Surface control approach for growth of cerium oxide on flower-like molybdenum disulfide nanosheets enables superior removal of uremic toxins

Due to the high incidence of kidney disease, there is an urgent need to develop wearable artificial kidneys. This need is further exacerbated by the coronavirus disease 2019 pandemic. However, the dialysate regeneration system of the wearable artificial kidney has a low adsorption capacity for urea, which severely limits its application. Therefore, nanomaterials that can effectively remove uremic toxins, especially urea, to regenerate dialysate are required and should be further investigated and developed. Herein, flower-like molybdenum disulphide (MoS2) nanosheets decorated with highly dispersed cerium oxide (CeO2) were prepared (MoS2/CeO2), and their adsorption performances for urea, creatinine, and uric acid were studied in detail. Due to the open interlayer structures and the combination of MoS2 and CeO2, which can provide abundant adsorption active sites, the MoS2/CeO2 nanomaterials present excellent uremic toxin adsorption activities. Further, uremic toxin adsorption capacities were also assessed using a self-made fixed bed device under dynamic conditions, with the aim of developing MoS2/CeO2 for the practical adsorption of uremic toxins. In addition, the biocompatibility of MoS2/CeO2 was systematically analyzed using hemocompatibility and cytotoxicity assays. Our data suggest that MoS2/CeO2 can be safely used for applications requiring close contact with blood. Our findings confirm that novel 2-dimensional nanomaterial adsorbents have significant potential for dialysis fluid regeneration. © 2022

Identification and high-throughput quantification of baicalein and its metabolites in plasma and urine

Ethnopharmacological relevance: Scutellaria baicalensis Georgi. contains varieties of function compounds, and it has been used as traditional drug for centuries. Baicalein is the highest amount of flavonoid found in Scutellaria baicalensis Georgi., which exerts various pharmacological activities and might be a promising drug to treat COVID-19. Aim of the study: The present work aims to investigate the metabolism of baicalein in humans after oral administration, and study the pharmacokinetics of BA and its seven metabolites in plasma and urine. Materials and methods: The metabolism profiling and the identification of baicalein metabolites were performed on HPLC-Q-TOF. Then a column-switching method named MPX™-2 system was applied for the high-throughput quantificationof BA and seven metabolites. Results: Seven metabolites were identified using HPLC-Q-TOF, including sulfate, glucuronide, glucoside, and methyl-conjugated metabolites. Pharmacokinetic study found that BA was extensively metabolized in vivo, and only 5.65% of the drug remained intact in the circulatory system after single dosing. Baicalein-7-O-sulfate and baicalein-6-O-glucuronide-7-O-glucuronide were the most abundant metabolites. About 7.2% of the drug was excreted through urine and mostly was metabolites. Conclusion: Seven conjugated metabolites were identified in our assay. A high-throughput HPLC-MS/MS method using column switch was established for quantifying BA and its metabolites. The method has good sensitivity and reproducibility, and successfully applied for the clinical pharmacokinetic study of baicalein and identified metabolites. We expect that our results will provide a metabolic and pharmacokinetic foundation for the potential application of baicalein in medicine. © 2022

A Method to Monitor Activity of SARS-CoV-2 Nsp3 from Cells

SARS-CoV-2 protease Nsp3 is a therapeutic target for developing anti-SARS-CoV-2 drugs. Nsp3 is a large multi-spanning membrane protein, and its characterization in vitro has been challenging. Here we describe an in vitro assay to characterize the biochemical activity of full-length Nsp3 isolated from cells. The assay can be used to evaluate Nsp3 inhibitors. © 2023, The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.

Ligand-based discovery of coronavirus main protease inhibitors using MACAW molecular embeddings

Ligand-based drug design methods are thought to require large experimental datasets to become useful for virtual screening. In this work, we propose a computational strategy to design novel inhibitors of coronavirus main protease, M(pro). The pipeline integrates publicly available screening and binding affinity data in a two-stage machine-learning model using the recent MACAW embeddings. Once trained, the model can be deployed to rapidly screen large libraries of molecules in silico. Several hundred thousand compounds were virtually screened and 10 of them were selected for experimental testing. From these 10 compounds, 8 showed a clear inhibitory effect on recombinant M(pro), with half-maximal inhibitory concentration values (IC(50)) in the range 0.18-18.82 μM. Cellular assays were also conducted to evaluate cytotoxic, haemolytic, and antiviral properties. A promising lead compound against coronavirus M(pro) was identified with dose-dependent inhibition of virus infectivity and minimal toxicity on human MRC-5 cells.

