Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic and non-diabetic retinopathy: associated factors and anatomical correlation.

BACKGROUND: This study aims to investigate the factors affecting the vitreous levels of pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VGEF) among patients with pars plana vitrectomy (PPV). Also, this study correlates the levels of PEDF with RRD characteristics. METHODS: All patients who were scheduled for PPV for any indication were included in the study. They were divided into a case group which included patients with advanced PDR and a control group which included the remaining diagnoses. During the PPV, an undiluted vitreous sample was taken and the enzyme-linked immunosorbent assay method was utilized to measure the levels of VEGF and PEDF. RESULTS: Eighty eyes were involved. Patients diagnosed with advanced PDR and endophthalmitis exhibited higher levels of VEGF. PEDF was affected inversely by the age of the patients and PEDF levels were higher in RRD and endophthalmitis cases. In patients with RRD, the level of PEDF was higher if the tear was found inferiorly, if the macula was detached, and with a longer duration of RRD. CONCLUSIONS: This study highlights the clinical importance of those biomarkers. Anti-VEGF-based treatment is the mainstay against PDR. PEDF may show a promising predictive values regarding patients with RRD.

Network pharmacology, molecular simulation, and binding free energy calculation-based investigation of Neosetophomone B revealed key targets for the treatment of cancer.

In the current study, Neosetophomone B (NSP-B) was investigated for its anti-cancerous potential using network pharmacology, quantum polarized ligand docking, molecular simulation, and binding free energy calculation. Using SwissTarget prediction, and Superpred, the molecular targets for NSP-B were predicted while cancer-associated genes were obtained from DisGeNet. Among the total predicted proteins, only 25 were reported to overlap with the disease-associated genes. A protein-protein interaction network was constructed by using Cytoscape and STRING databases. MCODE was used to detect the densely connected subnetworks which revealed three sub-clusters. Cytohubba predicted four targets, i.e., fibroblast growth factor , FGF20, FGF22, and FGF23 as hub genes. Molecular docking of NSP-B based on a quantum-polarized docking approach with FGF6, FGF20, FGF22, and FGF23 revealed stronger interactions with the key hotspot residues. Moreover, molecular simulation revealed a stable dynamic behavior, good structural packing, and residues' flexibility of each complex. Hydrogen bonding in each complex was also observed to be above the minimum. In addition, the binding free energy was calculated using the MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) and MM/PBSA (Molecular Mechanics/Poisson-Boltzmann Surface Area) approaches. The total binding free energy calculated using the MM/GBSA approach revealed values of -36.85 kcal/mol for the FGF6-NSP-B complex, -43.87 kcal/mol for the FGF20-NSP-B complex, and -37.42 kcal/mol for the FGF22-NSP-B complex, and -41.91 kcal/mol for the FGF23-NSP-B complex. The total binding free energy calculated using the MM/PBSA approach showed values of -30.05 kcal/mol for the FGF6-NSP-B complex, -39.62 kcal/mol for the FGF20-NSP-B complex, -34.89 kcal/mol for the FGF22-NSP-B complex, and -37.18 kcal/mol for the FGF23-NSP-B complex. These findings underscore the promising potential of NSP-B against FGF6, FGF20, FGF22, and FGF23, which are reported to be essential for cancer signaling. These results significantly bolster the potential of NSP-B as a promising candidate for cancer therapy.

Semisynthesis, Characterization, and Biological Evaluation of Fluorinated Analogues of the Spirobisnaphthalene, Diepoxin-η.

Diepoxin-η (1) is a cytotoxic fungal metabolite belonging to the spirobisnaphthalene structural class. In this study, four mono fluorinated analogues (2-5) of diepoxin-η (1) were semisynthesized in a single-step by selectively fluorinating the naphthalene moiety with Selectfluor. The structures of 2-5 were elucidated using a set of spectroscopic and spectrometric techniques and were further confirmed by means of TDDFT-ECD and isotropic shielding tensors calculations. Compounds 2-5 showed equipotent cytotoxic activity to 1 when tested against OVCAR3 (ovarian) and MDA-MB-435 (melanoma) cancer cell lines with IC50 values that range from 5.7-8.2 µM.

Exploring the in vivo anti-cancer potential of Neosetophomone B in leukemic cells using a zebrafish xenograft model.

