Evaluation of α-Glucosidase Inhibition and Antihyperglycemic Activity of Extracts Obtained from Leaves and Flowers of Rumex crispus L.

Among antihyperglycemic drugs used for treating diabetes, α-glucosidase inhibitors generate the least adverse effects. This contribution aimed to evaluate the potential antidiabetic activity of Rumex crispus L. by testing its in vitro α-glucosidase inhibition and in vivo antihyperglycemic effects on rats with streptozotocin (STZ)-induced diabetes. Better inhibition of α-glucosidase was found with the methanol extract versus the n-hexane and dichloromethane extracts. The methanol extract of the flowers (RCFM) was more effective than that of the leaves (RCHM), with an IC50 of 7.3 ± 0.17 µg/mL for RCFM and 112.0 ± 1.23 µg/mL for RCHM. A bioactive fraction (F89s) also showed good α-glucosidase inhibition (IC50 = 3.8 ± 0.11 µg/mL). In a preliminary study, RCHM and RCFM at 150 mg/kg and F89s at 75 mg/kg after 30 days showed a significant effect on hyperglycemia, reducing glucose levels (82.2, 80.1, and 84.1%, respectively), and improved the lipid, renal, and hepatic profiles of the rats, comparable with the effects of metformin and acarbose. According to the results, the activity of R. crispus L. may be mediated by a diminished rate of disaccharide hydrolysis, associated with the inhibition of α-glucosidase. Thus, R. crispus L. holds promise for the development of auxiliary drugs to treat diabetes mellitus.

How glycobiology can help us treat and beat the COVID-19 pandemic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged during the last months of 2019, spreading throughout the world as a highly transmissible infectious illness designated as COVID-19. Vaccines have now appeared, but the challenges in producing sufficient material and distributing them around the world means that effective treatments to limit infection and improve recovery are still urgently needed. This review focuses on the relevance of different glycobiological molecules that could potentially serve as or inspire therapeutic tools during SARS-CoV-2 infection. As such, we highlight the glycobiology of the SARS-CoV-2 infection process, where glycans on viral proteins and on host glycosaminoglycans have critical roles in efficient infection. We also take notice of the glycan-binding proteins involved in the infective capacity of virus and in human defense. In addition, we critically evaluate the glycobiological contribution of candidate drugs for COVID-19 therapy such as glycans for vaccines, anti-glycan antibodies, recombinant lectins, lectin inhibitors, glycosidase inhibitors, polysaccharides, and numerous glycosides, emphasizing some opportunities to repurpose FDA-approved drugs. For the next-generation drugs suggested here, biotechnological engineering of new probes to block the SARS-CoV-2 infection might be based on the essential glycobiological insight on glycosyltransferases, glycans, glycan-binding proteins, and glycosidases related to this pathology.

Anacardium humile St. Hil as a novel source of antioxidant, antiglycation and α-amylase inhibitors molecules with potential for management of oxidative stress and diabetes.

