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Drug Metabolism and Disposition: the... May 2024The hepatitis C virus (HCV) poses a great risk to pregnant people and their developing fetus, yet no HCV antiviral treatment guidelines have been established. While...
The hepatitis C virus (HCV) poses a great risk to pregnant people and their developing fetus, yet no HCV antiviral treatment guidelines have been established. While there has been a substantial increase in the development of HCV antivirals, the effect they have on the developing fetus remains poorly defined. Many of these drugs are metabolized through the cytochrome P450 CYP3A pathway, which is mediated by cytochrome P450 3A7 (CYP3A7) in the fetus and developing infant. In this study, we sought to investigate the effect HCV antivirals have on CYP3A7 metabolism, as this CYP enzyme plays a vital role in proper fetal and neonatal development. Of the 13 HCV antivirals we investigated, 8 (∼62%) inhibited CYP3A7 metabolic activity by 50% or more at a concentration of 20 M. Furthermore, paritaprevir, asunaprevir, simeprevir, danoprevir, and glecaprevir all had observed half-maximal inhibitory concentrations between the range of 10 and 20 M, which is physiologically relevant in comparison with the K of dehydroepiandrosterone-sulfate (DHEA-S) oxidation (reported to be between 5 and 20 M). We also discovered that paritaprevir is a time-dependent inhibitor of CYP3A7, which shifts the IC ∼twofold from 11 M to 5 M. Upon further characterization, paritaprevir inactivates DHEA-S metabolism by CYP3A7, with K and K values of 4.66 M and 0.00954 minute, respectively. Depending on treatment plan and off-label drug use, HCV treatment could adversely affect the fetal-maternal communication axis by blocking fetal CYP3A7 metabolism of important endogenous hormones. SIGNIFICANCE STATEMENT: The prevalence of HCV in pregnant people is estimated at between 1% and 8% of the global population, yet little to no information exists about the risk antiviral treatment poses to the developing fetus. There is a potential risk of drugs adversely affecting mother-fetal communication by inhibiting fetal hepatic CYP3A7, an integral enzyme for estriol production. We discovered that five HCV antivirals inhibited DHEA-S metabolism by CYP3A7, and paritaprevir inactivated the enzyme. Our studies demonstrate the potential threat these drugs pose to proper fetal development.
Topics: Humans; Cytochrome P-450 CYP3A; Female; Antiviral Agents; Pregnancy; Oxidation-Reduction; Dehydroepiandrosterone Sulfate; Hepacivirus; Hepatitis C; Cytochrome P-450 CYP3A Inhibitors; Maternal-Fetal Exchange; Microsomes, Liver; Fetus
PubMed: 38267095
DOI: 10.1124/dmd.123.001434 -
Frontiers in Cardiovascular Medicine 2023Traf2 and Nck-interacting kinase (TNIK) is known for its regulatory role in various processes within cancer cells. However, its role within endothelial cells (ECs) has...
BACKGROUND
Traf2 and Nck-interacting kinase (TNIK) is known for its regulatory role in various processes within cancer cells. However, its role within endothelial cells (ECs) has remained relatively unexplored.
METHODS
Leveraging RNA-seq data and Ingenuity Pathway Analysis (IPA), we probed the potential impact of TNIK depletion on ECs.
RESULTS
Examination of RNA-seq data uncovered more than 450 Differentially Expressed Genes (DEGs) in TNIK-depleted ECs, displaying a fold change exceeding 2 with a false discovery rate (FDR) below 0.05. IPA analysis unveiled that TNIK depletion leads to the inhibition of the interferon (IFN) pathway [-log (-value) >11], downregulation of IFN-related genes, and inhibition of Hypercytokinemia/Hyperchemokinemia [-log (-value) >8]. The validation process encompassed qRT-PCR to evaluate mRNA expression of crucial IFN-related genes, immunoblotting to gauge STAT1 and STAT2 protein levels, and ELISA for the quantification of IFN and cytokine secretion in siTNIK-depleted ECs. These assessments consistently revealed substantial reductions upon TNIK depletion. When transducing HUVECs with replication incompetent E1-E4 deleted adenovirus expressing green fluorescent protein (Ad-GFP), it was demonstrated that TNIK depletion did not affect the uptake of Ad-GFP. Nonetheless, TNIK depletion induced cytopathic effects (CPE) in ECs transduced with wild-type human adenovirus serotype 5 (Ad-WT).
