Investigating the molecular function of UbcH10

UbcH10 is an E2-conjugating enzyme specific for the Anaphase-Promoting Complex/Cyclosome (APC/C) and a proto-oncogene product that is overexpressed in many human cancers. The molecular basis of UbcH10 function is not, however, completely understood. To investigate the molecular function of UbcH10 in more detail and identify novel UbcH10-interacting proteins, our laboratory had previously performed UbcH10 interactomic studies. As such, it was hypothesised that novel UbcH10-associated proteins might be novel APC/C substrates or APC/C regulators. To this end, we investigated the function of the novel UbcH10-interacting protein and RhoA-specific RhoGEF, PDZ-RhoGEF in more detail. It was determined that PDZ-RhoGEF associates with UbcH10 both in vitro and in vivo and is targeted for proteasomal degradation in early mitosis. In this regard, it was determined that PDZ-RhoGEF associates with Cdc20, at least in part, through a highly conserved KEN box present in PDZ-RhoGEF and that ablation of the KEN box stabilises PDZ-RhoGEF protein levels. Moreover, it was determined that PDZ-RhoGEF is phosphorylated upon a number of S/TP sites in mitosis by Cdk1 and that pharmacological inhibition of Cdk1 in combination with proteasomal inhibitors limits the degradation of PDZ-RhoGEF in mitosis. These data suggest that PDZ-RhoGEF is targeted for APC/C-Cdc20-mediated degradation in a Cdk1- dependent manner. Previous studies have suggested that UbcH10 might possess intrinsic E3 ubiquitin ligase activity. As such it was hypothesized that UbcH10 autoubiquitylation activity might affect UbcH10 function and that UbcH10 E3 ligase activity represented a potential therapeutic target. To this end, it was shown that UbcH10 possesses intrinsic E3 ligase activity and is able to undergo extensive autopolyubiquitylation independent of the APC/C, on one or more lysine acceptor residues. Mutational analyses determined that K119 is the major lysine acceptor residue for polyubiquitin chain formation both in vitro and in vivo. In this regard, it was also determined that UbcH10 can assemble polyubiquitin chains with K6, K11 and K48 homotypic ubiquitin linkages. A high-throughput quantitative UbcH10 ubiquitylation assay for drug-screening was also developed and confirmed the requirement for lysine acceptor residues in UbcH10 autopolyubiquitylation activity. These data indicate that UbcH10 can potentially modify its own activity through self-polyubiquitylation and that UbcH10 E3 ligase activity could potentially be targeted pharmacologically in order to inhibit UbcH10 function

Pectin: A Bioactive Food Polysaccharide with Cancer Preventive Potential

Pectin is an acidic heteropolysaccharide found in the cell walls and the primary and middle lamella of land plants. To be authorized as a food additive, industrial pectins must meet strict guidelines set forth by the Food and Agricultural Organization and must contain at least 65% polygalacturonic acid to achieve the E440 level. Fruit pectin derived from oranges or apples is commonly used in the food industry to gel or thicken foods and to stabilize acid-based milk beverages. It is a naturally occurring component and can be ingested by dietary consumption of fruit and vegetables. Preventing long-term chronic diseases like diabetes and heart disease is an important role of dietary carbohydrates. Colon and breast cancer are among the diseases for which data suggest that modified pectin (MP), specifically modified citrus pectin (MCP), has beneficial effects on the development and spread of malignancies, in addition to its benefits as a soluble dietary fiber. Cellular and animal studies and human clinical trials have provided corroborating data. Although pectin has many diverse functional qualities, this review focuses on various modifications used to develop MP and its benefits for cancer prevention, bioavailability, clinical trials, and toxicity studies. This review concludes that pectin has anti-cancer characteristics that have been found to inhibit tumor development and proliferation in a wide variety of cancer cells. Nevertheless, further clinical and basic research is required to confirm the chemopreventive or therapeutic role of specific dietary carbohydrate molecules.info:eu-repo/semantics/publishedVersio

Breast cancer awareness and breast self-examination among future female university graduates: comparison between medical and non-medical students