ETHNOPHARMACOLOGICAL RELEVANCE: The substantial increase in diabetes cases worldwide has been a major public health problem, and the use of medicinal plants can be considered an interesting alternative to control the disease and its complications. Anacardium humile St. Hill. (Anacardiaceae) is a typical plant from the Brazilian savanna, popularly known for its antidiarrheal, expectorant, antidiabetic and anti-inflammatory properties, however, few studies have fully described its biological properties. This study aimed to investigate in vitro and ex vivo the antioxidant and antiglycation potential of A. humile ethanolic extract, its organic fractions and three isolated molecules (quercetin, catechin and gallic acid), their capacity to inhibit the glycolytic enzyme α-amylase, as well as their cytotoxic effects against RAW264.7 macrophages. MATERIAL AND METHODS: The ethanolic extract of A. humile, its organic fractions and three isolated molecules (catechin, quercetin and gallic acid) were tested for their antioxidant (ORAC, FRAP and DPPH) and antiglycation (BSA/Fructose, BSA/Methylglyoxal, Arginine/Methylglyoxal and Lysine/Methylglyoxal) capacities, and also for its potential to inhibit the enzyme α-amylase. Additionally, bioactive compounds present in the A. humile leaves fractions were elucidated by an HPLC-ESIMS/MS analysis. RESULTS: The analysis showed relevant antioxidant activity of DCM (1264.85 ± 76.90 µM Trolox eq/g ORAC; 216.71 ± 1.04 µM Trolox eq/g FRAP and 3.03 ± 0.08 IC50 µg/mL IC50 DPPH) and EtOAc (1300.11 ± 33.04 ORAC, 236.21 ± 23.86 FRAP and 3.03 ± 0.14 µg/mL IC50 DPPH) fractions and also of the isolated molecules, mainly gallic acid (1291.19 ± 8.41 µM Trolox eq/g ORAC, 1103.52 ± 31.48 µM Trolox eq/g FRAP and 0.78 ± 0.11 µg/mL IC50 DPPH). Concerning the antiglycation activity, all samples inhibited over 88% in the BSA-FRU method. In the BSA-MGO and ARG-MGO methods, the Hex, DCM, EtOAc fractions and the isolated molecule catechin stood out. However, in the LYS-MGO model, only the isolated molecules showed significant results. In α-amylase assay, all fractions, for exception Hex, presented notable inhibition capacity with low IC50 values, especially DCM, EtOAc, ButOH and H2O (IC50 0.56 ± 0.10, 0.84 ± 0.01, 0.74 ± 0.03 and 0.79 ± 0.06 µg/mL, respectively). Tests using hepatic tissue showed a notorious capacity of the DCM, AcOEt and ButOH fractions, as well as of the isolated molecules to inhibit lipid peroxidation and ROS production, and also to preserve thiol groups. Molecules of great antioxidant potential were found in our samples, such as kaempferol, quercetin, catechin, gallic acid and luteolin. CONCLUSION: A. humile extract and its organic fractions showed promising antioxidant and antiglycation potential and a prominent capacity to inhibit the α-amylase enzyme. Hence, this study presents new results and stimulates further research to elucidate the biological properties of A. humile and its capacity to manage DM and its complications.

Molecules Isolated from Mexican Hypoglycemic Plants: A Review.

Like in many developing countries, in Mexico, the use of medicinal plants is a common practice. Based on our own field experience, there are at least 800 plants used for treating diabetes nowadays. Thus, their investigation is essential. In this context, this work aims to provide a comprehensive and critical review of the molecules isolated from Mexican hypoglycemic plants, including their source and target tested. In the last few years, some researchers have focused on the study of Mexican hypoglycemic plants. Most works describe the hypoglycemic effect or the mechanism of action of the whole extract, as well as the phytochemical profile of the tested extract. Herein, we analyzed 85 studies encompassing 40 hypoglycemic plants and 86 active compounds belonging to different classes of natural products: 28 flavonoids, 25 aromatic compounds, other than flavonoids, four steroids, 23 terpenoids, 4 oligosaccharides, and 1 polyalcohol. These compounds have shown to inhibit α-glucosidases, increase insulin secretion levels, increase insulin sensitivity, and block hepatic glucose output. Almost half of these molecules are not common metabolites, with a narrow taxonomic distribution, which makes them more interesting as lead molecules. Altogether, this analysis provides a necessary inventory useful for future testing of these active molecules against different hypoglycemic targets, to get a better insight into the already described mechanisms, and overall, to contribute to the knowledge of Mexican medicinal plants.

