Seroprevalence and risk factors associated with bovine tuberculosis in cattle in Eastern Bhutan.

Bovine tuberculosis (bTB) is a chronic zoonotic disease affecting cattle of all age groups including wild animals. It poses a significant threat to public health and high economic losses to dairy farmers. While the disease has been eradicated from most of the developed countries through extensive surveillance, testing and culling strategy, it is endemic in Africa, Asia, and the Middle East countries. Currently, there is limited research regarding the prevalence of bTB in cattle in Bhutan. This study aimed to determine the seroprevalence of bTB in cattle in six districts of eastern Bhutan. A two-stage probability proportional to size (PPS) sampling strategy was used to determine the number of animals from which serum samples needed to be collected in each district and sub-district. All farms and cattle for sampling were randomly selected from the data in the annual livestock census of 2020. The samples were tested using bTB ELISA test kit. The seroprevalence and their 95% confidence intervals were calculated. Logistic regression models were constructed to assess the influence of various individual animal and environmental risk factors (breed, age, sex, source of animal, body condition scores of animals, respiratory system status) associated with sero-positivity in animals. The study revealed an apparent seroprevalence of 2.57% (25/971 cattle; 95% CI:1.58-3.57), with an estimated true seroprevalence of 0.91% (95% CI: 0.0-2.81). However, none of the variables were found to be significantly associated with bTB seroprevalence in cattle. We recommend, further sampling and employment of confirmatory testing to fully ascertain the extent of bTB in the cattle herds in eastern Bhutan for prevention and control.

A Quality Improvement Initiative to Minimize Unnecessary Chest X-Ray Utilization in Pediatric Asthma Exacerbations.

Background: Current national guidelines recommend against chest X-rays (CXRs) for patients with acute asthma exacerbation (AAE). The overuse of CXRs in AAE has become a concern, prompting the need for a quality improvement (QI) project to decrease CXR usage through guideline-based interventions. We aimed to reduce the percentage of CXRs not adhering to national guidelines obtained for pediatric patients presenting to the Emergency Department (ED) with AAE by 50% within 12 months of project initiation. Methods: We conducted this study at a New York City urban level-2 trauma center. The team was composed of members from the ED and pediatric departments. Electronic medical records of children aged 2 to 18 years presenting with AAE were evaluated. Monthly data on CXR utilization encompassing instances where the ordered CXR did not adhere to guidelines was collected before and after implementing interventions. The interventions included provider education, visual reminders, printed cards, grand-round presentations, and electronic medical records modifications. Results: The study encompassed 887 eligible patients with isolated AAE. Baseline data revealed a mean preintervention CXR noncompliance rate of 37.5% among children presenting to the ED with AAE. The interventions resulted in a notable decrease in unnecessary CXR utilization, reaching 16.7%, a reduction sustained throughout subsequent months. Conclusions: This QI project successfully reduced unnecessary CXR utilization in pediatric AAE. A multi-faceted approach involving education, visual aids, and electronic reminders aligned clinical practice with evidence-based guidelines. This QI initiative is a potential template for other healthcare institutions seeking to curtail unnecessary CXR usage in pediatric AAE.

Increased expression of long non-coding RNA FIRRE promotes hepatocellular carcinoma by HuR-CyclinD1 axis signaling.

There is a critical need to understand the disease processes and identify improved therapeutic strategies for hepatocellular carcinoma (HCC). The long noncoding RNAs (lncRNAs) display diverse effects on biological regulations. The aim of this study was to identify a lncRNA as a potential biomarker of HCC and investigate the mechanisms by which the lncRNA promotes HCC progression using human cell lines and in vivo. Using RNA-Seq analysis, we found that lncRNA FIRRE was significantly upregulated in hepatitis C virus (HCV) associated liver tissue and identified that lncRNA FIRRE is significantly upregulated in HCV-associated HCC compared to adjacent non-tumor liver tissue. Further, we observed that FIRRE is significantly upregulated in HCC specimens with other etiologies, suggesting this lncRNA has the potential to serve as an additional biomarker for HCC. Overexpression of FIRRE in hepatocytes induced cell proliferation, colony formation, and xenograft tumor formation as compared to vector-transfected control cells. Using RNA pull-down proteomics, we identified HuR as an interacting partner of FIRRE. We further showed that the FIRRE-HuR axis regulates cyclin D1 expression. Our mechanistic investigation uncovered that FIRRE is associated with an RNA-binding protein HuR for enhancing hepatocyte growth. Together, these findings provide molecular insights into the role of FIRRE in HCC progression.

