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Natural Toxins and Medicine

Natural Toxins and Medicine


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How are natural venoms and toxins (e.g. spider and snake venoms) used to make antidotes? In other words, what is in that venom that is part of a harmful substance but, when used correctly, can actually help us, and why can these molecules help or harm in different situations?

Also, why are we looking to natural toxins to produce new medicines instead of synthetic chemicals we could make or already have?


You are probably thinking about antivenom using immune serum.

You give the venom to a host animal to induce an immune response, and then purify (to the extent possible) antibodies collected in serum from that animal, and then inject these to the patient to neutralize the venom. You don't use the venom directly.

Isolating components of venom could also allow for screening for molecules that will bind to them strongly and possibly block their action, though I'm not aware of specific antidotes that have been produced this way.


Natural Toxins and Medicine - Biology

Natural Antidotes To Biological Toxins

Americans have grown so accustomed to relying upon prescription medications that they will probably have difficulty believing there are natural compounds as close as the kitchen cupboard that are potent antidotes against biological warfare. These natural antibiotics and antioxidants may give unvaccinated people who have been exposed to biological or chemical weapons enough time to secure professional care. They may even save lives.

It is a fact that chaotic events will make it difficult to obtain appropriate treatment even if it were available. So we must learn more about natural antidotes.

Furthermore, it is clear that antidotes to biological attacks need to be employed at home or the workplace in an expedient manner. The idea of the masses running to obtain medical care or vaccines at doctor's offices, clinics or hospitals needs to be abandoned if civilian defense against biological weapons is to become a reality.

1. GARLIC The Garlic Information Center in Britain indicates that deadly anthrax is most susceptible to garlic.

Garlic is a broad-spectrum antibiotic that even blocks toxin production by germs. [Journal Nutrition, March 2001]

In one test garlic was found to be a more potent antibiotic than penicillin, ampicillin, doxycycline, streptomycin and cephalexin, some of the very same antibiotic drugs used in the treatment of anthrax.

Garlic was found to be effective against nine strains of E. coli, Staph and other bugs. [Fitoterapia, Volume 5, 1984] Freshly cut cloves of garlic or garlic powder may be beneficial.

The antibiotic activity of one milligram of allicin, the active ingredient in garlic, equals 15 units of penicillin. [Koch and Lawson, Garlic: The Science and Therapeutic Application, 2nd edition, Williams & Wilkins, Baltimore 1996] Garlic capsules that certify their allicin content are preferred and may provide 5-10 milligrams of allicin, which is equivalent to 75-150 units of penicillin.

2. SULFUR-BEARING ANTIOXIDANTS

The anthrax bacterium's toxicity emanates from its ability to kill macrophage cells which are part of the immune system.

Studies have shown that sulfur-bearing antioxidants (alpha lipoic acid, N-acetyl cysteine, taurine) and VITAMIN C, which elevate levels of glutathione, a natural antioxidant within the body, counters the toxicity produced by anthrax. [Molecular Medicine, November 1994 Immunopharmacology, January 2000 Applied Environmental Microbiology, May 1979]

The above sulfur compounds can be obtained from health food stores and taken in doses ranging from 100-500 mg.

Vitamin C should be the buffered alkaline form (mineral ascorbates) rather than the acidic form (ascorbic acid) and should be combined with bioflavonoids which prolong vitamin C's action in the blood circulation.

The powdered form of vitamin C is recommended to achieve optimal dosing. A tablespoon of vitamin C powder (about 10,000 mgs) can be added to juice. Good products are Twinlab's Super Ascorbate C powder and Alacer's powdered vitamin C.

Melatonin, a sleep-inducing hormone available at most health food stores, has been shown to help prevent lethal toxins from anthrax exposure. [Cell Biology Toxicology, Volume 16, 2000] It could be taken at bedtime in doses ranging from 5-20 mg. Melatonin boosts glutathione levels during sleep.

Of additional interest, one of the methods by which MUSTARD GAS works is its ability to bring about cell death by depleting cell levels of glutathione [eMedicine Journal, April 9, 2001] So GLUTATHIONE is also an antidote for mustard gas poisoning.

5. IRON and METAL-BINDING CHELATORS.

Virtually all bacteria, viruses and fungi depend upon IRON as a growth factor. [Iron & Your Health, T.F. Emery, CRC Press, 1991] Iron-chelating (removing) drugs and antibiotics (Adriamycin, Vancomycin, others) are effective against pathogens. The PLAUGE (Yersinia pestis), botulism, smallpox and antrax could all be potentially treated with non-prescription metal-binding chelators. For example, iron removal retards the growth of the plague. [Medical Hypotheses, January 1980] The biological activity of the botulinum toxin depends upon iron, and metal chelators may be beneficial. [Infection Immunology, October 1989, Toxicon, July, 1997].