Neosetophomone B (NSP-B) is a unique meroterpenoid fungal secondary metabolite that has previously demonstrated promising anti-cancer properties against various cancer cell lines in vitro. However, its in vivo anti-cancer potential remaines unexplored. To fill this gap in our knowledge, we tested NSP-B's in vivo anti-cancer activity using a zebrafish model, an organism that has gained significant traction in biomedical research due to its genetic similarities with humans and its transparent nature, allowing real-time tumor growth observation. For our experiments, we employed the K562-injected zebrafish xenograft model. Upon treating these zebrafish with NSP-B, we observed a marked reduction in the size and number of tumor xenografts. Delving deeper, our analyses indicated that NSP-B curtailed tumor growth and proliferation of leukemic grafted xenograft within the zebrafish. These results show that NSP-B possesses potent in vivo anti-cancer properties, making it a potential novel therapeutic agent for addressing hematological malignancies.

Neosetophomone B induces apoptosis in multiple myeloma cells via targeting of AKT/SKP2 signaling pathway.

Multiple myeloma (MM) is a hematologic malignancy associated with malignant plasma cell proliferation in the bone marrow. Despite the available treatments, drug resistance and adverse side effects pose significant challenges, underscoring the need for alternative therapeutic strategies. Natural products, like the fungal metabolite neosetophomone B (NSP-B), have emerged as potential therapeutic agents due to their bioactive properties. Our study investigated NSP-B's antitumor effects on MM cell lines (U266 and RPMI8226) and the involved molecular mechanisms. NSP-B demonstrated significant growth inhibition and apoptotic induction, triggered by reduced AKT activation and downregulation of the inhibitors of apoptotic proteins and S-phase kinase protein. This was accompanied by an upregulation of p21Kip1 and p27Cip1 and an elevated Bax/BCL2 ratio, culminating in caspase-dependent apoptosis. Interestingly, NSP-B also enhanced the cytotoxicity of bortezomib (BTZ), an existing MM treatment. Overall, our findings demonstrated that NSP-B induces caspase-dependent apoptosis, increases cell damage, and suppresses MM cell proliferation while improving the cytotoxic impact of BTZ. These findings suggest that NSP-B can be used alone or in combination with other medicines to treat MM, highlighting its importance as a promising phytoconstituent in cancer therapy.

Vitreous Levels of Vascular Endothelial Growth Factor and Platelet-Derived Growth Factor in Patients with Proliferative Diabetic Retinopathy: A Clinical Correlation.

Background: The global epidemic status of diabetic retinopathy (DR) and its burden presents an ongoing challenge to health-care systems. It is of great interest to investigate potential prognostic biomarkers of DR. Such markers could aid in detecting early stages of DR, predicting DR progression and its response to therapeutics. Herein, we investigate the prognostic value of intravitreal concentrations of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) in a DR cohort. Materials and methods: Vitreous sample acquisition was conducted at King Abdullah University Hospital (KAUH) between December 2020 and June 2022. Samples were obtained from any patient scheduled to undergo a pars plana vitrectomy (PPV) for any indication. Included patients were categorized into a DR group or a corresponding non-diabetic (ND) control group. Demographics, clinicopathological variables, standardized laboratory tests results, and optical coherence tomography (OCT) data were obtained for each included individual. Intravitreal concentrations of VEGF and PDGF were assessed using commercial enzyme-linked immunosorbent assay (ELISA). Results: A total of 80 eyes from 80 patients (DR group: n = 42 and ND control group: n = 38) were included in the analysis. The vitreous VEGF levels were significantly higher in the DR group compared to the ND control group (DR group 5744.06 ± 761.5 pg/mL versus ND control group 817.94 ± 403.1 pg/mL, p = 0.0001). In addition, the vitreous PDGF levels were also significantly higher in the DR group than those in the ND control group (DR group 4031.51 ± 410.2 pg/mL versus ND control group 2691.46 ± 821.0 pg/mL, p = 0.001). Bassline differences between test groups and clinical factors impacting VEGF and PDGF concentrations were investigated as well. Multiple regression analysis indicated PDGF as the sole independent risk factor affecting best-corrected visual acuity (BCVA) at the last follow-up visit: the higher the PDGF vitreous levels, the worst the BCVA. Conclusions: Vitreous concentrations of VEGF and PDGF are correlated with DR severity and may exhibit a possible prognostic potential value in DR. Further clinical and experimental data are warranted to confirm the observed findings and to help incorporate them into daily practice.

