which has a unique identity incorporating both basic and applied areas of research. Basic immunopharmacological research is concerned with the underlying mechanisms by which endogenous and synthetic chemicals interact with the cells of the immune system. Important areas of research include the actions of chemicals such as lymphokines, cytokines, complement, kinins, autacoids, drugs, and even neuropeptides on immune function. Applied immunopharmacology is concerned with the development and testing of new immunomodulatory drugs which will be of benefit to clinical medicine but also as basic research tools. In the past, the two fields of immunology and pharmacology have contributed to each other in many significant ways. Immunology has contributed to pharmacological research by the development of antibodies which are frequently used today as specific probes for the quantitative and qualitative analysis of many different classes of chemicals of interest. Pharmacology has contributed to the field of immunology by providing basic pharmacological information on subjects such as the mediators of hypersensitivity reactions and inflammation. In the future, the truly hybrid field of immunopharmacology promises to have an expanding role in clinical medicine and basic research. This prediction is based on the observation that recombinant lymphokines and newly discovered immunomodulatory substances have begun to enter the clinic in ever increasing numbers. Future immunopharmacological research will include the study of the pharmacology of these lymphokines but also the rational development of new drugs that act as antagonists or agonists for the endogenous lymphokines that normally regulate the immune response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of acute steroidogenesis,peroxisome proliferator-activated receptors and CYP3A/PXR in salmon interrenal tissues by tributyltin and the second messenger activator,forskolin

There are uncertainties regarding the role of sex steroids in sexual development and reproduction of gastropods, leading to the recent doubts as to whether organotin compounds do inhibit steroidogenic enzymes in these species. These doubts have led us to suspect that organotin compounds may affect other target molecules, particularly signal transduction molecules or secondary mediators of steroid hormone and lipid synthesis/metabolism. Therefore, we have studied the effects of TBT exposure through food on acute steroidogenesis, PPARs and CYP3A responses in the presence and absence of a cyclic AMP (cAMP) activator, forskolin. Two experiments were performed. Firstly, juvenile salmon were force-fed once with diet containing TBT doses (0.1, 1 and 10 mg/kg fish) dissolved in ethanol and sampled after 72 h. Secondly, fish exposed to solvent control and 10 mg/kg TBT for 72 h were transferred to new tanks and exposed to waterborne forskolin (200 μg/L) for 2 and 4 h. Our data show that juvenile salmon force-fed TBT showed modulations of multiple biological responses in interrenal tissues that include, steroidogenesis (cAMP/PKA activities; StAR and P450scc mRNA, and plasma cortisol), and mRNA for peroxisome proliferator-activated receptor (PPAR) isoforms (α, β, γ), acyl-CoA oxidase-1 (ACOX1) and CYP3A/PXR (pregnan X receptor). In addition, forskolin produced differential effects on these responses both singly and also in combination with TBT. Overall, combined forskolin and TBT exposure produced higher effects compared with TBT exposure alone, for most of the responses (cortisol, PPARβ, ACOX1 and CYP3A). Interestingly, forskolin produced PPAR isoform-specific effects when given singly or in combination with TBT. Several TBT mediated toxicity in fish that includes thymus reduction, decrease in numbers of lymphocytes, inhibition of gonad development and masculinization, including the imposex phenomenon have been reported. When these effects are considered with the present findings, it suggests that studies on mechanisms of action or field studies may reveal endocrine, reproductive or other effects of TBT at lower concentrations than those reported to date from subchronic tests of fishes. Since the metabolic fate of organotin compounds may contribute to the toxicity of these chemicals, the present findings may represent some new aspects of TBT toxicity not previously reported.     

Bloom dynamics and chemical defenses of benthic cyanobacteria in the Indian River Lagoon,Florida

Cyanobacterial blooms are predicted to become more prominent in the future as a result of increasing seawater temperatures and the continued addition of nutrients to coastal waters. Many benthic marine cyanobacteria have potent chemical defenses that protect them from top down pressures and contribute to the persistence of blooms. Blooms of benthic cyanobacteria have been observed along the coast of Florida and within the Indian River Lagoon (IRL), a biodiverse estuary system that spans 250 km along Florida’s east coast. In this study, the cyanobacterial bloom progression at three sites within the central IRL was monitored over the course of two summers. The blooms consisted of four unique cyanobacterial species, including the recently described Okeania erythroflocculosa. The cyanobacteria produced a range of known bioactive compounds including malyngolide, lyngbyoic acid, microcolins A–B, and desacetylmicrocolin B. Ecologically-relevant assays showed that malyngolide inhibited the growth of marine fungi (Dendryphiella salina and Lindra thalassiae); microcolins A–B and desacetylmicrocolin B inhibited feeding by a generalist herbivore, the sea urchin Lytechinus variegatus; and lyngbyoic acid inhibited fungal growth and herbivore feeding. These chemical defenses likely contribute to the persistence of cyanobacterial blooms in the IRL during the summer growing period.     

