ß-glucuronidase as a biomarker for assessing the exposure to anticholinergic pesticides: A meta-analysis.

INTRODUCTION: The human exposure to anticholinergic pesticides has been associated with the development of various diseases. Therefore, several biomarkers have been proposed for biomonitoring human exposure to anticholinergic pesticides. OBJECTIVE: This work evaluated the effect of human exposure to anticholinergic pesticides on ß-glucuronidase (GUSB) levels. METHODS: A systematic review was performed using PubMed, Web of Science, Scopus, and EBSCO databases up to December 2021. The statistical analysis employed standardized mean differences and meta-regression. And the trial sequential analysis was performed. RESULTS: Nine studies were included. A monotonic relationship was observed between poisoning severity and GUSB. Furthermore, BuChE levels were correlated with GUSB levels. CONCLUSIONS: The results indicated that GUSB levels could be used as a possible diagnosis biomarker in poisoning related to anticholinergic pesticide exposure. However, the use of GUSB to assess the chronic exposure to anticholinergic pesticides could be only performed in recent exposure (≈ 7 days after last exposure).

The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters

A well-tolerated and cost-effective oral drug that blocks SARS-CoV-2 growth and dissemination would be a major advance in the global effort to reduce COVID-19 morbidity and mortality. Here, we show that the oral FDA-approved drug nitazoxanide (NTZ) significantly inhibits SARS-CoV-2 viral replication and infection in different primate and human cell models including stem cell-derived human alveolar epithelial type 2 cells. Furthermore, NTZ synergizes with remdesivir, and it broadly inhibits growth of SARS-CoV-2 variants B.1.351 (beta), P.1 (gamma), and B.1617.2 (delta) and viral syncytia formation driven by their spike proteins. Strikingly, oral NTZ treatment of Syrian hamsters significantly inhibits SARS-CoV-2-driven weight loss, inflammation, and viral dissemination and syncytia formation in the lungs. These studies show that NTZ is a novel host-directed therapeutic that broadly inhibits SARS-CoV-2 dissemination and pathogenesis in human and hamster physiological models, which supports further testing and optimization of NTZ-based therapy for SARS-CoV-2 infection alone and in combination with antiviral drugs.

SARS-CoV-2 Infection After Vaccination: Kidney Transplant Recipient Profile and Disease Evolution in a Single Center.

BACKGROUND: SARS-CoV-2 infection has had a major impact on kidney transplant patients. Recent evidence suggests that solid organ transplant recipients who received mRNA vaccines reach low immunization rates. There are only few reports about the risk factors and severity of COVID-19 in these patients. Our single center experience describes the patient profile and disease evolution observed in this vulnerable group after inoculation. MATERIAL AND METHODS: Retrospective cohort study with kidney transplant patients who received a COVID-19 vaccine before testing positive for SARS-CoV-19 using polymerase chain reaction. Demographic characteristics and clinical information are described and compared with our previous series of patients who were infected before the initiation of the vaccination rollout. RESULTS: Sixteen kidney transplant recipients diagnosed with COVID-19 after being vaccinated were included and compared with our previous series of 76 unvaccinated patients who were positive for COVID-19. No differences were found among risk factors such as age, time after transplant, hypertension, and obesity between groups (P value > .05). After COVID-19 diagnosis among inoculated patients, 10 patients were hospitalized, and 4 of who met the criteria for admission to the intensive care unit. Three patients died of COVID-19 complications. Despite this, the incidence of infections has decreased after vaccination rollout (P value < .05). CONCLUSIONS: Patients' risk profiles remain constant among recipients who were positive for COVID-19 between waves. We did not find significant differences in hospitalization and severity rates in this reduced group of patients. However, the overall incidence in our kidney transplant population has decreased.

Discovery of a SARS-CoV-2 Broadly-Acting Neutralizing Antibody with Activity against Omicron and Omicron + R346K Variants

The continual emergence of SARS-CoV-2 variants of concern, in particular the newly emerged Omicron (B.1.1.529) variant, has rendered ineffective a number of previously EUA approved SARS-CoV-2 neutralizing antibody therapies. Furthermore, even those approved antibodies with neutralizing activity against Omicron are reportedly ineffective against the subset of Omicron variants that contain a R346K substitution, demonstrating the continued need for discovery and characterization of candidate therapeutic antibodies with the breadth and potency of neutralizing activity required to treat newly diagnosed COVID-19 linked to recently emerged variants of concern. Following a campaign of antibody discovery based on the vaccination of Harbour H2L2 mice with defined SARS-CoV-2 spike domains, we have characterized the activity of a large collection of Spike-binding antibodies and identified a lead neutralizing human IgG1 LALA antibody, STI-9167. STI-9167 has potent, broad-spectrum neutralizing activity against the current SARS-COV-2 variants of concern and retained activity against the Omicron and Omicron + R346K variants in both pseudotype and live virus neutralization assays. Furthermore, STI-9167 nAb administered intranasally or intravenously provided protection against weight loss and reduced virus lung titers to levels below the limit of quantitation in Omicron-infected K18-hACE2 transgenic mice. With this established activity profile, a cGMP cell line has been developed and used to produce cGMP drug product intended for use in human clinical trials.