In vitro evaluation of Neosetophomone B inducing apoptosis in cutaneous T cell lymphoma by targeting the FOXM1 signaling pathway.

BACKGROUND: Cutaneous T cell lymphoma (CTCL) is a T cell-derived non-Hodgkin lymphoma primarily affecting the skin, with treatment posing a significant challenge and low survival rates. OBJECTIVE: In this study, we investigated the anti-cancer potential of Neosetophomone B (NSP-B), a fungal-derived secondary metabolite, on CTCL cell lines H9 and HH. METHODS: Cell viability was measured using Cell counting Kit-8 (CCK8) assays. Apoptosis was measured by annexin V/PI dual staining. Immunoblotting was performed to examine the expression of proteins. Applied Biosystems' high-resolution Human Transcriptome Array 2.0 was used to examine gene expression. RESULTS: NSP-B induced apoptosis in CTCL cells by activating mitochondrial signaling pathways and caspases. We observed downregulated expression of BUB1B, Aurora Kinases A and B, cyclin-dependent kinases (CDKs) 4 and 6, and polo-like kinase 1 (PLK1) in NSP-B treated cells, which was further corroborated by Western blot analysis. Notably, higher expression levels of these genes showed reduced overall and progression-free survival in the CTCL patient cohort. FOXM1 and BUB1B expression exhibited a dose-dependent reduction in NSP-B-treated CTCL cells.FOXM1 silencing decreased cell viability and increased apoptosis via BUB1B downregulation. Moreover, NSP-B suppressed FOXM1-regulated genes, such as Aurora Kinases A and B, CDKs 4 and 6, and PLK1. The combined treatment of Bortezomib and NSP-B showed greater efficacy in reducing CTCL cell viability and promoting apoptosis compared to either treatment alone. CONCLUSION: Our findings suggest that targeting the FOXM1 pathway may provide a promising therapeutic strategy for CTCL management, with NSP-B offering significant potential as a novel treatment option.

Cyclin dependent kinase inhibitor 3 (CDKN3) upregulation is associated with unfavorable prognosis in clear cell renal cell carcinoma and shapes tumor immune microenvironment: A bioinformatics analysis.

Cell cycle regulatory proteins plays a pivotal role in the development and progression of many human malignancies. Identification of their biological functions as well as their prognostic utility presents an active field of research. As a continuation of the ongoing efforts to elucidate the molecular characteristics of clear cell renal cell carcinoma (ccRCC); we present a comprehensive bioinformatics study targeting the prognostic and mechanistic role of cyclin-dependent kinase inhibitor 3 (CDKN3) in ccRCC. The ccRCC cohort from the Cancer Genome Atlas Program was accessed through the UCSC Xena browser to obtain CDKN3 mRNA expression data and their corresponding clinicopathological variables. The independent prognostic signature of CDKN3 was evaluated using univariate and multivariate Cox logistic regression analysis. Gene set enrichment analysis and co-expression gene functional annotations were used to discern CDKN3-related altered molecular pathways. The tumor immune microenvironment was evaluated using TIMER 2.0 and gene expression profiling interactive analysis. CDKN3 upregulation is associated with shortened overall survival (hazard ratio [HR] = 2.325, 95% confident interval [CI]: 1.703-3.173, P < .0001) in the Cancer Genome Atlas Program ccRCC cohort. Univariate (HR: 0.426, 95% CI: 0.316-0.576, P < .001) and multivariate (HR: 0.560, 95% CI: 0.409-0.766, P < .001) Cox logistic regression analyses indicate that CDKN3 is an independent prognostic variable of the overall survival. High CDKN3 expression is associated with enrichment within the following pathways including allograph rejection, epithelial-mesenchymal transition, mitotic spindle, inflammatory response, IL-6/JAK/STAT3 signaling, spermatogenesis, TNF-α signaling via NF-kB pathway, complement activation, KRAS signaling, and INF-γ signaling. CDKN3 is also associated with significant infiltration of a wide spectrum of immune cells and correlates remarkably with immune-related genes. CDKN3 is a poor prognostic biomarker in ccRCC that alters many molecular pathways and impacts the tumor immune microenvironment.

ANO4 Expression Is a Potential Prognostic Biomarker in Non-Metastasized Clear Cell Renal Cell Carcinoma.

