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Nutrients Jun 2024Understanding the role of biased taste T1R2/T1R3 G protein-coupled receptors (GPCR) agonists on glycosylated receptor signaling may provide insights into the opposing...
Artificial and Natural Sweeteners Biased T1R2/T1R3 Taste Receptors Transactivate Glycosylated Receptors on Cancer Cells to Induce Epithelial-Mesenchymal Transition of Metastatic Phenotype.
Understanding the role of biased taste T1R2/T1R3 G protein-coupled receptors (GPCR) agonists on glycosylated receptor signaling may provide insights into the opposing effects mediated by artificial and natural sweeteners, particularly in cancer and metastasis. Sweetener-taste GPCRs can be activated by several active states involving either biased agonism, functional selectivity, or ligand-directed signaling. However, there are increasing arrays of sweetener ligands with different degrees of allosteric biased modulation that can vary dramatically in binding- and signaling-specific manners. Here, emerging evidence proposes the involvement of taste GPCRs in a biased GPCR signaling crosstalk involving matrix metalloproteinase-9 (MMP-9) and neuraminidase-1 (Neu-1) activating glycosylated receptors by modifying sialic acids. The findings revealed that most natural and artificial sweeteners significantly activate Neu-1 sialidase in a dose-dependent fashion in RAW-Blue and PANC-1 cells. To confirm this biased GPCR signaling crosstalk, BIM-23127 (neuromedin B receptor inhibitor, MMP-9i (specific MMP-9 inhibitor), and oseltamivir phosphate (specific Neu-1 inhibitor) significantly block sweetener agonist-induced Neu-1 sialidase activity. To assess the effect of artificial and natural sweeteners on the key survival pathways critical for pancreatic cancer progression, we analyzed the expression of epithelial-mesenchymal markers, CD24, ADLH-1, E-cadherin, and N-cadherin in PANC-1 cells, and assess the cellular migration invasiveness in a scratch wound closure assay, and the tunneling nanotubes (TNTs) in staging the migratory intercellular communication. The artificial and natural sweeteners induced metastatic phenotype of PANC-1 pancreatic cancer cells to promote migratory intercellular communication and invasion. The sweeteners also induced the downstream NFκB activation using the secretory alkaline phosphatase (SEAP) assay. These findings elucidate a novel taste T1R2/T1R3 GPCR functional selectivity of a signaling platform in which sweeteners activate downstream signaling, contributing to tumorigenesis and metastasis via a proposed NFκB-induced epigenetic reprogramming modeling.
Topics: Humans; Epithelial-Mesenchymal Transition; Receptors, G-Protein-Coupled; Sweetening Agents; Cell Line, Tumor; Matrix Metalloproteinase 9; Neoplasm Metastasis; Glycosylation; Signal Transduction; Phenotype; Animals; Taste; Cell Movement; Neuraminidase
PubMed: 38931195
DOI: 10.3390/nu16121840 -
Emerging Microbes & Infections Jun 2024The proportion of human isolates with reduced neuraminidase inhibitors (NAIs) susceptibility in highly pathogenic avian influenza (HPAI) H7N9 virus was as high as 13%....
The proportion of human isolates with reduced neuraminidase inhibitors (NAIs) susceptibility in highly pathogenic avian influenza (HPAI) H7N9 virus was as high as 13%. These drug-resistant strains showed good replication capacity without serious loss of fitness. At the presence of oseltamivir, R229I substitution were found in HA1 region of the HPAI H7N9 virus before NA R292 K appeared. HPAI H7N9 or H7N9/PR8 recombinant viruses were developed to study whether HA R229I could increase the fitness of the H7N9 virus bearing NA 292 K. Replication efficiency was assessed in MDCK or A549 cells. Neuraminidase enzyme activity and receptor-binding ability were analyzed. The pathogenicity in C57 mice was evaluated. Antigenicity analysis was conducted through a two-way HI test, in which the antiserum was obtained from immunized ferrets. Transcriptomic analysis of MDCK infected with HPAI H7N9 24hpi was done. It turned out that HA R229I substitution from oseltamivir induction in HA1 region increased 1)replication ability in MDCK(< 0.05) and A549(< 0.05), 2)neuraminidase enzyme activity, 3)binding ability to both α2,3 and α2,6 receptor, 4)pathogenicity to mice(more weight loss; shorter mean survival day; viral titer in respiratory tract, < 0.05; Pathological changes in pneumonia), 5) transcriptome response of MDCK, of the H7N9 virus bearing NA 292 K. Besides, HA R229I substitution changed the antigenicity of H7N9/PR8 virus (>4-fold difference of HI titer). It indicated that through the fine-tuning of the HA-NA balance, R229I increased the fitness and change the antigenicity of a H7N9 virus bearing NA 292 K. Public health attention of this mechanism needs to be drawn.