Background: Breast cancer is a common health problem among females in Saudi Arabia. The disease account for 27% of all female malignancies representing 25.1% of all newly diagnosed female cancers. The objectives of the current study were to assess the level of carcinoma breast awareness of female university students, Majmaah University in Saudi Arabia and to compare the level of awareness, breast self-examination and breast cancer screening between medical and non-medical students.Methods: The current study was a cross-sectional, conducted among female students in Majmaah University in Saudi Arabia. The stratified and the systematic sampling were employed to select the colleges and the students respectively. The sample size was calculated as 325. Data was collected by a pre tested questionnaire and analyzed by SPSS.Results: The university students who acquired good knowledge were 111 (34.2%). Students who acquired average and poor knowledge were 42.2% and 23.6% respectively. Medical students who had good knowledge were 37.6% compared to 26.9% of non-medical students.  The results showed that 94 (28.9%) of the participants practice breast self-examination and 25 (7.6%) performed a screening test.Conclusions: The study concluded that Majmaah University students’ awareness of carcinoma breast is low. There is no significant difference in the level of awareness between students of medical colleges and those of non-medical colleges. The level of practicing breast self-examination and performing screening test for carcinoma breast among female university students is low. There is a significant difference in performing carcinoma breast screening test between medical and non-medical students.

Surgical Approaches to Congenital Anomalies of Esophagus

With prevalence of about 1 in 3000 live births, pediatric surgeons commonly deal with esophageal abnormalities, which may provide substantial clinical complications. Surprisingly, the embryologic processes underlying esophageal atresia (EA) with or without tracheoesophageal fistula (TEF), one of the hallmark disease entities of pediatric surgery, have only lately been largely uncovered. When it comes to the treatment of congenital esophageal abnormalities, notably esophageal atresia and tracheoesophageal fistula, surgical methods are essential. In order to address the anatomical abnormalities and restore normal function, surgical correction is often necessary in the care of congenital esophageal anomalies, including esophageal atresia and tracheoesophageal fistula. In this review we are going to cover surgical approaches to repair those malformations, long-term outcomes, and latest developments in esophageal surgical approaches

In vitro cytotoxicity of Withania somnifera (L.) roots and fruits on oral squamous cell carcinoma cell lines: a study supported by flow cytometry, spectral, and computational investigations

Oral cancer is a severe health problem that accounts for an alarmingly high number of fatalities worldwide. Withania somnifera (L.) Dunal has been extensively studied against various tumor cell lines from different body organs, rarely from the oral cavity. We thus investigated the cytotoxicity of W. somnifera fruits (W-F) and roots (W-R) hydromethanolic extracts and their chromatographic fractions against oral squamous cell carcinoma (OSCC) cell lines [Ca9-22 (derived from gingiva), HSC-2, HSC-3, and HSC-4 (derived from tongue)] and three normal oral mesenchymal cells [human gingival fibroblast (HGF), human periodontal ligament fibroblast (HPLF), and human pulp cells (HPC)] in comparison to standard drugs. The root polar ethyl acetate (W-R EtOAc) and butanol (W-R BuOH) fractions exhibited the strongest cytotoxicity against the Ca9-22 cell line (CC50 = 51.8 and 40.1 μg/mL, respectively), which is relatively the same effect as 5-FU at CC50 = 69.4 μM and melphalan at CC50 = 36.3 μM on the same cancer cell line. Flow cytometric analysis revealed changes in morphology as well as in the cell cycle profile of the W-R EtOAc and W-R BuOH-treated oral cancer Ca9-22 cells compared to the untreated control. The W-R EtOAc (125 μg/mL) exerted morphological changes and induced subG1 accumulation, suggesting apoptotic cell death. A UHPLC MS/MS analysis of the extract enabled the identification of 26 compounds, mainly alkaloids, withanolides, withanosides, and flavonoids. Pharmacophore-based inverse virtual screening proposed that BRD3 and CDK2 are the cancer-relevant targets for the annotated withanolides D (18) and O (12), and the flavonoid kaempferol (11). Molecular modeling studies highlighted the BRD3 and CDK2 as the most probable oncogenic targets of anticancer activity of these molecules. These findings highlight W. somnifera’s potential as an affordable source of therapeutic agents for a range of oral malignancies

Ceiba pentandra ethyl acetate extract improves doxorubicin antitumor outcomes against chemically induced liver cancer in rat model: a study supported by UHPLC-Q-TOF-MS/MS identification of the bioactive phytomolecules

