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.

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.

Withania somnifera root powder protects againist post-traumatic stress disorder-induced memory impairment.

Post-traumatic stress disorder (PTSD) is precipitated by exposure to severe traumatic events such as wars, natural disasters, catastrophes, or other traumatic events. Withania somnifera (WS) Dunal (family: Solanaceae) known traditionally as "Ashwaghanda" is used widely in ayurvedic medicine, and known to have positive role in neurodegenerative diseases. In this study, WS effect on impairment of memory due to PTSD was studied in animal models. Single-prolonged stress rat model, which consisted of restrain for 2 h, forced swimming for 20 min, rest for 15 min, and diethyl ether exposure for 1-2 min, was used to induce PTSD animals. The WS root powder extract was administered orally at a dose of 500 mg/kg/day. The radial arm water maze (RAWM) was used to assess spatial learning and memory. Enzymatic assays were used to evaluate changes in oxidative stress biomarkers in the hippocampus following treatments. The result showed that PTSD resulted in short- and long- term memory impairments. Administration of WS prevented this impairment of memory induced by PTSD. Furthermore, WS prevented PTSD induced changes in oxidative stress biomarker in the hippocampus. For quality assessment, the methanolic extract for WS was subjected to UHPLC analysis. A calibration curve for isowithanone as a marker compound was constructed. WS roots content of isowithanone was found to be 0.23% (w/w). In conclusion, WS administration prevented PTSD induced memory impairment probably through preserving changes in antioxidant mechanisms in the hippocampus.

Cytotoxic Homoisoflavones from the Bulbs of Bellevalia eigii.

Eight new and 10 known compounds were isolated from an organic extract of the bulbs of Bellevalia eigii as part of a search for anticancer leads from native plants of Jordan. Of these, the series of 16 homoisoflavonoids (1-16) comprise the seven new analogues 7-O-methyl-3'-hydroxy-3,9-dihydropunctatin (3), 6-hydroxy-7-O-methyl-3,9-dihydropunctatin (6), 7,4'-di-O-methyl-3'-hydroxy-3,9-dihydropunctatin (9), 7-O-methylpunctatin (10), 7-O-methyl-3'-hydroxypunctatin (13), 5-hydroxy-7,8-dimethoxychroman-4-one (14), and 7-O-methyl-8-demethoxy-3-hydroxy-3,9-dihydropunctatin (15). The known ferulic acid-derived acrylamide (17) and the new methylthioacrylate bellegimycin (18) are also reported. The structures were elucidated using a set of spectroscopic and spectrometric techniques; the absolute configurations of compounds 1-9, 15, and 16 were determined using ECD spectroscopy, while a modified Mosher's ester method was used for compound 18. Optical rotation data for the known compounds 1, 2, and 8 are reported here for the first time. The cytotoxic activities of all compounds were evaluated using the MDA-MB-435 (melanoma) and HT-29 (colon) cancer cell lines. Compounds 4 and 9 were the most potent on the latter cell line, with IC50 values of 1.0 and 1.1 µM, respectively. Compounds 1-18 were assessed for antimicrobial activity using a collection of bacteria and fungi; compounds 4 and 12 showed promising activity against the bacterium Mycobacterium smegmatis with MIC values of 17 and 24 µg/mL, respectively.

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.

Efficacy and tolerability of sulforaphane in the therapeutic management of cancers: a systematic review of randomized controlled trials.

