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  • 1
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    Online Resource
    Therapeutic Potential of a Novel Vitamin D3 Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor Binding
    MDPI AG ; 2022
    In:  Biomolecules Vol. 12, No. 7 ( 2022-07-08), p. 960-
    Details
    In: Biomolecules, MDPI AG, Vol. 12, No. 7 ( 2022-07-08), p. 960-
    Abstract: The regulation of vitamin D3 actions in humans occurs mainly through the Cytochrome P450 24-hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25-hydroxycholecalciferol (25(OH)D3) and 1,25-dihydroxycholecalciferol (1,25(OH)2D3), which is the first step of vitamin D catabolism. An abnormal status of the upregulation of CYP24A1 occurs in many diseases, including chronic kidney disease (CKD). CYP24A1 upregulation in CKD and diminished activation of vitamin D3 contribute to secondary hyperparathyroidism (SHPT), progressive bone deterioration, and soft tissue and cardiovascular calcification. Previous studies have indicated that CYP24A1 inhibition may be an effective strategy to increase endogenous vitamin D activity and decrease SHPT. This study has designed and synthesized a novel C-24 O-methyloxime analogue of vitamin D3 (VD1-6) to have specific CYP24A1 inhibitory properties. VD1-6 did not bind to the vitamin D receptor (VDR) in concentrations up to 10−7 M, assessed by a VDR binding assay. The absence of VDR binding by VD1-6 was confirmed in human embryonic kidney HEK293T cultures through the lack of CYP24A1 induction. However, in silico docking experiments demonstrated that VD1-6 was predicted to have superior binding to CYP24A1, when compared to that of 1,25(OH)2D3. The inhibition of CYP24A1 by VD1-6 was also evident by the synergistic potentiation of 1,25(OH)2D3-mediated transcription and reduced 1,25(OH)2D3 catabolism over 24 h. A further indication of CYP24A1 inhibition by VD1-6 was the reduced accumulation of the 24,25(OH)D3, the first metabolite of 25(OH)D catabolism by CYP24A1. Our findings suggest the potent CYP24A1 inhibitory properties of VD1-6 and its potential for testing as an alternative therapeutic candidate for treating SHPT.
    Type of Medium: Online Resource
    ISSN: 2218-273X
    URL: Article
    DOI: 10.3390/biom12070960
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2701262-1
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  • 2
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    Canary Seed (Phalaris canariensis L.) Peptides Prevent Obesity and Glucose Intolerance in Mice Fed a Western Diet
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 23 ( 2022-11-29), p. 14927-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 23 ( 2022-11-29), p. 14927-
    Abstract: Previous research showed that canary seed (Phalaris canariensis L.) peptides (CSP) possess robust in vitro antiobesity properties via inhibition of pancreatic lipase (PL). Nevertheless, no studies have yet explored their antiobesity properties in vivo. Consequently, we investigated the effects of CSP in C57BL/6J mice under a Western diet (WD). Mice were assigned into groups and fed a normal diet (ND) or a WD accompanied by an oral dose of CSP (250 or 500 mg/kg/day), orlistat (40 mg/kg/day), or distilled water. The results showed that consuming CSP can provide metabolic benefits, including preventing weight gain by up to 20%, increasing glucose tolerance, and reducing insulin, leptin, and LDL/VLDL levels in plasma. Conversely, total ghrelin was unaffected by CSP-500, but decreased by CSP-250, and amplified by orlistat. Surprisingly, CSP-250 was more effective in preventing weight gain and promoting satiety than CSP-500. Parallel to this, protein absorption in CSP-500 was decreased, supported by a rise in fecal crude protein (+3.5%). Similarly, fecal fat was increased by orlistat (38%) and was unaffected by CSP-250 (3.0%) and CSP (3.0%), comparatively to WD (2.5%). Despite this, both CSP treatments were equally effective in decreasing hepatic steatosis and avoiding hyperlipidemia. Furthermore, the enzymatic analysis showed that CSP-PL complexes dissociated faster (15 min) than orlistat-PL complexes (41 min). Lastly, CSP did not affect expression of hepatic lipid oxidation genes ACO and PPAR-α, but reduced the expression of the hydrolase gene LPL, and lipogenesis related genes FAS and ACC. Taken together, these results suggest that CSP antiobesity mechanism relies on lipid metabolism retardation to increase fat transit time and subsequently suppress hunger.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms232314927
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 3
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    Oxidative Stress Protection by Canary Seed (Phalaris canariensis L.) Peptides in Caco-2 Cells and Caenorhabditis elegans
    MDPI AG ; 2022
    In:  Nutrients Vol. 14, No. 12 ( 2022-06-10), p. 2415-
    Details
    In: Nutrients, MDPI AG, Vol. 14, No. 12 ( 2022-06-10), p. 2415-
