SARS-CoV-2 infects human pancreatic beta cells and elicits beta cell impairment.
Emerging evidence points toward an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While preexisting diabetes is associated with severe COVID-19, it is unclear whether COVID-19 severity is a cause or consequence of diabetes. To mechanistically link COVID-19 to diabetes, we tested whether insulin-producing pancreatic beta cells can be infected by SARS-CoV-2 and cause beta cell depletion. We found that the SARS-CoV-2 receptor, ACE2, and related entry factors (TMPRSS2, NRP1, and TRFC) are expressed in beta cells, with selectively high expression of NRP1. We discovered that SARS-CoV-2 infects human pancreatic beta cells in patients who succumbed to COVID-19 and selectively infects human islet beta cells invitro. We demonstrated that SARS-CoV-2 infection attenuates pancreatic insulin levels and secretion and induces beta cell apoptosis, each rescued by NRP1 inhibition. Phosphoproteomic pathway analysis of infected islets indicates apoptotic beta cell signaling, similar to that observed in type 1 diabetes (T1D). In summary, our study shows SARS-CoV-2 can directly induce beta cell killing.
View details for DOI 10.1016/j.cmet.2021.05.013
View details for PubMedID 34081912
SARS-CoV-2 entry factors are expressed in nasal, ocular, and oral tissues: implications for COVID-19 prophylaxes/therapeutics
MOSBY-ELSEVIER. 2021: AB2
View details for Web of Science ID 000629158000005
ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs.
2020; 11 (1): 5453
The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.
View details for DOI 10.1038/s41467-020-19145-6
View details for PubMedID 33116139
Inferior Meatus Augmentation Procedure (IMAP) to Treat Empty Nose Syndrome: A Pilot Study.
Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery
Our understanding of empty nose syndrome (ENS) continues to evolve. Prior studies evaluating airway augmentation to treat ENS did not use validated disease-specific questionnaires, making the true impact of these surgeries unclear. We present a case series of 10 patients with ENS (11 procedures) who underwent the inferior meatus augmentation procedure (IMAP) between September 2014 and May 2017. Subjective outcomes of IMAP included comparisons of preoperative and postoperative assessments (1 week, 1 month, 3 months, 6 months) using the Empty Nose Syndrome 6-item Questionnaire (ENS6Q), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder 7-item Scale (GAD-7), and Sino-Nasal Outcome Test-22 (SNOT-22). The decrement in ENS6Q scores observed maintained statistical significance at 6 months (P ≤ .001). Similar results were achieved with PHQ-9, GAD-7, and SNOT-22 (P ≤ .01, P ≤ .01, P ≤ .001, respectively). IMAP can dramatically improve the quality of life of ENS patients regarding both ENS-specific symptoms and psychological well-being.
View details for DOI 10.1177/0194599819900263
View details for PubMedID 31935161
Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers.
medRxiv : the preprint server for health sciences
We investigated the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of healthy human donors. We detected ACE2 protein expression within the cilia organelle of ciliated airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during respiratory transmission. We further determined whether ACE2 expression in the cilia of upper respiratory cells was influenced by patient demographics, clinical characteristics, co-morbidities, or medication use, and found no evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) increases ACE2 protein expression.
View details for DOI 10.1101/2020.05.08.20092866
View details for PubMedID 32511516
View details for PubMedCentralID PMC7273284
Ethacridine inhibits SARS-CoV-2 by inactivating viral particles in cellular models.
bioRxiv : the preprint server for biology
More than a million people have now died from COVID-19, because of infection with the SARS-CoV-2 coronavirus. Currently, the FDA has approved remdesivir, an inhibitor of SARS-CoV-2 replication, to treat COVID-19, though very recent data from WHO showed little if any COVID19 protective effect. Here we report that ethacridine, a safe and potent antiseptic use in humans, effectively inhibits SARS-CoV-2, at very low concentrations (EC 50 ~ 0.08 μ M). Ethacridine was identified through a high-throughput screening of an FDA-approved drug library in living cells using a fluorescent assay. Interestingly, the main mode of action of ethacridine is to inactivate virus particles, preventing binding to the host cells. Thus, our work has identified a potent drug with a distinct mode of action against SARS-CoV-2.
View details for DOI 10.1101/2020.10.28.359042
View details for PubMedID 33140048
View details for PubMedCentralID PMC7605555
Evolution of the endoscopic modified Lothrop procedure: A systematic review and meta-analysis.
2018; 128 (2): 317–26
OBJECTIVE: Since first described in the 1990s, the endoscopic modified Lothrop procedure (EMLP) has been the subject of a growing body of literature. We performed a review to compare indications and outcomes of EMLP in an early cohort of publications (1990-2008) versus a contemporary cohort (2009-2016) and compare outcomes associated with follow-up ≥2 years versus <2 years.DATA SOURCES: PubMed, SCOPUS and Cochrane databases.REVIEW METHODS: An English-language search of the PubMed and Ovid databases was conducted to identify publications from 1990 to 2016 reporting clinical outcomes of EMLP. Meta-analysis was performed using Statistical Analysis System 9.4.RESULTS: A total of 1,205 patients were abstracted from 29 articles with a mean follow-up of 29.1 ± 10.3 months. The overall rate of significant or complete symptom improvement was 86.5% (95% confidence interval [CI]: 84.2%-88.7%). The overall patency rate was 90.7% (95% CI: 89.1%-92.3%), with a revision rate of 12.6% (95% CI: 10.6%-14.3%). Compared to the early cohort, patients in the contemporary cohort underwent EMLP more often for tumors (P < .001), had higher rates of complete or significant symptom improvement (90.0% vs. 82.6 %, P < .001); and trended toward greater patency rates (92.1% vs. 88.6%, P = .052). Compared to the short-term follow-up cohort, the long-term cohort showed no differences in symptom improvement or patency, but the revision rate was higher (14.5% vs. 9.2%, P = .016).CONCLUSIONS: In the last decade, EMLP has been performed more frequently for tumors. Recent studies have demonstrated improved symptom outcomes and a trend toward improved patency rates. The revision rate increased significantly when follow-up exceeded 2 years. Laryngoscope, 128:317-326, 2018.
View details for PubMedID 28921539
Glycolysis and the Hexosamine Biosynthetic Pathway as Novel Targets for Upper and Lower Airway Inflammation
ALLERGY ASTHMA & IMMUNOLOGY RESEARCH
2018; 10 (1): 6–11
Glycolysis is a process that rapidly converts glucose to lactate to produce adenosine triphosphate (ATP) under anaerobic conditions and occurs in all eukaryotic and prokaryotic cells. On the other hand, the hexosamine biosynthetic pathway (HBP) converts glucose to intermediate products like UDP-N-acetylglucosamine, which is critical for post-translational modifications of proteins, such as protein glycosylation. These 2 pathways are well known to contribute to glucose metabolism, but recent studies indicate modulation of these pathways can alter immune system function. In this review article, the authors present results suggesting how cellular metabolism, including glycolysis and the HBP, occurs in immune cells, and the immunologic significances of such activities. In addition, they provide a review of the literature on the effects of glycolysis and the HBP on various autoimmune, immunologic, and allergic diseases. Finally, the authors briefly introduce the results of their research on the immunologic effects of HBP supplementation (glucosamine) in animal models of allergic disease.
View details for PubMedID 29178672
View details for PubMedCentralID PMC5705485
- Mediators of Allergic Asthma and Rhinosinusitis MEDIATORS OF INFLAMMATION 2017: 7405245