Semaglutide and obesity: beyond the nutritional and lifestyle intervention?

Semaglutide is the second marketed glucagon-like peptide 1 receptor agonist that can be used safely and efficiently in non-diabetic people with excess weight, providing a new milestone in the pharmacological treatment of obesity. This narrative review aims to describe the clinical actions of this new drug in weight management in non-diabetic patients along with possible side-effects and dropout reasons. To accomplish this, the PubMed database was searched to retrieve the most relevant clinical studies published to date on this topic, using the following keywords "semaglutide and obesity". Currently, semaglutide is on the market in two formulations, the once-weekly subcutaneous (s.c.) semaglutide and once-daily oral semaglutide. Data in the literature on the anti-obesity action of semaglutide are available for both routes of administration of the drug, with a prevalence of studies using the s.c. one. However, given its dosage, oral semaglutide may provide greater attractiveness and better treatment adherence, but further research is needed in this field.

Red Wine and Sexual Function in Men: An Original Point of View.

Red wine is a rich source of nutrients whose biological properties have inspired numerous scientific studies. Indeed, it has been widely reported that there is a correlation between the positive health effects of moderate consumption of red wine and its phenolic content, which, due to its antioxidant activity, has proved to be useful in the improvement of various diseases, such as cardiovascular diseases, metabolic syndrome, cognitive disorders, depression, and cancer. It is a common opinion that the antioxidant activity of red wine is to be ascribed to its entire content of polyphenols, which act synergistically and not as a single component. Furthermore, this health-promoting effect of red wine can also be linked to its ethanol content, which has shown a wide array of biological properties. Beyond this evidence, very little is known about a possible correlation between moderate consumption of red wine and male sexual function. This brief review aimed to evaluate the effects of moderate consumption of red wine on erectile function. To accomplish this, Pubmed and Google Scholar databases were searched to retrieve the most relevant studies on this topic. The evidence so far collected has shown that red wine, if consumed in moderation, can be potentially beneficial for patients with erectile dysfunction as well as can positively influence reproductive function through mechanisms that depend on the vasorelaxant properties of red wine and its antioxidant properties.

The Use of Ellagic Acid and Annona Muricata Improves Semen Quality in Men with High-Risk Papillomavirus Infection.

Background: Few data are currently available on the treatment of patients with HPV infection. In particular, there is no agreement on the use of antioxidants in these patients. Ellagic acid and annona muricata appear to improve HPV clearance in infected women. However, it is presently unknown whether they could enhance the clearance of HPV infection in infertile male patients. Aim: To evaluate the effects of a commercially available combined compound containing ellagic acid and annona muricata on semen quality in patients with documented papillomavirus (HPV) infection, and on the frequency of HPV DNA detection in seminal fluid after treatment. In addition, anti-sperm antibodies and the percentage of spermatozoa with fragmented DNA were evaluated. Materials and methods: This was a retrospective case-control study including patients attending our center for infertility. Fifty selected patients who were positive for high risk (HR)-HPV with available semen analysis results were consecutively enrolled. Patients were classified into two groups, according to the clinician's decision to either administer ellagic acid 100 mg and annona muricata 100 mg (combined tablet formulation) for a period of three months (Group A; 25 patients), or to re-evaluate HPV DNA after a period of active surveillance only (protected sexual intercourse) (Group B; 25 patients). Results: Group A patients had a mean age of 31.0 ± 11.0 years, while Group B was 33.0 ± 8.0 years old (p > 0.05). After three months of treatment with ellagic acid and annona muricata, all conventional seminal parameters improved more significantly in Group A than in Group B patients: sperm concentration = 45 mil/mL vs. 20 mil/mL (p < 0.05); sperm progressive motility = 45% vs. 18% (p < 0.05); and normal sperm morphology = 18% vs. 6% (p < 0.05). After the treatment, the frequency of persistence of HPV DNA in the seminal fluid was significantly lower in Group A patients compared to those in Group B (12/25 = 48% vs. 22/25 = 88%; p < 0.05). Finally, after 3 months, Group A showed a significant reduction in anti-sperm antibodies and in the percentage of spermatozoa with fragmented DNA. Conclusion: The results of this study demonstrate, for the first time, the effects of a commercially available combined compound containing ellagic acid and annona muricata on semen quality in patients with HR-HPV infection, and that this therapy is also associated with a significant reduction in the persistence of HPV DNA in the seminal fluid.