Safety of COVID-19 vaccines in children with inborn errors of metabolism in terms of developing metabolic decompensation.

AIM: There are no recommended guidelines or clinical studies on safety of COVID-19 vaccines in patients with inborn errors of metabolism (IEMs). Here, we aimed to examine the relationship between COVID-19 vaccination and metabolic outcome in paediatric IEM patients. METHODS: Patients with IEM between the ages of 12 and 18 were enrolled. Term metabolic decompensation was defined as acute disruption in metabolic homeostasis due to vaccination. Clinical and biochemical markers were compared between pre- and post-vaccination periods. RESULTS: Data from a total of 36 vaccination episodes in 18 patients were included. Thirteen patients had intoxication-type metabolic disorders including organic acidemia (OA), urea cycle disorders (UCDs), maple syrup urine disease (MSUD) and phenylketonuria (PKU); 4 patients had energy metabolism disorders including fatty acid metabolism disorders and LIPIN 1 deficiency; and 1 patient had glycogen storage disorder (GSD) type 5. Seventeen patients received BNT162b2, and 1 received CoronaVac because of an underlying long QT syndrome. Fatty acid metabolism disorders, LIPIN 1 deficiency and GSD type 5 were included in the same group named 'metabolic myopathies'. In two PKU patients, plasma phenylalanine level increased significantly within 24 h following the second dose of vaccination. None of the OA, UCD, MSUD and metabolic myopathy patients experienced acute metabolic attack and had emergency department admission due to metabolic decompensation within 1 month after vaccination. CONCLUSIONS: COVID-19 vaccines did not cause acute metabolic decompensation in a cohort of 18 children with IEM.

Iron Dyshomeostasis in COVID-19: Biomarkers Reveal a Functional Link to 5-Lipoxygenase Activation.

Coronavirus disease 2019 (COVID-19) is characterized by a broad spectrum of clinical symptoms. After acute infection, some subjects develop a post-COVID-19 syndrome known as long-COVID. This study aims to recognize the molecular and functional mechanisms that occur in COVID-19 and long-COVID patients and identify useful biomarkers for the management of patients with COVID-19 and long-COVID. Here, we profiled the response to COVID-19 by performing a proteomic analysis of lymphocytes isolated from patients. We identified significant changes in proteins involved in iron metabolism using different biochemical analyses, considering ceruloplasmin (Cp), transferrin (Tf), hemopexin (HPX), lipocalin 2 (LCN2), and superoxide dismutase 1 (SOD1). Moreover, our results show an activation of 5-lipoxygenase (5-LOX) in COVID-19 and in long-COVID possibly through an iron-dependent post-translational mechanism. Furthermore, this work defines leukotriene B4 (LTB4) and lipocalin 2 (LCN2) as possible markers of COVID-19 and long-COVID and suggests novel opportunities for prevention and treatment.

Screening and identification of potential MERS-CoV papain-like protease (PLpro) inhibitors; Steady-state kinetic and Molecular dynamic studies.

MERS-CoV belongs to the coronavirus group. Recent years have seen a rash of coronavirus epidemics. In June 2012, MERS-CoV was discovered in the Kingdom of Saudi Arabia, with 2,591 MERSA cases confirmed by lab tests by the end of August 2022 and 894 deaths at a case-fatality ratio (CFR) of 34.5% documented worldwide. Saudi Arabia reported the majority of these cases, with 2,184 cases and 813 deaths (CFR: 37.2%), necessitating a thorough understanding of the molecular machinery of MERS-CoV. To develop antiviral medicines, illustrative investigation of the protein in coronavirus subunits are required to increase our understanding of the subject. In this study, recombinant expression and purification of MERS-CoV (PLpro), a primary goal for the development of 22 new inhibitors, were completed using a high throughput screening methodology that employed fragment-based libraries in conjunction with structure-based virtual screening. Compounds 2, 7, and 20, showed significant biological activity. Moreover, a docking analysis revealed that the three compounds had favorable binding mood and binding free energy. Molecular dynamic simulation demonstrated the stability of compound 2 (2-((Benzimidazol-2-yl) thio)-1-arylethan-1-ones) the strongest inhibitory activity against the PLpro enzyme. In addition, disubstitutions at the meta and para locations are the only substitutions that may boost the inhibitory action against PLpro. Compound 2 was chosen as a MERS-CoV PLpro inhibitor after passing absorption, distribution, metabolism, and excretion studies; however, further investigations are required.