Phytic acid (IP6), derived as an extract from rice bran, is the most potent natural iron chelator and has strong antibiotic and antioxidant action. [Free Radical Biology Medicine, Volume 8, 1990 Journal Biological Chemistry, August 25, 1987]

IP6 has been found to have similar iron-chelating properties as desferrioxamine, a drug commonly used to kill germs, tumor cells or to remove undesirable minerals from the body. [Biochemistry Journal, September 15, 1993] IP6 rice bran extract (2000-4000 mg) should be taken in between meals with filtered or bottled water only (no juice).

The antibacterial, antiseptic action of plant oils has been described in recent medical literature and may be helpful in fighting biological toxins. [Journal Applied Microbiology, Volume 88, 2000] A potent natural antibiotic, more powerful than many prescription antibiotics, is oil of oregano.

One study showed that oregano completely inhibited the growth of 25 germs such as Staphylococcus aureas, Escherichia coli, Yersinia enterocolitica and Pseudomonas aeruginosa. [Journal Food Protection, July 2001]

Oregano has been shown to be effective in eradicating intestinal parasites in humans. [Phytotherapy Research, May 2000]

Wild oregano, which is quite different than the variety on most kitchen spice racks, has over 50 antibacterial compounds. Just one part wild oregano oil in 4000 dilution sterilizes contaminated water. [London Times, May 8, 2001]

Oregano powder from whole leaf oregano is available as OregamaxTM capsules (North American Herb & Spice Co.) A spectacular development in natural antibiotic therapy is the manufacture of oregano powder from 100% pure oregano oil, producing one of the most potent antibiotics known. It has recently become available under the trade name OregacinTM (North American Herb & Spice Co.). It costs about $1 per pill, but this is a far cry from the $16 per pill for Vancomycin, known as most potent prescription antibiotic.

North American Herb & Spice Co.

Nature also provides nerve gas antitoxins. Nerve gas interrupts the normal transmission of nerve impulses by altering levels of acetycholinesterase, the enzyme that degrades the nerve transmitter acetycholine. Huperzine A, a derivative of Chinese Club Moss, has been suggested as a pre-treatment against nerve gases. [Annals Pharmacology France, January 2000]

The Walter Reed Army Institute of Research conducted studies which revealed that huperzine A protects against nerve gas poisoning in a superior manner to physostigmine, a long-standing anti-nerve toxin drug. [Defense Technical Information Center Review, Volume 2, December 1996]

Huperzine A is available as a food supplement at most health food stores. Suggested dosage is 150 mcg per day. Pretreatment is advised prior to nerve gas exposure.

SUMMARY. The threat of biological warfare is real and concern over preparedness of the civilian population and medical professionals is growing. There is virtually no practical way that vaccines, antibiotics or other treatment can be delivered to a frightened populace in a timely manner during a crisis. The current strategy of having an unprotected citizenry travel to physicians' offices or hospitals to receive prophylactic care or treatment is unfeasible. The public must be armed with preventive or therapeutic agents in their vehicles, homes and the workplace.

Natural antibiotics and antitoxins are well documented in the medical literature, but overlooked by health authorities. These antidotes are readily available for the public to acquire and place in an emergency biological response kit.


An Overview of Natural Toxins in Food

Reported by Dr. Anna S.P. TANG, Research Officer,
Risk Assessment Section, Centre for Food Safety

What are Natural Toxins in Food?

As opposed to man-made chemicals such as pesticides, veterinary drugs or environmental pollutants that get into our food supply, toxins can be present due to their natural occurrence in food. Natural toxins found inherently in foods of plant and animal origins can be harmful when consumed in sufficient quantities.

Where do They Come From?

Toxic compounds are produced by a variety of plants and animals. Natural toxins may be present serving specific function in the plant and animal or evolved as chemical defense against predators, insects or microorganisms. These chemicals have diverse chemical structures and are vastly different in nature and toxicity.

Natural Toxins Present in Food of Plant Origin

Of over 300,000 different plant species in the world, at least 2,000 species are considered to be poisonous. Cases of poisoning are often reported when wild species of mushrooms, berries or other plants are ingested. Globally, only hundreds of plant species are commonly eaten, yet many of them can become toxic to the body if they are taken in excess or if they are not properly treated before consumption. Depending on the species, the edible parts of plants vary, which may include foliage, buds, stems, roots, fruits and tubers, and so are their poisonous parts.

Plants from the same genera may exhibit similar or vastly different toxicities. The amount and the distribution of the toxins present in a plant vary according to the species as well as the geographical conditions where it is grown.