Momordicine-I Suppresses Head and Neck Cancer Growth by Reprogrammimg Immunosuppressive Effect of the Tumor-Infiltrating Macrophages and B Lymphocytes.

Head and neck cancer (HNC) is prevalent worldwide, and treatment options are limited. Momordicine-I (M-I), a natural component from bitter melon, shows antitumor activity against these cancers, but its mechanism of action, especially in the tumor microenvironment (TME), remains unclear. In this study, we establish that M-I reduces HNC tumor growth in two different immunocompetent mouse models using MOC2 and SCC VII cells. We demonstrate that the anticancer activity results from modulating several molecules in the monocyte/macrophage clusters in CD45+ populations in MOC2 tumors by single-cell RNA sequencing. Tumor-associated macrophages (TAM) often pose a barrier to antitumor effects, but following M-I treatment, we observe a significant reduction in the expression of Sfln4, a myeloid cell differentiation factor, and Cxcl3, a neutrophil chemoattractant, in the monocyte/macrophage populations. We further find that the macrophages must be in close contact with the tumor cells to inhibit Sfln4 and Cxcl3, suggesting that these TAMs are impacted by M-I treatment. Coculturing macrophages with tumor cells shows inhibition of Agr1 expression following M-I treatment, which is indicative of switching from M2 to M1 phenotype. Furthermore, the total B-cell population in M-I-treated tumors is significantly lower, whereas spleen cells also show similar results when cocultured with MOC2 cells. M-I treatment also inhibits PD1, PD-L1, and FoxP3 expression in tumors. Collectively, these results uncover the potential mechanism of M-I by modulating immune cells, and this new insight can help to develop M-I as a promising candidate to treat HNCs, either alone or as adjuvant therapy.

Antimicrobial Consumption in the Livestock Sector in Bhutan: Volumes, Values, Rates, and Trends for the Period 2017-2021.

Data on the use of antimicrobials in humans and livestock may provide evidence to guide policy changes to mitigate the risk of antimicrobial resistance (AMR). However, there is limited information available about antimicrobial use in livestock in low- and middle-income countries, even though these nations are most vulnerable to the impact of AMR. This study aimed to assess the consumption of veterinary antimicrobials in Bhutan and identify areas for improvement to reduce the use of antimicrobials in livestock. National data on livestock numbers and annual procurement of veterinary antimicrobials over five years (2017-2021) were used to calculate rates of antimicrobial consumption and annual national expenditure on veterinary antimicrobials in Bhutan. The rate of antimicrobial consumption in Bhutan was 3.83 mg per population correction unit, which is lower than most countries in Europe, comparable with the rates of consumption in Iceland and Norway, and approximately 120-fold lower than published rates of antimicrobial consumption in South Asian countries, including Nepal and Pakistan. The low rates of antimicrobial consumption by the animal health sector in Bhutan could be attributable to stronger governance of antimicrobial use in Bhutan, higher levels of compliance with regulation, and better adherence to standard guidelines for antimicrobial treatment of livestock.

Targeting Lin28 axis enhances glypican-3-CAR T cell efficacy against hepatic tumor initiating cell population.

Overexpression of Lin28 is detected in various cancers with involvement in the self-renewal process and cancer stem cell generation. In the present study, we evaluated how the Lin28 axis plays an immune-protective role for tumor-initiating cancer cells in hepatocellular carcinoma (HCC). Our result using HCC patient samples showed a positive correlation between indoleamine 2,3-dioxygenase-1 (IDO1), a kynurenine-producing enzyme with effects on tumor immune escape, and Lin28B. Using in silico prediction, we identified a Sox2/Oct4 transcriptional motif acting as an enhancer for IDO1. Knockdown of Lin28B reduced Sox2/Oct4 and downregulated IDO1 in tumor-initiating hepatic cancer cells. We further observed that inhibition of Lin28 by a small-molecule inhibitor (C1632) suppressed IDO1 expression. Suppression of IDO1 resulted in a decline in kynurenine production from tumor-initiating cells. Inhibition of the Lin28 axis also impaired PD-L1 expression in HCC cells. Consequently, modulating Lin28B enhanced in vitro cytotoxicity of glypican-3 (GPC3)-chimeric antigen receptor (CAR) T and NK cells. Next, we observed that GPC3-CAR T cell treatment together with C1632 in a HCC xenograft mouse model led to enhanced anti-tumor activity. In conclusion, our results suggest that inhibition of Lin28B reduces IDO1 and PD-L1 expression and enhances immunotherapeutic potential of GPC3-CART cells against HCC.