Background: Over the past decade, transcriptome profiling has elucidated many pivotal pathways involved in oncogenesis. However, a detailed comprehensive map of tumorigenesis remains an enigma to solve. Propelled research has been devoted to investigating the molecular drivers of clear cell renal cell carcinoma (ccRCC). To add another piece to the puzzle, we evaluated the role of anoctamin 4 (ANO4) expression as a potential prognostic biomarker in non-metastasized ccRCC. Methods: A total of 422 ccRCC patients with the corresponding ANO4 expression and clinicopathological data were obtained from The Cancer Genome Atlas Program (TCGA). Differential expression across several clinicopathological variables was performed. The Kaplan-Meier method was used to assess the impact of ANO4 expression on the overall survival (OS), progression-free interval (PFI), disease-free interval (DFI), and disease-specific survival (DSS). Univariate and multivariate Cox logistic regression analyses were conducted to identify independent factors modulating the aforementioned outcomes. Gene set enrichment analysis (GSEA) was used to discern a set of molecular mechanisms involved in the prognostic signature. Tumor immune microenvironment was estimated using xCell. Results: ANO4 expression was upregulated in tumor samples compared to normal kidney tissue. Albeit the latter finding, low ANO4 expression is associated with advanced clinicopathological variables such as tumor grade, stage, and pT. In addition, low ANO4 expression is linked to shorter OS, PFI, and DSS. Multivariate Cox logistic regression analysis identified ANO4 expression as an independent prognostic variable in OS (HR: 1.686, 95% CI: 1.120-2.540, p = 0.012), PFI (HR: 1.727, 95% CI: 1.103-2.704, p = 0.017), and DSS (HR: 2.688, 95% CI: 1.465-4.934, p = 0.001). GSEA identified the following pathways to be enriched within the low ANO4 expression group: epithelial-mesenchymal transition, G2-M checkpoint, E2F targets, estrogen response, apical junction, glycolysis, hypoxia, coagulation, KRAS, complement, p53, myogenesis, and TNF-α signaling via NF-κB pathways. ANO4 expression correlates significantly with monocyte (ρ = -0.1429, p = 0.0033) and mast cell (ρ = 0.1598, p = 0.001) infiltration. Conclusions: In the presented work, low ANO4 expression is portrayed as a potential poor prognostic factor in non-metastasized ccRCC. Further experimental studies should be directed to shed new light on the exact molecular mechanisms involved.

The effect of beetroot juice on airway inflammation in a murine model of asthma.

The effects of beetroot juice on airways inflammation, cytokine levels, and oxidative stress biomarkers were evaluated using an allergen-induced murine model of asthma. Ovalbumin (OVA)-sensitized and challenged BALB/c mice were used as an asthma model. BALB/c mice were randomly assigned into four groups: control (Ova sensitization and normal saline challenge), control and beetroot (Ova sensitization and normal saline challenge plus beetroot juice), Ova S/C [Ova sensitization and challenge (Ova S/C)], Ova S/C and beetroot juice (Ova S/C plus beetroot juice). The bronchoalveolar lavage fluid (BALF) was analyzed for total and differential inflammatory cells count. The levels of cytokines [interleukin (IL)-10, IL-13, and IL-18], and oxidative stress biomarkers [glutathione peroxidase (GPx), catalase, and thiobarbituric acid reactive substances (TBARS)] were analyzed in the lung tissue. Simultaneous administration of beetroot juice and Ova S/C significantly increased the total inflammatory cells compared to the control (p = .0001) and Ova S/C (p = .013) groups and significantly increased the number of eosinophils (p ˂ .0001) and macrophages (p ˂ .0001) compared to the control. Moreover, the simultaneous administration of beetroot juice and Ova S/C did not affect the level of IL-10, IL-13, IL-18, GPx, or TBARS compared to the control (p > .05), but it significantly increased the level of catalase (p = .002). Results suggest that beetroot juice aggravates asthma by enhancing airway inflammation. However, it does not affect airway inflammation in healthy mice. PRACTICAL APPLICATIONS: Asthma is a chronic airway inflammatory disease that is characterized by variable degrees of airways inflammation and obstruction. Paradox data are reported in the literature regarding beetroot and asthma. The present study revealed that beetroot juice exacerbates asthma by enhancing airway inflammation. However, it is safe and has no effects on airway inflammation in healthy mice. Patients having asthma or a history of asthma are advised to avoid the consumption of beetroot.

Weak complexation of 5-fluorouracil with ß-cyclodextrin, carbonate, and dianhydride crosslinked ß-cyclodextrin: in vitro and in silico studies.