Aportes de la biotecnología al diagnóstico y tratamiento de la enfermedad renal crónica y comorbilidades frecuentes / Biotechnology contribution to the diagnosis and treatment of chronic kidney disease and frequent comorbidities

Este trabajo tiene como objetivo revisar las contribuciones de la biotecnología, en relación con el tratamiento, diagnóstico y la monitorización de la enfermedad renal crónica (ERC) y sus comorbilidades más frecuentes, especialmente la anemia. En relación con los tratamientos, enfocamos el desarrollo de productos biofarmacéuticos como los agentes estimulantes de la eritropoyesis (ESA), que fueron los primeros biofármacos utilizados para el tratamiento de la anemia asociada a la ERC; analizamos sus características y utilización actual después de varios años de experiencia clínica, así como también otras alternativas en desarrollo. Revisamos distintos tipos de bioterapias, la utilización de las células estromales mesenquimales de médula ósea (MSC) y tratamientos alternativos con modificaciones dietarias, que se basan en la asociación entre la microbiota intestinal de los pacientes renales crónicos y sus condiciones fisiopatológicas. Finalmente, en relación con el diagnóstico y monitorización, nos referimos al estudio y validación de biomarcadores diagnósticos, predictivos y terapéuticos que han permitido optimizar los resultados clínicos en este tipo de pacientes. (AU)

The aim of this work is to review the contributions of biotechnology, in relation to the treatment, diagnosis and monitoring of chronic kidney disease (CKD) and its most frequent comorbidities, especially anemia. Regarding the treatment, we focus on the development of biopharmaceutical products such as erythropoiesis stimulating agents (ESA), which were the first biopharmaceuticals used to treat anemia associated with chronic kidney disease (CKD). We analyzed their characteristics and their current use after several years of clinical experience, as well as other alternatives in development. We also review different types of biotherapies, the use of bone marrow mesenchymal stromal cells (MSC) and alternative treatments with dietary modifications, which are based on the association between the intestinal microbiota of chronic kidney patients and their pathophysiological conditions. Finally, in relation to diagnosis and monitoring, we refer to the study and validation of diagnostic, predictive and therapeutic biomarkers that have made clinical results possible to be optimized in this type of patient. (AU)

Bioactive Polyphenols from Southern Chile Seaweed as Inhibitors of Enzymes for Starch Digestion.

The increment of non-communicable chronic diseases is a constant concern worldwide, with type-2 diabetes mellitus being one of the most common illnesses. A mechanism to avoid diabetes-related hyperglycemia is to reduce food digestion/absorption by using anti-enzymatic (functional) ingredients. This research explored the potential of six common Chilean seaweeds to obtain anti-hyperglycemic polyphenol extracts, based on their capacity to inhibit key enzymes related with starch digestion. Ethanol/water hot pressurized liquid extraction (HPLE), which is an environmentally friendly method, was studied and compared to conventional extraction with acetone. Total polyphenols (TP), antioxidant activity, cytotoxicity and inhibition capacity on α-glucosidase and α-amylase were analyzed. Results showed that the Durvillaea antarctica (cochayuyo) acetone extract had the highest TP content (6.7 ± 0.7 mg gallic acid equivalents (GAE)/g dry seaweed), while its HPLE ethanol/water extract showed the highest antioxidant activity (680.1 ± 11.6 µmol E Trolox/g dry seaweed). No extract affected cell viability significantly. Only cochayuyo produced extracts having relevant anti-enzymatic capacity on both studied enzymes, showing a much stronger inhibition to α-glucosidase (even almost 100% at 1000 µg/mL) than to α-amylase. In conclusion, from the Chilean seaweeds considered in this study, cochayuyo is the most suitable for developing functional ingredients to moderate postprandial glycemic response (starchy foods), since it showed a clear enzymatic inhibition capacity and selectivity.