Peptidomimetics in Silico.

Endogenous peptides as part of physiological processes are targets of interest when it comes to finding desirable therapeutics which are able to modulate molecular interactions. The major limits presented by peptides when they are used as drugs have motivated the research of the synthesis of peptidomimetics obtained through chemical modification and the use of in silico approaches. Here recent works on the discovery of peptidomimetics by computational methods are reported. Together with molecular dynamic simulations, the use of pharmacophore research simulations helps to gain insight into and understand the molecular determinants underlying the physiological processes.

Quantum Chemical and Molecular Dynamics Studies of MUC1 Calix[4,8]arene Scaffold Based Anticancer Vaccine Candidates.

Functional antitumor vaccine constructs are the basis for active tumor immunotherapy, which is useful in the treatment of many types of cancers. MUC1 is one key glycoprotein for targeting and designing new strategies for multicomponent vaccines. Two self-adjuvant tetravalent vaccine candidates were prepared by clustering four or eight PDTRP MUC1 core epitope sequences on calixarene scaffolds. In this work, the different activities of two molecules with calix[4]arene and calix[8]arene skeleton are rationalized. Quantum mechanics, docking, and molecular dynamics structural optimization were first carried out followed by metadynamics to calculate the energy profiles. Further insights were obtained by complementarity studies of molecular fields. The molecular modeling results are in strong agreement with the experimental in vivo immunogenicity data. In conclusion, the overall data shows that, in the designing of anticancer vaccines, scaffold flexibility has a pivotal role in obtaining a suitable electrostatic, hydrophobic, and steric complementarity with the biological target.

Unravelling the Antiproliferative Activity of 1,2,5-oxadiazole Derivatives.

AIM: To develop several new derivatives aimed to complete the studies concerning the antiproliferative profile of the oxadiazole derivative MD77. MATERIALS AND METHODS: The substitution pattern around the phenyl rings of this compound was analyzed through the synthesis of positional isomers and of analogues bearing different substituents at the para positions (2-12). RESULTS: The results of the antiproliferative activity of these derivatives versus HCT-116 and HeLa cancer cell lines shed light on the effects of the presence, nature and position of such substituents. Notably, derivative 4, a regioisomer of 1 in which the substituents at the para positions of the phenyl rings were inverted, showed the best antiproliferative profile, exhibiting a significant activity also against MCF7 and MDA-MB 468 cancer cell lines. CONCLUSION: Preliminary results showed the ability of compound 4 to reduce the viability of cancer cells by counteracting human recombinant topoisomerase II α relaxation activity.

Exploring the Biological Activity of a Library of 1,2,5-Oxadiazole Derivatives Endowed With Antiproliferative Activity.

BACKGROUND/AIM: The identification of a series of oxadiazole-based compounds, as promising antiproliferative agents, has been previously reported. The aim of this study was to explore the SAR of newly-synthesized oxadiazole derivatives and identify their molecular targets. MATERIALS AND METHODS: A small library of 1,2,5-oxadiazole derivatives was synthetized and their antiproliferative activity was tested by the MTT assay. Their interaction with topoisomerase I was evaluated and a molecular docking study was performed. RESULTS: Several candidates showed cytotoxicity towards two human tumor cell lines, HCT-116 (colorectal carcinoma) and HeLa (cervix adenocarcinoma). Some derivatives exhibited inhibitory effects on the catalytic activity of topoisomerase I and this effect was supported by docking studies. CONCLUSION: The enzyme inhibition results, although not directly related to cytotoxicity, suggest that a properly modified 1,2,5 oxadiazole scaffold could be considered for the development of new anti-topoisomerase agents.

A field-based disparity analysis of new 1,2,5-oxadiazole derivatives endowed with antiproliferative activity.

