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Fulltext Quantification of intracellular payload release from polymersome nanoparticles

Scarpa E, Bailey JL, Janeczek AA, Stumpf PS, Johnston AH, Oreffo RO, et al.

Sci Rep, 2016 07 11;6:29460.
PMID: 27404770 DOI: 10.1038/srep29460

Polymersome nanoparticles (PMs) are attractive candidates for spatio-temporal controlled delivery of therapeutic agents. Although many studies have addressed cellular uptake of solid nanoparticles, there is very little data available on intracellular release of molecules encapsulated in membranous carriers, such as polymersomes. Here, we addressed this by developing a quantitative assay based on the hydrophilic dye, fluorescein. Fluorescein was encapsulated stably in PMs of mean diameter 85 nm, with minimal leakage after sustained dialysis. No fluorescence was detectable from fluorescein PMs, indicating quenching. Following incubation of L929 cells with fluorescein PMs, there was a gradual increase in intracellular fluorescence, indicating PM disruption and cytosolic release of fluorescein. By combining absorbance measurements with flow cytometry, we quantified the real-time intracellular release of a fluorescein at a single-cell resolution. We found that 173 ± 38 polymersomes released their payload per cell, with significant heterogeneity in uptake, despite controlled synchronisation of cell cycle. This novel method for quantification of the release of compounds from nanoparticles provides fundamental information on cellular uptake of nanoparticle-encapsulated compounds. It also illustrates the stochastic nature of population distribution in homogeneous cell populations, a factor that must be taken into account in clinical use of this technology.
Fulltext Favipiravir for treating COVID-19

Korula P, Alexander H, John JS, Kirubakaran R, Singh B, Tharyan P, et al.

Cochrane Database Syst Rev, 2024 Feb 05;2(2):CD015219.
PMID: 38314855 DOI: 10.1002/14651858.CD015219.pub2

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to challenge the health workforce and societies worldwide. Favipiravir was suggested by some experts to be effective and safe to use in COVID-19. Although this drug has been evaluated in randomized controlled trials (RCTs), it is still unclear if it has a definite role in the treatment of COVID-19.
OBJECTIVES: To assess the effects of favipiravir compared to no treatment, supportive treatment, or other experimental antiviral treatment in people with acute COVID-19.
SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, MEDLINE, Embase, the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease, and three other databases, up to 18 July 2023.
SELECTION CRITERIA: We searched for RCTs evaluating the efficacy of favipiravir in treating people with COVID-19.
DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures for data collection and analysis. We used the GRADE approach to assess the certainty of evidence for each outcome.
MAIN RESULTS: We included 25 trials that randomized 5750 adults (most under 60 years of age). The trials were conducted in Bahrain, Brazil, China, India, Iran, Kuwait, Malaysia, Mexico, Russia, Saudi Arabia, Thailand, the UK, and the USA. Most participants were hospitalized with mild to moderate disease (89%). Twenty-two of the 25 trials investigated the role of favipiravir compared to placebo or standard of care, whilst lopinavir/ritonavir was the comparator in two trials, and umifenovir in one trial. Most trials (24 of 25) initiated favipiravir at 1600 mg or 1800 mg twice daily for the first day, followed by 600 mg to 800 mg twice a day. The duration of treatment varied from five to 14 days. We do not know whether favipiravir reduces all-cause mortality at 28 to 30 days, or in-hospital (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.49 to 1.46; 11 trials, 3459 participants; very low-certainty evidence). We do not know if favipiravir reduces the progression to invasive mechanical ventilation (RR 0.86, 95% CI 0.68 to 1.09; 8 trials, 1383 participants; very low-certainty evidence). Favipiravir may make little to no difference in the need for admission to hospital (if ambulatory) (RR 1.04, 95% CI 0.44 to 2.46; 4 trials, 670 participants; low-certainty evidence). We do not know if favipiravir reduces the time to clinical improvement (defined as time to a 2-point reduction in patients' admission status on the WHO's ordinal scale) (hazard ratio (HR) 1.13, 95% CI 0.69 to 1.83; 4 trials, 721 participants; very low-certainty evidence). Favipiravir may make little to no difference to the progression to oxygen therapy (RR 1.20, 95% CI 0.83 to 1.75; 2 trials, 543 participants; low-certainty evidence). Favipiravir may lead to an overall increased incidence of adverse events (RR 1.27, 95% CI 1.05 to 1.54; 18 trials, 4699 participants; low-certainty evidence), but may result in little to no difference inserious adverse eventsattributable to the drug (RR 1.04, 95% CI 0.76 to 1.42; 12 trials, 3317 participants; low-certainty evidence).
AUTHORS' CONCLUSIONS: The low- to very low-certainty evidence means that we do not know whether favipiravir is efficacious in people with COVID-19 illness, irrespective of severity or admission status. Treatment with favipiravir may result in an overall increase in the incidence of adverse events but may not result in serious adverse events.
Fulltext Cytotoxic Effect of Thymoquinone-Loaded Nanostructured Lipid Carrier (TQ-NLC) on Liver Cancer Cell Integrated with Hepatitis B Genome, Hep3B