Hepatocellular carcinoma (HCC) is a prevalent cancer worldwide. Late-stage detection, ineffective treatments, and tumor recurrence contribute to the low survival rate of the HCC. Conventional chemotherapeutic drugs, like doxorubicin (DOX), are associated with severe side effects, limited effectiveness, and tumor resistance. To improve therapeutic outcomes and minimize these drawbacks, combination therapy with natural drugs is being researched. Herein, we assessed the antitumor efficacy of Ceiba pentandra ethyl acetate extract alone and in combination with DOX against diethylnitrosamine (DENA)-induced HCC in rats. Our in vivo study significantly revealed improvement in the liver-function biochemical markers (ALT, AST, GGT, and ALP), the tumor marker (AFP-L3), and the histopathological features of the treated groups. A UHPLC-Q-TOF-MS/MS analysis of the Ceiba pentandra ethyl acetate extract enabled the identification of fifty phytomolecules. Among these are the dietary flavonoids known to have anticancer, anti-inflammatory, and antioxidant qualities: protocatechuic acid, procyanidin B2, epicatechin, rutin, quercitrin, quercetin, kaempferol, naringenin, and apigenin. Our findings highlight C. pentandra as an affordable source of phytochemicals with possible chemosensitizing effects, which could be an intriguing candidate for the development of liver cancer therapy, particularly in combination with chemotherapeutic drugs

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Biomedical applications of selective metal complexes of indole, benzimidazole, benzothiazole and benzoxazole: A review (From 2015 to 2022)

Indole, benzoxazole benzothiazole and benzimidazole are excellent classes of organic heterocyclic compounds. These compounds show significant application in pharmacy, industries, dyes, medicine, polymers and food packages. These compounds also form metal complexes with copper, zinc, cadmium, nickel, cobalt, platinum, gold, palladium chromium, silver, iron, and other metals that have shown to be significant applications. Recently, researchers have attracted enormous attention toward heterocyclic compounds such as indole, benzimidazole, benzothiazole, benzoxazole, and their complexes due to their excellent medicinal applications such as anti-ulcerogenic, anti-cancer, antihypertensive, antifungal, anti-inflammatory, antitubercular, antiparasitic, anti-obesity, antimalarial, antiglycation, antiviral potency, antineuropathic, analgesic antioxidant, antihistaminic, and antibacterial potentials. In this article, we summarize the medicinal applications of these compounds as well as their metal complexes. We hope this article will help researchers in designing and synthesizing novel and potent compounds with significant applications in various fields

Assessment of solid-dosage drug nanonization by theoretical advanced models: Modeling of solubility variations using hybrid machine learning models

Production of solid-dosage drug nanoparticles was assessed by theoretical models to investigate the possibility of drug treatment via supercritical green processing. Nanonization can enhance drug solubility and consequently its bioavailability which is of great importance for pharmaceutical industry. This research presents a comparative study of three different regression models including Gaussian process regression, k-nearest neighbors, and multi-layer perceptron for predicting solvent density and solubility of Hyoscine drug. The models optimized using political optimizer (PO) algorithm. The results showed that all three optimized methods were able to predict density and solubility with high accuracy. PO-GPR achieved the highest R2 score for solubility (0.9984) and same for density (0.9999). The PO-MLP model achieved the high R2 score for density (0.9997) and the second-highest score for solubility (0.9945). PO-KNN also showed good performance for density (R2 = 0.9557) and solubility (R2 = 0.9783) but was outperformed by the other two models. In terms of RMSE and AARD%, PO-GPR and PO-MLP achieved lower error rates compared to PO-KNN. Overall, the results suggest that PO-GPR and PO-MLP are promising methods for predicting density and solubility of values. The models were useful for the application of drug nanonization and can be used to optimize the process

Epidemiological Trends of Acute Chemical Poisoning among Children over a Recent Three-Year Period in Saudi Arabia

Acute intoxication from chemicals is a major medical emergency that can result in illness and mortality. This retrospective study aims to evaluate acute chemical poisoning incidents among children in Saudi Arabia from 2019 to 2021. A total of 3009 children were recorded as being chemically intoxicated. The SPSS/PC statistics package was used for the statistical analysis. The acute chemical poisoning incidents that occurred in the age groups were <1 year: 237 (7.8%), 1–5 years: 2301 (76.4%), 6–12 years: 214 (7.1%), and 13–19 years: 257 (8.5%). The mean rate of acute chemical poisoning in the northern region was 40.1%. The most common poisonous agents were organic solvents (20.4%) and disinfection agents (22.7%). Interestingly, there is a significant relationship between the different types of acute chemical poisoning and various factors, including gender, age, the location where acute chemical intoxication occurred, the type of exposure, and whether these were intentional or unintentional events. The data suggest that the northern region of Saudi Arabia has had the highest number of recorded incidents of acute chemical poisoning over the last three years (2019–2021). Individuals between 1–5 years old were the worst hit. Organic solvents and detergents were to blame for the acute unintentional chemical poisonings that took place in homes. Therefore, educating the public about chemical poisoning and reducing children’s exposure to toxic chemicals requires educational programs, which may help to reduce chemical poisoning occurrence