Metabolic Activation of PARP as a SARS-CoV-2 Therapeutic Target-Is It a Bait for the Virus or the Best Deal We Could Ever Make with the Virus? Is AMBICA the Potential Cure?

The COVID-19 pandemic has had a great impact on global health and is an economic burden. Even with vaccines and anti-viral medications we are still scrambling to get a balance. In this perspective, we have shed light upon an extremely feasible approach by which we can control the SARS-CoV-2 infection and the associated complications, bringing some solace to this ongoing turmoil. We are providing some insights regarding an ideal agent which could prevent SARS-CoV-2 multiplication. If we could identify an agent which is an activator of metabolism and is also bioactive, we could prevent corona activation (AMBICA). Some naturally occurring lipid molecules best fit this identity as an agent which has the capacity to replenish our host cells, specifically immune cells, with ATP. It could also act as a source for providing a substrate for host cell PARP family members for MARylation and PARylation processes, leading to manipulation of the viral macro domain function, resulting in curbing the virulence and propagation of SARS-CoV-2. Identification of the right lipid molecule or combination of lipid molecules will fulfill the criteria. This perspective has focused on a unique angle of host-pathogen interaction and will open up a new dimension in treating COVID-19 infection.

Absorption, distribution, metabolism and excretion of 14C-Emvododstat following a single oral dose in rats and dogs.

Emvododstat is a potent inhibitor of dihydroorotate dehydrogenase and is now in clinical development for the treatment of acute myeloid leukaemia and COVID-19.Following an oral dose administration in Long-Evans rats, 14C-emvododstat-derived radioactivity was widely distributed throughout the body, with the highest distribution in the endocrine, fatty, and secretory tissues and the lowest in central nervous system.Following a single oral dose of 14C-emvododstat in rats, 54.7% of the dose was recovered in faeces while less than 0.4% of dose was recovered in urine 7 days post-dose. Emvododstat was the dominant radioactive component in plasma and faeces.Following a single oral dose of 14C-emvododstat in dogs, 75.2% of the dose was recovered in faeces while 0.5% of dose was recovered in urine 8 days post-dose. Emvododstat was the dominant radioactive component in faeces, while emvododstat and its two metabolites (O-desmethyl emvododstat and emvododstat amide bond hydrolysis product) were the major circulating radioactivity in dog plasma.

FDG-avid lymph nodes (LN) in response to vaccines for SARS-CoV-2

Aim/Introduction: Vaccines against SARS-CoV-2 virus were developed due to the impetuous coronavirus pandemic. Vaccines hold a possibility to provoke side effects. The aim of our study was to examine the impact of COVID-19 vaccination on the incidence and duration of false-positive FDG-avid lymphadenopathy after vaccination with different types of vaccines and to determine its relationship with age, gender, and vaccine type. Material(s) and Method(s): The retrospective study included 103 patients who met the following criteria:18F-FDG PET/CT scan performed (in the period from August 2021 to December 2021) for staging or restaging of diagnosed oncological diseases at different time periods after vaccination Pfizer-BioNTech, Moderna-BioNTech and Oxford-AstraZeneca. Exclusion criteria were incomplete information about vaccination, patients with a diagnosed malignant lymphoproliferative disease, concomitant benign pathology of the lymphatic system, history of acute viral infection up to 3 months from the date of PET/CT. Result(s): False-positive reactive lymphadenopathy was identified in 35 (34%) of 103 patients included in our study cohort, which occurred during the first 2 weeks to 12 weeks after vaccination and manifested as increased metabolic activity in regional non-enlarged lymph nodes: ipsilateral axillary lymph nodes of levels I-III, as well as cervical LN of levels IV and VB). A significant moderate decline in metabolic activity in the LN over time was reported, as well as a decrease in the detection rate of PET-positive reactive findings with time. The results showed a trend of a positive relationship - the occurrence of reactive lymphadenopathy more often in women than in men. The detection rate, as well as the intensity of the activity of glucose metabolism, were higher in patients under the age of 50 compared to those >= 50 years. However, we did not find significant differences between the studied types of vaccines (p >0.05). Conclusion(s): Multidisciplinary physician awareness is essential regarding the possibility of false-positive FDG lymphadenopathy in relation to local inflammation and as a manifestation of the immune response due to COVID-19 RNA vaccination and adenoviral vector-based vaccine up to 12 weeks after injection, in order to optimize the clinical interpretation of hybrid scan results that determine the subsequent therapeutic approach of cancer patients. The results of the present study demonstrate the importance of vaccination on the contralateral side of the tumor drainage, as well as taking a thorough anamnesis. Keywords: FDG PET/CT, false positive lymphadenopathy, vaccination.

