Anti-prostate cancer metabolites from the soil-derived Aspergillus neoniveus

Prostate cancer (PCa) ranks as one of the most commonly diagnosed malignancies worldwide. Toxicity, lack of clinical efficacy, and development of resistance phenotypes are the main challenges in the control of prostate malignancies. Notably, castration-resistance prostate cancer (CRPCa) is a highly aggressive and metastatic phenotype of the disease with a poor prognosis and very limited therapeutic options. Herein, we report the isolation and genotypic identification of a soil-derived fungus Aspergillus neoniveus using the PCR-based internal transcribed spacer (ITS) region amplification approach. HPLC/MS investigation of the metabolic profile of the ethyl acetate extract from the fungal biomass revealed tentative identification of forty-five compounds belonging to various chemical classes including γ-butyrolactones, alkaloids, phenolics, and quinoids. Furthermore, the chromatographic purification of microbial extract enabled the identification of nervonic acid methyl ester (1) for the first time from endophytic fungi, as well as acetyl aszonalenin (2), and butyrolactone II (3) for the first time from A. neoniveus. The chemical frameworks of the isolated compounds were identified via extensive spectral analysis including 1 and 2D NMR and MS. The X-ray crystal structure and absolute configuration of acetyl aszonalenin (2) were also determined. Additionally, screening of in vitro anticancer activity of the fungal extract revealed its potential antiproliferative and anti-migratory activities against five different prostate cancer cells (PC3, PC-3M, DU-145, CWR-R1ca, and 22Rv1), including different cells with the castration-resistance phenotype. Moreover, the isolated metabolites significantly inhibited the proliferation, migration, and colonization of human prostate cancer cells at low micromolar levels, thus providing credence for future investigation of these metabolites in relevant anti-prostate cancer animal models. Furthermore, computational target prediction tools identified the cannabinoid G-protein coupled receptors type 1 (CB1) as a potential biological target mediating, at least in part, the anticancer effects of acetylaszonalenin (2). Moreover, molecular modeling and docking studies revealed a favorable binding pose at the CB1 receptor orthosteric ligand pocket aided by multiple polar and hydrophobic interactions with critical amino acids. In conclusion, the Aspergillus neoniveus-derived prenylated indole alkaloid acetylaszonalenin has promising anticancer activity and is amenable to further hit-to-lead optimization for the control of prostate malignancies via modulating CB1 receptor

Unveiling the therapeutic potential of exogenous β-hydroxybutyrate for chronic colitis in rats: novel insights on autophagy, apoptosis, and pyroptosis

Ulcerative colitis (UC) is a chronic relapsing inflammatory disease of the colorectal area that demonstrates a dramatically increasing incidence worldwide. This study provides novel insights into the capacity of the exogenous β-hydroxybutyrate and ketogenic diet (KD) consumption to alleviate dextran sodium sulfate (DSS)-induced UC in rats. Remarkably, both interventions attenuated disease activity and colon weight-to-length ratio, and improved macro and microstructures of the damaged colon. Importantly, both β-hydroxybutyrate and KD curbed the DSS-induced aberrant NLRP3 inflammasome activation as observed in mRNA and protein expression analysis. Additionally, inhibition of the NLRP3/NGSDMD-mediated pyroptosis was detected in response to both regimens. In parallel, these modalities attenuated caspase-1 and its associated consequences of IL-1β and IL-18 overproduction. They also mitigated apoptosis as indicated by the inactivation of caspase-3. The anti-inflammatory effects of BHB and KD were confirmed by the reported decline in the levels of inflammatory markers including MPO, NFκB, IL-6, and TNF-α. Moreover, these interventions exhibited antioxidative properties by reducing ROS production and improving antioxidative enzymes. Their effectiveness in mitigating UC was also evident in the renovation of normal intestinal epithelial barrier function, as shown by correcting the discrepancies in the levels of tight junction proteins ZO-1, OCLN, and CLDN5. Furthermore, their effects on the intestinal microbiota homeostasis were investigated. In terms of autophagy, exogenous β-hydroxybutyrate upregulated BECN-1 and downregulated p62, which may account for its superiority over KD in attenuating colonic damage. In conclusion, this study provides experimental evidence supporting the potential therapeutic use of β-hydroxybutyrate or β-hydroxybutyrate-boosting regimens in UC

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10&nbsp;years; 78.2% included were male with a median age of 37&nbsp;years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Development and adaptation of a strength-based job interview training tool for transition age youth on the autism spectrum using community engaged methods

