Identification of estrogen receptor agonists among hydroxylated polychlorinated biphenyls using classification-based quantitative structure-activity relationship models.

Identification of estrogen receptor (ER) agonists among environmental toxicants is essential for assessing the potential impact of toxicants on human health. Using 2D autocorrelation descriptors as predictor variables, two binary logistic regression models were developed to identify active ER agonists among hydroxylated polychlorinated biphenyls (OH-PCBs). The classifications made by the two models on the training set compounds resulted in accuracy, sensitivity and specificity of 95.9 %, 93.9 % and 97.6 % for ERα dataset and 91.9 %, 90.9 % and 92.7 % for ERß dataset. The areas under the ROC curves, constructed with the training set data, were found to be 0.985 and 0.987 for the two models. Predictions made by models I and II correctly classified 84.0 % and 88.0 % of the test set compounds and 89.8 % and 85.8% of the cross-validation set compounds respectively. The two classification-based QSAR models proposed in this paper are considered robust and reliable for rapid identification of ERα and ERß agonists among OH-PCB congeners.

Development and Validation of Predictive Quantitative Structure-Activity Relationship Models for Estrogenic Activities of Hydroxylated Polychlorinated Biphenyls.

Disruption of the endocrine system by hydroxylated polychlorinated biphenyls (OH-PCBs) is hypothesized, among other potential mechanisms, to be mediated via nuclear receptor binding. Due to the high cost and lengthy time required to produce high-quality experimental data, empirical data to support the nuclear receptor binding hypothesis are in short supply. In the present study, two quantitative structure-activity relationship models were developed for predicting the estrogenic activities of OH-PCBs. Findings revealed that model I (for the estrogen receptor α dataset) contained five two-dimensional (2D) descriptors belonging to the classes autocorrelation, Burden modified eigenvalues, chi path, and atom type electrotopological state, whereas model II (for the estrogen receptor ß dataset) contained three 2D and three 3D descriptors belonging to the classes autocorrelation, atom type electrotopological state, and Radial Distribution Function descriptors. The internal and external validation metrics reported for models I and II indicate that both models are robust, reliable, and suitable for predicting the estrogenic activities of untested OH-PCB congeners. Environ Toxicol Chem 2023;42:823-834. © 2023 SETAC.

In silico prediction of nuclear receptor binding to polychlorinated dibenzofurans and its implication on endocrine disruption in humans and wildlife.

Polychlorinated dibenzofurans (PCDFs) are known to cause endocrine disruption in humans and wildlife but the mechanisms underlying this disruption have not been adequately investigated. In this paper, the susceptibility of the endocrine system to disruption by PCDF congeners via nuclear receptor binding was studied using molecular docking simulation. Findings revealed that some PCDF congeners exhibit high probabilities of binding to androgen receptor in its agonistic and antagonistic conformations. In depth molecular docking analysis of the receptor-ligand complexes formed by PCDFs with androgen receptor in its agonistic and antagonistic conformations showed that, these complexes were stabilized by electrostatic, van der Waals, pi-effect and hydrophobic interactions. It was also observed that PCDF molecules mimic the modes of interaction observed in androgen-testosterone and androgen-bicalutamide complexes, utilizing between 65 and 83% of the amino acid residues used by the co-crystallized ligands for binding. This computational study suggests that some PCDF congeners may act as agonists and antagonists of androgen receptor in humans and wildlife via inapproprate binding to the receptor.

Relationship Between Serum Albumin Levels And The Outcome Of Split-Thickness Skin Graft In Burn Injury Patients.

Burn injury is still a global health problem due to its high incidence. Healing of burn wounds requires an optimal state of the body that is characterized by serum albumin level, especially in the category of patients that require skin graft to cover the wound caused by the deep burn. This study investigates the relationship between albumin levels and the outcome of split-thickness skin graft (STSG) and obtains a tolerance limit for albumin levels that can be successful in STSG. This was a prospective cohort study at our Plastic Surgery Center in Bandung, West Java, Indonesia from June 2019 to November 2020. Fortyseven burn injury patients who had undergone STSG qualified as the study subjects based on the criteria set. Of these patients, 85.11% were male and 68.08% were in the productive age. Preoperative albumin level has no significant correlation with graft outcome (P>0.05). Area Under the Curve (AUC) is 0.758; (95% CI: 0.605, 0.910). The optimal cut-off point for albumin levels is 2.175 (sensitivity of 0.78 and a specificity of 0.714). In our study, graft healing has no significant correlation with albumin levels. Further study is needed to assess the relationship between serum albumin levels (preoperative and postoperative) with outcome of the graft, and assess infection status.