A series of 1,2,5-oxadiazoles were synthesized as new potential antiproliferative agents. The in vitro cytotoxic activity evaluation of title compounds through MTT assay revealed that some of them showed significant activity against the HCT-116 cancer cell line. The field-based disparity analysis provided indications about the electrostatic, hydrophobic, and shape features underlying the cytotoxicity, suggesting that increasing the negative electrostatic field on the heterocyclic core of the structure has positive effects on the activity. The structure-activity relationships (SAR) around a particular compound can be explained allowing for a structural rationale for the differences in activity. The SAR provided by this series of compounds can be exploited to carry out further lead optimization.

Design, synthesis and docking study of novel coumarin ligands as potential selective acetylcholinesterase inhibitors.

New coumaryl-thiazole derivatives with the acetamide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and in vitro tested as acetylcholinesterase (AChE) inhibitors. 2-(diethylamino)-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetamide (6c, IC50 value of 43 nM) was the best AChE inhibitor with a selectivity index of 4151.16 over BuChE. Kinetic study of AChE inhibition revealed that 6c was a mixed-type inhibitor. Moreover, the result of H4IIE hepatoma cell toxicity assay for 6c showed negligible cell death. Molecular docking studies were also carried out to clarify the inhibition mode of the more active compounds. Best pose of compound 6c is positioned into the active site with the coumarin ring wedged between the residues of the CAS and catalytic triad of AChE. In addition, the coumarin ring is anchored into the gorge of the enzyme by H-bond with Tyr130.

Discovery of a New Class of Sortase A Transpeptidase Inhibitors to Tackle Gram-Positive Pathogens: 2-(2-Phenylhydrazinylidene)alkanoic Acids and Related Derivatives.

A FRET-based random screening assay was used to generate hit compounds as sortase A inhibitors that allowed us to identify ethyl 3-oxo-2-(2-phenylhydrazinylidene)butanoate as an example of a new class of sortase A inhibitors. Other analogues were generated by changing the ethoxycarbonyl function for a carboxy, cyano or amide group, or introducing substituents in the phenyl ring of the ester and acid derivatives. The most active derivative found was 3-oxo-2-(2-(3,4dichlorophenyl)hydrazinylidene)butanoic acid (2b), showing an IC50 value of 50 µM. For a preliminary assessment of their antivirulence properties the new derivatives were tested for their antibiofilm activity. The most active compound resulted 2a, which showed inhibition of about 60% against S. aureus ATCC 29213, S. aureus ATCC 25923, S. aureus ATCC 6538 and S. epidermidis RP62A at a screening concentration of 100 µM.

How does binding of imidazole-based inhibitors to heme oxygenase-1 influence their conformation? Insights combining crystal structures and molecular modelling.

Heme oxygenase-1 (HO-1) inhibition is associated with antitumor activity. Imidazole-based analogues show effective and selective inhibitory potency of HO-1. In this work, five single-crystal structures of four imidazole-based compounds are presented, with an in-depth structural analysis. In order to study the influence of the conformation of the ligands on binding to protein, conformational data from crystallography are compared with quantum mechanics analysis and molecular docking studies. Molecular docking of imidazole-based analogues in the active site of HO-1 is in good agreement with the experimental structures. Inhibitors interact with the heme cofactor and a hydrophobic pocket (Met34, Phe37, Val50, Leu147 and Phe214) in the HO-1 binding site. An alternate binding mode can be hypothesized for some inhibitors in the series.

Active targeting strategies for anticancer drug nanocarriers.

Chemotherapy at present remains the main form of treatment for cancer, though there is no clinically available antineoplastic drug that acts selectively on the tumor mass. For this reason, the scientific research is focused towards the development of novel cancer therapies and drug delivery strategies, like drug targeting, that would enhance the therapeutic efficacy of drugs while reducing their side toxicity. This review describes tree types of nanoparticles used in active targeting for cancer treatment: liposomes, lipid and polymer nanoparticles, and micelles. The opportunities and challenges achieved by the proposed strategies of active targeting have been highlighted, as well as the necessity to conciliate the targeting efficiency of drug nanocarriers with their longevity in the bloodstream.