Objectives: This paper presents a systematic review aimed at assessing the therapeutic potential of sulforaphane (SFN) in the treatment of diverse cancer types. Methods: Following Cochrane guidelines for systematic reviews, we conducted an exhaustive search of electronic databases up to May 12, 2023, encompassing PubMed, Cochrane, Embase, Web of Science, Google Scholar, Natural Medicines, ProQuest, ClinicalTrials.gov, and ICTRP. Studies were included if they were human-based RCTs involving cancer patients where SFN was the primary experimental treatment. The Cochrane Risk of Bias tool for RCTs (RoB2) was used for quality assessment. Results: Eight studies investigating the efficacy and safety of SFN in prostate cancer (PCa), breast cancer, pancreatic cancer, and melanoma were identified and included in the review. The dosing regimens were variable and inconsistent across the studies. SFN treatment led to statistically significant alterations in several vital genes and histological biomarkers across the studies. However, it did not impact some other key genes. Although not statistically significant, SFN improved overall survival in pancreatic cancer patients. The results on prostate-specific antigen (PSA) were inconsistent in PCa. None of the studies reported significant differences between SFN and comparative controls in terms of adverse events. Conclusion: SFN has emerged as a promising and safe therapeutic agent for diverse cancer types. Nevertheless, the high levels of methodological and clinical heterogeneity across the included studies precluded the possibility of conducting meta-analyses. Further robust clinical investigations to conclusively ascertain the chemotherapeutic potential of SFN in the management of various cancer forms are needed. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022323788, identifier CRD42022323788.

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.

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.

Liquid chromatography-mass spectroscopy and liquid chromatography-ultraviolet/visible photodiode array analysis of selected colchicum species.

An in-house strategy to dereplicate colchicinoid alkaloids was recently developed by our team. It aimed at quickly identifying Colchicum constituents using LC-MS (liquid chromatography-mass spectroscopy) and LC-UV/Vis PDA (liquid chromatography-ultraviolet/ visible photodiode array) techniques. In this project, our goal was to validate the developed method through analysing the alkaloid-rich fractions of three Colchicum species that had been previously studied phytochemically using the traditional bioactivity-guided fractionation methodology. The analysed species were Colchicum tauri Siehe ex Stefanoff, Colchicum stevenii Kunth, and Colchicum tunicatum Feinbr., all belonging to the family Colchicaceae. In addition to identifying the compounds previously isolated and characterized by the traditional methodology, the new strategy succeeded in tentatively identifying a set of known compounds, but new to the species.

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.

Perceptions and experiences of undergraduate pharmacy students and alumni toward research after exposure to undergraduate research courses.

Introduction: Academic institutions have a duty to equip health professional students with the requisite research skills to ensure the implementation of evidence-based practice. This study aims to determine the perceptions of pharmacy students and alumni toward research after completing Undergraduate Research in Pharmacy Courses (URPCs) at the College of Pharmacy-Qatar University (CPH-QU). Methods: A cross-sectional survey was conducted. All CPH-QU alumni (n = 238), and all third- and fourth-year professional students who had completed at least one URPC at the time of conducting the study (n = 42) were approached. The questionnaire contained items relating to research experience and perceptions of significance, confidence in conducting research, actual and anticipated outcomes, and motivation for future research. A Theoretical Domains Framework informed the development of selected items. Results: The response rate was 72.1% (202/280); however, the usable rate was 95.5% (193/202). The participants gave positive responses relating to their perceptions of research significance {Median = 5.0 [Interquartile range (IQR) = 1.0], Minimum-Maximum = 1-5}, confidence in conducting research [Median = 4.0 (IQR = 1.0), Minimum-Maximum = 1-5], actual and anticipated outcomes [Median = 4.0 (IQR = 1.0), Minimum-Maximum = 1-5], and motivation for future research plans [Median = 4.0 (IQR = 1.0), Minimum-Maximum = 1-5]. The majority of participants perceived non-confidence in using data analysis software [72 (39.4% non-confidence)] and a high proportion of participants were non-confident in conducting data analysis [45 (24.6% non-confidence)]. More than half reported publishing at least one peer-reviewed article [99 (54.4% agreement)] from their courses and were highly motivated to consider post-graduate degrees in pharmacy [132 (73.3% agreement)]. Conclusions: Incorporating URPCs into CPH-QU curriculum has potentially improved students and alumni's perceptions of research. Action is needed to improve confidence in different aspects of research.

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.

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.

Association of pharmacy students' cultural beliefs with perceived knowledge, beliefs, confidence, and experience with complementary medicine.