    Abstract: During oxidative stress, degenerative diseases such as atherosclerosis, Alzheimer’s, and certain cancers are likely to develop. Recent research on canary seed (Phalaris canariensis) peptides has demonstrated the high in vitro antioxidant potential. Thus, this study aimed to assess the cellular and in vivo antioxidant capacity of a low-molecular-weight ( 〈 3 kDa) canary seed peptide fraction (CSPF) using Caco-2 cells and the Caenorhabditis elegans model. The results show that the CSPF had no cytotoxicity effect on Caco-2 cells at any tested concentration (0.3–2.5 mg/mL). Additionally, the cellular antioxidant activity (CAA) of the CSPF was concentration-dependent, and the highest activity achieved was 80% by the CSPF at 2.5 mg/mL. Similarly, incubation with the CSPF significantly mitigated the acute and chronic oxidative damage, extending the lifespan of the nematodes by 88 and 61%, respectively. Furthermore, it was demonstrated that the CSPF reduced the accumulation of reactive oxygen species (ROS) to safe levels after sub-lethal doses of pro-oxidant paraquat. Quantitative real-time PCR revealed that the CSPF increased the expression of oxidative-stress-response-related gene GST-4. Overall, these results show that the CSPFs relied on GST-4 upregulation and scavenging of free radicals to confer oxidative stress protection and suggest that a CSPF can be used as a natural antioxidant in foods for health applications.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu14122415
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2518386-2
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  • 4
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    Brief Mental Health Disorder Screening Questionnaires and Use with Public Safety Personnel: A Review
    MDPI AG ; 2021
    In:  International Journal of Environmental Research and Public Health Vol. 18, No. 7 ( 2021-04-03), p. 3743-
    Details
    In: International Journal of Environmental Research and Public Health, MDPI AG, Vol. 18, No. 7 ( 2021-04-03), p. 3743-
    Abstract: Brief mental health disorder screening questionnaires (SQs) are used by psychiatrists, physicians, researchers, psychologists, and other mental health professionals and may provide an efficient method to guide clinicians to query symptom areas requiring further assessment. For example, annual screening has been used to help identify military personnel who may need help. Nearly half (44.5%) of Canadian public safety personnel (PSP) screen positive for one or more mental health disorder(s); as such, regular mental health screenings for PSP may be a valuable way to support mental health. The following review was conducted to (1) identify existing brief mental health disorder SQs; (2) review empirical evidence of the validity of identified SQs; (3) identify SQs validated within PSP populations; and (4) recommend appropriately validated brief screening questionnaires for five common mental health disorders (i.e., generalized anxiety disorder (GAD), major depressive depression (MDD), panic disorder, posttraumatic stress disorder, alcohol use disorder). After reviewing the psychometric properties of the identified brief screening questionnaires, we recommend the following four brief screening tools for use with PSP: the Patient Health Questionnaire-4 (screening for MDD and GAD), the Brief Panic Disorder Symptom Screen—Self-Report, the Short-Form Posttraumatic Checklist-5, and the Alcohol Use Disorders Identification Test-Consumption.
    Type of Medium: Online Resource
    ISSN: 1660-4601
    URL: Article
    DOI: 10.3390/ijerph18073743
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2175195-X
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  • 5
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    SARS-CoV-2 Detection and Culture in Different Biological Specimens from Immunocompetent and Immunosuppressed COVID-19 Patients Infected with Two Different Viral Strains
    MDPI AG ; 2023
    In:  Viruses Vol. 15, No. 6 ( 2023-05-29), p. 1270-
    Details
    In: Viruses, MDPI AG, Vol. 15, No. 6 ( 2023-05-29), p. 1270-
    Abstract: Introduction—The dynamics of SARS-CoV-2 shedding and replication in humans remain incompletely understood. Methods—We analyzed SARS-CoV-2 shedding from multiple sites in individuals with an acute COVID-19 infection by weekly sampling for five weeks in 98 immunocompetent and 25 immunosuppressed individuals. Samples and culture supernatants were tested via RT-PCR for SARS-CoV-2 to determine viral clearance rates and in vitro replication. Results—A total of 2447 clinical specimens were evaluated, including 557 nasopharyngeal swabs, 527 saliva samples, 464 urine specimens, 437 anal swabs and 462 blood samples. The SARS-CoV-2 genome sequences at each site were classified as belonging to the B.1.128 (ancestral strain) or Gamma lineage. SARS-CoV-2 detection was highest in nasopharyngeal swabs regardless of the virus strain involved or the immune status of infected individuals. The duration of viral shedding varied between clinical specimens and individual patients. Prolonged shedding of potentially infectious virus varied from 10 days up to 191 days, and primarily occurred in immunosuppressed individuals. Virus was isolated in culture from 18 nasal swab or saliva samples collected 10 or more days after onset of disease. Conclusions—Our findings indicate that persistent SARS-CoV-2 shedding may occur in both competent or immunosuppressed individuals, at multiple clinical sites and in a minority of subjects is capable of in vitro replication.
