Comparative Binding Study of Gliptins to Bacterial DPP4-like Enzymes for the Treatment of Type 2 Diabetes Mellitus (T2DM).

The role of the gut microbiota and its interplay with host metabolic health, particularly in the context of type 2 diabetes mellitus (T2DM) management, is garnering increasing attention. Dipeptidyl peptidase 4 (DPP4) inhibitors, commonly known as gliptins, constitute a class of drugs extensively used in T2DM treatment. However, their potential interactions with gut microbiota remain poorly understood. In this study, we employed computational methodologies to investigate the binding affinities of various gliptins to DPP4-like homologs produced by intestinal bacteria. The 3D structures of DPP4 homologs from gut microbiota species, including Segatella copri, Phocaeicola vulgatus, Bacteroides uniformis, Parabacteroides merdae, and Alistipes sp., were predicted using computational modeling techniques. Subsequently, molecular dynamics simulations were conducted for 200 ns to ensure the stability of the predicted structures. Stable structures were then utilized to predict the binding interactions with known gliptins through molecular docking algorithms. Our results revealed binding similarities of gliptins toward bacterial DPP4 homologs compared to human DPP4. Specifically, certain gliptins exhibited similar binding scores to bacterial DPP4 homologs as they did with human DPP4, suggesting a potential interaction of these drugs with gut microbiota. These findings could help in understanding the interplay between gliptins and gut microbiota DPP4 homologs, considering the intricate relationship between the host metabolism and microbial communities in the gut.

Computational strategies for the discovery of biological functions of health foods, nutraceuticals and cosmeceuticals: a review.

Scientific and consumer interest in healthy foods (also known as functional foods), nutraceuticals and cosmeceuticals has increased in the recent years, leading to an increased presence of these products in the market. However, the regulations across different countries that define the type of claims that may be made, and the degree of evidence required to support these claims, are rather inconsistent. Moreover, there is also controversy on the effectiveness and biological mode of action of many of these products, which should undergo an exhaustive approval process to guarantee the consumer rights. Computational approaches constitute invaluable tools to facilitate the discovery of bioactive molecules and provide biological plausibility on the mode of action of these products. Indeed, methodologies like QSAR, docking or molecular dynamics have been used in drug discovery protocols for decades and can now aid in the discovery of bioactive food components. Thanks to these approaches, it is possible to search for new functions in food constituents, which may be part of our daily diet, and help to prevent disorders like diabetes, hypercholesterolemia or obesity. In the present manuscript, computational studies applied to this field are reviewed to illustrate the potential of these approaches to guide the first screening steps and the mechanistic studies of nutraceutical, cosmeceutical and functional foods.

Structure-Based Design and Synthesis of Stapled 10Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases.

Following a rational design, a series of macrocyclic ("stapled") peptidomimetics of 10Panx1, the most established peptide inhibitor of Pannexin1 (Panx1) channels, were developed and synthesized. Two macrocyclic analogues SBL-PX1-42 and SBL-PX1-44 outperformed the linear native peptide. During in vitro adenosine triphosphate (ATP) release and Yo-Pro-1 uptake assays in a Panx1-expressing tumor cell line, both compounds were revealed to be promising bidirectional inhibitors of Panx1 channel function, able to induce a two-fold inhibition, as compared to the native 10Panx1 sequence. The introduction of triazole-based cross-links within the peptide backbones increased helical content and enhanced in vitro proteolytic stability in human plasma (>30-fold longer half-lives, compared to 10Panx1). In adhesion assays, a "double-stapled" peptide, SBL-PX1-206 inhibited ATP release from endothelial cells, thereby efficiently reducing THP-1 monocyte adhesion to a TNF-α-activated endothelial monolayer and making it a promising candidate for future in vivo investigations in animal models of cardiovascular inflammatory disease.

Identification of the phospholipid binding regions of the envelope E protein of flaviviruses by molecular dynamics.

The Flavivirus genus comprise several important human pathogens, including dengue, West Nile, Yellow fever, Japanese encephalitis, Zika, and tick-borne encephalitis viruses. These enveloped viruses affect more than 2 billion people in the world, mainly in less developed countries. Although some vaccines exist for some flaviviruses, these vaccines are not universally available due to many factors and since their infections are a world-wide public health issue, the development of antiviral molecules is fundamental. Flavivirus membranes, through the help of the envelope E glycoprotein, fuse with endosomal compartments in a pH-dependent way to release their genome into the cytoplasm and require specific lipids, such as bis(monoacylglycero)phosphate (BMP), for efficient fusion. The fundamental role the envelope E protein has on viral entry and membrane fusion suggest that it is an essential antiviral target. In this work, we have used atomistic molecular dynamics simulations to study the binding of the head-group of BMP to the tip of the envelope E proteins of ZIKV, DENV, TBEV and JEV viruses whose three-dimensional structures are known. Our results indicate that, apart from the fusion loop, there are different amino acid residues in different regions of the envelope E proteins of flaviviruses capable of binding the head-group of BMP. These regions should work together to accomplish the binding and fusion of the envelope and endosomal membranes and represent a new target to develop and design potent and effective antiviral agents capable of blocking flavivirus-endosome membrane fusion. [Formula: see text].