SUMMARY
Our findings suggest that TNIK plays a crucial role in regulating the EC response to virus infections through modulation of the IFN pathway.
PubMed: 38264262
DOI: 10.3389/fcvm.2023.1213428 -
Prevalence of JC Polyomavirus in Patients with Neuroinvasive Disease of Unknown Etiology in Croatia.Medicina (Kaunas, Lithuania) Dec 2023: John Cunningham polyomavirus (JCPyV) is a highly prevalent virus in the human population. The prevalence of JCPyV in patients with central nervous system disorders has...
: John Cunningham polyomavirus (JCPyV) is a highly prevalent virus in the human population. The prevalence of JCPyV in patients with central nervous system disorders has not been examined extensively. The aim of this study was to analyze the prevalence of JCPyV DNA/antibodies in patients with neuroinvasive diseases (NID) of unknown etiology. : The study included 132 patients with NID (febrile headache, meningitis, encephalitis) tested from January 2021 to December 2022. The control group consisted of 47 asymptomatic individuals. In patients with NID, serum and cerebrospinal fluid (CSF) samples were collected in the acute phase of the disease. CSF samples were tested for JCPyV DNA (PCR), while serum samples were tested for JCPyV IgG antibodies (ELISA). In controls, serum samples were tested for JCPyV IgG antibodies (ELISA). : JCPyV DNA was not detected in any of the CSF samples from patients with NID. JCPyV IgG antibodies were detected in 88.6% of patients and 74.5% of controls ( < 0.001). In the patients' group, a significant difference in the IgG prevalence was observed between males (94.6%) and females (81.0%). In addition, significant differences in the seropositivity between age groups were found. The lowest seroprevalence (28.6%) was in patients less than 20 years, followed by a sharp increase in the 20-29-year group (69.2%), after which the seroprevalence remained stable (90.0-94.1%) in patients up to 69 years. All patients older than 70 years were JCPyV IgG-seropositive. No significant difference in the seroprevalence was found in patients presenting with febrile headache (81.6%), meningitis (93.3%), or meningoencephalitis (91.3%). No difference in the seropositivity between genders was found in controls. Although the seropositivity steadily increased in older participants, these differences were not significant. Analyzing the JCPyV antibody levels in patients with NID, the median antibody titers differed significantly between groups, ranging from 248 AU/mL (younger age groups) to 400 AU/mL (older age groups). : Higher seroprevalence in the patients' group highlights the need to further investigate the possible association of JCPyV and NID.
Topics: Humans; Female; Male; Aged; JC Virus; Croatia; Prevalence; Seroepidemiologic Studies; Fever; Headache; Immunoglobulin G; DNA; Meningitis
PubMed: 38256330
DOI: 10.3390/medicina60010069 -
Genes Dec 2023The resistance of silkworms to nuclear polyhedrosis virus (BmNPV) is controlled by a major dominant gene and multiple modifying genes. Given the presence of modified...
The resistance of silkworms to nuclear polyhedrosis virus (BmNPV) is controlled by a major dominant gene and multiple modifying genes. Given the presence of modified genes, it is difficult to determine the main gene by positional cloning. In this study, the main anti-BmNPV gene of BmNPV-resistant silkworm variety N was introduced into the susceptible variety Su to breed the near-isogenic line SuN with BmNPV resistance. The infection process of BmNPV in the hemolymph of Su and SuN was analyzed using the cell analysis system TissueFAXS PLUS. According to the law of infection and proliferation, hemolymph was extracted every 6 h for two-dimensional electrophoresis (2-DE) analysis and quantitative real-time polymerase chain reaction (qRT-PCR). Seven DEPs were found in comparisons between Su and SuN by 2-DE analysis. Among them, acid phosphatase, storage protein, and phenoloxidase can prevent pathogen invasion, which may play a role against BmNPV. Polyamine oxidase plays an important role in energy metabolism, which may be indirectly involved in the process of resisting BmNPV. Most of the transcriptional expression profiles of the seven DEPs were consistent with the 2-DE results. This study can provide a reference for the identification of anti-BmNPV genes and the breeding of BmNPV-resistant silkworm varieties.