Molecular Changes in Relation to Alcohol Consumption and Hepatocellular Carcinoma.

Alcohol is the one of the major causes of liver diseases and promotes liver cirrhosis and hepatocellular carcinoma (HCC). In hepatocytes, alcohol is converted to acetaldehyde, which causes hepatic steatosis, cellular apoptosis, endoplasmic reticulum stress, peroxidation, production of cytokines and reduces immune surveillance. Endotoxin and lipopolysaccharide produced from intestinal bacteria also enhance the production of cytokines. The development of hepatic fibrosis and the occurrence of HCC are induced by these alcohol metabolites. Several host genetic factors have recently been identified in this process. Here, we reviewed the molecular mechanism associated with HCC in alcoholic liver disease.

Blood Clots Per Rectum in a Pediatric Patient With Salmonella Enteritis: A Case Report.

Infection is a common cause of hematochezia in children. While infectious diarrhea can present with bloody stools, it is rare to have the passage of frank blood clots per rectum in the pediatric population. This is a case of a seven-year-old male who presented with vomiting, diarrhea, severe abdominal pain, and passage of blood clots per rectum. As symptoms progressed, consideration of non-infectious causes was investigated and subsequently ruled out. The stool polymerase chain reaction (PCR) was positive for Salmonella species, while stool culture was negative for any enteropathogen. This report highlights the unusual occurrence of the passage of blood clots per rectum in a child with salmonella enterocolitis.

c-JUN inhibits mTORC2 and glucose uptake to promote self-renewal and obesity.

Metabolic syndrome is associated with obesity, insulin resistance, and the risk of cancer. We tested whether oncogenic transcription factor c-JUN metabolically reprogrammed cells to induce obesity and cancer by reduction of glucose uptake, with promotion of the stemness phenotype leading to malignant transformation. Liquid alcohol, high-cholesterol, fat diet (HCFD), and isocaloric dextrin were fed to wild-type or experimental mice for 12 months to promote hepatocellular carcinoma (HCC). We demonstrated 40% of mice developed liver tumors after chronic HCFD feeding. Disruption of liver-specific c-Jun reduced tumor incidence 4-fold and improved insulin sensitivity. Overexpression of c-JUN downregulated RICTOR transcription, leading to inhibition of the mTORC2/AKT and glycolysis pathways. c-JUN inhibited GLUT1, 2, and 3 transactivation to suppress glucose uptake. Silencing of RICTOR or c-JUN overexpression promoted self-renewal ability. Taken together, c-JUN inhibited mTORC2 via RICTOR downregulation and inhibited glucose uptake via downregulation of glucose intake, leading to self-renewal and obesity.

Circulatory Exosomes from COVID-19 Patients Trigger NLRP3 Inflammasome in Endothelial Cells.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces inflammatory response, cytokine storm, venous thromboembolism, coagulopathy, and multiple organ damage. Resting endothelial cells prevent coagulation, control blood flow, and inhibit inflammation. However, it remains unknown how SARS-CoV-2 induces strong molecular signals in distant cells for immunopathogenesis. In this study, we examined the consequence of human endothelial cells, microvascular endothelial cells (HMEC-1), and liver endothelial cells (TMNK-1) to exosomes isolated from plasma of mild or severe COVID-19 patients. We observed a significant induction of NLRP3, caspase-1, and interleukin-1ß (IL-1ß) mRNA expression in endothelial cells following exposure to exosomes from severe COVID-19 patients compared with that from patients with mild disease or healthy donors. Activation of caspase-1 was noted in the endothelial cell culture medium following exposure to the COVID-19 exosomes. Furthermore, COVID-19 exosomes significantly induced mature IL-1ß secretion in both HMEC-1 and TMNK-1 endothelial cell culture medium. Thus, our results demonstrated for the first time that exosomes from COVID-19 plasma trigger NLRP3 inflammasome in endothelial cells of distant organs resulting in IL-1ß secretion and inflammatory response. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health problem. Although the vaccine controls infection, understanding the molecular mechanism of pathogenesis will help in developing future therapies. Furthermore, several investigators predicted the involvement of endothelial cell-related inflammation in SARS-CoV-2 infection and using extracellular vesicles as a cargo to carry a drug or vaccine for combating SARS-CoV-2 infection. However, the mechanism by which endothelial cells are inflamed remains unknown. Our present study highlights that exosomes from severe COVID-19 patients can enhance inflammasome activity in distant endothelial cells for augmentation of immunopathogenesis and opens an avenue for developing therapies.