First experience of using casirivimab/imdevimab in COVID-19 in the Russian Federation.

The lack of effective etiotropic therapy is a serious challenge in the treatment of patients with COVID-19. The recent emergence of a new class of medications neutralizing monoclonal antibodies against the SARS-CoV-2 spike protein allows to partially solve this problem. This article presents a clinical case of a patient with an increased risk of COVID-19 complications (paroxysmal atrial fibrillation, atherogenic dyslipidemia, impaired carbohydrate tolerance) who was treated with 600 mg casirivimab and 600 mg imdevimab by intravenous infusion. A significant improvement in the patient's well-being was noted within the first 24 hours: normalization of body temperature, stool, reduction of weakness, disappearance of arthralgia and myalgia. After 48 hours, a negative test result for SARS-CoV-2 RNA was obtained, which altogether made it possible to state the recovery. There were no adverse events during and after therapy. The casirivimab and imdevimab monoclonal antibody combination may be considered as a promising etiotropic treatment for COVID-19. Copyright © 2022, Dynasty Publishing House.

Steroids - Exploitation

Corticosteroids, more specifically glucocorticoids are one of the most prescribed drugs. Corticosteroids are adrenal hormones that serve significant physiologic activities such as modulating glucose metabolism, protein catabolism, calcium metabolism, bone turnover control, immunosuppression, and down-regulation of inflammatory cascade. Corticosteroids are regarded life-saving due to their various effects and have been used therapeutically to treat broad range of auto-immune, rheumatologic, inflammatory, neoplastic, and viral illnesses.However, the therapeutic benefits of glucocorticoids are restricted by the adverse effects. The most serious side effects of corticosteroids are associated with the use of higher doses for longer periods and OTC availability in specific pharmacies, which leads to dependency, as well as its usage in mild and moderate server instances, which is contrary to guidelines. In the recent times the use of corticosteroids has been multiplied with the emergence of the Covid -19 pandemic. WHO and the standard guidelines has recommended the usage of corticosteroids in critically ill covid-19 patients but their usage in mild and moderate cases caused more harm than benefit. This illicit usage has resulted in the development of opportunistic fungal illnesses such as mucormycosis, posing an extra risk to patients in terms of quality of life and finances. Other adverse effects of systemic corticosteroids include morphological changes, increased blood sugar levels, delayed wound healing, infections, decreased bone density, truncal obesity, cataracts, glaucoma, blood pressure abnormalities, and muscle fibre atrophy.In this review we want to discuss the significance and detrimental effects of corticosteroids emphasizing on the recent times i.e., COVID-19.