PubMed: 38922326
DOI: 10.1080/22221751.2024.2373314 -
Emerging Infectious Diseases Jul 2024Since May 2023, a novel combination of neuraminidase mutations, I223V + S247N, has been detected in influenza A(H1N1)pdm09 viruses collected in countries spanning 5...
Since May 2023, a novel combination of neuraminidase mutations, I223V + S247N, has been detected in influenza A(H1N1)pdm09 viruses collected in countries spanning 5 continents, mostly in Europe (67/101). The viruses belong to 2 phylogenetically distinct groups and display ≈13-fold reduced inhibition by oseltamivir while retaining normal susceptibility to other antiviral drugs.
Topics: Oseltamivir; Influenza A Virus, H1N1 Subtype; Humans; Antiviral Agents; Influenza, Human; Neuraminidase; Drug Resistance, Viral; Phylogeny; Mutation
PubMed: 38916572
DOI: 10.3201/eid3007.240480 -
Microbiology Spectrum Jun 2024Outbreaks of influenza A viruses are generally seasonal and cause annual epidemics worldwide. Due to their frequent reassortment and evolution, annual surveillance is of...
Outbreaks of influenza A viruses are generally seasonal and cause annual epidemics worldwide. Due to their frequent reassortment and evolution, annual surveillance is of paramount importance to guide vaccine strategies. The aim of this study was to explore the molecular epidemiology of influenza A virus and nasopharyngeal microbiota composition in infected patients in Saudi Arabia. A total of 103 nasopharyngeal samples from 2015 and 12 samples from 2022 were collected from patients positive for influenza A. Sequencing of influenza A as well as metatranscriptomic analysis of the nasopharyngeal microbiota was conducted using Oxford Nanopore sequencing. Phylogenetic analysis of hemagglutinin, neuraminidase segments, and concatenated influenza A genomes was performed using MEGA7. Whole-genome sequencing analysis revealed changing clades of influenza A virus: from 6B.1 in 2015 to 5a.2a in 2022. One sample containing the antiviral resistance-mediating mutation S247N toward oseltamivir and zanamivir was found. Phylogenetic analysis showed the clustering of influenza A strains with the corresponding vaccine strains in each period, thus suggesting vaccine effectiveness. Principal component analysis and alpha diversity revealed the absence of a relationship between hospital admission status, age, or gender of infected patients and the nasopharyngeal microbial composition, except for the infecting clade 5a.2a. The opportunistic pathogens , , and were the most common species detected. The molecular epidemiology appears to be changing in Saudi Arabia after the COVID-19 pandemic. Antiviral resistance should be carefully monitored in future studies. In addition, the disease severity of patients as well as the composition of the nasopharyngeal microbiota in patients infected with different clades should also be assessed.IMPORTANCEIn this work, we have found that the clade of influenza A virus circulating in Riyadh, KSA, has changed over the last few years from 6B.1 to 5a.2a. Influenza strains clustered with the corresponding vaccine strains in our population, thus emphasizing vaccine effectiveness. Metatranscriptomic analysis showed no correlation between the nasopharyngeal microbiome and the clinical and/or demographic characteristics of infected patients. This is except for the 5a.2a strains isolated post-COVID-19 pandemic. The influenza virus is among the continuously evolving viruses that can cause severe respiratory infections. Continuous surveillance of its molecular diversity and the monitoring of anti-viral-resistant strains are thus of vital importance. Furthermore, exploring potential microbial markers and/or dysbiosis of the nasopharyngeal microbiota during infection could assist in the better management of patients in severe cases.