Metabolic snapshot of plasma samples reveals new pathways implicated in SARS-CoV-2 pathogenesis

Despite of the scientific and human efforts to understand COVID-19, there are questions still unanswered. Variations in the metabolic reaction to SARS-CoV-2 infection could explain the striking differences in the susceptibility to infection and the risk of severe disease. Here, we used untargeted metabolomics to examine novel metabolic pathways related to SARS-CoV-2 susceptibility and COVID-19 clinical severity using capillary electrophoresis coupled to a time-of-flight mass spectrometer (CE-TOF-MS) in plasma samples. We included 27 patients with confirmed COVID-19 early after symptom onset who were prospectively followed and 29 healthcare workers heavily exposed to SARS-CoV-2 but with low susceptibility to infection ( nonsusceptible). We found that the metabolite profile was predictive of the study group. We identified a total of 55 metabolites as biomarkers of SARS-CoV-2 susceptibility or COVID-19 clinical severity. We report the discovery of new plasma biomarkers for COVID-19 that provide mechanistic explanations for the clinical consequences of SARS-CoV-2, including mitochondrial and liver dysfunction as a consequence of hypoxemia (citrulline, citrate, and BAIBA), energy production and amino acid catabolism (L-glycine, L-alanine, L-serine, L-proline, L-aspartic acid and L-histidine), endothelial dysfunction and thrombosis (citrulline, L-ADMA, 2-AB, and Neu5Ac), and we found interconnections between these pathways. In summary, in this first report of the metabolomic profile of individuals with severe COVID-19 and SARS-CoV-2 susceptibility by CE-MS, we define several metabolic pathways implicated in SARS-CoV-2 susceptibility and COVID-19 clinical progression that could be developed as biomarkers of COVID-19.

Hepatitis C Virus Drugs Simeprevir and Grazoprevir Synergize with Remdesivir to Suppress SARS-CoV-2 Replication in Cell Culture

Effective control of COVID-19 requires antivirals directed against SARS-CoV-2 virus. Here we assess ten available HCV protease inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS- CoV-2 Mpro and HCV NS3/4A proteases, and virtual docking experiments show that all ten HCV drugs can potentially bind into the Mpro binding cleft. Seven of these HCV drugs inhibit SARS-CoV-2 Mpro protease activity, while four dock well into the PLpro substrate binding cleft and inhibit PLpro protease activity. These same seven HCV drugs inhibit SARS-CoV-2 virus replication in Vero and/or human cells, demonstrating that HCV drugs that inhibit Mpro, or both Mpro and PLpro, suppress virus replication. Two HCV drugs, simeprevir and grazoprevir synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, thereby increasing remdesivir inhibitory activity as much as 10-fold. HighlightsO_LISeveral HCV protease inhibitors are predicted to inhibit SARS-CoV-2 Mpro and PLpro. C_LIO_LISeven HCV drugs inhibit Mpro enzyme activity, four HCV drugs inhibit PLpro. C_LIO_LISeven HCV drugs inhibit SARS-CoV-2 replication in Vero and/or human cells. C_LIO_LIHCV drugs simeprevir and grazoprevir synergize with remdesivir to inhibit SARS- CoV-2. C_LI eTOC blurbBafna, White and colleagues report that several available hepatitis C virus drugs inhibit the SARS-CoV-2 Mpro and/or PLpro proteases and SARS-CoV-2 replication in cell culture. Two drugs, simeprevir and grazoprevir, synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir antiviral activity as much as 10-fold. O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/422511v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1c12181org.highwire.dtl.DTLVardef@7ed993org.highwire.dtl.DTLVardef@1fe56aaorg.highwire.dtl.DTLVardef@ebc34e_HPS_FORMAT_FIGEXP M_FIG C_FIG

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms.

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We explore several plausible avenues of activity including antiviral and host-mediated actions. We propose that the principal famotidine mechanism of action for COVID-19 involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release.

Characterization of Huh7 cells after the induction of insulin resistance and post-treatment with metformin.

Liver-specific insulin resistance is associated with the development of the main challenges in metabolism, resulting in dyslipidemia, hyperinsulinemia and hyperglycemia. In vitro models developed for researching hepatic insulin resistance are limited and employed cell lines without similar characteristics to primary human hepatocytes. The Huh7 cell line has been established as a model with similar characteristics to primary human hepatocytes. In addition, it has been identified in the Huh7 cell line that infection with the hepatitis C virus induces insulin resistance. Therefore, we analyzed the induction of insulin resistance (IR) in the Huh7 cell line using an overdosage of insulin and treatment with metformin for its reversal, with the purpose of establishing an insulin resistance model useful for metabolic and pharmacological studies. Insulin-resistant Huh7 (Huh7-IR) showed a reduction in Glut2, glycogen levels, and glucose uptake stimulated by insulin or tyrosine phosphorylation from the ß-fraction of insulin receptor post-insulin stimulation, with an increase of glucose production and lipid intracellular content. These biomarkers are frequently observed in insulin-resistant hepatic cells. Moreover, treatment of Huh7-IR with 0.5, 1 or 2 mM of metformin by 24 h decreased the biomarkers associated with an insulin-resistant state. These results suggest that Huh7-IR could be used as an in vitro system to research hepatic insulin resistance in metabolic and pharmacological studies.