Miglustate para manifestações neurológicas da doença de niemann-pick tipo c (NPC) / Miglustate para manifestações neurológicas da doença de niemann-pick tipo c (NPC)

CONTEXTO: A doença de Niemann-Pick C é uma doença genética rara causada por mutações nos genes NPC 1 e NPC 2. A apresentação clínica é heterogênea e envolve sintomas neurológicos (alteração de movimentos oculares, cognição, prejuízos no desenvolvimento neurológico, alterações de manipulação, linguagem, deambulação e deglutição, crises convulsivas), sistêmicos/ viscerais (hepatomegalia, esplenomegalia, icterícia) e psiquiátricos. Não existe cura para a doença até o momento. O tratamento é baseado em cuidados paliativos, com o objetivo de melhorar a qualidade de vida, reduzir incapacidade e diminuir a progressão da doença. Atualmente, o miglustate é a única terapia modificadora da doença aprovada para uso no tratamento de manifestações neurológicas da NPC. TECNOLOGIa: Miglustate (Zavesca®). PERGUNTA: Qual a eficácia e a segurança do miglustate via oral para o tratamento da doença de Niemann-Pick C? EVIDÊNCIAS CIENTÍFICAS: Foram realizadas buscas nas bases de dados Medline (via Pubmed) e Embase. Foram localizados 525 estudos, sendo doze incluídos neste PTC. Os estudos que avaliaram a eficácia e a segurança do miglustate para o tratamento de manifestações neurológicas da Doença de Niemann-Pick Tipo C mostraram que a intervenção não resultou em ganhos significativos na sobrevida, bem como diferenças em deambulação, deglutição e cognição em relação aos controles (12 meses). Movimentos oculares apresentaram diferença significante apenas quando se excluiu o grupo de pacientes em uso de benzodiazepínicos, classe de medicamentos que poderia interferir nos parâmetros oculares avaliados. Estudos de extensão que incluíram apenas pacientes adultos e pediátricos mostraram que houve tendência à estabilização da maioria dos parâmetros. Em um estudo em que se avaliou a eficácia do miglustate em 24 meses, observou-se que, daqueles que completaram os 24 meses de tratamento, houve melhora da função cognitiva nos primeiros 12 meses, com posterior declínio, retornando a escores próximos dos basais. Os resultados foram controversos quanto ao status de episódios convulsivos: em dois estudos, que incluíram pacientes com as mesmas formas de doença, encontrou-se, em um deles, que houve estabilização em dois terços da amostra, enquanto em outro, cerca de 21% apresentou piora dos episódios convulsivos, com novas crises e cataplexia. Quanto à segurança do medicamento, os eventos adversos mais comuns foram os gastrointestinais (diarreia, flatulência e desconforto abdominal), perda de peso (sem prejuízo no crescimento na amostra pediátrica) e tremores. Outros eventos menos frequentemente relatados, foram trombocitopenia, fadiga, cefaleia, alterações comportamentais, surtos psiquiátricos e novas convulsões. A qualidade metodológica do conjunto da evidência científica advinda desses estudos é baixa, visto que o único ensaio clínico incluído neste PTC teve qualidade metodológica incerta, já que deixou de mencionar aspectos importantes para avaliação de sua robustez metodológica. Os demais estudos tiveram alto risco de viés. ANÁLISE DE CUSTO EFETIVIDADE (ACE): A ACE foi conduzida sob a perspectiva do SUS e o horizonte temporal considerado foi de 12 meses. Os parâmetros de efetividade foram baseados no aumento de 2 pontos em escala de função cognitiva (MEEM) obtidos em ensaio clínico randomizado. Os custos de procedimentos fornecidos pelo SUS para os cuidados paliativos foram obtidos da tabela SIGTAP e incluíram a passagem de gastrostomia e acompanhamento fonoaudiológico e fisioterápico. Os custos dos medicamentos foram obtidos do painel de preços de saúde e incluíram anticonvulsivantes e miglustate. A inclusão do miglustate ao tratamento atualmente oferecido (cuidados paliativos) resultou em razão de custo-efetividade incremental de R$459.120,00. