Physalis angulata L. is an annual herb widely used in popular medicine for the treatment of a variety of pathologies. Here, we tested immunomodulatory activities of physalins, seco-steroids purified from P. angulata extracts. Addition of physalins B, F or G, but not D, caused a reduction in nitric oxide production by macrophages stimulated with lipopolysaccaride and interferon-gamma. In the presence of physalin B, macrophages stimulated with lipopolysaccaride, alone or in combination with interferon-gamma, produced lower levels of tumour necrosis factor (TNF)-alpha, interleukin-6 and interleukin-12. The inhibitory activity of physalin B, unlike that of dexamethasone, was not reversed by RU486 [(4-dimethylamino) phenyl-17beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one], an antiglucocorticoid. Physalin B-treated mice had lower levels of serum TNF-alpha than control mice after lipopolysaccaride challenge. More importantly, mice injected with physalins B, F or G survived after a lethal lipopolysaccaride challenge. These results demonstrate that seco-steroids from P. angulata are potent immunomodulatory substances and act through a mechanism distinct from that of dexamethasone.

Physalis angulata is a solanaceae widely used in folk medicine in various tropical countries in the world. We have previously described that seco-steroids (physalins) purified from P. angulata are potent inhibitors of macrophage activation, blocking the production of pro-inflammatory cytokines and LPS-induced lethality. Herein we investigated the immunomodulatory activities of these substances in lymphocyte proliferation and cytokine production and in transplantation. The addition of physalins B, F or G to concanavalin A-activated splenocyte cultures induced a concentration-dependent inhibition of proliferation. Physalin B also inhibited IL-2 production by Con A-activated spleen cells. The addition of 2 mug/ml physalin B to mixed lymphocyte reaction (MLR) caused a 100% inhibition of proliferation. More importantly, treatment of mice with physalin B, F or G prevented the rejection of allogeneic heterotopic heart transplant. Our results demonstrate the suppressive activity of physalins B, F and G in lymphocyte function and indicate the potential use of physalins as immunosuppressive agents for treatments of pathologies in which inhibition of immune responses is desired.

1 Reperfusion of an ischaemic tissue is associated with an intense inflammatory response and inflammation-mediated tissue injury. Physalins, a group of substances with secosteroidal chemical structure, are found in Physalis angulata stems and leaves. Here, we assessed the effects of physalins on the local, remote and systemic injuries following intestinal ischaemia and reperfusion (I/R) in mice and compared with the effects of dexamethasone. 2 Following I/R injury, dexamethasone (10 mg kg À1 ) or physalin B or F markedly prevented neutrophil influx, the increase in vascular permeability in the intestine and the lungs. Maximal inhibition occurred at 20 mg kg À1 . Moreover, there was prevention of haemorrhage in the intestine of reperfused animals. 3 Dexamethasone or physalins effectively suppressed the increase in tissue (intestine and lungs) and serum concentrations of TNF-a. Interestingly, treatment with the compounds was associated with enhancement of IL-10. 4 The anti-inflammatory effects of dexamethasone or physalins were reversed by pretreatment with the corticoid receptor antagonist RU486 (25 mg kg À1 ). The drug compounds suppressed steady-state concentrations of corticosterone, but did not alter the reperfusion-associated increase in levels of corticosterone. The IL-10-enhancing effects of the drugs were not altered by RU486. 5 In conclusion, the in vivo anti-inflammatory actions of physalins, natural steroidal compounds, appear to be mostly due to the activation of glucocorticoid receptors. Compounds derived from these natural secosteroids may represent novel therapeutic options for the treatment of inflammatory diseases.

Far-Manguinhos/FIOCRUZ -Rua Sizenando Nabuco, 100 -Manguinhos -21041-250 -Rio de Janeiro -RJ Recebido em 1/6/98; aceito em 25/6/99 GENUS PHYSALIS -A REVISION OF WITHASTEROIDS. This review describes results on the chemistry and spectroscopic data of some ergostane derivatives named withasteroids which have been obtained from Physalis genus. The main aim of this report is concerned with the description and characterization of Physalins. These natural product substances are C28 seco steroid lactone type compounds that have been shown biological activities against human illness such as immunodeficiency, neoplasic tumors, inflammatory process and tropical endemic diseases. Physalins appear to be a source for new drugs to be apply as medicine.Keywords: Physalis; Physalins; Withasteroids. REVISÃO INTRODUÇÃOOs vitaesteróides são substâncias que reproduzem o esqueleto intacto ou modificado do ergostano [1][2][3][4] . Estes derivados do ergostano são constituintes polioxigenados presentes, preponderantemente, nas espécies de Solanaceae. Tal ocorrência, porém, não se limita àquela família, como a princípio alguns pesquisadores faziam crer 4 , já que este grupo de substâncias também pode ser encontrado nas Leguminoseae 5,6 e Taccacedae 7 . A família Solanaceae inclui uma ampla variedade de plantas que são econômica e farmacologicamente importantes. • Características e classificação dos vitaesteróidesOs vitaesteróides possuem função lactônica em C-26, fornecendo uma variedade de estruturas classificadas em oito grupos, cujos os esqueletos básicos encontram-se representados pelas estruturas de 1 a 8 (Fig. 1).• vitanolidos (1)• vitanolidos "modificados" (anéis A ou D aromatizados 2,3)• vitafisalinas (4) • acnistinas (5) • ixocarpalactonas (6) • perulactonas (7) • fisalinas (8) Investigações mais recentes visam esclarecer as relações biogenéticas 8,9 entre os grupos acima mencionados. Tais correlações implicam em acentuadas modificações nos esqueletos carbocíclios, na cadeia lateral ou em ambos. Como exemplos, citam-se os aroamtizados nos anéis A e D, os epóxi-lactóis, dentre outros.Aqueles oito grupos estruturais encontram-se distribuídos nos gêneros abaixo, pertencentes a família Solanaceae.• Acnistus• Witheringia Observa-se uma grande diversificação estrutural de derivados ergostânicos nestes gêneros cabendo a Withania e Physalis a maior produção de vitanolídos e fisalinas respectivamente 3 . Figura 1. Esqueletos básicos de vitaesteróides.Witaferina A (9), o primeiro vitanolído isolado de Withania sonnifera, teve sua estrutura totalmente elucidada por Lavie e colaboradores, em 1965 10 , seguindo-se várias outras descobertas, descrições de diferentes e diversificados tipos deste grupo de esteróides, provindos da família Solanaceae 11a,b • VitanolídosDentre os vitaesteróides representados por seus esqueletos básicos (1 a 8), os vitanolídos são os mais abundantes, sendo normalmente mencionados como precursores das vitafisalinas e acnistinas.Subdividem-se em duas classes principais de acordo com a

Complex physalin metabolites present in the capsules of the fruit of

Our results demonstrate the potent antileishmanial activity of physalins, especially physalin F, and suggest these molecules as the basis for the development of new therapeutic options for cutaneous leishmaniasis.

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The antimalarial activities of physalins B, D, F, and G (1-4), isolated from Physalis angulata, were investigated. In silico analysis using the similarity ensemble approach (SEA) database predicted the antimalarial activity of each of these compounds, which were shown using an in vitro assay against Plasmodium falciparum. However, treatment of P. berghei-infected mice with 3 increased parasitemia levels and mortality, whereas treatment with 2 was protective, causing a parasitemia reduction and a delay in mortality in P. berghei-infected mice. The exacerbation of in vivo infection by treatment with 3 is probably due to its potent immunosuppressive activity, which is not evident for 2.