Long noncoding RNA ELDR promotes cell cycle progression in normal oral keratinocytes through induction of a CTCF-FOXM1-AURKA signaling axis.

Long noncoding RNAs (lncRNAs) have gained widespread attention as a new layer of regulation in biological processes during development and disease. The lncRNA ELDR (EGFR long noncoding downstream RNA) was recently shown to be highly expressed in oral cancers as compared to adjacent nontumor tissue, and we previously reported that ELDR may be an oncogene as inhibition of ELDR reduces tumor growth in oral cancer models. Furthermore, overexpression of ELDR induces proliferation and colony formation in normal oral keratinocytes (NOKs). In this study, we examined in further detail how ELDR drives the neoplastic transformation of normal keratinocytes. We performed RNA-seq analysis on NOKs stably expressing ELDR (NOK-ELDR), which revealed that ELDR enhances the expression of cell cycle-related genes. Expression of Aurora kinase A and its downstream targets Polo-like kinase 1, cell division cycle 25C, cyclin-dependent kinase 1, and cyclin B1 (CCNB1) are significantly increased in NOK-ELDR cells, suggesting induction of G2/M progression. We further identified CCCTC-binding factor (CTCF) as a binding partner of ELDR in NOK-ELDR cells. We show that ELDR stabilizes CTCF and increases its expression. Finally, we demonstrate the ELDR-CTCF axis upregulates transcription factor Forkhead box M1, which induces Aurora kinase A expression and downstream G2/M transition. These findings provide mechanistic insights into the role of the lncRNA ELDR as a potential driver of oral cancer during neoplastic transformation of normal keratinocytes.

Circulatory exosomes from COVID-19 patients trigger NLRP3 inflammasome in endothelial cells

SARS-CoV-2 infection induces inflammatory response, cytokine storm, venous thromboembolism, coagulopathy, and multiple organ damage. Resting endothelial cells prevent coagulation, control blood flow and inhibit inflammation. However, it remains unknown how SARS-CoV-2 induces strong molecular signals in distant cells for immunopathogenesis. In this study, we examined the consequence of human endothelial cells (microvascular endothelial cells (HMEC-1) and liver endothelial cells (TMNK-1)) to exosomes from plasma of severe COVID-19 patients. We observed a significant induction of NLRP3, caspase-1 and IL-1{beta} mRNA expression in the endothelial cells following exposure to exosomes from plasma of COVID-19 patients as compared to that of healthy donors. Activation of caspase-1 was noted in the endothelial cell culture medium following exposure to the COVID-19 exosomes. Further, COVID-19 exosomes significantly induced mature IL-1{beta} secretion in the endothelial cell culture medium. Thus, our results demonstrated for the first time that exosomes from COVID-19 plasma trigger NLRP3 inflammasome in endothelial cells of distant organs.

Neonatal encephalopathy prediction of poor outcome with diffusion-weighted imaging connectome and fixel-based analysis.

BACKGROUND: Better biomarkers of eventual outcome are needed for neonatal encephalopathy. To identify the most potent neonatal imaging marker associated with 2-year outcomes, we retrospectively performed diffusion-weighted imaging connectome (DWIC) and fixel-based analysis (FBA) on magnetic resonance imaging (MRI) obtained in the first 4 weeks of life in term neonatal encephalopathy newborns. METHODS: Diffusion tractography was available in 15 out of 24 babies with MRI, five each with normal, abnormal motor outcome, or death. All 15 except one underwent hypothermia as initial treatment. In abnormal motor and death groups, DWIC found 19 white matter pathways with severely disrupted fiber orientation distributions. RESULTS: Using random forest classification, these disruptions predicted the follow-up outcomes with 89-99% accuracy. These pathways showed reduced integrity in abnormal motor and death vs. normal tone groups (p < 10-6). Using ranked supervised multi-view canonical correlation and depicting just three of the five dimensions of the analysis, the abnormal motor and death were clearly differentiated from each other and the normal tone group. CONCLUSIONS: This study suggests that a machine-learning model for prediction using early DWIC and FBA could be a possible way of developing biomarkers in large MRI datasets having clinical outcomes. IMPACT: Early connectome and FBA of clinically acquired DWI provide a new noninvasive imaging tool to predict the long-term motor outcomes after birth, based on the severity of white matter injury. Disrupted white matter connectivity as a novel neonatal marker achieves high accuracy of 89-99% to predict 2-year motor outcomes using conventional machine-learning classification. The proposed neonatal marker may allow better prognostication that is important to elucidate neural repair mechanisms and evaluate treatment modalities in neonatal encephalopathy.