PubMed: 38904365
DOI: 10.1128/spectrum.00665-24 -
Scientific Reports Jun 2024Short influenza postexposure prophylaxis (PEP) showed high efficacy in adults, but studies in children are lacking. This randomized open-label pilot trial aimed to... (Randomized Controlled Trial)
Randomized Controlled Trial
Short influenza postexposure prophylaxis (PEP) showed high efficacy in adults, but studies in children are lacking. This randomized open-label pilot trial aimed to verify noninferiority of a 3- versus 7-day prophylaxis with oral oseltamivir in hospitalized children. Influenza contacts were randomized to the 3- or 7-day group and efficacy, relative risk of adverse events (AEs), and the cumulative costs of drugs and AEs management were compared. The intention-to-treat (ITT) analysis included 59 children (n = 28 and n = 31 in the 3- and 7-day group, respectively). The efficacy was 100% (95% CI 87.7-100%) versus 93.6% (95% CI 78.6-99.2%) in the 3- and 7-day group; the differences were statistically insignificant. A per-protocol (PP) analysis including 56 patients (n = 27 and n = 29, respectively) showed 100% (95% CI 87.2-100%) and 93.1% (95% CI 77.2-99.2%) efficacy, respectively, without statistical significance. Differences were within the predefined noninferiority margin with an efficacy difference Δ = 6.45 percentage points (p.p.) with 1-sided 95% CI (- 2.8, - 1.31, p = 0.86; ITT) and Δ = 6.9 p.p. (1-sided 95% CI - 2.83, - 1.27, p = 0.85; PP). Adverse events did not differ significantly, while the cumulative costs of the prophylaxis and AEs management were higher in the 7-day group (median 10.5 euro vs. 4.5 euro, p < 0.01). This pilot study showed the noninferiority of the 3-day versus 7-day PEP, which was associated with lower costs.Trial registration number: NCT04297462, 5th March 2020, restrospectively registered.
Topics: Humans; Oseltamivir; Influenza, Human; Male; Female; Pilot Projects; Post-Exposure Prophylaxis; Child; Antiviral Agents; Child, Preschool; Infant; Child, Hospitalized; Treatment Outcome; Adolescent
PubMed: 38902383
DOI: 10.1038/s41598-024-65244-5 -
Antiviral Research Jun 2024We compared the duration of fever in children infected with A(H1N1)pdm09, A(H3N2), or influenza B viruses following treatment with baloxavir marboxil (baloxavir) or...
Duration of fever in children infected with influenza A(H1N1)pdm09, A(H3N2) or B virus and treated with baloxavir marboxil, oseltamivir, laninamivir, or zanamivir in Japan during the 2012-2013 and 2019-2020 influenza seasons.
We compared the duration of fever in children infected with A(H1N1)pdm09, A(H3N2), or influenza B viruses following treatment with baloxavir marboxil (baloxavir) or neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, or laninamivir). This observational study was conducted at 10 outpatient clinics across 9 prefectures in Japan during the 2012-2013 and 2019-2020 influenza seasons. Patients with influenza rapid antigen test positive were treated with one of four anti-influenza drugs. The type/subtype of influenza viruses were identified from MDCK or MDCK SIAT1 cell-grown samples using two-step real-time PCR. Daily self-reported body temperature after treatment were used to evaluate the duration of fever by treatment group and various underlying factors. Among 1742 patients <19 years old analyzed, 452 (26.0%) were A(H1N1)pdm09, 827 (48.0%) A(H3N2), and 463 (26.0%) influenza B virus infections. Among fours treatment groups, baloxavir showed a shorter median duration of fever compared to oseltamivir in univariate analysis for A(H1N1)pdm09 virus infections (baloxavir, 22.0 h versus oseltamivir, 26.7 h, P < 0.05; laninamivir, 25.5 h, and zanamivir, 25.0 h). However, this difference was not significant in multivariable analyses. For A(H3N2) virus infections, there were no statistically significant differences observed (20.3, 21.0, 22.0, and 19.0 h) uni- and multivariable analyses. For influenza B, baloxavir shortened the fever duration by approximately 15 h than NAIs (20.3, 35.0, 34.3, and 34.1 h), as supported by uni- and multivariable analyses. Baloxavir seems to have comparable clinical effectiveness with NAIs on influenza A but can be more effective for treating pediatric influenza B virus infections than NAIs.