Ethnobotany,ethnopharmacology and toxicity of Jatropha curcas L. (Euphorbiaceae): A review

Jatropha curcas L. (Euphorbiaceae) is a multiple purpose plant with potential for biodiesel production and medicinal uses. It has been used for treatment of a wide spectrum of ailments related to skin, cancer, digestive, respiratory and infectious diseases. This review aims to provide an up-to-date survey of information available on botany, traditional uses, phytochemistry, pharmacology and toxicity of J. curcas. Establishing a scientific basis that explains its ethnopharmacological uses in order to facilitate and guide future research. The review covers literature available from 1960 to 2012 collected from scientific journals, books and electronic searches such as Google scholar, Web of Science and ScienceDirect. Ethnomedicinal uses of J. curcas have been reported from many countries in Africa, Asia, South America and the Middle East for almost 100 different types of ailments. The phytochemical studies have shown the presence of many secondary metabolites including diterpeniods, sesquiterpenoids, alkaloids, flavonoids, phenols, lignans, coumarins and cyclic peptides. Crude extracts and isolated compounds from J. curcas show a wide range of pharmacological activities, such as anti-inflammatory, antioxidant, antimicrobial, antiviral, anticancer, antidiabetic, anticoagulant, hepatoprotective, analgesic and abortifacient effects. J. curcas has been a widely used source of medicine for decades in many cultures. The present review reveals that J. curcas is a valuable source of medicinally important molecules and provides convincing support for its future use in modern medicine.     

Chemical activation of a food deprivation signal extends lifespan

Model organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug‐like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the perception of food and which normally acts to decrease glutamate signals. Our results describe the activation of a dietary restriction response through the pharmacological masking of a novel sensory pathway that signals the presence of food. This suggests that primary sensory pathways may represent novel targets for human pharmacology.     

Cadmium Exposure in the South Korean Population: Implications of Input Assumptions for Deterministic Dietary Assessment

Dietary exposure to Cadmium (Cd) is of increasing interest globally because of the adverse health effects of Cd arising from multiple sources. The assumptions used when undertaking deterministic assessment of Cd in global or regional diets have implications when applied to specific national cases representing local variation in food composition and consumption patterns different from global or regional norms. We have conducted deterministic dietary Cd exposure assessments for the South Korean population using a variety of schemes for point estimation. Consumption data from the Korean Nutrition Survey (2001 to 2003) and monitoring data from the Korea Food and Drug Administration were used as the basis for the exposure estimates. The average daily per capita Cd exposure was 14 μ g for the South Korean population, representing about 27% of tolerable daily intake (TDI) and is similar to that reported in other countries. The hazard index (HI, the ratio of total Cd exposure to the TDI) typically ranged from 0.3 to 0.9 depending on assumptions used in deterministic estimates of dietary exposure. Even though the current exposure of the South Korean population at large is found to be safe on the basis of these estimates, consideration of high-end patterns of Cd level and consumption suggests the need for continued vigilance in dietary Cd monitoring.     

巴西人参化学成分和药理活性研究进展

巴西人参原产于南美洲,当地人把它当做具有壮阳、增强体质等作用的草药。巴西人参已在我国广西、浙江等地引种栽培成功,现代研究发现,其主要含有三萜和三萜皂苷类、甾体类等多种化学成分,具有抗肿瘤、抗炎、保护胃黏膜等药理活性。本文通过对近年来巴西人参的研究情况进行综述,阐明已有的化学物质基础和药理作用,为其进一步的深入研究和开发提供理论依据。     

Systems pharmacology and enhanced pharmacodynamic models for understanding antibody-based drug action and toxicity

Pharmacokinetic (PK) and pharmacodynamic (PD) models seek to describe the temporal pattern of drug exposures and their associated pharmacological effects produced at micro- and macro-scales of organization. Antibody-based drugs have been developed for a large variety of diseases, with effects exhibited through a comprehensive range of mechanisms of action. Mechanism-based PK/PD and systems pharmacology models can play a major role in elucidating and integrating complex antibody pharmacological properties, such as nonlinear disposition and dynamical intracellular signaling pathways triggered by ligation to their cognate targets. Such complexities can be addressed through the use of robust computational modeling techniques that have proven powerful tools for pragmatic characterization of experimental data and for theoretical exploration of antibody efficacy and adverse effects. The primary objectives of such multi-scale mathematical models are to generate and test competing hypotheses and to predict clinical outcomes. In this review, relevant systems pharmacology and enhanced PD (ePD) models that are used as predictive tools for antibody-based drug action are reported. Their common conceptual features are highlighted, along with approaches used for modeling preclinical and clinically available data. Key examples illustrate how systems pharmacology and ePD models codify the interplay among complex biology, drug concentrations, and pharmacological effects. New hybrid modeling concepts that bridge cutting-edge systems pharmacology models with established PK/ePD models will be needed to anticipate antibody effects on disease in subpopulations and individual patients.     