Topics: Animals; Bombyx; Nucleopolyhedroviruses; Proteomics; Genes, Dominant
PubMed: 38254949
DOI: 10.3390/genes15010059 -
Pathogens (Basel, Switzerland) Jan 2024Previous studies have noted that persons living with human immunodeficiency virus (HIV) experience persistent lung dysfunction after an episode of community-acquired...
Previous studies have noted that persons living with human immunodeficiency virus (HIV) experience persistent lung dysfunction after an episode of community-acquired pneumonia (CAP), although the underlying mechanisms remain unclear. We hypothesized that inflammation during pneumonia triggers increased tissue damage and accelerated pulmonary fibrosis, resulting in a gradual loss of lung function. We carried out a prospective cohort study of people diagnosed with CAP and/or HIV between 2016 and 2018 in three clinical institutions in Medellín, Colombia. Clinical data, blood samples, and pulmonary function tests (PFTs) were collected at baseline. Forty-one patients were included, divided into two groups: HIV and CAP (n = 17) and HIV alone (n = 24). We compared the concentrations of 17 molecules and PFT values between the groups. Patients with HIV and pneumonia presented elevated levels of cytokines and chemokines (IL-6, IL-8, IL-18, IL-1RA, IL-10, IP-10, MCP-1, and MIP-1β) compared to those with only HIV. A marked pulmonary dysfunction was evidenced by significant reductions in FEF25, FEF25-75, and FEV1. The correlation between these immune mediators and lung function parameters supports the connection between pneumonia-associated inflammation and end organ lung dysfunction. A low CD4 cell count (<200 cells/μL) predicted inflammation and lung dysfunction. These results underscore the need for targeted clinical approaches to mitigate the adverse impacts of CAP on lung function in this population.
PubMed: 38251391
DOI: 10.3390/pathogens13010084 -
Antiviral Research Feb 2024JC polyomavirus (JCPyV) is a nonenveloped, double-stranded DNA virus that infects the majority of the population. Immunocompetent individuals harbor infection in their...
JC polyomavirus (JCPyV) is a nonenveloped, double-stranded DNA virus that infects the majority of the population. Immunocompetent individuals harbor infection in their kidneys, while severe immunosuppression can result in JCPyV spread to the brain, causing the neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Due to a lack of approved therapies to treat JCPyV and PML, the disease results in rapid deterioration, and is often fatal. In order to identify potential antiviral treatments for JCPyV, a high-throughput, large-scale drug screen was performed using the National Institutes of Health Clinical Collection (NCC). Drugs from the NCC were tested for inhibitory effects on JCPyV infection, and drugs from various classes that reduced JCPyV infection were identified, including receptor agonists and antagonists, calcium signaling modulators, and enzyme inhibitors. Given the role of calcium signaling in viral infection including Merkel cell polyomavirus and simian virus 40 polyomavirus (SV40), calcium signaling inhibitors were further explored for the capacity to impact JCPyV infection. Calcium and calmodulin inhibitors trifluoperazine (TFP), W-7, tetrandrine, and nifedipine reduced JCPyV infection, and TFP specifically reduced viral internalization. Additionally, TFP and W-7 reduced infection by BK polyomavirus, SV40, and SARS-CoV-2. These results highlight specific inhibitors, some FDA-approved, for the possible treatment and prevention of JCPyV and several other viruses, and further illuminate the calcium and calmodulin pathway as a potential target for antiviral drug development.
Topics: Humans; Calcium; Calmodulin; Neurodegenerative Diseases; Leukoencephalopathy, Progressive Multifocal; Polyomavirus Infections; JC Virus; Simian virus 40; Antiviral Agents; Sulfonamides
PubMed: 38246207
DOI: 10.1016/j.antiviral.2024.105817 -
Scientific Reports Jan 2024Genetic recombination is one of the major evolution processes of HIV-1. Despite their great genetic divergence, HIV-1 groups M and O can generate HIV-1/MO intergroup...