IntroductionKessler Foundation Strength Identification and Expression (KF-STRIDE) is a strength-based job interview training tool developed for young adults on the autism spectrum. The intervention is based on a positive psychology framework to increase knowledge of character strengths, and how to relate them to a future employer. The current study sought to evaluate the acceptability, usability and feasibility of KF-STRIDE, as well as to guide adaptations to improve the tool’s ability to meet the needs of those on the spectrum.MethodsMixed methods (post-intervention surveys, and semi-structured interviews with key stakeholders) were used to inform the evaluation and consequent adaptations of KF-STRIDE.ResultsThe major findings of the study were that KF-STRIDE was found to be largely acceptable and usable. Importantly, however, our qualitative analysis revealed modifications that could help to better suit the needs of young adults on the spectrum, which included the incorporation of additional skills (i.e. etiquette, practicing hygiene) and more opportunities to practice job interviewing. Thus, we altered the implementation of the intervention to be web-based to improve accessibility. We incorporated the presence of an animated character to deliver the content, to eliminate the need for a highly trained interventionist.DiscussionKF-STRIDE was modified to increase access by incorporating feedback from the autism community. Future directions include assessing the efficacy of KF-STRIDE in young adults on the spectrum to identify whether employment outcomes are improved after using the tool

Recent advances in MRI in the preoperative assessment of anorectal malformations

Objective: To prospectively evaluate the diagnostic accuracy of triplanar 2D magnetic resonance (MR) images versus the post processing reconstructed MR images generated from a single 3D VISTA sequence in children with anorectal malformations compared with the operative findings as the Golden standard. Materials and methods: This study had institutional review board approval, and informed consent was obtained from all participants. There were 20 patients with anorectal anomalies age range (2 months–3.5 years), referred from the pediatric surgery unit for preoperative MRI. The 2D sequences included Coronal TSE T2 WI parallel to the plane of the anal canal as seen on the sagittal images, and Axial TSE T2 WI oblique, perpendicular to the coronal plane. Sagittal T2 weighted 3D-sequence; volumetric isotropic turbo spin echo acquisition (VISTA) was taken parallel to the mid-sagittal plane. Results: Comparing the two MR imagining protocols the acquisition time of the sagittal 3D sequence (6 min 42 s) was shorter than the total acquisition time of the 2D sequences (10 min 12 s) without jeopardizing the image quality or accuracy of the diagnostic information. MRI depicted the fistula in 94% (16 out of 17) of patients who were clinically proven fistulous, which is a privilege to detect associated anomalies on the same examination. The frequency of associated anomalies was 100% in high anorectal malformations (ARMs), 64% in intermediate and only 20% in low ARMs. From these associated anomalies vertebral anomalies were seen in 50% of patients. Concomitant cord anomalies were encountered in 60% of those with vertebral anomalies the most common of which was tethered cord observed in 35% of the patients. Conclusion: MRI is a valuable diagnostic tool to diagnose type and level of ARM in addition to the privilege of associated anomalies detection on the same examination. The 3D sequence acquisition with multiplanar reconstruction has the advantage of time saving without compromise on image quality or the diagnostic accuracy compared to 2D images

Synthesis, Antimicrobial Activity and Molecular Docking of Novel Thiourea Derivatives Tagged with Thiadiazole, Imidazole and Triazine Moieties as Potential DNA Gyrase and Topoisomerase IV Inhibitors

To develop new antimicrobial agents, a series of novel thiourea derivatives incorporated with different moieties 2&ndash;13 was designed and synthesized and their biological activities were evaluated. Compounds 7a, 7b and 8 exhibited excellent antimicrobial activity against all Gram-positive and Gram-negative bacteria, and the fungal Aspergillus flavus with minimum inhibitory concentration (MIC) values ranged from 0.95 &plusmn; 0.22 to 3.25 &plusmn; 1.00 &mu;g/mL. Furthermore, cytotoxicity studies against MCF-7 cells revealed that compounds 7a and 7b were the most potent with IC50 values of 10.17 &plusmn; 0.65 and 11.59 &plusmn; 0.59 &mu;M, respectively. On the other hand, the tested compounds were less toxic against normal kidney epithelial cell lines (Vero cells). The in vitro enzyme inhibition assay of 8 displayed excellent inhibitory activity against Escherichia coli DNA B gyrase and moderate one against E. coli Topoisomerase IV (IC50 = 0.33 &plusmn; 1.25 and 19.72 &plusmn; 1.00 &micro;M, respectively) in comparison with novobiocin (IC50 values 0.28 &plusmn; 1.45 and 10.65 &plusmn; 1.02 &micro;M, respectively). Finally, the molecular docking was done to position compound 8 into the E. coli DNA B and Topoisomerase IV active pockets to explore the probable binding conformation. In summary, compound 8 may serve as a potential dual E. coli DNA B and Topoisomerase IV inhibitor