BACKGROUND AND PURPOSE: Culture has been shown to inform patients' acceptance and use of complementary medicine (CM) treatment. It is unknown how a pharmacist or pharmacy student's culture may be associated with perceptions of CM relating to patient care. Gaining a better understanding of this concept within student populations may inform educational needs for programs situated within culturally diverse settings. The purpose of this study was to explore how pharmacy students' cultural beliefs influence perceived knowledge, confidence, and practice with respect to CM. EDUCATIONAL ACTIVITY AND SETTING: A cross-sectional survey was distributed to all undergraduate pharmacy (professional years 1-4) and postgraduate doctor of pharmacy students. Results from the item "CM is an important aspect of my culture" were correlated with all other items using Spearman's correlation coefficient. FINDINGS: Senior students who had completed a two-credit hour course appeared to be more confident in their practice skills relating to CM and showed positive correlations with culture and effectiveness of CM. Senior students acknowledged the importance of CM knowledge as a student and within pharmacy practice. Junior students showed a positive correlation with culture and past use. SUMMARY: Pharmacy students in the Ccollege of pharmacy were positive towards the use of CM, with culture playing an important role. Students who perceived CM as an important aspect of their culture were more confident in their practice skills relating to CM. Future research is required to assess impact of students' cultural beliefs on practice.

Thiostrepton inhibits growth and induces apoptosis by targeting FoxM1/SKP2/MTH1 axis in B-precursor acute lymphoblastic leukemia cells.

Forkhead box M1 (FoxM1) is a transcription factor that plays an important role in the etiology of many cancers, however, its role has not been elucidated in B-precursor acute lymphoblastic leukemia (B-pre-ALL). In the current study, we showed that the downregulation of FoxM1 by its inhibitor thiostrepton inhibited cell viability and induced caspase-dependent apoptosis in a panel of B-pre-ALL cell lines. Thiostrepton led downregulation of FoxM1 accompanied by decreased expression of Aurora kinase A, B, matrix metalloproteinases, and oncogene SKP2 as well as MTH1. Downregulation of the FoxM1/SKP2/MTH1 axis led to increase in the Bax/Bcl2 ratio and suppression of antiapoptotic proteins. Thiostrepton-mediated apoptosis was prevented by N-acetyl cysteine, a scavenger of reactive oxygen species. Co-treatment of B-pre-ALL with subtoxic doses of thiostrepton and bortezomib potentiated the proapoptotic action. Altogether, our results suggest that targeting FoxM1expression could be an attractive strategy for the treatment of B-pre-ALL.

Acceptance and attitudes toward COVID-19 vaccines: A cross-sectional study from Jordan.

Vaccines are effective interventions that can reduce the high burden of diseases globally. However, public vaccine hesitancy is a pressing problem for public health authorities. With the availability of COVID-19 vaccines, little information is available on the public acceptability and attitudes towards the COVID-19 vaccines in Jordan. This study aimed to investigate the acceptability of COVID-19 vaccines and its predictors in addition to the attitudes towards these vaccines among public in Jordan. An online, cross-sectional, and self-administered questionnaire was instrumentalized to survey adult participants from Jordan on the acceptability of COVID-19 vaccines. Logistic regression analysis was used to find the predictors of COVID-19 vaccines' acceptability. A total of 3,100 participants completed the survey. The public acceptability of COVID-19 vaccines was fairly low (37.4%) in Jordan. Males (OR = 2.488, 95CI% = 1.834-3.375, p < .001) and those who took the seasonal influenza vaccine (OR = 2.036, 95CI% = 1.306-3.174, p = .002) were more likely to accept COVID-19 vaccines. Similarly, participants who believed that vaccines are generally safe (OR = 9.258, 95CI% = 6.020-14.237, p < .001) and those who were willing to pay for vaccines (OR = 19.223, 95CI% = 13.665-27.042, p < .001), once available, were more likely to accept the COVID-19 vaccines. However, those above 35 years old (OR = 0.376, 95CI% = 0.233-0.607, p < .001) and employed participants (OR = 0.542, 95CI% = 0.405-0.725, p < .001) were less likely to accept the COVID-19 vaccines. Moreover, participants who believed that there was a conspiracy behind COVID-19 (OR = 0.502, 95CI% = 0.356-0.709, p < .001) and those who do not trust any source of information on COVID-19 vaccines (OR = 0.271, 95CI% = 0.183-0.400, p < .001), were less likely to have acceptance towards them. The most trusted sources of information on COVID-19 vaccines were healthcare providers. Systematic interventions are required by public health authorities to reduce the levels of vaccines' hesitancy and improve their acceptance. We believe these results and specifically the low rate of acceptability is alarming to Jordanian health authorities and should stir further studies on the root causes and the need of awareness campaigns. These interventions should take the form of reviving the trust in national health authorities and structured awareness campaigns that offer transparent information about the safety and efficacy of the vaccines and the technology that was utilized in their production.