Genetic recombination is one of the major evolution processes of HIV-1. Despite their great genetic divergence, HIV-1 groups M and O can generate HIV-1/MO intergroup recombinants. The current description of 20 HIV-1/MO unique recombinant forms suggests a possible benefit of the recombination. The aim of this work was to study in vitro the replicative potential of HIV-1/MO recombinant forms. This analysis was based on a simple recombination pattern, [O-M], harboring a breakpoint in Vpr. A chimeric infectious molecular clone, pOM-TB-2016 was synthesized from HIV-1/M subtype B and HIV-1/O subgroup T and recombinant viruses were obtained by transfection/co-culture. To compare the replicative potential of these viruses, two markers were monitored in culture supernatants: Reverse Transcriptase (RT) activity and P24 antigen concentration. The results showed a superiority of the group M parental virus compared to group O for both markers. In contrast, for the recombinant virus, RT activity data did not overlap with the concentration of P24 antigen, suggesting a hybrid behavior of the recombinant, in terms of enzyme activity and P24 production. These results highlighted many hypotheses about the impact of recombination on replicative potential and demonstrated again the significant plasticity of HIV genomes and their infinite possibility of evolution.
Topics: Humans; HIV-1; HIV Infections; Recombination, Genetic; HIV Seropositivity; Orthopoxvirus; Parents
PubMed: 38242913
DOI: 10.1038/s41598-024-51873-3 -
Systematic Reviews Jan 2024The interaction between modelers and policymakers is becoming more common due to the increase in computing speed seen in recent decades. The recent pandemic caused by...
BACKGROUND
The interaction between modelers and policymakers is becoming more common due to the increase in computing speed seen in recent decades. The recent pandemic caused by the SARS-CoV-2 virus was no exception. Thus, this study aims to identify and assess epidemiological mathematical models of SARS-CoV-2 applied to real-world data, including immunization for coronavirus 2019 (COVID-19).
METHODOLOGY
PubMed, JSTOR, medRxiv, LILACS, EconLit, and other databases were searched for studies employing epidemiological mathematical models of SARS-CoV-2 applied to real-world data. We summarized the information qualitatively, and each article included was assessed for bias risk using the Joanna Briggs Institute (JBI) and PROBAST checklist tool. The PROSPERO registration number is CRD42022344542.
FINDINGS
In total, 5646 articles were retrieved, of which 411 were included. Most of the information was published in 2021. The countries with the highest number of studies were the United States, Canada, China, and the United Kingdom; no studies were found in low-income countries. The SEIR model (susceptible, exposed, infectious, and recovered) was the most frequently used approach, followed by agent-based modeling. Moreover, the most commonly used software were R, Matlab, and Python, with the most recurring health outcomes being death and recovery. According to the JBI assessment, 61.4% of articles were considered to have a low risk of bias.
INTERPRETATION
The utilization of mathematical models increased following the onset of the SARS-CoV-2 pandemic. Stakeholders have begun to incorporate these analytical tools more extensively into public policy, enabling the construction of various scenarios for public health. This contribution adds value to informed decision-making. Therefore, understanding their advancements, strengths, and limitations is essential.
Topics: Humans; United States; SARS-CoV-2; COVID-19; Pandemics; Vaccination; Outcome Assessment, Health Care
PubMed: 38229123
DOI: 10.1186/s13643-023-02411-1 -
Annals of Internal Medicine Feb 2024The efficacy of the BNT162b2 vaccine in pediatrics was assessed by randomized trials before the Omicron variant's emergence. The long-term durability of vaccine... (Observational Study)
Observational Study
BACKGROUND
The efficacy of the BNT162b2 vaccine in pediatrics was assessed by randomized trials before the Omicron variant's emergence. The long-term durability of vaccine protection in this population during the Omicron period remains limited.