Chemical and biological characterization of Melaleuca subulata (Cheel) Craven leaves’ volatile constituents supported by chemometric analysis and molecular docking

Abstract Background The genus Melaleuca (Myrtaceae) comprises dozens of essential oil (EO)-rich species that are appreciated worldwide for their various medicinal values. Additionally, they are renowned in traditional medicine for their antimicrobial, antifungal, and other skin-related activities. The current study investigated the chemical profile and skin-related activities of volatile constituents derived from M. subulata (Cheel) Craven (Synonym Callistemon subulatus) leaves cultivated in Egypt for the first time. Methods The volatile components were extracted using hydrodistillation (HD), headspace (HS), and supercritical fluid (SF). GC/MS and Kovat’s retention indices were implemented to identify the volatile compounds, while the variations among the components were assessed using Principal Component Analysis and Hierarchical Cluster Analysis. The radical scavenging activity was assessed using 2,2-diphenyl-1-picrylhydrazyl (DPPH), oxygen radical absorbance capacity (ORAC) and β-carotene assays. Moreover, the anti-aging effect was evaluated using anti-elastase, and anti-collagenase, while the antimicrobial potential was deduced from the agar diffusion and broth microdilution assays. Lastly, the molecular docking study was executed using C-docker protocol in Discovery Studio 4.5 to rationalize the binding affinity with targeted enzymes. Results The SF extraction approach offered the highest EO yield, being 0.75%. According to the GC/MS analysis, monoterpene hydrocarbons were the most abundant volatile class in the HD oil sample (54.95%), with α-pinene being the most copious component (35.17%). On the contrary, the HS and SF volatile constituents were pioneered with oxygenated monoterpenes (72.01 and 36.41%) with eucalyptol and isopulegone being the most recognized components, representing 67.75 and 23.46%, respectively. The chemometric analysis showed segregate clustering of the three extraction methods with α-pinene, eucalyptol, and isopulegone serving as the main discriminating phytomarkers. Concerning the bioactivity context, both SF and HD-EOs exhibited antioxidant effects in terms of ORAC and β-carotene bleaching. The HD-EO displayed potent anti-tyrosinase activity, whereas the SF-EO exhibited significant anti-elastase properties. Moreover, SF-EO shows selective activity against gram-positive skin pathogens, especially S. aureus. Ultimately, molecular docking revealed binding scores for the volatile constituents; analogous to those of the docked reference drugs. Conclusions M. subulata leaves constitute bioactive volatile components that may be indorsed as bioactive hits for managing skin aging and infection, though further in vivo studies are recommended

Cyanobacteria Application Ameliorates Floral Traits and Outcrossing Rate in Diverse Rice Cytoplasmic Male Sterile Lines

In rice, cytoplasmic male sterility (CMS) represents an irreplaceable strategy for producing high-yielding hybrid rice based on the commercial exploitation of heterosis. Thereupon, enhancing floral traits and outcrossing rates in CMS lines increase hybrid seed production and ensure global food security. The exogenous application of cyanobacteria could enhance outcrossing rates in CMS lines and, accordingly, hybrid rice seed production. In the present study, we aimed at exploring the impact of cyanobacteria implementation such as Anabaena oryzae, Nostoc muscorum, and their mixture to promote the floral traits, outcrossing rates, and seed production in hybrid rice. The impact of cyanobacteria (Anabaena Oryza (T2), Nostoc muscorum (T3), and their combination (T4) versus the untreated control (T1) was investigated for two years on the growth, floral, and yield traits of five diverse CMS lines, namely IR69625A (L1), IR58025A (L2), IR70368A (L3), G46A (L4), and K17A(L5). The evaluated CMS lines exhibited significant differences in all measured floral traits (days to heading (DTH), total stigma length (TSL), stigma width (SW), duration of spikelet opening (DSO), spikelet opening angle (SOA)). Additionally, L4 displayed the uppermost total stigma length and stigma width, whereas L1 and L5 recorded the best duration of spikelet opening and spikelet opening angle. Notably, these mentioned CMS lines exhibited the highest plant growth and yield traits, particularly under T4 treatment. Strong positive relationships were distinguished between the duration of the spikelet opening, panicle exertion, panicle weight, seed set, grain yield, total stigma length, spikelet opening angle, stigma width, and number of fertile panicles per hill. Cyanobacteria is a potential promising tool to increase floral traits and seed production in hybrid rice