In general, plant organs that are important for survival and reproduction, such as flowers and seeds, will concentrate defense compounds. These compounds may be more rapidly synthesised or stored at certain stages of critical growth, i.e. in buds, young tissue or seedlings as in the case of potato sprouts.

Common examples of natural toxins in food plants include glycoalkaloids in potatoes, cyanide-generating compounds in bitter apricot seeds and bamboo shoots, enzyme inhibitors and lectins in soya beans, green beans and other legumes.

Illustration: Sprouted potatoes

Illustration: Ginkgo seeds

Illustration: Bamboo shoots

Natural Toxins Present in Food of Animal Origin

Natural toxin of animal origin may be a product of metabolism or a chemical that is passed along the food chain. While poisoning after eating terrestrial animals is relatively uncommon, poisoning due to marine toxins occurs in many parts of the world. Marine toxins produced by toxic microalgae are accumulated in shellfish, crustacean and finfish following their consumption. Tetrodotoxin, a potent marine neurotoxin, is thought to be produced by certain bacteria. It is found in over 90 species of puffer fish and may cause lethality after ingested even a small amount. Seafood poisoning commonly reported in coral reef fish is due to the presence of ciguatoxin that may be found in more than 300 species of fish. Histamine produced by bacterial spoilage of scombroid fish causes another kind of seafood poisoning.

There are approximately 1,200 species of poisonous and venomous animals in the world. While most of them are not used as food, care must be taken to avoid the poisonous glands or tissue containing the toxins when these animals are used as food. Glands of some animals that are not considered poisonous or venomous when ingested can also cause food poisoning such as gall-bladder of grass carp which contains the cyprinol related chemicals.

Illustration: Leopard coral grouper

Illustration: Potato grouper

Illustration: Hump head wrasse

Toxic Effects and Food Poisoning

Natural toxins in food can cause both acute and chronic health effects with a range of clinical symptoms. Acute symptoms range from mild gastrointestinal upset, neurological symptoms, respiratory paralysis to fatality. This is more likely among the susceptible groups of the population such as children and the elderly. Within hours if not shorter, acute symptoms are seen following ingestion of various marine toxins in shellfish and other seafood. Acute poisoning is also seen in the consumption of wild mushrooms or inadequately treated plants such as ginkgo seeds and bitter apricot seeds. Chronic toxicity is seen more often in poisoning caused by plants toxins such as many alkaloids. Pyrrolizidine alkaloids that are present in weeds in crops and in certain plants may cause toxicity to the liver over prolonged consumption. The amount of food that would cause toxic effects depends on the toxin level present as well as individual susceptibility.

Risk Reduction Measures

In some cases, appropriate methods of food processing and thorough cooking can be employed to destroy or reduce the level of toxin. In other cases where the toxin cannot be reduced or removed, intake should be limited. Thorough cooking destroys enzyme inhibitors and lectins of beans. Soaking in water, and boiling also remove some cyanide-generating compounds in the foods concerned. Removal of gonads, skin, and parts of certain fish eliminates toxins concentrated in these tissues. In general, whether a substance poses harm depends on its concentration, amount of intake and the health status of individual since the body can detoxify low levels of many potentially dangerous substances. As a rule of thumb, the public should follow the conventional ways of food processing that are known to be safe, and maintain a balanced and varied diet so that exposures to certain types of natural toxins can be kept to a safe level.


All natural

Natural products research focuses on the chemical properties, biosynthesis and biological functions of secondary metabolites. As our scientific understanding of all things 'natural' is rapidly expanding, we should also make time to communicate the subtleties of chemical distinctions to the public.

Natural products are a central theme of research at the interface of chemistry and biology. The complex structures captivate the chemical thinking of scientists, both by offering countless opportunities to flex synthetic organic muscles and by engaging chemical intuition in thinking about how these molecules might have originated in the cell. Elucidating the relevant biochemical pathways and deciphering the roles of the compounds within a biological setting, on the other hand, pushes our understanding of small-molecule mechanisms in biology. Though all natural products have served to inspire intellectual inquiry, one of the most intriguing classes of molecules is the terpenes. These highly diverse and amply decorated scaffolds remind us that, amidst our growing chemical and biological understanding, open questions remain. Accordingly, the collection of articles in this special issue demonstrates that ongoing research on natural products, and terpenes in particular, is flourishing. But against this backdrop of significant scientific advances in understanding the chemistry and biology of naturally occurring small molecules, there is a need for increased public awareness of what it means to be 'natural'.