Ingestão regular do suco de laranja vermelha reduz pressão arterial de adultos / Regular intake of red orange juice reduces blood pressure in adults

Objetivo - Investigar a ingestão regular do suco de laranja vermelha sobre a pressão arterial, variáveis antropométricas e dietéticas de indivíduos adultos. Métodos - Os indivíduos do grupo experimental, formado por 19 homens e 16 mulheres, receberam 750 mL/dia de suco de laranja vermelha pasteurizado durante 8 semanas. Foram realizadas avaliação antropométrica, dietética e hemodinâmica. Todas as avaliações foram realizadas no início do período experimental e após o tratamento dietético com o suco de laranja. Resultados - Não houve alteração nas variáveis antropométricas após a ingestão do suco de laranja vermelha. A pressão arterial sistólica reduziu significativamente entre os participantes eutróficos que consumiram suco de laranja vermelha e a diastólica reduziu entre os participantes com excesso de peso. Houve aumento significativo da ingestão de vitamina C e folato durante o período experimental. Conclusão - O consumo regular do suco de laranja vermelha mostrou propriedade hipotensora, sugerindo atividade protetora cardiovascular em indivíduos adultos. Portanto, seria interessante incentivar o consumo de frutas cítricas, pois são exclusivas fontes dietéticas de flavanonas.

Objective - This study aimed to investigate the regular ingestion of red orange juice on blood pressure, anthropometric and diet variables of adults. Methods - The individuals in the experimental group, composed by 19 men and 16 women received 750 mL / d of pasteurized red orange juice for 8 weeks. All volunteers were evaluated for anthropometric, dietary and hemodynamic parameters in the beginning and at the end of the experimental period. Results - There was no change in the variables anthropometric after ingestion of red orange juice. The systolic blood pressure reduced significantly among eutrophic participants supplemented with red orange juice and the diastolic blood pressure reduced among the pre-obese participants. There were significant increases in vitamin C and folate intakes during the experimental period. Conclusion - Regular consumption of red orange juice has shown hypotensive properties, suggesting cardiovascular protective activity in adults. So it would be beneficial to encourage the consumption of citrus fruits as they are unique dietary sources of flavanones.

Serum-stable, long-circulating paclitaxel-loaded colloidal carriers decorated with a new amphiphilic PEG derivative.

The paper describes sterically stabilized lipid nanocapsules (LNC) and multilamellar liposomes (MLV) coated using a new amphiphilic conjugate of PEG(2000) with a 2-alkyl-lipoamino acid (LAA). A complement activation assay (CH50) and uptake experiments by THP-1 macrophage cells were used to assess in vitro the effectiveness of the PEG-LAA derivative of modifying the surface behavior of nanocarriers. Administered to rats or Swiss mice, respectively, the PEG(2000)-LAA-modified LNC and MLV showed plasma half-lives longer than the corresponding naked carriers. To assess the ability of nanocarriers to specifically reach tumor sites, paclitaxel (PTX)-loaded LNC and MLV were administered subcutaneously to rats implanted with a 9L glioma. Animals treated with saline or naked LNC and MLV underwent a quick expansion of tumor mass, up to a volume of 2000 mm(3) 25 days after the injection of tumor cells. On the contrary, treatment with a PEG-LAA modified LNC carrier reduced the growth of the tumor volume, which did not exceed 1000 mm(3) by day 25. Analogous positive results were obtained with the liposomal systems. The experimental findings confirmed that these new PEG-LAA conjugates allow to obtain sterically stable nanocarriers that behave effectively and in a comparable or even better way than the (phospho)lipid PEG derivatives commercially available.