Emerging role of lncRNA ELDR in development and cancer.

Whole-genome sequencing and transcriptome analysis revealed more than 90% of the human genome transcribes noncoding RNAs including lncRNAs. From the beginning of the 21st century, lncRNAs have gained widespread attention as a new layer of regulation in biological processes. lncRNAs are > 200 nucleotides in size, transcribed by RNA polymerase II, and share many similarities with mRNAs. lncRNA interacts with DNA, RNA, protein, and miRNAs, thereby regulating many biological processes. In this review, we have focused mainly on LINC01156 [also known as the EGFR long non-coding downstream RNA (ELDR) or Fabl] and its biological importance. ELDR is a newly identified lncRNA and first reported in a mouse model, but it has a human homolog. The human ELDR gene is closely localized downstream of epidermal growth factor receptor (EGFR) gene at chromosome 7 on the opposite strand. ELDR is highly expressed in neuronal stem cells and associated with neuronal differentiation and mouse brain development. ELDR is upregulated in head and neck cancer, suggesting its role as an oncogene and its importance in prognosis and therapy. Publicly available RNA-seq data further support its oncogenic potential in different cancers. Here, we summarize all the aspects of ELDR in development and cancer, highlighting its future perspectives in the context of mechanism.

Akt inhibitor augments anti-proliferative efficacy of a dual mTORC1/2 inhibitor by FOXO3a activation in p53 mutated hepatocarcinoma cells.

Hepatocellular carcinoma (HCC) is one of the most common malignancy-related deaths. p53 mutation in HCC associates with worse clinicopathologic features including therapeutic limitation. A combination of targeted therapy may have some advantages. Akt/mTOR signaling contributes to the regulation of cell proliferation and cell death. Akt inhibitor (AZD5363) and mTORC1/2 dual inhibitor (AZD8055) are in a clinical trial for HCC and other cancers. In this study, we examined whether these inhibitors successfully induce antiproliferative activity in p53 mutant HCC cells, and the underlying mechanisms. We observed that a combination of AZD5363 and AZD8055 treatment synergizes antiproliferative activity on p53 mutated or wild-type HCC cell lines and induces apoptotic cell death. Mechanistic insights indicate that a combination of AZD5363 and AZD8055 activated FOXO3a to induce Bim-associated apoptosis in p53 mutated HCC cells, whereas cells retaining functional p53 enhanced Bax. siRNA-mediated knock-down of Bim or Bax prevented apoptosis in inhibitor-treated cells. We further observed a combination of treatment inhibits phosphorylation of FOXO3a and protects FOXO3a from MDM2 mediated degradation by preventing the phosphorylation of Akt and SGK1. FOXO3a accumulates in the nucleus under these conditions and induces Bim transcription in p53 mutant HCC cells. Combination treatment in the HCC cells expressing wild-type p53 causes interference of FOXO3a function for direct interaction with functional p53 and unable to induce Bim-associated cell death. On the other hand, Bim-associated cell death occurs in p53 mutant cells due to uninterrupted FOXO3a function. Overall, our findings suggested that a combined regimen of dual mTORC1/2 and Akt inhibitors may be an effective therapeutic strategy for HCC patients harboring p53 mutation.

Diverse roles of bitter melon (Momordica charantia) in prevention of oral cancer.