In the public eye, products dubbed 'natural' and 'organic' are typically viewed as good and wholesome, whereas 'chemicals' have negative connotations. Beyond being a frequent source of amusement for scientists, and organic chemists in particular, this prevailing viewpoint has consequences. In the consumer market, it has manifested itself in one case as a lawsuit between companies producing artificial sugar, both of whom claim their product is more akin to 'real' sugar (http://pubs.acs.org/cen/news/85/i16/8516notw5.html). In the agricultural sector, there are significant public misconceptions about the potential dangers and benefits of genetically modified crops (http://www.nature.com/nature/focus/gm/index.html). The emerging field of synthetic biology faces a related challenge in maintaining open communication with the public about the risks and rewards of engineering organisms (http://www.nature.com/nature/journal/v438/n7067/edsumm/e051124-01.html), for instance, to produce small-molecule therapeutics.

But what is 'natural'? The simplest definition for a natural product is a small molecule that is produced by a biological source. However, one challenge in classifying chemicals as natural or non-natural is the limited extent to which natural products have been characterized. As Fischbach and Clardy point out, many biosynthetic enzymes are nonspecific, which results in the production of multiple 'natural' analogs (Commentary, p. 353). Similarly, the ongoing discovery of new microorganisms and the subsequent identification of the natural products they produce suggests, as Axel Brakhage, director of the Hans Knöll Institute puts it, that we're “only at the tip of the iceberg” in identifying the entirety of natural products (Elements, p. 367). Indeed, new research in this issue reexamines the natural products that make up the dauer pheromone, finding two new compounds that account for the bulk of the biological response (Letters, p. 420 News & Views, p. 368). With so many compounds undiscovered, the definition of a natural small molecule is clearly a moving target.

In contrast, for cases in which the chemical structure of a small molecule has been determined, defining natural (for a scientist) becomes easy. Whether a natural product is isolated from a native organism, synthesized in a laboratory (Review, p. 396), biosynthesized in vitro, or isolated from a metabolically engineered organism (Perspective, p. 387), if the resultant compound is chemically equivalent to the original natural product, it is natural. In contrast, even if a molecule is produced by biosynthetically engineering a microbe (Perspective, p. 379), if it is not a naturally occurring small molecule, it is not natural. However, this type of engineering represents an important source of potential new therapeutics, and the existence of many natural product 'analogs' among currently used drugs (J. Nat. Prod. 66, 1022–1037, 2003) defies the simplistic public connection between natural and good.

Despite society's association of 'natural' with wholesome products, we all know that natural products include toxins and poisons, and even compounds that are required for life at low concentrations can become dangerous at high concentrations. Gershenzon and Dudareva discuss some of the ways that natural products are used in defense (Review, p. 408), highlighting chemicals used by plants to poison herbivores directly and to protect the plant indirectly by attracting predators. Schmidt et al. tackle the question of how to make use of these and related plant-derived compounds. In a discussion of the challenges in regulating natural product concentrations in botanical extracts, they point out that lax or poorly defined regulations have eroded consumer confidence in these products, despite the 'natural' moniker (Commentary, p. 360).

The many uses of 'natural' and the subtle distinctions between some cases of natural and non-natural clearly leave room for debate. However, better communication between scientists and the public is the first step in putting public debates on scientific footing. Indeed, Strobel and Strobel have taken on one aspect of this challenge in an undergraduate educational program in which students collect and culture new microorganisms and then isolate and identify the natural products they produce (Commentary, p. 356). The practical research experience of these young scientists will cement their understanding of the definition and significance of natural products imbuing the public with similar enthusiasm for chemical principles should be a community goal. With ideas like this as our guide, it's time to move beyond advertising gimmicks and fearmongering as pseudoscientific slogans and progress into real scientific dialogue.


You might also Like

Very informative site on looking into the perspective of science. anon999144 November 4, 2017

It seems that science is everywhere and in everything we encounter. How do they all work together? anon262930 April 22, 2012

Very helpful but doesn't answer my question. Why does science have an inability to stand alone from other fields? anon229270 November 13, 2011

Natural science is a big contribution to science. It is now the most distinguished source of any natural information people may find. And the different divisions of natural science, especially psychology, give more explanations about why people became like that and like this. In short, why people have different attitudes.

There are lots of questions that we can't find the answers to by just asking ourselves. And we can answer those through natural sciences! Please help us to understand why sciences are very important to us living things. PelesTears July 2, 2010

I believe that some natural sciences are closely related to the social sciences. Biology and biochemistry are perfect examples. From what I know, when these sciences study the effects of substances on the brain, the behaviors as well as physical reactions are studied.

When scientists study a new drug, doctors look for both physical and mental side effects. Drug studies also make conclusions on the physiological effects of the drug. They want to know whether these drugs are working as designed, and if the outcome justifies the side effects.

This is just one example that I can think of where two branches of science overlap, but I am sure there are others.