Background and purpose: Several pharmaceutical formulations were investigated to improve the solubility of 5-fluorouracil to enhance bioavailability and therapeutic efficacy. This study aimed to examine the potential use of cyclodextrin-based nanosponges for the incorporation of 5-fluorouracil and to investigate the use of different crosslinking agents on the properties of the resulting drug carrier. 5-Fluorouracil complexation with ß-cyclodextrin was also studied to explain the unexpected results of weak 5-fluorouracil incorporation in nanosponge. Experimental approach: Nanosponges were synthesized by crosslinking ß-cyclodextrin with two different crosslinkers; diphenyl carbonate and ethylenediaminetetraacetic dianhydride. The incorporation of 5-fluorouracil into ß-cyclodextrin and the prepared nanosponges were assessed by NMR, FTIR, PXRD, DSC, and TGA. In addition, an in vitro release study was carried out to evaluate the potential use of ß-cyclodextrin- based nanosponges as pharmaceutical formulations for 5-fluorouracil. Findings / Results: Physicochemical characterization of the dried formulations indicated the complexation of 5-fluorouracil with the ß-cyclodextrin polymer. Despite that, no clear manifestation of 5-fluorouracil encapsulation in the prepared ß-cyclodextrin-based nanosponge was detected. Furthermore, no significant differences were observed in the release profiles of 5-fluorouracil, ß-cyclodextrin complex, and ß- cyclodextrin-based nanosponge, suggesting weak complexation and instability in aqueous solutions. EDTA- crosslinked ß-cyclodextrin-based nanosponge showed a slight improvement in 5-fluorouracil solubility with a faster initial rate of 5-fluorouracil release. Conclusion and implications: This study suggested weak complexation between 5-fluorouracil and the ß- cyclodextrin polymer or nanosponges. Crosslinking of ß-cyclodextrin with EDTA dianhydride crosslinker showed an enhancement in 5-fluorouracil saturation solubility combined with a faster initial rate of drug release.

A Prospective Non-Randomized Open-Label Comparative Study of The Effects of Matcha Tea on Overweight and Obese Individuals: A Pilot Observational Study.

Matcha tea has been used as an adjunct in weight loss programs. The weight loss effects of matcha tea were evaluated in a prospective non-randomized open-label comparative study of overweight and obese individuals who followed a specified low-calorie diet (LCD) plan. A total of 40 participants were enrolled and assigned to either matcha tea or control groups. The matcha tea group followed a LCD plan and received matcha tea once daily, whereas the control group followed only the LCD diet plan. The study lasted 12 weeks. The main outcome measures included anthropometric measurements, fasting blood glucose, hemoglobin A1c (HbA1c), lipid profile, obesity-related hormone peptides, pro-inflammatory and anti-inflammatory cytokines, and oxidative stress biomarkers. Thirty-four participants had completed the study. The matcha tea and control groups showed significant reductions in body weight, body mass index, waist circumference, water content, minerals, and fat mass at week 12. The post-treatment body composition and anthropometric measurements were not significantly different between the two groups. The matcha tea group showed a potential increase in HDL-C, a potential decrease in blood glucose, and a potential increase in HbA1c. Furthermore, the study indicated a potential decrease in insulin and leptin levels, a potential increase in the activity of superoxide dismutase, and a potential decreased activity of glutathione peroxidase. IL-10 was increased by matcha tea consumption. The data suggest that matcha tea may have some potential effect on weight loss, along with anti-inflammatory properties. The findings of this study will be used to design a multicenter randomized clinical trial to examine the potential weight loss benefits of matcha tea.

Homoisoflavonoids from the bulbs of Bellevalia longipes and an assessment of their potential cytotoxic activity.

Seven undescribed homoisoflavonoids were identified from the bulbs of Bellevalia longipes Post (Asparagaceae) as well as thirteen known and one natural homoisoflavonoid that had been reported as a synthetic product previously. A general approach for recognizing homoisoflavonoids via NMR spectroscopy data were presented. The undescribed compounds were: 8-dehydroxy-5-O-demethyl-6-hydroxyscillapersicone, 6-methoxyscillapersicone, 5-O-demethyl-6-methoxyscillapersicone, 8-O-methylscillapersicone, 4'-O-methylscillapersicone, 4',8-O,O-dimethylscillapersicone, 3'-O-methylscillapersicone, and 3-hydroxy-desmethylophiopogonanone A. Structures were determined based on analysis of HRMS and NMR data, while absolute configurations were assigned using ECD spectroscopy. Human cancer cell lines were used to assess the cytotoxic activities of the isolated compounds, where 3-dehydroxy-3'-hydroxyeucomol showed IC50 values of 0.62 µM, 5.36 µM, and 2.52 µM, when tested against MDA-MB-435 (melanoma), MDA-MB-231 (breast), and OVCAR3 (ovarian) cells, respectively.

Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis.

Abnormal expression of Forkhead box protein M1 (FOXM1) and serine/threonine kinase Budding uninhibited by benzimidazoles 1 (BUB1B) contributes to the development and progression of several cancers, including chronic myelogenous leukemia (CML). However, the molecular mechanism of the FOXM1/BUB1B regulatory network and the role of Neosetophomone-B (NSP-B) in leukemia remains unclear. NSP-B, a meroterpenoid fungal secondary metabolite, possesses anticancer potential in human leukemic cells lines; however, the underlying mechanism has not been elucidated. The present study aimed to explore the role of NSP-B on FOXM1/BUB1B signaling and the underlying molecular mechanism of apoptosis induction in leukemic cells. We performed gene expression profiling of NSP-B-treated and untreated leukemic cells to search for differentially expressed genes (DEGs). Interestingly BUB1B was found to be significantly downregulated (logFC -2.60, adjusted p = 0.001) in the treated cell line with the highest connectivity score among cancer genes. Analysis of TCGA data revealed overexpression of BUB1B compared to normal in most cancers and overexpression was associated with poor prognosis. BUB1B also showed a highly significant positive correlation with FOXM1 in all the TCGA cancer types. We used human leukemic cell lines (K562 and U937) as an in vitro study model to validate our findings. We found that NSP-B treatment of leukemic cells suppressed the expression of FOXM1 and BUB1B in a dose-dependent manner. In addition, NSP-B also resulted in the downregulation of FOXM1-regulated genes such as Aurora kinase A, Aurora kinase B, CDK4, and CDK6. Suppression of FOXM1 either by siRNA or NSP-B reduced BUB1B expression and enhanced cell survival inhibition and induction of apoptosis. Interestingly combination treatment of thiostrepton and NSP-B suppressed of cell viability and inducted apoptosis in leukemic cells via enhancing the activation of caspase-3 and caspase-8 compared with single-agent treatment. These results demonstrate the important role of the FOXM1/BUB1B pathway in leukemia and thus a potential therapeutic target.

Understanding Reciprocity Among University Students in Low-Resource Settings: Validation and Measurement Using a Mixed-Methods Approach.

Objectives: This study aimed to investigate reciprocity among university students in low-resource settings using a convergent mixed-methods approach in Jordan. The study operationalized the effort-reward imbalance (ERI) model which is a sociological framework used to predict occupational-related health outcomes. The basic theory of ERI model assumes that an imbalance of effort and reward predicts adverse health outcomes. Methods: The research involved two studies, Study I (n = 833) to quantitatively measure ERI and Study II to collect qualitative data (n = 44) on the drivers of ERI among university students. In Study I, a modified Arabic version of the ERI questionnaire was used. The study measured ERI and investigated the reliability and validity of the Arabic version of the ERI model questionnaire. In Study II, data were collected from focus groups and personal interviews and thematic analysis was used. Results: The results suggested that ERI was associated with poor academic performance (OR=2.31, 95% CI 1.60-3.32), absenteeism (OR=1.66, 95% CI 1.21-2.27), low exercise level (OR=2.02, 95% CI 1.49-2.74) and poor self-reported health (OR=1.12, 95% CI 1.08-1.30). Three major themes emerged, namely high academic load, financial pressures and negative influence on the students' performance, wellbeing and health to explain effort-reward imbalance. Conclusions: Results suggest that ERI among university students is multi-faceted and is not bound only to academic-related demands and that the extrinsic factors such as the economic context of Jordan is among drivers of ERI.

Anticancer activity of Neosetophomone B by targeting AKT/SKP2/MTH1 axis in leukemic cells.

