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Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disorder, whose prevalence in women varies from 6 to 10% in the reproductive period. It can lead to health complications, such as menstrual dysfunction, infertility, hirsutism, acne and metabolic syndrome. The biggest difficulties with this syndrome is to recognize its etiopathogenesis and select the best therapy. This study is a systematic review, which carried out an electronic search in the following databases SCIELO, LILACS, PUBMED, selected 34 articles. The purpose of the review is: to understand the therapeutic methods available for treatment, although there is no cure for the syndrome, the aim of the approach is to minimize the clinical signs and improve the quality of life of these women. The first therapy to be used is the change in lifestyle and changes in the diet, in the background medications are applied. Treatment must be individualized according to the complaints of each patient.

Toxoplasmosis is able to cause death and/or sequelae in foetuses from pregnant women and immunocompromised individuals. The early diagnosis, able to differentiate acute from chronic phases, is essential to define the treatment against this disease and minimize the risk of complications. Here we describe a peptide derived from microneme 8 (pMIC8) protein of Toxoplasma gondii, able to distinguish the phase of infection. By using human and mice serum samples with different infection times, we assessed the ability of pMIC8 to interact with antibodies present in early of infection, and compared the results obtained with soluble antigen of T. gondii (STAg). The results showed that pMIC8 was recognized more precisely with antibodies present in serum samples from individuals with time of infection below 3 months, followed by those between 4 and 6 months of infection. Based on these results, it is possible to conclude that the association of immunoassays using STAg and pMIC8 as antigen preparations can be used to distinguish acute from chronic infections.

It has been described that the metalloprotease BmooMP-alpha-I purified from Bothrops moojeni snake venom is able to hydrolyze the TNF molecule. However, this observation has been based mainly on in vitro investigation, in addition to molecular modeling and docking approaches. Considering that there is no in vivo study to demonstrate the biological effects of this enzyme, the major aim to the present work was to investigate whether the BmooMP-alpha-I has any anti-inflammatory efficacy by setting up a murine experimental design of colitis induced by dextran sulfate sodium (DSS). For this purpose, C57BL/6 mice were divided into six groups, as follows: (i) animals without intestinal inflammation, (ii) animals without intestinal inflammation treated with BmooMP-alpha-I (50 μg/animal/day), and (iii) animals with intestinal inflammation induced by 3% of DSS, (iv) mice with intestinal inflammation induced by DSS and treated with BmooMP-alpha-I enzyme at the 50, 25, or 12.5 μg/animal/day dosages by intraperitoneal route. Clinical signs of colitis were observed daily for calculating the morbidity scores, cytokine measurements, and histological features. We observed that the animals treated with different doses of the enzyme presented a remarkable improvement of colitis signs, as confirmed by a significant increase of the intestine length in comparison to the DSS group. Also, no difference was observed between the groups treated with the enzyme or vehicle, as the colon length of these animals was slightly lower than that of the group of healthy animals, without induction of intestinal inflammation. The cytokine quantification in supernatants of intestinal tissue homogenates showed a significant reduction of 38% in IFN-gamma levels, when the animals were treated with 50 μg of the BmooMP-alpha-I compared to the animals receiving DSS only. A significant reduction of 39% in TNF levels was also observed in all doses of treatment with BmooMP-alpha-I, in addition to a significant reduction of 35% in the amount of IL-12p40. Histological examinations revealed that the BmooMP-alpha-I 50 μg treated group preserved colon architecture and goblet cells and reduced the ulcer area, when compared with DSS mice, which showed typical inflammatory changes in tissue architecture, such as ulceration, crypt dilation, loss of tissue architecture, and goblet cell depletion, accompanied by a significant cell infiltration. In conclusion, our results suggest that the improvement of clinical scores and histological findings related to BmooMP-alpha-I treatment in this experimental model could be attributed to the metalloprotease ability to modulate cytokine production locally at the inflamed intestine. These findings highlight the potential anti-inflammatory role and effectiveness of this enzyme as a therapeutic alternative in this type of immunopathological condition.