Sustainability is a new interdisciplinary science that studies the relationship between the natural, social and formal sciences. The science uses mathematics and statistics to understand the effects of economic and socio-cultural forces on the natural world.

A few top tier universities are establishing sustainability programs. Arizona State University in Tempe actually has a sustainability school that offers post-graduate degrees all the way up to the doctorate level. They have sustainability degrees that concentrate on engineering, the social sciences, and the natural sciences.

Arizona State is also working to establish a standard definition of the field of sustainability. The school was established in 2006, and has already become one of the top environmental science related programs in the country.


Boosting crop yields by using genetic engineering to help plants discard natural toxins

Credit: Delta Farm Press

You don’t need to imagine. That is exactly what happens every day when an estimated 815 million people around the globe go hungry. In the short term, the problem is likely to get worse as the population grows, diets change and urban sprawl forces farmers to produce more food on less land. Recent reports suggest that by the time children born today reach their 30s, the planet must increase food production by at least 70 percent.

As a biochemist, I started my career in biomedical research, but I shifted to agricultural research in 2013 because everybody needs to eat. Now I’m working with an international research project exploring how to boost food production. The goal of Realizing Increased Photosynthetic Efficiency (RIPE) is to increase the efficiency of photosynthesis – the process plants use to convert energy from the sun into the food we eat. In our most recent publication we’ve shown that it is possible to dramatically boost crop yield, by enabling the plant to get rid of its toxins more quickly.

It’s critical that we begin developing new crops now because it can still take at least a decade for agricultural innovations to reach farmers.

Photorespiration is an energy-demanding process

When it comes to photosynthesis, plants use sunlight to power a chemical reaction that converts carbon dioxide and water to sugars, oxygen and energy. But that isn’t the only chemical reaction that occurs in plants. A quirk in the evolution of the protein, called Rubisco, is that sometimes instead of converting carbon dioxide during photosynthesis, it uses oxygen instead. This produces waste products such as glycolate and ammonia, which can be toxic to plants and slow or stunt their growth.

By BlueRingMedia/shutterstock.com

To remove these toxic chemicals, another process needs to kick into gear. Photorespiration is a part of natural plant metabolism that recycles these toxins. It is a necessary process in major crops including rice, wheat and soybeans, as well as most fruit and vegetable crops.

Recycling these toxic byproducts sucks up a huge portion of the plants’ energy – and can inhibit the plant’s growth by more than 30 percent. At higher temperatures, plants tend to increase the amount of oxygen they convert, so as growing season temperatures rise and heat waves strike, up to 50 percent of the energy generated from photosynthesis can be required for photorespiration to recycle toxins in major crops like wheat and soybeans. That slashes yields in the hotter and drier regions of the world, such as sub-Saharan Africa and Southeast Asia, where food is most needed.

To meet the growing demand for increased food production, I worked with an international team to explore whether speeding up photorespiration might boost crop yields.

Making photorespiration faster

The work, led by Professor Christine Raines and lead author Patricia Lopez-Calgano from the University of Essex and the United States Department of Agriculture-Agricultural Research Service (USDA-ARS), explored whether this modification could boost the production of tobacco plants.

Researcher Patricia Lopez working with tobacco seedlings in the lab. Image credit: Monica Kennedy, CC BY-ND

We managed to speed up the recycling of these toxins by designing plants that produce more of a protein, called the H-protein, that is already present in our crop plants and plays a role in photorespiration. Previous work in the lab using the small plant Arabidopsis, the “lab rat” of plant research, suggested that increasing the quantity of H-protein could speed up photorespiration and enable our plants to grow larger. Our team translated this idea from the lab to the field using a strain of tobacco, Nicotiana tabacum, which we grew outside at a research field station near the University of Illinois at Urbana-Champaign where I work as a USDA-ARS scientist.

We discovered pretty quickly that we had to carefully control the quantity of the H-protein we engineered plants to produce. Too much H-protein in all parts of the plant was harmful, stunting growth and reducing yield of tobacco leaves. Thus, we fine-tuned our approach and engineered plants that manufactured the H-protein only in the leaves. This increased photosynthesis and plant growth, probably because of faster recycling of the toxic chemicals.

Harnessing biotechnology to improve crops

We tested our hypothesis in tobacco because it is an excellent model for proof-of-concept research. It is easy to genetically engineer and only has a four-month life cycle, allowing us to conduct several trials in one field season. This allows us to test various genetic modifications in tobacco and then translate those discoveries to make improvements in targeted food crops.

To fine-tune the expression of the H-protein, the team engineered the tobacco using DNA from a close relative, Solanum tuberosum, or potato. Using a known sequence of potato DNA, we were able to boost the H-protein specifically in the desired leaf tissue. That proved to be the key to increasing yield without harming the plant.