巴西人参化学成分和药理活性研究进展

巴西人参原产于南美洲,当地人把它当做具有壮阳、增强体质等作用的草药。巴西人参已在我国广西、浙江等地引种栽培成功,现代研究发现,其主要含有三萜和三萜皂苷类、甾体类等多种化学成分,具有抗肿瘤、抗炎、保护胃黏膜等药理活性。本文通过对近年来巴西人参的研究情况进行综述,阐明已有的化学物质基础和药理作用,为其进一步的深入研究和开发提供理论依据。     

Regime Shifts in the Anthropocene: Drivers,Risks, and Resilience

Many ecosystems can experience regime shifts: surprising, large and persistent changes in the function and structure of ecosystems. Assessing whether continued global change will lead to further regime shifts, or has the potential to trigger cascading regime shifts has been a central question in global change policy. Addressing this issue has, however, been hampered by the focus of regime shift research on specific cases and types of regime shifts. To systematically assess the global risk of regime shifts we conducted a comparative analysis of 25 generic types of regime shifts across marine, terrestrial and polar systems; identifying their drivers, and impacts on ecosystem services. Our results show that the drivers of regime shifts are diverse and co-occur strongly, which suggests that continued global change can be expected to synchronously increase the risk of multiple regime shifts. Furthermore, many regime shift drivers are related to climate change and food production, whose links to the continued expansion of human activities makes them difficult to limit. Because many regime shifts can amplify the drivers of other regime shifts, continued global change can also be expected to increase the risk of cascading regime shifts. Nevertheless, the variety of scales at which regime shift drivers operate provides opportunities for reducing the risk of many types of regime shifts by addressing local or regional drivers, even in the absence of rapid reduction of global drivers.     

TOPS-MODE model of multiplexing neuroprotective effects of drugs and experimental-theoretic study of new 1,3-rasagiline derivatives potentially useful in neurodegenerative diseases

The interest on computational techniques for the discovery of neuroprotective drugs has increased due to recent fail of important clinical trials. In fact, there is a huge amount of data accumulated in public databases like CHEMBL with respect to structurally heterogeneous series of drugs, multiple assays, drug targets, and model organisms. However, there are no reports of multi-target or multiplexing Quantitative Structure–Property Relationships (mt-QSAR/mx-QSAR) models of these multiplexing assay outcomes reported in CHEMBL for neurotoxicity/neuroprotective effects of drugs. Accordingly, in this paper we develop the first mx-QSAR model for multiplexing assays of neurotoxicity/neuroprotective effects of drugs. We used the method TOPS-MODE to calculate the structural parameters of drugs. The best model found correctly classified 4393 out of 4915 total cases in both training and validation. This is representative of overall train and validation Accuracy, Sensitivity, and Specificity values near to 90%, 98%, and 80%, respectively. This dataset includes multiplexing assay endpoints of 2217 compounds. Every one compound was assayed in at least one out of 338 assays, which involved 148 molecular or cellular targets and 35 standard type measures in 11 model organisms (including human). The second aim of this work is the exemplification of the use of the new mx-QSAR model with a practical case of study. To this end, we obtained again by organic synthesis and reported, by the first time, experimental assays of the new 1,3-rasagiline derivatives 3 different tests: assay (1) in absence of neurotoxic agents, (2) in the presence of glutamate, and (3) in the presence of H₂O₂. The higher neuroprotective effects found for each one of these assays were for the stereoisomers of compound 7: compound 7b with protection = 23.4% in assay (1) and protection = 15.2% in assay (2); and for compound 7a with protection = 46.2% in assay (3). Interestingly, almost all compounds show protection values >10% in assay (3) but not in the other 2 assays. After that, we used the mx-QSAR model to predict the more probable response of the new compounds in 559 unique pharmacological tests not carried out experimentally. The results obtained are very significant because they complement the pharmacological studies of these promising rasagiline derivatives. This work paves the way for further developments in the multi-target/multiplexing screening of large libraries of compounds potentially useful in the treatment of neurodegenerative diseases.