Brain FDG PET imaging of patients with persistent post- COVID-19 fatigue

Aim/Introduction: A recent report prepared by the Centers for Disease Control and Prevention indicates that 71% of patients experience persistent fatigue even after recovery from the acute phase of COVID-19 infection. We investigated if post-COVID-19 fatigue is associated with alterations in brain metabolism and microstructure to better understand the underlying neurobiological mechanism. Material(s) and Method(s): Brain F-18 FDG PET and diffusion tensor magnetic resonance imaging (DTIMR) were performed in 12 patients experiencing persistent post- COVID-19 fatigue that lasted more than six weeks post-discharge from hospitalization or discontinued home isolation after acute SARS-CoV-2 infection (fatigue group, Male:Female = 6:6, mean > SD age 35.7 > 13.8 years, Chalder fatigue scale score 8.3 > 2.2, time since COVID-19 diagnosis 7.9 > 5.5 months) and 9 recovered patients without such fatigue (non-fatigue group, M:F = 3:6, age 25.6 > 9.2, fatigue score 1.6 > 1.5, time since COVID-19 diagnosis 8.0 > 6.0 months). A commercially available normative brain FDG PET database (MIMneuro, v7.0.5, MIM Software, Inc.) was used to derive z scores for regional cerebral glucose metabolism. Fractional anisotropy (FA) values were extracted from DTI-MR datasets. Twotailed t-tests were performed for group comparison and P < 0.05 was considered statistically significant. Result(s): The fatigue group demonstrated significantly higher regional cerebral glucose metabolism in the left inferior and middle cerebellar peduncle (P = 0.001 and 0.043, respectively), left middle temporal gyrus (P = 0.002), left parahippocampal gyrus (P = 0.029), primary visual cortex (P = 0.031), supplementary motor area (P = 0.036), supramarginal gyrus (P = 0.044), and lower metabolism in the left precentral gyrus (P = 0.001) when compared to the non-fatigue group. The fatigue group also demonstrated significantly higher FA values in the left and right middle frontal gyrus (P = 0.014 and 0.038, respectively), left precentral gyrus (P = 0.024), right superior frontal gyrus (P =0.032), right postcentral gyrus (P = 0.047), left superior parietal gyrus (P = 0.048), and corpus callosum (P = 0.016) when compared to the nonfatigue group. Conclusion(s): Patients experiencing persistent fatigue after recovering from acute SARS-CoV-2 infection demonstrated significant changes in regional cerebral glucose metabolism and microstructure, when compared to those individuals without on-going fatigue symptoms. The altered cerebral metabolic and microstructural profile may help to better understand the neurobiological mechanism for management of patients suffering from lingering post-COVID-19 fatigue.

Developmental Risk Factors of Young Children with Inherited Metabolic Disorders During the COVID-19 Pandemic

Objective: Coronavirus disease 2019 (COVID-19) pandemic has led to emergence of new developmental risk factors. Developmental risk factors for young children with inherited metabolic disorders have not been studied based on a comprehensive framework. We aimed to determine the developmental risk factors of young children with inherited metabolic disorders during COVID-19 pandemic based on bioecological theory. Material(s) and Method(s): In a cross-sectional design, children aged 0-42 months that who had appointments at Ankara University School of Medicine Department of Pediatrics (AUDP) Pediatric Metabolism Division with the diagnoses of inherited metabolic disorders were recruited between October 1st, 2020 to January 1st, 2021. Developmental risk factors were assessed with a semi-structured interview based on questions of the Expanded Guide for Monitoring Child Development revised for the pandemic at AUDP Developmental Pediatrics Division. Result(s): The sample consisted of 95 children with inherited metabolic disorders (median age:25, IQR: 17-35 months, 57.9% boys). Most children (54 children, 56.8%) had amino-acid metabolism disorders. Child-related developmental risk factors included new behavioral problems in most of the sample (53 children, 55.8%) and increased screen time in 26 children (27.3%). As family-related developmental risk factors, 40 children (42.1%) were living with a family member diagnosed with major depression. In environment-related developmental risk factors;41 families (43.2%) experienced a decrease in their household income and 21 (22.1%) loss of job during the pandemic, 17 (17.9%) delay in health care follow up visits, 8 of 28 (28.6%) discontinuity of intervention and rehabilitation services. Participation in life was severely limited in 42 (44.2%) children with inherited metabolic disorders. Conclusion(s): Apart from life threatening medical problems, children and their families in Turkey and potentially in other low- and middle-income countries face multiple developmental risk factors. Preventable or reducible risk factors should be addressed to support these children's development in this pandemic and beyond. Copyright © 2022 Ankara Pediatric Hematology Oncology Training and Research Hospital. All rights reserved.

METABOLIC BIOLOGICAL MARKERS FOR DIAGNOSING AND MONITORING THE COURSE OF TUBERCULOSIS.