Initially, I was skeptical that boosting the production of a single protein out of thousands in the plant could have such a dramatic impact on crop yield. But, after two years of field trials, my colleagues and I have demonstrated that increasing H-protein levels leads to larger plants, boosting the crop yield by 27-47 percent.

Author Paul South measures the rate of photosynthesis in the tobacco plants in a field site in Illinois. Image Credit: Claire Benjamin, CC BY-ND

You might wonder whether plants with extra H-protein are safe to eat? It is too early to answer that question. Once we have engineered “high H-protein food crops” these plants must be proved safe, which includes allergen and environmental impact before these transgenic plants will be approved by the FDA and USDA.

These higher-yielding crops would be genetically modified organisms

Because part of the DNA comes from a foreign source (potato), these plants are considered genetically modified organisms, or GMOs. There’s no doubt that the idea of using GMOs as part of our food source is quite controversial.

Many individuals have rejected the use of GMO technology, and some countries have prohibitions or restrictions of the use in their food supply. However, many studies have shown extensive evidence that GMOs are safe to eat, including this definitive report by the National Academies of Sciences, Engineering and Medicine. We believe it is important to have this technology to increase crop productivity so farmers and consumers will have many high-yielding options available to them.

A shot of the field where South and his colleagues test their genetically modified tobacco plants. This image was taken by a drone in 2017. Image credit: Beau Barber, CC BY-ND

There are different techniques to create new crops, including traditional crop breeding techniques, GMOs and more recently CRISPR-based gene editing technology – which allow us to directly rewrite a plant’s DNA without adding foreign genes. But regardless of the technique, the goal is the same: produce plants that can thrive in farmers’ fields to create a more secure and sustainable food supply for everyone.

Our next goal is to bump up levels of the H-protein in important food crops including legumes – soybean and cowpea – as well as the root crop cassava, which are major staple foods worldwide. If we can increase the production of these target plants by between 27 and 47 percent, similar to what was observed in this study, it will go a long way toward meeting the goal of feeding another 2 to 3 billion people by 2050.

Paul South is a Postdoctoral Researcher at the Carl R. Woese Institute for Genomic Biology at the University of Illinois at Urbana-Champaign

This article was originally published at The Conversation as “Helping plants remove natural toxins could boost crop yields by 47 percent” and has been republished here with permission.

The GLP featured this article to reflect the diversity of news, opinion and analysis. The viewpoint is the author’s own. The GLP’s goal is to stimulate constructive discourse on challenging science issues.


ANTIOXIDANTS

An antioxidant is a molecule stable enough to donate an electron to a rampaging free radical and neutralize it, thus reducing its capacity to damage. These antioxidants delay or inhibit cellular damage mainly through their free radical scavenging property.[30] These low-molecular-weight antioxidants can safely interact with free radicals and terminate the chain reaction before vital molecules are damaged. Some of such antioxidants, including glutathione, ubiquinol, and uric acid, are produced during normal metabolism in the body.[31] Other lighter antioxidants are found in the diet. Although there are several enzymes system within the body that scavenge free radicals, the principle micronutrient (vitamins) antioxidants are vitamin E (α-tocopherol), vitamin C (ascorbic acid), and B-carotene.[32] The body cannot manufacture these micronutrients, so they must be supplied in the diet.

History

The term antioxidant originally was used to refer specifically to a chemical that prevented the consumption of oxygen. In the late 19th and early 20th century, extensive study was devoted to the uses of antioxidants in important industrial processes, such as the prevention of metal corrosion, the vulcanization of rubber, and the polymerization of fuels in the fouling of internal combustion engines.[33]

Early research on the role of antioxidants in biology focused on their use in preventing the oxidation of unsaturated fats, which is the cause of rancidity.[34] Antioxidant activity could be measured simply by placing the fat in a closed container with oxygen and measuring the rate of oxygen consumption. However, it was the identification of vitamins A, C, and E as antioxidants that revolutionized the field and led to the realization of the importance of antioxidants in the biochemistry of living organisms.[35,36] The possible mechanisms of action of antioxidants were first explored when it was recognized that a substance with antioxidative activity is likely to be one that is itself readily oxidized.[37] Research into how vitamin E prevents the process of lipid peroxidation led to the identification of antioxidants as reducing agents that prevent oxidative reactions, often by scavenging ROS before they can damage cells.[38]

Antioxidant defense system

Antioxidants act as radical scavenger, hydrogen donor, electron donor, peroxide decomposer, singlet oxygen quencher, enzyme inhibitor, synergist, and metal-chelating agents. Both enzymatic and nonenzymatic antioxidants exist in the intracellular and extracellular environment to detoxify ROS.[39]