    Type of Medium: Online Resource
    ISSN: 1999-4915
    URL: Article
    DOI: 10.3390/v15061270
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2516098-9
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  • 6
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    Topical Inserts: A Versatile Delivery Form for HIV Prevention
    MDPI AG ; 2019
    In:  Pharmaceutics Vol. 11, No. 8 ( 2019-08-01), p. 374-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 11, No. 8 ( 2019-08-01), p. 374-
    Abstract: The development of topical inserts for the prevention of sexually transmitted infections (STIs), particularly human immunodeficiency virus (HIV), represents a promising alternative to oral and parenteral pre-exposure prophylaxis (PrEP) dosage forms. They may be used for vaginal and/or rectal administration of a variety of agents with antiviral activity. Topical inserts deliver drugs to the portal of viral entry, i.e., the genital or rectal mucosa, with low systemic exposure, and therefore are safer and have fewer side effects than systemic PrEP agents. They may dissolve fast, releasing the active drugs within minutes of insertion, or slowly for long-acting drug delivery. Furthermore, they are user-friendly being easy to administer, discreet and highly portable. They are also economical and easy to manufacture at scale and to distribute, with excellent stability and shelf-life. Altogether, topical inserts represent a particularly promising form of drug delivery for HIV and STI prevention. Highlighted within this review are end-user acceptability research dedicated to understanding preferred attributes for this form of drug delivery, advantages and disadvantages of the formulation platform options, considerations for their development, clinical assessment of select placebo prototypes, future directions, and the potential impact of this dosage form on the HIV prevention landscape.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics11080374
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2527217-2
    SSG: 15,3
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  • 7
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    Identification of a New Endo-β-1,4-xylanase Prospected from the Microbiota of the Termite Heterotermes tenuis
    MDPI AG ; 2022
    In:  Microorganisms Vol. 10, No. 5 ( 2022-04-26), p. 906-
    Details
    In: Microorganisms, MDPI AG, Vol. 10, No. 5 ( 2022-04-26), p. 906-
    Abstract: Xylanases are hemicellulases that break down xylan to soluble pentoses. They are used for industrial purposes, such as paper whitening, beverage clarification, and biofuel production. The second-generation bioethanol production is hindered by the enzymatic hydrolysis step of the lignocellulosic biomass, due to the complex arrangement established among its constituents. Xylanases can potentially increase the production yield by improving the action of the cellulolytic enzyme complex. We prospected endo-β-1,4-xylanases from meta-transcriptomes of the termite Heterotermes tenuis. In silico structural characterization and functional analysis of an endo-β-1,4-xylanase from a symbiotic protist of H. tenuis indicate two active sites and a substrate-binding groove needed for the catalytic activity. No N-glycosylation sites were found. This endo-β-1,4-xylanase was recombinantly expressed in Pichia pastoris and Escherichia coli cells, presenting a molecular mass of approximately 20 kDa. Enzymatic activity assay using recombinant endo-β-1,4-xylanase was also performed on 1% xylan agar stained with Congo red at 30 °C and 40 °C. The enzyme expressed in both systems was able to hydrolyze the substrate xylan, becoming a promising candidate for further analysis aiming to determine its potential for application in industrial xylan degradation processes.