Discovery of 2-aryl and 2-pyridinylbenzothiazoles endowed with antimicrobial and aryl hydrocarbon receptor agonistic activities.

Benzothiazole is a privileged scaffold in medicinal chemistry present in diverse bioactive compounds with multiple pharmacological applications such as analgesic, anticonvulsant, antidiabetic, anti-inflammatory, anticancer and radioactive amyloidal imagining agents. We reported in this work the study of sixteen functionalized 2-aryl and 2-pyridinylbenzothiazoles as antimicrobial agents and as aryl hydrocarbon receptor (AhR) modulators. The antimicrobial activity against Gram-positive (S. aureus and M. luteus) and Gram-negative (P. aeruginosa, S. enterica and E. coli) pathogens yielded MIC ranging from 3.13 to 50 µg/mL and against the yeast C. albicans, the benzothiazoles displayed MIC from 12.5 to 100 µg/mL. All compounds showed promising antibiofilm activity against S. aureus and P. aeruginosa. The arylbenzothiazole 12 displayed the greatest biofilm eradication in S. aureus (74%) subsequently verified by fluorescence microscopy. The ability of benzothiazoles to modulate AhR expression was evaluated in a cell-based reporter gene assay. Six benzothiazoles (7, 8-10, 12, 13) induced a significant AhR-mediated transcription and interestingly compound 12 was also the strongest AhR-agonist identified. Structure-activity relationships are suggested herein for the AhR-agonism and antibiofilm activities. Furthermore, in silico predictions revealed a good ADMET profile and druglikeness for the arylbenzothiazole 12 as well as binding similarities to AhR compared with the endogenous agonist FICZ.

Targeting the aryl hydrocarbon receptor with a novel set of triarylmethanes.

The aryl hydrocarbon receptor (AhR) is a chemical sensor upregulating the transcription of responsive genes associated with endocrine homeostasis, oxidative balance and diverse metabolic, immunological and inflammatory processes, which have raised the pharmacological interest on its modulation. Herein, a novel set of 32 unsymmetrical triarylmethane (TAM) class of structures has been synthesized, characterized and their AhR transcriptional activity evaluated using a cell-based assay. Eight of the assayed TAM compounds (14, 15, 18, 19, 21, 22, 25, 28) exhibited AhR agonism but none of them showed antagonist effects. TAMs bearing benzotrifluoride, naphthol or heteroaromatic (indole, quinoline or thiophene) rings seem to be prone to AhR activation unlike phenyl substituted or benzotriazole derivatives. A molecular docking analysis with the AhR ligand binding domain (LBD) showed similarities in the binding mode and in the interactions of the most potent TAM identified 4-(pyridin-2-yl (thiophen-2-yl)methyl)phenol (22) compared to the endogenous AhR agonist 5,11-dihydroindolo[3,2-b]carbazole-12-carbaldehyde (FICZ). Finally, in silico predictions of physicochemical and biopharmaceutical properties for the most potent agonistic compounds were performed and these exhibited acceptable druglikeness and good ADME profiles. To our knowledge, this is the first study assessing the AhR modulatory effects of unsymmetrical TAM class of compounds.

Prophylactic Use of Laser Light and Methylene Blue on Ischemia and Liver Reperfusion Injury.

OBJECTIVE: This study aimed to evaluate the effect of hepatic preconditioning with laser light in the presence of methylene blue (MB) in the liver ischemia-reperfusion injury process. METHOD: Forty male Wistar rats were divided into 8 experimental groups (n = 5). Saline (.5 mL) or MB (15 mg/kg) was injected intravenously (inferior vena cava). After 2 minutes, 660 nm laser light was applied at a dose of 112.5 DE. Fifteen minutes after the application of saline or MB, 1 hour partial ischemia followed by 15 minutes of reperfusion was applied when the rats were sacrificed. The mitochondrial function parameters (O2 consumption rates in states 3 and 4 and the respiratory control ratio), osmotic swelling, and determination of malondialdehyde were evaluated. Hepatic function was studied using the serum determination of the alanine aminotransferase and aspartate aminotransferase enzymes. RESULTS AND CONCLUSIONS: MB therapy alone showed the capacity of preserving the rate of oxygen consumption in the mitochondrial respiratory state of the group submitted to ischemia compared to the sham group. However, when combined with low-intensity laser therapy, it failed to replicate the relevant protective effects in relation to oxidative phosphorylation or the mitochondrial membrane ischemia/reperfusion injury. Whether or not MB was combined with laser treatment, it was shown to be efficient in reducing oxidative stress. In relation to alanine aminotransferase enzymes, whether or not laser treatment was combined with MB had a protective effect on the hepatic lesion, whereas in relation to aspartate aminotransferase enzymes only laser treatment was able to provide this protection.

Finding medical reasons for psychiatric behavior.