Mechanism of action of antioxidants

Two principle mechanisms of action have been proposed for antioxidants.[40] The first is a chain- breaking mechanism by which the primary antioxidant donates an electron to the free radical present in the systems. The second mechanism involves removal of ROS/reactive nitrogen species initiators (secondary antioxidants) by quenching chain-initiating catalyst. Antioxidants may exert their effect on biological systems by different mechanisms including electron donation, metal ion chelation, co-antioxidants, or by gene expression regulation.[41]

Levels of antioxidant action

The antioxidants acting in the defense systems act at different levels such as preventive, radical scavenging, repair and de novo, and the fourth line of defense, i.e., the adaptation.

The first line of defense is the preventive antioxidants, which suppress the formation of free radicals. Although the precise mechanism and site of radical formation in vivo are not well elucidated yet, the metal-induced decompositions of hydroperoxides and hydrogen peroxide must be one of the important sources. To suppress such reactions, some antioxidants reduce hydroperoxides and hydrogen peroxide beforehand to alcohols and water, respectively, without generation of free radicals and some proteins sequester metal ions.

Glutathione peroxidase, glutathione-s-transferase, phospholipid hydroperoxide glutathione peroxidase (PHGPX), and peroxidase are known to decompose lipid hydroperoxides to corresponding alcohols. PHGPX is unique in that it can reduce hydroperoxides of phospholipids integrated into biomembranes. Glutathione peroxidase and catalase reduce hydrogen peroxide to water.

The second line of defense is the antioxidants that scavenge the active radicals to suppress chain initiation and/or break the chain propagation reactions. Various endogenous radical-scavenging antioxidants are known: some are hydrophilic and others are lipophilic. Vitamin C, uric acid, bilirubin, albumin, and thiols are hydrophilic, radical-scavenging antioxidants, while vitamin E and ubiquinol are lipophilic radical-scavenging antioxidants. Vitamin E is accepted as the most potent radical-scavenging lipophilic antioxidant.

The third line of defense is the repair and de novo antioxidants. The proteolytic enzymes, proteinases, proteases, and peptidases, present in the cytosol and in the mitochondria of mammalian cells, recognize, degrade, and remove oxidatively modified proteins and prevent the accumulation of oxidized proteins.

The DNA repair systems also play an important role in the total defense system against oxidative damage. Various kinds of enzymes such as glycosylases and nucleases, which repair the damaged DNA, are known.

There is another important function called adaptation where the signal for the production and reactions of free radicals induces formation and transport of the appropriate antioxidant to the right site.[42]


Natural Voltage-Gated Sodium Channel Ligands: Biosynthesis and Biology

Terrific toxins: Living organisms produce highly potent small molecule neurotoxins as forms of self-defense. A subset of these toxins target voltage-gated sodium channels, a potential target for non-opioid pain management in humans. The biosynthetic pathways of these channel-disrupting ligands are discussed in the context of biocatalytic applications.

Abstract

Natural product biosynthetic pathways are composed of enzymes that use powerful chemistry to assemble complex molecules. Small molecule neurotoxins are examples of natural products with intricate scaffolds which often have high affinities for their biological targets. The focus of this Minireview is small molecule neurotoxins targeting voltage-gated sodium channels (VGSCs) and the state of knowledge on their associated biosynthetic pathways. There are three small molecule neurotoxin receptor sites on VGSCs associated with three different classes of molecules: guanidinium toxins, alkaloid toxins, and ladder polyethers. Each of these types of toxins have unique structural features which are assembled by biosynthetic enzymes and the extent of information known about these enzymes varies among each class. The biosynthetic enzymes involved in the formation of these toxins have the potential to become useful tools in the efficient synthesis of VGSC probes.


Medical Competencies

The AAMC-HHMI report lists eight competencies to be attained in medical education, including applications of physics and chemistry (M2) and genetics (M3). It does not include any specific applications of evolution. Competency M1 is “apply knowledge of molecular, biochemical, cellular, and systems-level mechanisms that maintain homeostasis, and of the dysregulation of these mechanisms, to the prevention, diagnosis, and management of disease.” This describes the application of proximate knowledge to the body and disease. A parallel competency to bring in the evolutionary half of biology, perhaps M1b, would be “apply knowledge of evolutionary factors that have shaped the body and its regulatory systems to the prevention, diagnosis, and management of disease.”


Combining synthetic, natural toxins could disarm cancer, drug-resistant bacteria

Cancer researchers from Rice University suggest that a new human-made drug that's already proven effective at killing cancer and drug-resistant bacteria could best deliver its knockout blow when used in combination with drugs made from naturally occurring toxins.