Estado nutricional como fator de risco para doenças cardiovasculares entre funcionários de uma universidade privada / Nutritional status as a risk factor for cardiovascular diseases among employees of a private university

Introdução - Atualmente a obesidade é um dos maiores problemas de saúde pública, está associada a outras doenças crônicas não transmissíveis, como as cardiovasculares, que são a principal causa de mortalidade no país. O presente trabalho investigou o estado nutricional como fator de risco cardiovascular em 30 indivíduos adultos de uma universidade privada do município de São José do Rio Preto (SP). Material e Métodos - Os métodos utilizados para a avaliação antropométrica foram: peso, altura e circunferência da cintura. Para a avaliação dietética foi utilizado o recordatório alimentar de 24 horas. Para verificar a adequação das refeições ingeridas, os conteúdos de energia e macronutrientes foram comparados com as recomendações diárias. Resultados - A prevalência de obesidade foi de 13,4%, sobrepeso 33,3%. O risco para o desenvolvimento de doenças cardiovasculares de acordo com a circunferência da cintura esteve presente em 31,8% das mulheres e 62,5% dos homens. Observou-se que 50% das mulheres e 37,5% dos homens tiveram consumo excessivo de energia. O consumo em excesso de proteína e lipídeo foi mais prevalente no sexo feminino, enquanto que o de carboidrato foi mais frequente no sexo masculino. Conclusões - Foi observado que grande parte dos participantes tiveram excesso de peso e medida de circunferência da cintura acima dos valores estabelecidos como limite de normalidade, bem como consumo excessivo de energia. Esses resultados indicam uma maior probabilidade de desenvolvimento de doenças crônicas não transmissíveis, especialmente as cardiovasculares, sendo necessária a adoção de medidas preventivas e atenção em saúde.

Introduction - Nowadays the obesity is one of the great public health problems, associated to other not transmissible chronic diseases, like the cardiovascular ones, that are the main cause of mortality in the country. The present research investigated the nutritional status as risk factor cardiovascular in 30 adult individuals of a private university in the city of São José do Rio Preto (SP). Material and Methods - The used methods for the anthropometric evaluation were: weight, stature and circumference of waist. For the dietetics evaluation was used the 24-hour food recollection. To verify the fitness of eaten food, the content of energy and macronutrients was compared to the daily recommendations. Results - The prevalence of obesity was 13,4%, overweight 33,3%. The risk for developing cardiovascular diseases in agreement with circumference of waist it was present in 31,8% of women and 62,5% of the men. It was observed that 50% of the women and 37,5% of the men had excessive consume of energy. The consume in excess of protein and lipid was more prevalent in the female sex, while the carbohydrate was more frequent in the male sex. Conclusions - It was observed that most of the participants were overweight and measure waist circumference values above the established limits of normal and excessive energy consumption. These results indicatea great probability of developing not transmissible chronic diseases, specially the cardiovascular ones, being necessary adoption of preventive measures and attention to health.

Insuficiência de cálcio e ferro na merenda escolar em unidades municipais de ensino fundamental / Calcium and iron insufficiency in the meals of municipal units of elementary school

Este estudo avaliou os teores de cálcio, ferro, zinco e vitamina C da merenda escolar em unidades municipais de ensino na cidade de Araraquara (SP). Foram coletadas amostras em duplicata das refeições distribuídas diariamente em 90% das pré-escolas municipais (CER) e 60% das escolas municipais de ensino fundamental (EMEF), durante os meses de abril e maio de 2002. Os minerais: cálcio, ferro e zinco foram determinados por espectroscopia de emissão atômica. A vitamina C foi estimada adotando-se como referência às informações contidas em Tabela Nacional de Composição de Alimentos. A quantidade dos minerais e da vitamina C encontrada na merenda foi comparada com as recomendações nutricionais da Nutritional Research Council (1999, 2000, 2002) preconizado para a faixa etária considerada na pesquisa. A merenda continha quantidade insuficiente de cálcio em 45% das pré-escolas e 67% das escolas de ensino fundamental, e em ferro em 38% das pré-escolas e 50% das escolas de ensino fundamental. O conteúdo de vitamina C da merenda de 76% das pré-escolas e 67% das escolas de ensino fundamental esteve acima de 50% da recomendação. O zinco esteve acima de 50% da recomendação na merenda de 90% das pré-escolas e 83% das escolas de ensino fundamental. Concluiu-se que há necessidade de melhorar a qualidade nutricional da merenda, principalmente no tocante ao conteúdo de cálcio e ferro, visando reduzir a prevalência de deficiência destes micronutrientes entre os pré-escolares e escolares beneficiados pelo programa de alimentação escolar