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO (AIO): A AIO foi conduzida sob a perspectiva do Sistema Único de Saúde em horizonte temporal de 5 anos (2020-2024). Foi considerado tratamento contínuo, com consumo de 180 cápsulas/paciente/mês (total de 2160 cápsulas/ ano). Considerando que o diagnóstico da doença é tardio e, muitas vezes, realizado somente quando as alterações neurológicas já estão instaladas, considerou-se que 100% dos pacientes portadores da doença de Niemann-Pick C deveriam receber o tratamento. Foram realizadas três simulações: (1) O acesso ao tratamento abrangeria todos os pacientes portadores da condição (100%); (2) O acesso ao medicamento ao longo dos cinco anos ocorreria de modo gradual (50%- 60%-70%-80%-90%); e (3) População elegível baseada em estimativas da Interfarma (100 pacientes elegíveis no país). Na simulação 1, o custo em 5 anos seria de R$ 1.781.458.228,70. Já na simulação 2, o impacto orçamentário de 2020 a 2024 seria de R$ 1.393.210.574,12 e na simulação 3, de R$172.681.200. CONSIDERAÇÕES FINAIS: As evidências disponíveis não são conclusivas quanto aos ganhos clinicamente relevantes para o paciente com alterações neurológicas decorrentes da Doença de Niemann-Pick Tipo C. De acordo com a melhor evidência disponível, para um desfecho clinicamente pouco importante (movimento sacádico ocular), o subgrupo que mais se beneficia do tratamento é aquele que não faz uso de benzodiazepínicos. Os desfechos de estabilidade e melhora são descritivos, sem grupo comparador atrelado e não refletem significância estatística. A definição de melhora e estabilidade é subjetiva do ponto de vista da significância clínica dos desfechos avaliados. A qualidade global da evidência para todos os desfechos apresentados foi muito baixa. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Considerando a escassez de estudos com boa qualidade metodológica e baixa qualidade da evidência, os membros da CONITEC, em sua 76ª reunião ordinária, no dia 03 de abril de 2019, recomendaram que a matéria fosse disponibilizada em consulta pública com recomendação preliminar pela não incorporação no SUS do miglustate para tratamento de sintomas neurológicos da doença de Niemann-Pick tipo C. CONSULTA PÚBLICA: Foram recebidas 921 contribuições de pessoa física e 3 de pessoa jurídica, sendo que, a maioria (92%) discordou da recomendação preliminar pela não incorporação no SUS do miglustate para tratamento de sintomas neurológicos da doença de Niemann-Pick tipo C. A indústria fabricante do medicamento realizou 4 cenários de impacto orçamentário com base nos dados de prevalência (a); nos dados da Interfarma para doentes com NPC (b); na população ajustada (c); e baseado na população com referência nos dados da Interfarma. No primeiro cenário o acesso a 100% dos pacientes resultaria em um impacto orçamentário (AIO) em 5 anos de R$ 839.176.344,30 e o acesso progressivo de 10% ao ano, iniciando por 50%, acumulado de 50 anos foi de R$590.534.879,08. Para o segundo cenário, não foram apresentados resultados. Para o terceiro, com acesso progressivo (50% - 90%), o AIO em 5 anos foi de R$312.884.146,08. No último cenário com acesso de 100%, o AIO em 5 anos estimado foi de R$ 27.437.597,72. Após análise dos resultados da CP, a CONITEC entendeu que não houve argumentação suficiente para alterar sua recomendação inicial. RECOMENDAÇÃO FINAL: Os membros da CONITEC presentes na 78ª reunião do plenário no dia 06/06/2019 deliberaram por recomendar a não incorporação do miglustate para o tratamento de manifestações neurológicas da doença de Niemann-Pick tipo C. Foi assinado o Registro de Deliberação nº 451/2019. DECISÃO: Não incorporar o miglustate para manifestações neurológicas da doença de NiemannPick tipo C, no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 35, publicada no Diário Oficial da União nº 141, seção 1, página 89, em 24 de julho de 2019.