En raison d'une incidence restant élevée, les brûlures demeurent un problème de santé publique. Leur guérison nécessite une optimisation de l'état général, reflété par l'albuminémie, en particulier chez les patients ayant besoin de greffes. Cette étude évalue la corrélation entre l'albuminémie et l'intégration des Greffes de Peau Mince (GPM), en recherchant un seuil bas d'albuminémie avant GPM. Elle a été conduite dans le service de chirurgie plastique de l'hôpital de Bandung, dans l'ouest de l'île de Java, entre juin 2019 et novembre 2020, auprès de 47 patients brûlés ayant besoin d'une GPM (85,11% d'hommes dont 68,08% en âge de travailler). Nous n'avons pas trouvé de relation significative entre l'albuminémie préopératoire et l'intégration des greffes (p > 0,05 ; aire sous courbe ROC 0,758 ; IC95 0,605 à 0,910). La limite optimale de l'albuminémie est de 21,75 g/L, amenant une sensibilité de 0,78 et une spécificité de 0,714. Devant cette absence de significativité, il est nécessaire de prolonger les études à la recherche d'une albuminémie (pré- et post- opératoire) permettant d'améliorer l'intégration des greffes et de réduire l'incidence des infections.

Emphysematous pyelonephritis in an infant from Sokoto, north-western Nigeria.

INTRODUCTION: Emphysematous pyelonephritis is a life-threatening necrotising bacterial infection of the kidneys. It is rare among children and can be fatal if not promptly identified and treated. CASE PRESENTATION: A 7-month-old male infant presented to the Emergency Paediatric Unit of Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria, on 12 November 2019 with a 5-day history of fever and vomiting, and a 3-day history of a progressively enlarging, left-side abdominal mass. There was associated excessive crying on micturition, refusal to feed and weight loss. He looked ill and was in respiratory distress, irritable, febrile (38.8 °C), moderately dehydrated and pale. His weight and length were 5.5 kg and 64 cm. He had a tender, firm and ballotable abdominal mass on the left flank measuring 8 cm × 10 cm. His pulse rate was 140 beats/min, blood pressure 60/40 millimetres of mercury and respiratory rate was 65 cycles/min. He had widespread coarse crepitations and normal heart sounds on chest auscultation. MANAGEMENT AND OUTCOME: An initial diagnosis of sepsis was made. Other considerations were nephroblastoma and neuroblastoma. Ceftriaxone and blood transfusion were commenced with subsequent administration of intravenous fluids. Further radiologic investigations revealed emphysematous pyelonephritis. The patient had percutaneous drainage and extended spectrum ß-lactamase-producing Escherichia coli (sensitive to meropenem) which was isolated from the aspirate culture after 48 h of incubation. Meropenem could not be commenced because of non-availability and high cost. The patient subsequently deteriorated and died from septic shock. CONCLUSION: Emphysematous pyelonephritis has a fulminant course when not diagnosed promptly and treated adequately.

A computational insight into endocrine disruption by polychlorinated biphenyls via non-covalent interactions with human nuclear receptors.

Production of polychlorinated biphenyls (PCBs) was banned a long time ago because of their harmful health effects but humans continue to be exposed to residual PCBs in the environment. In this study, the susceptibility of human nuclear receptors to binding by PCBs was investigated using molecular docking simulation. Findings revealed that PCBs belonging to ortho-substituted, mono-ortho-substituted and non-ortho-substituted congeners could bind to agonistic conformations of androgen (AR), estrogen (ER α and ER ß), glucocorticoid (GR) and thyroid hormone (TR α and TR ß) receptors as well as antagonistic conformation of androgen receptor (AR an) but only ortho-substituted and mono-ortho-substituted PCBs could bind to estrogen receptors in their antagonistic conformations (ER α an and ER ß an). Further molecular docking analyses showed that PCBs mimic the modes of interaction observed for the co-crystallized ligands in the crystal structures of the affected receptors, utilizing 81%, 83%, 78%, 60%, 75%, 60%, 86%, 100% and 75% of the amino acid residues utilized by the co-crystallized ligands for binding in AR, AR an, ER α, ER α an, ER ß, ER ß an, GR, TR α and TR ß respectively. This computational study suggests that PCBs may cause endocrine disruption via formation of non-covalent interactions with androgen, estrogen, glucocorticoid and thyroid hormone receptors.