PubMed: 38897317
DOI: 10.1016/j.antiviral.2024.105938 -
World Journal of Otorhinolaryngology -... Jun 2024The aim of this study was to assess the relative efficacy of medications used following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on...
OBJECTIVE
The aim of this study was to assess the relative efficacy of medications used following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on self-reported alterations in taste and/or smell function.
METHODS
Seven hundred and fourteen persons with self-reported postcoronavirus disease 2019 (post-COVID-19) chemosensory disorders were personally interviewed regarding specific medications they were administered following the acute phase of the disease. The dependent measure-self-reported total recovery of chemosensory symptoms-was subjected to stepwise logistic regression. Independent predictors included demographic and clinical variables, in addition to specific medications used to mitigate disease symptoms (i.e., systemic corticosteroids, oseltamivir, vitamin C, ibuprofen, hydroxychloroquine, azithromycin, ivermectin, nitazoxanide, anticoagulants, and zinc).
RESULTS
The median time between COVID-19 symptom onset and the interviews was 81 days (interquartile range: 60-104). Of the 714 subjects, 249 (34.9%) reported total recovery of their chemosensory function; 437 (61.2%) had at least one treatment since the beginning of the disease. Women and those with more comorbidities had undergone more treatments. The recovery rates of the treated and nontreated groups did not differ significantly. Nonetheless, respondents who had used nitazoxanide tended to have a higher rate of self-reported taste or smell recovery. Those who took oral zinc were less likely to improve.
CONCLUSIONS
No medication employed during the first months after SARS-CoV-2 infection had a clear positive effect on returning self-reported smell or taste function to normal, although nitrazoxide trended in a positive direction. Oral zinc had a negative effect on the reported recovery of these senses.
PubMed: 38855284
DOI: 10.1002/wjo2.183 -
Pakistan Journal of Medical Sciences 2024We assessed the effectiveness of oral Hydroxychloroquine (HC), Azithromycin (AZ) and Oseltamivir (OS), alone or combined, among patients hospitalized with mildly...
OBJECTIVE
We assessed the effectiveness of oral Hydroxychloroquine (HC), Azithromycin (AZ) and Oseltamivir (OS), alone or combined, among patients hospitalized with mildly symptomatic coronavirus infectious disease (COVID-19).
METHODS
Following the approval of the National Bioethics Committee and prospective registration (clinicaltrials.gov NCT04338698), a multicenter randomized clinical trial of adaptive design was conducted at 10 multispecialty hospitals in Pakistan. Patients were randomized into seven treatment groups. Starting April 15, 2020, consenting, eligible, otherwise healthy adult patients or those with co-morbidities under control, were recruited if they presented with mildly symptomatic COVID-19 (scored 3 on a 7-point ordinal scale anchored between 1 = not hospitalized, able to undertake normal activities, to 7 = death) confirmed by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Two primary outcomes were assessed by day seven: Turning qRT-PCR negative; and clinical improvement of two points from the baseline. Outcome rates were compared using a chi-square test. Multiple imputations were applied to handle missing data. An interim data analysis was carried out on July 19, 2020, following which the study continued without treatment group changes. Data Safety and Monitoring Board advised to stop recruitment due to its futility on January 18, 2021.
RESULTS
Of 471 patients randomized, a total of 426 (90.4%) completed the follow-up for primary outcomes. Based on imputed data analyses at day seven: Total qRT-PCR negative cases were 137/471 (29%, 95% CI 25.0 - 33.4). By day seven, a total of 111/471 (23.5%, 95% CI 19.8 - 27.6) showed clinical improvement. No serious or non-serious adverse event was reported.
