For a less attentive eye, the ground cherry or mullaca is just scrub. Also called Chinese lantern, it is a 1-meter tall bush, with a thin trunk, oval leaves and delicate yellow flowers, which grows in pastures, plantations and by the roadsides. Abundant in hot regions, this plant has been used for ages by peoples from Asia, Africa and Latin America in teas and infusions against asthma, hepatitis, malaria and rheumatism. Researchers from Bahia and Rio de Janeiro have now found out that at least three molecules extracted from the leaves and the trunk of this bush help to regulate the defense system of the organism and are up to 30 times more potent than some of the medicines most used to relieve inflammations, as they attest in an article published in January in the European Journal of Pharmacology.
But these molecules, called physalins, chemically classified as steroids, still have to undergo other experiments before concluding that they can really replace drugs like dexomethasone and hydrocortisone, which, in excess, can jeopardize the production of sexual and other hormones, essential for the development of the body. “These are the tests that will indicate whether physalins can be used safely on human beings”, explains immunologist Milena Soares, from the Oswaldo Cruz Foundation (Fiocruz) in Salvador. She is the coordinator of this research, which is part of the Millennium Institute of the Semi-Arid, a program of the Ministry of Science and Technology intended to investigate the pharmacological potential plants that are native or exclusive to the region from the north of Minas Gerais to Piauí.
Identified at the beginning of the 70’s, the molecules extracted from the ground cherry were called physalins in a reference to the scientific name of the plant, Physalis angulata, also called wild tomato for giving fruit similar to little tomatoes, encapsulated in leaves that form a sort of bladder (in Greek, Physalis means bladder). More than the widespread popular use of this plant, what most intrigued Milena was the molecular structure of the physalins, very similar to the structure of glucocorticoids, hormones produced by the organism that regulate the activity of the immune system and act as a basis for the industrial production of dexomethasone and hydrocortisone. One of the doubts was to find out whether physalins would also act like glucocorticoids and inhibit the activity of the defense cells.
Macrophages under control
Milena and her team decide to put them to the acid test and to find out if the proteins from the ground cherry were as efficient as glucocorticoids. In a series of experiments, carried out in collaboration with a group from Fiocruz in Rio, the researcher applied physalins of types B, F and G in doses that varied from 0.01 microgram per milliliter to 2 micrograms per milliliter in test tubes with a mixture rich in one of the main kinds of cell from the immune system, macrophages. When activated, macrophages reach the place of the infection and release nitric oxide, a chemical messenger that recruits other defense cells to eliminate damaged cells or to combat invading microorganisms. Usually benefic, this activation becomes harmful when done in excess.
The results were surprising. In higher doses, one of the physalins, type B, reduced the production of nitric oxide by 90% – an efficiency 30 times superior to that of equivalent doses of dexomethasone. More detailed analyses revealed that the action of physalin B is not limited to nitric oxide. The steroid from the ground cherry, as was proved in this work, prevents the production of another two chemical messengers, interleukins 6 and 12. High doses of physalin B reduced the levels of interleukin 6 by 60% and of interleukin 12 by 90%. They also reduced by one third the production of the tumor necrosis factor alpha. One of the proteins released by macrophages, the tumor necrosis factor assists the immune system in eliminating foreign microorganisms. At high levels, though, it brings down blood pressure and the oxygenation of the tissues, a situation known as endotoxic shock, which can lead to death.
With the test tube stage behind them, the researchers from Fiocruz tested the effects of physalins on mice, since the results in the organism can be very different. They applied in these rodents lethal doses of a molecule made up of sugar and fat a lipopolysaccharide from the membrane of bacteria that activates the immune system and stimulates the intensive production of tumor necrosis factor alpha. Next, they gave varied doses of the three physalins to separate groups of mice. All the animals showed signs of endotoxic shock, with their fur bristling and tremors, and they could hardly manage to move. The symptoms in those that were given physalins, though, were much milder. And, what is most important, all the mice treated with high doses (1 milligram) of these molecules from the ground cherry survived, while the untreated animals died. “This test showed that physalins have a sufficiently potent action to prevent the animals from dying”, Milena notes.
In a complementary experiment, the team from Bahia also found that physalins, by an as yet unknown mechanism, block the organism’s chemical messengers in a different way from dexomethasone. The researchers gave different groups of mice ground cherry proteins and dexomethasone. Next, they applied a compound that works as an antidote to dexomethasone, which, as expected, cut the effect of the glucocorticoid, but and here is the unexpected bit did not show any action on physalins. While she is waiting for the results of the safety tests, Milena is thinking ahead and planning a more daring step: investigating whether these compounds would be sufficiently potent to control a more exacerbated immune response, such as is to be seen in the case of transplants of organs.
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