Oral squamous cell carcinoma (OSCC) is one of the common lethal malignancies which is increasing rapidly in the world. Increasing risks from alcohol and tobacco habits, lack of early detection markers, lack of effective chemotherapeutic agents, recurrence and distant metastasis make the disease more complicated to manage. Laboratory-based studies and epidemiological studies indicate important roles of nutraceuticals to manage different cancers. The plant bitter melon (Momordica charantia) is a good source of nutrients and bio-active phytochemicals such as triterpenoids, triterpene glycosides, phenolic acids, flavonoids, lectins, sterols and proteins. The plant is widely grown in Asia, Africa, and South America. Bitter melon has traditionally been used as a folk medicine and Ayurvedic medicine in Asian culture to treat diseases such as diabetes, since ancient times. The crude extract and some of the isolated pure compounds of bitter melon show potential anticancer effects against different cancers. In this review, we shed light on its effect on OSCC. Bitter melon extract has been found to inhibit cell proliferation and metabolism, induce cell death and enhance the immune defense system in the prevention of OSCC in vitro and in vivo. Thus, bitter melon may be used as an attractive chemopreventive agent in progression towards OSCC clinical study.

Hepatitis C Virus Evades Interferon Signaling by Suppressing Long Noncoding RNA Linc-Pint Involving C/EBP-ß.

Hepatitis C virus (HCV) regulates many cellular genes in modulating the host immune system for benefit of viral replication and long-term persistence in a host for chronic infection. Long noncoding RNAs (lncRNAs) play an important role in the regulation of many important cellular processes, including immune responses. We recently reported that HCV infection downregulates lncRNA Linc-Pint (long intergenic non-protein-coding RNA p53-induced transcript) expression, although the mechanism of repression and functional consequences are not well understood. In this study, we demonstrate that HCV infection of hepatocytes transcriptionally reduces Linc-Pint expression through CCAAT/enhancer binding protein ß (C/EBP-ß). Subsequently, we observed that the overexpression of Linc-Pint significantly upregulates interferon alpha (IFN-α) and IFN-ß expression in HCV-replicating hepatocytes. Using unbiased proteomics, we identified that Linc-Pint associates with DDX24, which enables RIP1 to interact with IFN-regulatory factor 7 (IRF7) of the IFN signaling pathway. We furthermore observed that IFN-α14 promoter activity was enhanced in the presence of Linc-Pint. Together, these results demonstrated that Linc-Pint acts as a positive regulator of host innate immune responses, especially IFN signaling. HCV-mediated downregulation of Linc-Pint expression appears to be one of the mechanisms by which HCV may evade innate immunity for long-term persistence and chronicity. IMPORTANCE The mechanism by which lncRNA regulates the host immune response during HCV infection is poorly understood. We observed that Linc-Pint was transcriptionally downregulated by HCV. Using a chromatin immunoprecipitation (ChIP) assay, we showed inhibition of transcription factor C/EBP-ß binding to the Linc-Pint promoter in the presence of HCV infection. We further identified that Linc-Pint associates with DDX24 for immunomodulatory function. The overexpression of Linc-Pint reduces DDX24 expression, which in turn results in the disruption of DDX24-RIP1 complex formation and the activation of IRF7. The induction of IFN-α14 promoter activity in the presence of Linc-Pint further confirms our observation. Together, our results suggest that Linc-Pint acts as a positive regulator of host innate immune responses. Downregulation of Linc-Pint expression by HCV helps in escaping the innate immune system for the development of chronicity.

Exosomes from COVID-19 Patients Carry Tenascin-C and Fibrinogen-ß in Triggering Inflammatory Signals in Cells of Distant Organ.

SARS-CoV-2 infection can cause cytokine storm and may overshoot immunity in humans; however, it remains to be determined whether virus-induced soluble mediators from infected cells are carried by exosomes as vehicles to distant organs and cause tissue damage in COVID-19 patients. We took an unbiased proteomic approach for analyses of exosomes isolated from plasma of healthy volunteers and COVID-19 patients. Our results revealed that tenascin-C (TNC) and fibrinogen-ß (FGB) are highly abundant in exosomes from COVID-19 patients' plasma compared with that of healthy normal controls. Since TNC and FGB stimulate pro-inflammatory cytokines via the Nuclear factor-κB (NF-κB) pathway, we examined the status of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-C motif chemokine ligand 5 (CCL5) expression upon exposure of hepatocytes to exosomes from COVID-19 patients and observed significant increase compared with that from healthy subjects. Together, our results demonstrate that TNC and FGB are transported through plasma exosomes and potentially trigger pro-inflammatory cytokine signaling in cells of distant organ.