CONCLUSIONS
Among patients with mild COVID-19, there was no statistically significant difference in the effectiveness of oral antimalarial, antiviral, or antibiotic treatments. NCT04338698.
PubMed: 38827854
DOI: 10.12669/pjms.40.5.8757 -
Saudi Journal of Biological Sciences Jul 2024Still, there is no cure for the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-caused coronavirus disease 2019 (COVID19). The COVID19... (Review)
Review
Still, there is no cure for the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-caused coronavirus disease 2019 (COVID19). The COVID19 pandemic caused health emergencies which resulted in enormous medical and financial consequences worldwide including Saudi Arabia. Saudi Arabia is the largest Arab country of the Middle East. The urban setting of Saudi Arabia makes it vulnerable towards SARS-CoV-2 (SCV-2). Religious areas of this country are visited by millions of pilgrims every year for the Umrah and Hajj pilgrimage, which contributes to the potential COVID19 epidemic risk. COVID19 throws various challenges to healthcare professionals to choose the right drugs or therapy in clinical settings because of the lack of availability of newer drugs. Current drug development and discovery is an expensive, complex, and long process, which involves a high failure rate in clinical trials. While repurposing of United States Food and Drug Administration (US FDA)-approved antiviral drugs offers numerous benefits including complete pharmacokinetic and safety profiles, which significantly shorten drug development cycles and reduce costs. A range of repurposed US FDA-approved antiviral drugs including ribavirin, lopinavir/ritonavir combination, oseltamivir, darunavir, remdesivir, nirmatrelvir/ritonavir combination, and molnupiravir showed encouraging results in clinical trials in COVID19 treatment. In this article, several COVID19-related discussions have been provided including emerging variants of concern of, COVID19 pathogenesis, COVID19 pandemic scenario in Saudi Arabia, drug repurposing strategies against SCV-2, as well as repurposing of US FDA-approved antiviral drugs that might be considered to combat SCV-2 in Saudi Arabia. Moreover, drug repurposing in the context of COVID19 management along with its limitations and future perspectives have been summarized.
PubMed: 38799719
DOI: 10.1016/j.sjbs.2024.104023 -
Narra J Apr 2024Numerous prior studies have identified therapeutic targets that could effectively combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection,...
Numerous prior studies have identified therapeutic targets that could effectively combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, including the angiotensin-converting enzyme 2 (ACE2) receptor, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). In parallel, antiviral compounds like abacavir, acyclovir, adefovir, amantadine, amprenavir, darunavir, didanosine, oseltamivir, penciclovir, and tenofovir are under investigation for their potential in drug repurposing to address this infection. The aim of the study was to determine the effect of modifying the functional groups of the aforementioned antivirals in silico. Using the genetic optimization for ligand docking algorithm on software Maestro (version 11.1), the modified antivirals were docked onto ACE2 receptor, RdRp, and Mpro. Using QuickProp (Maestro v11.1), PASS (prediction of activity spectra for the substances), and altogether with SwissADME, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) of the modified antivirals, as well as their bioavailability and the predicted activity spectra, were determined. Discovery studio software was used to undertake post-docking analysis. Among the 10 antivirals, N(CH) derivative of darunavir, N(CH) derivative of amprenavir and NCH derivative of darunavir exhibited best binding affinities with ACE2 receptor (docking scores: -10.333, -9.527 and -9.695 kJ/mol, respectively). Moreover, NCH derivative of abacavir (-6.506 kJ/mol), NO derivative of didanosine (-6.877 kJ/mol), NCH derivative of darunavir (-7.618 kJ/mol) exerted promising affinity to Mpro. In conclusion, the results of the in silico screenings can serve as a useful information for future experimental works.
Topics: Antiviral Agents; Humans; Molecular Docking Simulation; SARS-CoV-2; Drug Repositioning; COVID-19 Drug Treatment; Models, Molecular; COVID-19; Angiotensin-Converting Enzyme 2; Pneumonia, Viral; Pandemics
PubMed: 38798846
DOI: 10.52225/narra.v4i1.319