Medical disease was the cause of the primary disability in the majority (61.2 percent) of 116 elderly psychiatric patients treated at Bellevue Hospital Center. A change in behavior signaled the onset of medical illness with acute brain syndrome. The history that documented a change in behavior was derived from sources other than the patient. It is important to obtain such history during admission evaluation of elderly persons who are confused or whose memory is impaired. Multidiciplinary services enabled many patients to improve so that they could return home rather than being institutionalized. Had such services been available before their admission, many patients might have avoided hospitalization. As a result of this study, the geriatrics unit at Bellevue Hospital Center began to devote its efforts to elderly persons in the community.

Mujeres violentadas durante el embarazo y el parto: experiencias de parteras en Jalisco, México / Abused women during pregnacy and childbirth : experience from midwives in Jalisco, Mexico

OBJETIVO: explorar la experiencia y perspectiva de parteras con mujeres violentadas durante el embarazo y el parto en Jalisco, México. METODOLOGIA: se llevó a cabo un estudio cualitativo en zona rural de Jalisco, México, entre mayo y octubre de 2011 con 24 parteras, utilizando la entrevista individual, modalidad historia de vida pautada y la asamblea participativa regional como técnicas de indagación; posteriormente, los discursos fueron analizados bajo el modelo actancial semiótico. RESULTADOS : familiaridad de las parteras con la violencia hacia la mujer durante el embarazo y el parto, atribuida principalmente a aspectos de género y ruralidad; señalan al binomio violencia-embarazo como factor de riesgo para presentar problemas obstétricos, siendo la violencia física la que más encuentran y a la pareja como principal agresor. Resalta su capacidad de diálogo y escucha activa en identificación de violencia. Refieren posibilidad de ser escuchadas en la generación de acciones frente a este problema. DISCUSION:necesidad de asumir una postura política estatal sobre la partería, que permita reconocer su papel en la sociedad y la posibilidad de incorporarlas en las acciones que hacen frente al problema de la violencia, y valorar los elementos propios de su ejercicio en la detección y manejo de estas mujeres.

OBJECTIVE:to explore the experiences and perspectives that a group of midwives from Jalisco, Mexico had with women who were abused during pregnancy and childbirth . METHODOLOGY: a qualitative study was conducted in a rural zone of Jalisco, Mexico, between May and October 2011 with 24 midwives. The techniques used to obtain the data were: individual interviews, life history, and the participatory regional assembly. After collecting the discourses, these were analyzed using the semiotic actantial model. RESULTS:the midwives are familiar with the violence exercised against women during the pregnancy and birth process; this is mainly attributed tolocation- and sex-related aspects,which in turn shows the combination of pregnancy and violence as a risk factor for obstetrical problems. In addition, physical violence was the most common type of abuse, and the woman’s partner was the main aggressor. Finally, the midwives’ ability to speak, listen and identify the cases of violence is worth mentioning. CONCLUSION: it is necessary to assume a political stance on midwives that would help recognize their goal in society and incorporate them into any actions taken to stop domestic violence while valuing the midwives’ efforts to identify and aid thesemothers.

Aspectos sociales de la muerte materna: análisis de 5 años en el hospital general de occidente: Jalisco, México / social aspects of maternal death: analysis of five years in the general hospital of the west: Jalisco, Mexico

Objetivo: Analizar los aspectos sociales de las muertes maternas ocurridas en el Hospital General de Occidente, Jalisco, México (2006-2010). Método: Se recurrió al archivo del hospital para identificar los expedientes de las muertes maternas ocurridas durante el periodo de estudio. Las fuentes de información fueron certificados de defunción, autopsia verbal, cuestionario confidencial y dictamen de las muertes. Se utilizó estadística descriptiva y medidas de tendencia central para el análisis de la información. Resultados: Se identificaron 22 muertes maternas, evidenciando un aumento de las muertes maternas durante el periodo de estudio. La edad media fue de 28,27 años, el 68,27 por ciento se dedicaba actividades del hogar, 45 por ciento vivían en unión libre, 55 por ciento no tenían registro de tener seguridad social, el 50 por ciento poseían estudios de primaria o menos, y solo 77,2 por ciento presentaba control prenatal. Conclusiones: La presencia de factores sociales, que además de los clínicos, y que inciden en la muerte materna, deben ser conocidos por el personal del servicio de obstetricia, y deben ser considerados para el diseño e implementación de acciones para disminuir la muerte materna en todos los niveles de atención.

Objective: Analyze the social aspects of the maternal mortality occurred in the Hospital General de Occident, Jalisco, Mexico (2006-2010). Method: It is resorted the archive of the hospital to identify files of maternal mortality during the study period. The sources of information were death certificates, verbal autopsy, confidential questionnaire and opinion of the deaths. We used descriptive statistics and measures of central tendency for the analysis of the information. Results: We identified 22 maternal deaths, demonstrating an ascending trend of maternal mortality during the study period. The mean age was 28.27 years old, 68.27 percent was dedicated to the home, 45 percent lived in free union, 55 percent had no record of social security, 50 percent had a primary education or less, and only 77.2 percent had prenatal control. Conclusions: The presence of social factors, in addition to clinicians, and that influence maternal death should be known for the obstetrics service personnel, and should be considered for the design and implementation of actions to reduce maternal death at all levels of care.