Theoretical study on endocrine disrupting effects of polychlorinated dibenzo-p-dioxins using molecular docking simulation.

Polychlorinated dibenzo-p-dioxins (PCDDs) are hypothesized to exert their toxic effects in wildlife and humans via endocrine disruption. However, very scanty information is available on the underlying molecular interactions that trigger this disruption. In this study, molecular docking simulation was used to predict the susceptibility of 12 nuclear receptors to disruption via PCDD bindings. Findings revealed that androgen (AR and AR an), estrogen (ER α and ER ß), glucocorticoid (GR) and thyroid hormone (TR α and TR ß) receptors are the most probable protein targets that bind to PCDDs. Further molecular docking analyses showed that PCDD molecules mimic the modes of interaction observed for the co-crystallized ligands of the affected receptors, resulting in the formation of ligand-receptor complexes that were stabilized through electrostatic, van der Waals, pi-effect and hydrophobic interactions with 18, 17, 17, 16, 18, eight and four amino acid residues in the active sites of AR, AR an, ER α, ER ß, GR, TR α and TR ß respectively. The commonalities of these interacting amino acid residues with those utilized by dihydrotestosterone in AR, bicalutamide in AR an, 17ß-estradiol in ER α, 17ß-estradiol in ER ß, cortisol in GR, thyromimetic GC-1 in TR α and thyromimetic GC-1 in TR ß are 86%, 74%, 94%, 80%, 82%, 50% and 43% respectively. The results obtained in this study provide supporting evidence that PCDD molecules may interfere with the endocrine system via binding interactions with some vital amino acid residues in the binding pockets of AR, ERs, GRs and TRs.

Telomerase activity in different clinical staging of colorectal adenocarcinoma.

Increased telomerase activity is proposed to be related with the proliferation of some gastrointestinal cancers, including colorectal adenocarcinoma. To date, little is known about the activity of telomerase in different clinical stagings of colorectal adenocarcinoma, which may reflect its association with the progression of colorectal adenocarcinoma. We will examine the activity of telomerase enzyme in different clinical stagings of colorectal adenocarcinoma to know whether it has diagnostic and prognostic value as a tumor marker in the management of colorectal adenocarcinoma. The telomerase activities of primary tumor and normal adjacent mucosa in 17 cases with different clinical stagings of colorectal adenocarcinoma were measured by TRAP assay during the period of 28 September 1998 to 28 February 1999. The activities of the enzyme were measured both qualitatively and quantitatively, and the diagnostic value was assessed by diagnostic test using 2 x 2 table contingency. The association between telomerase activities and other related factors were assessed by multivariate analysis. Increased telomerase activities were found in 82.4% (14/17) of colorectal adenocarcinoma, but in only 23.5% (4/17) of normal adjacent mucosa, which was significantly higher (p = 0.008) compared to that of normal mucosa. The mean values of telomerase activity between different clinical stagings were 0, 0.661, and 1.449 units/410 (g protein for Dukes' stage B, C, and D, respectively, which gave p value of 0.025 with ANOVA. Using a cut off level of 0.2-units/410 (g protein for positive activity, we revealed that the accuracy, sensitivity, and specificity were 77.77%, 82.35%, and 76.47%, respectively. There was no association found between the histopathologic grading of the tumor and telomerase activity. Increased telomerase activity was found in colorectal adenocarcinoma compared to the adjacent normal mucosa. Telomerase activity correlates well with the progression of colorectal adenocarcinoma. Therefore, telomerase enzyme may have a potential diagnostic and prognostic values in the management of colorectal adenocarcinoma.