Beyond model interpretability using LDA and decision trees for α-amylase and α-glucosidase inhibitor classification studies.

In this report are used two data sets involving the main antidiabetic enzyme targets α-amylase and α-glucosidase. The prediction of α-amylase and α-glucosidase inhibitory activity as antidiabetic is carried out using LDA and classification trees (CT). A large data set of 640 compounds for α-amylase and 1546 compounds in the case of α-glucosidase are selected to develop the tree model. In the case of CT-J48 have the better classification model performances for both targets with values above 80%-90% for the training and prediction sets, correspondingly. The best model shows an accuracy higher than 95% for training set; the model was also validated using 10-fold cross-validation procedure and through a test set achieving accuracy values of 85.32% and 86.80%, correspondingly. Additionally, the obtained model is compared with other approaches previously published in the international literature showing better results. Finally, we can say that the present results provided a double-target approach for increasing the estimation of antidiabetic chemicals identification aimed by double-way workflow in virtual screening pipelines.

Acarbose versus trans-chalcone: comparing the effect of two glycosidase inhibitors on obese mice.

OBJECTIVE: Acarbose and trans-chalcone are glucosidase inhibitors whose beneficial effects have been demonstrated in diabetes. The present study aimed at investigating their potential effects in obesity. MATERIALS AND METHODS: NMRI male mice (n = 48) were subjected to a high fat diet for four weeks, which induced an initial state of obesity. One control group was given normal rodent diet. Obese animals were then switched to normal rodent diet, and divided to four groups (n = 12 in each): untreated, sham (receiving grape seed oil), and experimental groups receiving acarbose and trans-chalcone (12 mg/kg) during eight weeks. Body weight, blood glucose and other biochemical parameters including triglycerides (TG), cholesterol, HDL, AST, and ALT were measured, as well as leptin, adiponectin, TNF-α, and total antioxidant capacity (TAC). Histological studies were performed on adipose cells and liver tissue samples. RESULTS: All factors were affected in a positive manner by acarbose, save for body weight, blood sugar and leptin levels, on which acarbose effects, although observable, were not statistically significant. Grape seed oil, used as a solvent for trans-chalcone was found to possess significant effect on TG and TAC, and had beneficial effects on other factors including liver enzymes and cholesterol. Trans-chalcone effects were significant on HDL, leptin and ALT. All compounds seemed to be able to affect fat deposition in liver tissue, and decrease the size of adipose tissue cells to some extent. CONCLUSION: In conclusion, the tested compounds were able to affect lipid accumulation in tissues and influence adipokines, which may result in an enhanced state with regard to inflammation and oxidative stress.

Treatment with acarbose in severe hypoglycaemia due to late dumping syndrome / Tratamiento con acarbosa en la hipoglicemia severa debido al síndrome de dumping tardío

BACKGROUND: We present a case of recurrent loss of consciousness, which was finally accurately diagnosed as late dumping syndrome twelve years after subtotal gastrectomy and successfully treated with acarbose. A 66-year old lean male was found unconscious repeatedly within one year. Oral glucose tolerance tests performed before and after acarbose treatment verified the diagnosis of late dumping syndrome. Acarbose can be used as a successful treatment modality for reactive hypoglycaemia due to late dumping syndrome by influencing the release of hormone.

ANTECEDENTES: Presentamos un caso de pérdida recurrente de conciencia, que fue finalmente diagnosticado con precisión como síndrome de dumping tardío, doce años después de la gastrectomía subtotal, y tratado con éxito con acarbosa. Un hombre magro de 66 años de edad fue encontrado inconsciente repetidas veces en un año. Las pruebas orales de tolerancia a la glucosa realizadas antes y después del tratamiento con acarbosa verificaron el diagnóstico de síndrome de dumping tardío. La acarbosa puede utilizarse como una modalidad de tratamiento acertado para la hipoglicemia reactiva debido al síndrome de dumping tardío por la influencia en la liberación de hormonas.