    Type of Medium: Online Resource
    ISSN: 2076-2607
    URL: Article
    DOI: 10.3390/microorganisms10050906
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2720891-6
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  • 8
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    Morphological and Molecular Perspectives on the Phylogeny, Evolution, and Classification of Weevils (Coleoptera: Curculionoidea): Proceedings from the 2016 International Weevil Meeting
    MDPI AG ; 2018
    In:  Diversity Vol. 10, No. 3 ( 2018-07-18), p. 64-
    Details
    In: Diversity, MDPI AG, Vol. 10, No. 3 ( 2018-07-18), p. 64-
    Abstract: The 2016 International Weevil Meeting was held immediately after the International Congress of Entomology (ICE). It built on the topics and content of the 2016 ICE weevil symposium Phylogeny and Evolution of Weevils (Coleoptera: Curculionoidea): A Symposium in Honor of Dr. Guillermo "Willy” Kuschel. Beyond catalyzing research and collaboration, the meeting was intended to serve as a forum for identifying priorities and goals for those who study weevils. The meeting consisted of 46 invited and contributed lectures, discussion sessions and introductory remarks presented by 23 speakers along with eight contributed research posters. These were organized into three convened sessions, each lasting one day: (1) weevil morphology; (2) weevil fossils, biogeography and host/habitat associations; and (3) molecular phylogenetics and classification of weevils. Some of the topics covered included the 1K Weevils Project, major morphological character systems of adult and larval weevils, weevil morphological terminology, prospects for future morphological character discovery, phylogenetic analysis of morphological character data, the current status of weevil molecular phylogenetics and evolution, resources available for phylogenetic and comparative genomic studies of weevils, the weevil fossil record, weevil biogeography and evolution, weevil host plants, evolutionary development of the weevil rostrum, resources available for weevil identification and the current status of and challenges in weevil classification.
    Type of Medium: Online Resource
    ISSN: 1424-2818
    URL: Article
    DOI: 10.3390/d10030064
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2518137-3
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  • 9
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    Vitamin D Status Impacts Genital Mucosal Immunity and Markers of HIV-1 Susceptibility in Women
    MDPI AG ; 2020
    In:  Nutrients Vol. 12, No. 10 ( 2020-10-17), p. 3176-
    Details
    In: Nutrients, MDPI AG, Vol. 12, No. 10 ( 2020-10-17), p. 3176-
    Abstract: While vitamin D insufficiency is known to impact a multitude of health outcomes, including HIV-1, little is known about the role of vitamin D-mediated immune regulation in the female reproductive tract (FRT). We performed a pilot clinical study of 20 women with circulating 25(OH)D levels 〈 62.5 nmol/L. Participants were randomized into either weekly or daily high-dose oral vitamin D supplementation groups. In addition to serum vitamin D levels, genital mucosal endpoints, including soluble mediators, immune cell populations, gene expression, and ex vivo HIV-1 infection, were assessed. While systemic vitamin D levels showed a significant increase following supplementation, these changes translated into modest effects on the cervicovaginal factors studied. Paradoxically, post-supplementation vitamin D levels were decreased in cervicovaginal fluids. Given the strong correlation between vitamin D status and HIV-1 infection and the widespread nature of vitamin D deficiency, further understanding of the role of vitamin D immunoregulation in the female reproductive tract is important.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu12103176
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2518386-2
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  • 10
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    Ex Vivo Drug Sensitivity Correlates with Clinical Response and Supports Personalized Therapy in Pediatric AML
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 24 ( 2022-12-18), p. 6240-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 24 ( 2022-12-18), p. 6240-
    Abstract: Acute myeloid leukemia (AML) is a heterogeneous disease that accounts for ~20% of all childhood leukemias, and more than 40% of children with AML relapse within three years of diagnosis. Although recent efforts have focused on developing a precise medicine-based approach towards treating AML in adults, there remains a critical gap in therapies designed specifically for children. Here, we present ex vivo drug sensitivity profiles for children with de novo AML using an automated flow cytometry platform. Fresh diagnostic blood or bone marrow aspirate samples were screened for sensitivity in response to 78 dose conditions by measuring the reduction in leukemic blasts relative to the control. In pediatric patients treated with conventional chemotherapy, comprising cytarabine, daunorubicin and etoposide (ADE), ex vivo drug sensitivity results correlated with minimal residual disease (r = 0.63) and one year relapse-free survival (r = 0.70; AUROC = 0.94). In the de novo ADE analysis cohort of 13 patients, AML cells showed greater sensitivity to bortezomib/panobinostat compared with ADE, and comparable sensitivity between venetoclax/azacitidine and ADE ex vivo. Two patients showed a differential response between ADE and bortezomib/panobinostat, thus supporting the incorporation of ex vivo drug sensitivity testing in clinical trials to further evaluate the predictive utility of this platform in children with AML.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14246240
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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