Novel Polymethoxylated Chalcones as Potential Compounds Against KRAS-Mutant Colorectal Cancers.

BACKGROUND/OBJECTIVE: KRAS-mutant colorectal cancers (CRC) are tumors that are associated with poor prognosis. However, no effective treatments are available to target them. Therefore, we designed and synthesized novel chalcone analogs, small organic molecules, to investigate their effects on KRAS-mutant CRC cells. METHODS: Fourteen new chalcone analogs were synthesized, optimized, characterized, and tested against two KRAS-mutant CRC cell lines (HCT-116 and LoVo), one p-53 and BRAF mutant CRC cell line (HT-29) and one normal immortalized colon cells (NCE-1 E6/E7). Effects on cell viability, apoptosis, cell cycle, migration, colony formation, EMT, and angiogenesis were investigated. RESULTS: Compounds 3 and 14 were the most effective. Compound 3 showed potent activity against HCT-116 and LoVo cell lines (GI50 of 6.10 µM and 7.00 µM, respectively). While compound 14 showed GI50 of 8.60 µM and 8.80 µM on HCT-116 and LoVo cell lines, respectively. Both compounds were approximately 2-3 times more selective toward cancer cells rather than normal colon cells. Compound 3 was effective in inducing apoptosis in HCT-116 cells via Bax upregulation and Bcl-2 downregulation. Invasion and metastasis of KRAS-mutant cells were modulated by compounds 3 and 14 through significant inhibition of cell migration and the prevention of colony formation. In addition, they reversed EMT by downregulation of EMT markers (vimentin, fascin, and ß- catenin) and upregulation of cell-cell adhesion marker, E-cadherin. Furthermore, compounds 3 and 14 had significantly inhibited angiogenesis in ovo. CONCLUSION: Compounds 3 and 14 represent potent and selective leads for KRAS-mutant CRC cells, thus, further in vitro and in vivo studies are necessary to confirm their effect on KRAS-mutant CRCs.

Cultural awareness and competence of pharmacy educators and learners from the perspective of pharmacy students at Qatar University: A mixed-methods approach.

BACKGROUND: Since healthcare professional educators and practitioners in Qatar are culturally diverse, the impact of this diversity on the education and training of healthcare students should be evaluated. This study, therefore, aims at examining pharmacy students' perspectives on the level of cultural awareness and competence of pharmacy educators and learners at Qatar University and the influence of cultural diversity on pharmacy education in Qatar. METHODS: A convergent mixed-methods design was adopted. The Cultural Awareness Scale (CAS) was utilized in the quantitative phase, which was administered on 122 pharmacy students at Qatar University College of Pharmacy (QU CPH), of whom 70 responded. The qualitative phase comprised four focus groups with a total of 23 students. The quantitative and qualitative data were collected concurrently, and the results were integrated. RESULTS: The findings suggest that the QU CPH is an institution of a culturally diverse community. Educators and students alike are generally culturally aware and sensitive; however, demonstration of a holistic awareness was hindered by a few barriers. This study suggests curricular changes to reinforce cultural competence, cultural inclusiveness, and the preservation of Qatar's cultural identity and values in the educational environment. CONCLUSIONS: The internationalization of pharmacy education in Qatar has inspired students and educators alike to achieve new dimensions of cultural awareness. To infuse passion and enthusiasm in learning while maintaining Qatar's cultural values and identity, healthcare professional educators, researchers, and policymakers are required to collaborate to promote culturally sensitive pharmacy education.