"One of the oldest tricks in fighting is the one-two punch -- you distract your opponent with one attack and deliver a knockout blow with another," said José Onuchic of Rice's Center for Theoretical Biological Physics (CTBP). "Combinatorial drug therapies employ that strategy at a cellular level.

"A wealth of research in recent years has shown that both cancer and bacteria can mount sophisticated, coordinated defenses against almost any drug," said Onuchic, Rice's Harry C. and Olga K. Wiess Professor of Physics and Astronomy, professor of chemistry, and biochemistry and cell biology. "By combining drugs, particularly those that place stress on different parts of the cell, we expect it will be possible to knock out either cancer cells or bacteria while simultaneously inhibiting their ability to become drug-resistant."

Onuchic and CTBP colleagues Eshel Ben-Jacob and Patricia Jennings reached their conclusions after analyzing several studies on anti-microbial peptides (AMPs), corkscrew-shaped chains of amino acids that kill Gram-negative bacteria. The CTBP team's ideas appear this week in the Proceedings of the National Academy of Sciences (PNAS) as a commentary on new findings from MD Anderson Cancer Center about a promising synthetic AMP called D-KLAKLAK-2. In its new research, MD Anderson researchers found D-KLAKLAK-2, which was already known to kill cancer cells, is also an effective drug against antibiotic-resistant Gram-negative bacteria.

"AMPs are produced naturally by a number of animals to fight bacteria," said Ben-Jacob, professor of biochemistry and cell biology at Rice and the Maguy-Glass Chair in Physics of Complex Systems and professor of physics and astronomy at Tel Aviv University. "AMPs are corkscrew-shaped. They do not harm the animals' own cells, but they penetrate and shred the double-layered membranes of Gram-negative bacteria."

Gram-negative bacteria are a class of pathogens that includes drug-resistant varieties of bacteria that cause pneumonia, sepsis and other deadly diseases.

Ben-Jacob said cancer researchers have previously shown that they can tag AMPs with special "marker" molecules that allow the AMPs to penetrate and kill cancer cells. The markers allow the AMPs to be taken inside the cancer cells, something they cannot normally do.

"Once inside the cancer cells, the AMPs target and damage the cell's power plant, an organelle called the mitochondria, which has a double-layered membrane that is remarkably similar to that of Gram-negative bacteria," he said.

Though research has shown that AMPs can kill cancer cells, scientists are concerned that cancer cells could develop resistance to the compounds. In part, this concern arises from the fact that AMPs are fairly common in nature and that some organisms already have genetic mutations that allow them to evade AMP attacks.

To circumvent these natural defenses, MD Anderson researchers Wadih Arap and Renata Pasqualini led an effort a few years ago to create a synthetic version of a natural corkscrew-shaped AMP called KLAKLAK-2. Like all naturally occurring AMPs, KLAKLAK-2 has a left-handed twist -- much like the threads of a screw that turn clockwise. To make the molecule more difficult for cancer cells to fight, the MD Anderson team built a right-handed, "counterclockwise" version of the molecule called D-KLAKLAK-2, with the "D" denoting right-handedness. In its most recent studies, which also appear this week in PNAS, the MD Anderson team found that D-KLAKLAK-2 is an effective killer of Gram-negative bacterial pathogens, including several types that have grown resistant to traditional antibiotics.

"Bacteria are notorious for their rapid development of drug resistance," Ben-Jacob said. "However, both bacteria and cancer have impaired ability to resist these man-made 'mirror' compounds because they cannot use the machinery they have evolved to disarm the right-handed weapons."

Onuchic said another advantage of therapies involving synthetic AMPs like D-KLAKLAK-2 is that the drugs can be administered in extremely small doses, which will reduce side effects.

The Rice team suggests maximizing the benefits of synthetic AMPs by using them in drug cocktails that act like a one-two punch for either bacteria or cancer.

Naturally occurring AMPs are chemical weapons that bacteria themselves have developed over millions of years in their never-ending war among themselves. The team reasons that combining these natural toxins with human-made mirror drugs will create the drug equivalent of a one-two punch. The combination should "confuse" bacteria and cancer and prevent them from rapidly becoming resistant to the human-made drugs.

"Nature is smarter than we are," Ben-Jacob said. "Time and again, we have seen that seemingly simple cellular foes like bacteria and cancer can learn to mount effective defenses against any new drug we create. It is time to accept them as sophisticated enemies. We should attack them in much the same way that a well-trained boxer or military commander would go after a wily opponent -- with multiple, coordinated blows of very different kinds."

Jennings is professor of chemistry and biochemistry at the University of California, San Diego. Research at CTBP is supported by the National Science Foundation and by the Cancer Prevention and Research Institute of Texas.



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