The international biomedical community has been currently facing a need to find a simple and most accessible type of analysis that helps to diagnose tuberculosis (TB) with the maximum reliability even before the onset of clinical manifestations. Tuberculosis results in more deaths than any other pathogen, second only to pneumonia caused by the SARS-CoV-2 virus, but the majority of infected people remain asymptomatic. In addition, it is important to develop methods to distinguish various forms of tuberculosis infection course at early stages and to reliably stratify patients into appropriate groups (persons with a rapidly progressing infection, chronic course, latent infection carriers). Immunometabolism investigates a relationship between bioenergetic pathways and specific functions of immune cells that has recently become increasingly important in scientific research. The host anti-mycobacteria immune response in tuberculosis is regulated by a number of metabolic networks that can interact both cooperatively and antagonistically, influencing an outcome of the disease. The balance between inflammatory and immune reactions limits the spread of mycobacteria in vivo and protects from developing tuberculosis. Cytokines are essential for host defense, but if uncontrolled, some mediators may contribute to developing disease and pathology. Differences in plasma levels of metabolites between individuals with advanced infection, LTBI and healthy individuals can be detected long before the onset of the major related clinical signs. Changes in amino acid and cortisol level may be detected as early as 12 months before the onset of the disease and become more prominent at verifying clinical diagnosis. Assessing serum level of certain amino acids and their ratios may be used as additional diagnostic markers of active pulmonary TB. Metabolites, including serum fatty acids, amino acids and lipids may contribute to detecting active TB. Metabolic profiles indicate about increased indolamine 2.3-di-oxygenase 1 (IDO1) activity, decreased phospholipase activity, increased adenosine metabolite level, and fibrous lesions in active vs. latent infection. TB treatment can be adjusted based on individual patient metabolism and biomarker profiles. Thus, exploring immunometabolism in tuberculosis is necessary for development of new therapeutic strategies. Copyright © 2022 Saint Petersburg Pasteur Institute. All rights reserved.

Targeting Virus-Induced Reprogrammed Cell Metabolism via Glycolytic Inhibitors: An Effective Therapeutic Approach Against SARS-CoV-2.

Reprogrammed cell metabolism has been observed in a wide range of viral infected cells. Viruses do not have their metabolism; they rely on the cellular metabolism of the host to ensure the energy and macromolecules requirement for replication. Like other viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) does not own its metabolism, but viral infected cells adopt aberrant cell metabolism. Infected viral cells, uses the energy and macromolecules to make their own copies, to do so they need to increase the rate of metabolism to ensure the requirement of macromolecules In contrast, the cellular metabolism of noninfected cells is more plastic than infected cells. Therefore, it is essential to examine the virus infection in the context of metabolic alterations of host cells. A novel therapeutic approach is urgently required to treat highly infectious COVID-19 disease and its pathogenesis. Interference of glucose metabolism might be a promising strategy to determine COVID-19 treatment options. Based on the recent research, this mini-review aims to understand the impact of reprogrammed cell metabolism in COVID-19 pathogenesis and explores the potential of targeting metabolic pathways with small molecules as a new strategy for the development of a novel drug to treat COVID-19 disease. This type of research line provides new hope in the development of antiviral drugs by targeting hijacked cell metabolism in case of viral diseases and also in COVID-19.

Trained immunity is induced in humans after immunization with an adenoviral vector COVID-19 vaccine.

BACKGROUND: Heterologous effects of vaccines are mediated by 'trained immunity' whereby myeloid cells are metabolically and epigenetically reprogrammed resulting in heightened responses to subsequent insults. Adenovirus vaccine vector has been reported to induce trained immunity in mice. Therefore, we sought to determine if the ChAdOx1 nCoV-19 vaccine (AZD1222), which uses an adenoviral vector, could induce trained immunity in vivo in humans. METHODS: Ten healthy volunteers donated blood on the day before receiving the ChAdOx1 nCoV-19 vaccine and on day 14, 56 and 90 post vaccination. Monocytes were purified from PBMC; cell phenotype was determined by flow cytometry, expression of metabolic enzymes were quantified by RT-qPCR and production of cytokines and chemokine in response to stimulation ex vivo were analyzed by multiplex ELISA. RESULTS: Monocyte frequency and count were increased in peripheral blood up to 3 months post vaccination compared with their own pre-vaccine control. Expression of HLA-DR, CD40 and CD80 was enhanced on monocytes for up to 3 months following vaccination. Moreover, monocytes had increased expression of glycolysis-associated enzymes 2 months post vaccination. Upon stimulation ex vivo with unrelated antigens, monocytes produced increased IL-1ß, IL-6, IL-10, CXCL1, and MIP-1α, and decreased TNF, compared with pre-vaccine controls. Resting monocytes produced more IFN-γ, IL-18, and MCP-1 up to 3 months post vaccination compared with pre-vaccine controls. CONCLUSION: These data provide evidence for the induction of trained immunity following a single dose of the ChAdOx1 nCoV-19 vaccine. FUNDING: This work was funded by The Health Research Board (EIA-2019-010) and Science Foundation Ireland Strategic Partnership Programme (Proposal ID 20/SPP/3685).