OBJECTIVE
To assess the effectiveness of BNT162b2 in preventing infection and severe diseases with various strains of the SARS-CoV-2 virus in previously uninfected children and adolescents.
DESIGN
Comparative effectiveness research accounting for underreported vaccination in 3 study cohorts: adolescents (12 to 20 years) during the Delta phase and children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase.
SETTING
A national collaboration of pediatric health systems (PEDSnet).
PARTICIPANTS
77 392 adolescents (45 007 vaccinated) during the Delta phase and 111 539 children (50 398 vaccinated) and 56 080 adolescents (21 180 vaccinated) during the Omicron phase.
INTERVENTION
First dose of the BNT162b2 vaccine versus no receipt of COVID-19 vaccine.
MEASUREMENTS
Outcomes of interest include documented infection, COVID-19 illness severity, admission to an intensive care unit (ICU), and cardiac complications. The effectiveness was reported as (1-relative risk)*100, with confounders balanced via propensity score stratification.
RESULTS
During the Delta period, the estimated effectiveness of the BNT162b2 vaccine was 98.4% (95% CI, 98.1% to 98.7%) against documented infection among adolescents, with no statistically significant waning after receipt of the first dose. An analysis of cardiac complications did not suggest a statistically significant difference between vaccinated and unvaccinated groups. During the Omicron period, the effectiveness against documented infection among children was estimated to be 74.3% (CI, 72.2% to 76.2%). Higher levels of effectiveness were seen against moderate or severe COVID-19 (75.5% [CI, 69.0% to 81.0%]) and ICU admission with COVID-19 (84.9% [CI, 64.8% to 93.5%]). Among adolescents, the effectiveness against documented Omicron infection was 85.5% (CI, 83.8% to 87.1%), with 84.8% (CI, 77.3% to 89.9%) against moderate or severe COVID-19, and 91.5% (CI, 69.5% to 97.6%) against ICU admission with COVID-19. The effectiveness of the BNT162b2 vaccine against the Omicron variant declined 4 months after the first dose and then stabilized. The analysis showed a lower risk for cardiac complications in the vaccinated group during the Omicron variant period.
LIMITATION
Observational study design and potentially undocumented infection.
CONCLUSION
This study suggests that BNT162b2 was effective for various COVID-19-related outcomes in children and adolescents during the Delta and Omicron periods, and there is some evidence of waning effectiveness over time.
PRIMARY FUNDING SOURCE
National Institutes of Health.
Topics: United States; Humans; Adolescent; Child; BNT162 Vaccine; COVID-19 Vaccines; COVID-19; Comparative Effectiveness Research; Hospitalization
PubMed: 38190711
DOI: 10.7326/M23-1754 -
Advanced Science (Weinheim,... Mar 2024Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno-associated virus (AAV)-mediated OTOF gene replacement therapy is...
Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno-associated virus (AAV)-mediated OTOF gene replacement therapy is extensively validated in Otof-deficient mice. However, the clinical safety and efficacy of AAV-OTOF is not reported. Here, AAV-OTOF is generated using good manufacturing practice and validated its efficacy and safety in mouse and non-human primates in order to determine the optimal injection dose, volume, and administration route for clinical trials. Subsequently, AAV-OTOF is delivered into one cochlea of a 5-year-old deaf patient and into the bilateral cochleae of an 8-year-old deaf patient with OTOF mutations. Obvious hearing improvement is detected by the auditory brainstem response (ABR) and the pure-tone audiometry (PTA) in these two patients. Hearing in the injected ear of the 5-year-old patient can be restored to the normal range at 1 month after AAV-OTOF injection, while the 8-year-old patient can hear the conversational sounds. Most importantly, the 5-year-old patient can hear and recognize speech only through the AAV-OTOF-injected ear. This study is the first to demonstrate the safety and efficacy of AAV-OTOF in patients, expands and optimizes current OTOF-related gene therapy and provides valuable information for further application of gene therapies for deafness.
Topics: Humans; Animals; Mice; Dependovirus; Hearing Loss, Sensorineural; Hearing; Deafness; Genetic Therapy
PubMed: 38189623
DOI: 10.1002/advs.202306788