Respiratory infection can be exacerbated by the high glucose concentration in the airway surface liquid (ASL). We investigated the effects of salbutamol and phlorizin on the pulmonary function, oxidative stress levels and SGLT1 activity in lung, pulmonary histopathological damages and survival rates of rats with sepsis. Sepsis was induced by cecal ligation and puncture surgery (CLP). Twenty-four hours after surgery, CLP rats were intranasally treated with saline, salbutamol or phlorizin. After 2 hours, animals were anesthetized and sacrificed. Sepsis promoted atelectasis and bronchial inflammation, and led to increased expression of SGLT1 on cytoplasm of pneumocytes. Salbutamol treatment reduced bronchial inflammation and promoted hyperinsuflation in CLP rats. The interferon-ɤ and Interleucin-1β concentrations in bronchoalveolar lavage (BAL) were closely related to the bronchial inflammation regulation. Salbutamol stimulated SGLT1 in plasma membrane; whereas, phlorizin promoted the increase of SGLT1 in cytoplasm. Phlorizin reduced catalase activity and induced a significant decrease in the survival rate of CLP rats. Taken together, sepsis promoted atelectasis and lung inflammation, which can be associated with SGLT1 inhibition. The loss of function of SGLT1 by phlorizin are related to the augmented disease severity, increased atelectasis, bronchial inflammation and a significant reduction of survival rate of CLP rats. Alternatively salbutamol reduced BAL inflammatory cytokines, bronchial inflammation, atelectasis, and airway damage in sepsis. These data suggest that this selective β2-adrenergic agonist may protect lung of septic acute effects.

It has been described that the metalloprotease BmooMP-alpha-I purified from Bothrops moojeni snake venom is able to hydrolyze the TNF molecule. However, this observation has been based mainly on in vitro investigation, in addition to molecular modeling and docking approaches. Considering that there is no in vivo study to demonstrate the biological effects of this enzyme, the major aim to the present work was to investigate whether the BmooMP-alpha-I has any anti-inflammatory efficacy by setting up a murine experimental design of colitis induced by dextran sulfate sodium (DSS). For this purpose, C57BL/6 mice were divided into six groups, as follows: (i) animals without intestinal inflammation, (ii) animals without intestinal inflammation treated with BmooMP-alpha-I (50 μg/animal/day), and (iii) animals with intestinal inflammation induced by 3% of DSS, (iv) mice with intestinal inflammation induced by DSS and treated with BmooMP-alpha-I enzyme at the 50, 25, or 12.5 μg/animal/day dosages by intraperitoneal route. Clinical signs of colitis were observed daily for calculating the morbidity scores, cytokine measurements, and histological features. We observed that the animals treated with different doses of the enzyme presented a remarkable improvement of colitis signs, as confirmed by a significant increase of the intestine length in comparison to the DSS group. Also, no difference was observed between the groups treated with the enzyme or vehicle, as the colon length of these animals was slightly lower than that of the group of healthy animals, without induction of intestinal inflammation. The cytokine quantification in supernatants of intestinal tissue homogenates showed a significant reduction of 38% in IFN-gamma levels, when the animals were treated with 50 μg of the BmooMP-alpha-I compared to the animals receiving DSS only. A significant reduction of 39% in TNF levels was also observed in all doses of treatment with BmooMP-alpha-I, in addition to a significant reduction of 35% in the amount of IL-12p40. Histological examinations revealed that the BmooMP-alpha-I 50 μg treated group preserved colon architecture and goblet cells and reduced the ulcer area, when compared with DSS mice, which showed typical inflammatory changes in tissue architecture, such as ulceration, crypt dilation, loss of tissue architecture, and goblet cell depletion, accompanied by a significant cell infiltration. In conclusion, our results suggest that the improvement of clinical scores and histological findings related to BmooMP-alpha-I treatment in this experimental model could be attributed to the metalloprotease ability to modulate cytokine production locally at the inflamed intestine. These findings highlight the potential anti-inflammatory role and effectiveness of this enzyme as a therapeutic alternative in this type of immunopathological condition.

CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico FAPEMIG - Fundação de Amparo a Pesquisa do Estado de Minas Gerais Doenças inflamatórias intestinais (DIIs) são doenças crônicas mediadas pela ativação da resposta imune. As DIIs são divididas em dois grupos principais, a colite ulcerativa e a doença de Crohn. Além disso, as DIIs são extremamente debilitantes para os pacientes. A produção exacerbada do fator de necrose tumoral (TNF) está relacionada ao dano intestinal durante a doença de Crohn e a diminuição de seus efeitos é uma importante intervenção terapêutica. Sabe-se que a infecção oral por Toxoplasma gondii induz inflamação intestinal, que envolve uma produção aumentada de TNF e isso mimetiza a resposta inflamatória que ocorre na doença de Crohn. BmooP-a-I é uma metaloprotease de peçonha de serpente isolada de Brothrops moojeni capaz de hidrolisar o TNF. Considerando estas evidências, o objetivo do presente trabalho foi avaliar se o tratamento com BmooP-a-I seria capaz de reduzir o efeito deletério da ileíte induzida em modelo murino de infecção oral por T. gondii. Para este propósito, induziu-se ileíte em camundongos C57BL/6 por meio da infecção oral com 50 cistos de T. gondii cepa Pru- GFP. Em seguida, os animais foram tratados com BmooPM-a-I ou inoculados com PBS como um grupo controle e amostras de baço, linfonodos mesentéricos e íleo foram coletadas no dia 7 pós-infecção para avaliação dos efeitos da metaloprotease nos animais infectados. Os índices de morbidade e mortalidade também foram determinados. Dentre os resultados obtidos, foi observado que o tratamento com BmooMP-a-I prolongou a sobrevida e diminuiu os sinais clínicos da doença, especialmente em relação à perda de peso. Além disso, o tratamento foi capaz de melhorar os aspectos macroscópico e microscópico das amostras de tecido intestinal. O tratamento também reduziu a produção de citocinas pró-inflamatórias, bem como a expressão de mediadores inflamatórios no linfonodo mesentérico. Em relação aos experimentos ex-vivo, observou-se uma redução da resposta dos esplenócitos das células dos linfonodos mesentéricos nos animais tratados. Em síntese, os resultados obtidos no presente trabalho evidenciam que o tratamento com a metaloprotease BmooP-a-I é capaz de reduzir a inflamação ileal induzida pela infecção oral por T. gondii, podendo-se hipotetizar que este tipo de tratamento pode também ser útil em outras doenças inflamatórias intestinais, como a doença de Crohn. Inflammatory bowel diseases (DIIs) are chronic immune mediated diseases. DIIs are divided into ulcerative colitis and Crohn’s disease. Also, DIIs are extremely debilitating for patients. The exacerbated production of TNF cytokine is related to the intestinal damage during Crohn’s disease and the neutralization of this cytokine has been suggested as a therapeutic intervention. Oral infection by Toxoplasma gondii induces intestinal inflammation through the overproduction of TNF, which is quite similar to the response during Crohn’s disease. BmooMP-a-I is a snake venom metalloprotease isolated from Brothrops moojeni, which is able to cleave TNF. Considering these pieces of information, we aimed to evaluate whether the treatment with BmooMP-a-I can reduce the deleterious effect of the T. gondii-induced ileitis. For this purpose, we induced ileitis in C57BL/6 mice by oral infection with 50 cysts of T. gondii. The animals were treated with BmooMP- a-I or inoculated with PBS as control and tissue samples were collected on day 7 postinfection to evaluate the metalloprotease effects on treated animals. Indices of morbidity and mortality were determined in addition to the cytokine profile production. It was observed that BmooMP-a-I treatment increased the survival rates of the infected animals, as well as reduced clinical signs of the survivals, particularly weight loss. Moreover, the metalloprotease treatment ameliorates the macroscopic and microscopic aspect of intestine. The treatment also reduced proinflammatory cytokine production and expression of inflammatory mediators by mesenteric lymph node cells. Additionally, occurred a reduction of ex vivo response of spleen and mesenteric lymph node cells. Overall, these findings constitute strong evidence that the BmooMP-a-I treatment is able to reduce ileal inflammation, making possible to hypothetize that this type of approach could be also helpful for treating of other inflammatory bowel diseases, such as Crohn’s disease. Dissertação (Mestrado)

Tumor necrosis factor (TNF) is a major cytokine in inflammatory processes and its deregulation plays a pivotal role in several diseases. Here, we report that a zinc metalloprotease extracted from Bothrops moojeni venom (BmooMP-alpha-I) inhibits TNF directly by promoting its degradation. This inhibition was demonstrated by both in vitro and in vivo assays, using known TLR ligands. These findings are supported by molecular docking results, which reveal interaction between BmooMP-alpha-I and TNF. The major cluster of interaction between BmooMP-alpha-I and TNF was confirmed by the structural alignment presenting Ligand Root Mean Square Deviation LRMS = 1.05 A and Interactive Root Mean Square Deviation IRMS = 1.01 A, this result being compatible with an accurate complex. Additionally, we demonstrated that the effect of this metalloprotease on TNF is independent of cell cytotoxicity and it does not affect other TLR-triggered cytokines, such as IL-12. Together, these results indicate that this zinc metalloprotease is a potential tool to be further investigated for the treatment of inflammatory disorders involving TNF deregulation.