Haron AS, Syed Alwi SS, Saiful Yazan L, Abd Razak R, Ong YS, Zakarial Ansar FH, et al.

Evid Based Complement Alternat Med, 2018;2018:1549805.
PMID: 30186351 DOI: 10.1155/2018/1549805

Thymoquinone (TQ), a bioactive compound found in Nigella sativa, cannot be orally consumed due to its lipophilicity. In order to overcome this low bioavailability, TQ is loaded into a colloidal drug carrier known as a nanostructured lipid carrier (NLC). This study aims to determine the antiproliferative effects of TQ and TQ-NLC on liver cancer cells integrated with the hepatitis B genome, Hep3B. The Hep3B was treated with TQ or TQ-NLC for 24, 48, and 72 hours via MTT assay. The results confirm that TQ or TQ-NLC inhibited the growth of Hep3B at IC50 <16.7 μM for 72 hours. TQ was also found to induce cell cycle arrest at the G1 checkpoint while TQ-NLC induced non-phase-specific cell cycle arrest. Further analysis using Annexin V staining confirmed the apoptotic induction of TQ or TQ-NLC via activation of caspases-3/7. In ROS management, TQ acted as a prooxidant (increased the level of ROS), while TQ-NLC acted as an antioxidant (reduced the level of ROS). Molecular analysis demonstrated that the GSH system and the Nrf2/Keap1 signaling pathway in Hep3B influenced the differential responses of the cells towards TQ or TQ-NLC. Hence, this study demonstrated that TQ and TQ-NLC have in vitro anticancer effects on the Hep3B.
The 18th International HLA & Immunogenetics workshop project report: Creating fully representative MHC reference haplotypes

Pollock NR, Farias TDJ, Kichula KM, Sauter J, Scholz S, Nii-Trebi NI, et al.

HLA, 2024 Jun;103(6):e15568.
PMID: 38923286 DOI: 10.1111/tan.15568

A fundamental endeavor of the International Histocompatibility and Immunogenetics Workshop (IHIW) was assembling a collection of DNA samples homozygous through the MHC genomic region. This collection proved invaluable for assay development in the histocompatibility and immunogenetics field, for generating the human reference genome, and furthered our understanding of MHC diversity. Defined by their HLA-A, -B, -C and -DRB1 alleles, the combined frequency of the haplotypes from these individuals is ~20% in Europe. Thus, a significant proportion of MHC haplotypes, both common and rare throughout the world, and including many associated with disease, are not yet represented. In this workshop component, we are collecting the next generation of MHC-homozygous samples, to expand, diversify and modernize this critical community resource that has been foundational to the field. We asked laboratories worldwide to identify samples homozygous through all HLA class I and/or HLA class II genes, or through whole-genome SNP genotyping or sequencing, to have extensive homozygosity tracts within the MHC region. The focus is non-Europeans or those having HLA haplotypes less common in Europeans. Through this effort, we have obtained samples from 537 individuals representing 294 distinct haplotypes, as determined by their HLA class I and II alleles, and an additional 50 haplotypes distinct in HLA class I or II alleles. Although we have expanded the diversity, many populations remain underrepresented, particularly from Africa, and we encourage further participation. The data will serve as a resource for investigators seeking to characterize variation across the MHC genomic region for disease and population studies.