COVID-19 Vaccines and the Virus: Impact on Drug Metabolism and Pharmacokinetics.

This article reports on an American Society of Pharmacology and Therapeutics, Division of Drug Metabolism and Disposition symposium held at Experimental Biology on April 2nd, 2022, in Philadelphia. As of July 2022, over 500 million people have been infected with SARS-CoV-2 (the virus causing COVID-19) and over 12,000,000,000 vaccine doses have been administered. Clinically significant interactions between viral infections and hepatic drug metabolism were first recognized over 40 years ago during a cluster of pediatric theophylline toxicity cases attributed to reduced hepatic drug metabolism amidst an influenza B outbreak. Today, a substantive body of research supports that the activated innate immune response generally decreases hepatic cytochrome P450 (CYP) activity. The interactions extend to drug transporters and other organs and have the potential to impact drug absorption, distribution, metabolism, and excretion (ADME). Based on this knowledge, altered ADME is predicted with SARS-CoV-2 infection or vaccination. The report begins with a clinical case exploring the possibility of SARS-CoV-2 vaccination increasing clozapine levels. This is followed by discussions of how SARS-CoV-2 infection or vaccines alter the metabolism and disposition of complex drugs, such as nanoparticles and biologics and small molecule therapies. The review concludes with a discussion of the effects of viral infections on placental amino acid transport and their potential to impact fetal development. The session improved our understanding of the impact of emerging viral infections and vaccine technologies on drug metabolism and disposition, which will help mitigate drug toxicity and improve drug and vaccine safety and effectiveness. Significance Statement Altered pharmacokinetics of small molecule and complex molecule drugs and fetal brain distribution of amino acids following SARS-CoV-2 infection or immunization are possible. The proposed mechanisms involve decreased liver CYP metabolism of small molecules, enhanced innate immune system metabolism of complex molecules and altered placental and fetal blood-brain barrier amino acid transport, respectively. Future research is needed to understand the effects of these interactions on adverse drug responses, drug and vaccine safety and effectiveness and fetal neurodevelopment.

Dysregulation of glutamine/glutamate metabolism in COVID-19 patients: A metabolism study in African population and mini meta-analysis.

Coronavirus disease 2019 (COVID-19) remains a serious global threat. The metabolic analysis had been successfully applied in the efforts to uncover the pathological mechanisms and biomarkers of disease severity. Here we performed a quasi-targeted metabolomic analysis on 56 COVID-19 patients from Sierra Leone in western Africa, revealing the metabolomic profiles and the association with disease severity, which was confirmed by the targeted metabolomic analysis of 19 pairs of COVID-19 patients. A meta-analysis was performed on published metabolic data of COVID-19 to verify our findings. Of the 596 identified metabolites, 58 showed significant differences between severe and nonsevere groups. The pathway enrichment of these differential metabolites revealed glutamine and glutamate metabolism as the most significant metabolic pathway (Impact = 0.5; -log10P = 1.959). Further targeted metabolic analysis revealed six metabolites with significant intergroup differences, with glutamine/glutamate ratio significantly associated with severe disease, negatively correlated with 10 clinical parameters and positively correlated with SPO2 (rs = 0.442, p = 0.005). Mini meta-analysis indicated elevated glutamate was related to increased risk of COVID-19 infection (pooled odd ratio [OR] = 2.02; 95% confidence interval [CI]: 1.17-3.50) and severe COVID-19 (pooled OR = 2.28; 95% CI: 1.14-4.56). In contrast, elevated glutamine related to decreased risk of infection and severe COVID-19, the pooled OR were 0.30 (95% CI: 0.20-0.44), and 0.44 (95% CI: 0.19-0.98), respectively. Glutamine and glutamate metabolism are associated with COVID-19 severity in multiple populations, which might confer potential therapeutic target of COVID-19, especially for severe patients.