Neosetophomone B (NSP-B), a meroterpenoid fungal secondary metabolite, was investigated for its anticancer potential in leukemic cell lines (K562 and U937). NSP-B treatment of leukemic cells suppressed cell viability by triggering apoptotic cell death. Apoptosis induced by NSP-B is triggered by mitochondrial signaling and caspase activation. Additionally, NSP-B treatment of leukemic cells causes AKT's inactivation accompanied by downregulation of SKP2 oncogene and MTH1 with a concomitant increase of p21Cip1and p27Kip1. Furthermore, NSP-B causes suppression of antiapoptotic proteins, including cIAP1, cIAP2, XIAP, survivin and BCl-XL. Overall, NSP-B reduces cell viability by mitochondrial and caspase-dependent apoptosis. The inhibition of AKT and SKP2 axis could be a promising therapeutic target for leukemia treatment.

Dereplication of Fungal Metabolites by NMR-Based Compound Networking Using MADByTE.

Strategies for natural product dereplication are continually evolving, essentially in lock step with advances in MS and NMR techniques. MADByTE is a new platform designed to identify common structural features between samples in complex extract libraries using two-dimensional NMR spectra. This study evaluated the performance of MADByTE for compound dereplication by examining two classes of fungal metabolites, the resorcylic acid lactones (RALs) and spirobisnaphthalenes. First, a pure compound database was created using the HSQC and TOCSY data from 19 RALs and 10 spirobisnaphthalenes. Second, this database was used to assess the accuracy of compound class clustering through the generation of a spin system feature network. Seven fungal extracts were dereplicated using this approach, leading to the correct prediction of members of both families from the extract set. Finally, NMR-guided isolation led to the discovery of three new palmarumycins (20-22). Together these results demonstrate that MADByTE is effective for the detection of specific compound classes in complex mixtures and that this detection is possible for both known and new natural products.

Natural resorcylic acid lactones: A chemical biology approach for anticancer activity.

Resorcylic acid lactones (RALs) are fungal polyketides that consist of a ß-resorcylic acid residue (2,4-dihydroxybenzoic acid) embedded in a macrolactone ring. RALs exhibit a broad range of biological activities, including anticancer activities. Following discovery of the selective Hsp90 inhibition activity of radicicol, the kinase inhibition activity of hypothemycin, monocillin II, 5Z-7-oxo-zeaenol, and L-783,277 RALs, and the nuclear factor kappa B (NF-κB) inhibition activity of the RAL zearalenone, have attracted great attention as potential therapeutics for cancer treatment. In this minireview, we focus on natural RALs that possess cytotoxic activities [IC50 values < 10 µM (or 4-5 µg/ml)], discussing their structures, isolation, occurrence, biological activities, and anticancer molecular mechanisms.

UPLC-HRESI-MS and GC-MS analysis of the leaves of Nicotiana glauca.

The alkaloid-rich fraction obtained by fractionation of the crude methanolic extract of the leaves of wild tobacco tree Nicotiana glauca Graham (Solanaceae) was analyzed using UPLC-MS and GC-MS. Anabasine, a piperidine alkaloid, was identified as the major constituent with approximately 60 % (m/m) of the alkaloid-rich fraction. In addition to anabasine, six secondary metabolites were identified using high-resolution UPLC-MS. Anabasine was quantified in the leaves to be 1 mg g-1 dry plant material. The GC-MS analysis revealed five compounds with anabasine as the major component, while nicotine was not detected. Moreover, GC-MS was used for the analysis of the volatile oil that was obtained by hydro-distillation from the leaves of N. glauca. The volatile plant oil was found to be rich in oxygenated sesquiterpenes (e.g., ß-bisabolol) and carboxylic acids and esters (e.g., ethyl linoleate and hexadecanoic acid), whereas anabasine was not detected.

Coumarins, dihydroisocoumarins, a dibenzo-α-pyrone, a meroterpenoid, and a merodrimane from Talaromyces amestolkiae.

Chemical investigation of an organic extract of a fungus isolated from submerged wood collected from fresh water (strain G173), identified as a Talaromyces amestolkiae (Eurotiales; Trichocomaceae), led to the isolation of three coumarins, three dihydroisocoumarins, a dibenzo-α-pyrone, a meroterpenoid, and a merodrimane. Three of the isolated compounds, namely 7-chloropestalasin A (3), 4-hydroxyaspergillumarin (6), and ent-thailandolide B (9) were new. The structures were elucidated using a combination of spectroscopic and spectrometric techniques. The absolute configurations of 2, 3, 5, and 6 were established via a modified Mosher's ester method, whereas for 9 a combination of TDDFT ECD and ORD calculations were employed. Compounds 1-9 were evaluated for antimicrobial activity against a group of bacteria and fungi.