Common manifestations of COVID-19 are respiratory and can extend from mild symptoms to severe acute respiratory distress. The severity of the illness can also extend from mild disease to life-threatening acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection can also affect the gastrointestinal tract, liver and pancreatic functions, leading to gastrointestinal symptoms. Moreover, SARS-CoV-2 can cause central and peripheral neurological manifestations, affect the cardiovascular system and promote renal dysfunction. Epidemiological data have indicated that cancer patients are at a higher risk of contracting the SARS-CoV-2 virus. Considering the multitude of clinical symptoms of COVID-19, the objective of the present review was to summarize their pathophysiology in previously healthy patients, as well as in those with comorbidities. The present review summarizes the current, though admittedly fluid knowledge on the pathophysiology and symptoms of COVID-19 infection. Although unclear issues still remain, the present study contributes to a more complete understanding of the disease, and may drive the direction of new research. The recognition of the severity of the clinical symptoms of COVID-19 is crucial for the specific therapeutic management of affected patients.

Biliary esophageal reflux at acidic pH is considered a risk factor in laryngopharyngeal cancer. We previously showed the key role NF- κ B in mediating acidic bile-induced pre-neoplastic events in hypopharyngeal cells, and that co-administration of specific NF- κ B inhibitor, BAY 11-7082, together with acidic bile, can effectively prevent its related oncogenic molecular effects. We hypothesize that the addition of BAY 11-7082 (10μM) either before or after application of acidic bile (400μM conjugated bile acids; pH 4.0), is capable of comparably blocking acidic bile-induced oncogenic molecular phenotypes in murine hypopharyngeal primary cells. We performed immunofluorescence, luciferase assay, western blot and qPCR analysis, demonstrating that 15-min of pre- or post-application of BAY 11-7082 effectively inhibits acidic bile-induced NF- κ B activation, transcriptional activation of RELA(p65), STAT3, EGFR, IL-6, bcl-2, W NT5A , “upregulation” of “oncomirs” miR-21, miR-155, miR-192 and “downregulation” of “tumor suppressor” miR-34a, miR-375, miR-451a. Our observations support the understanding that acidic bile-induced deregulation of anti-apoptotic or oncogenic factors, bcl-2 , STAT3, EGFR, IL-6, WNT5A , miR-21, miR-155, miR-375, is highly NF- κ B-dependent, showing that even post-application of inhibitor can suppress their deregulation. In conclusion, application of specific NF-κB inhibitor, has the capability of adequately blocking the early oncogenic molecular events produced by acidic bile whether it is applied pre or post exposure. In addition to therapeutic implications these findings provide a window of observation into the complex kinetics characterizing the mechanistic link between acidic bile and early neoplasia. Although BAY 11-7082 itself may not be suitable for clinical use, the application of other NF-κB inhibitors merits exploration.

Background: There is recent in vivo discovery documenting the carcinogenic effect of bile at strongly acidic pH 3.0 in hypopharynx, while in vitro data demonstrate that weakly acidic bile (pH 5.5) has a similar oncogenic effect. Because esophageal refluxate often occurs at pH > 4.0, here we aim to determine whether weakly acidic bile is also carcinogenic in vivo. Methods: Using 32 wild-type mice C57B16J, we performed topical application of conjugated primary bile acids with or without unconjugated secondary bile acid, deoxycholic acid (DCA), at pH 5.5 and controls, to hypopharyngeal mucosa (HM) twice per day, for 15 weeks. Results: Chronic exposure of HM to weakly acidic bile, promotes premalignant lesions with microinvasion, preceded by significant DNA/RNA oxidative damage, γH2AX (double strand breaks), NF-κB and p53 expression, overexpression of Bcl-2, and elevated Tnf and Il6 mRNAs, compared to controls. Weakly acidic bile, without DCA, upregulates the “oncomirs”, miR-21 and miR-155. The presence of DCA promotes Egfr, Wnt5a, and Rela overexpression, and a significant downregulation of “tumor suppressor” miR-451a. Conclusion: Weakly acidic pH increases the risk of bile-related hypopharyngeal neoplasia. The oncogenic properties of biliary esophageal reflux on the epithelium of the upper aerodigestive tract may not be fully modified when antacid therapy is applied. We believe that due to bile content, alternative therapeutic strategies using specific inhibitors of relevant molecular pathways or receptors may be considered in patients with refractory GERD.

Supraesophageal bile reflux at strongly acidic pH can cause hypopharyngeal squamous cell cancer, through activation of the oncogenic NF-κB-related pathway. We hypothesize that topical pre-or post-application of pharmacologic NF-κB inhibitor, BAY 11-7082 (0.25 μmol), on murine (C57BL/6J) HM (twice a day for 10 days) can effectively inhibit acidic bile (10 mmol/l; pH 3.0) induced oncogenic molecular events, similar to prior in vitro findings. We demonstrate that the administration of BAY 11-7082, either before or after acidic bile, eliminates NF-κB activation, prevents overexpression of Bcl2, Rela, Stat3, Egfr, Tnf, Wnt5a, and deregulations of miR-192, miR-504, linked to bile reflux-related hypopharyngeal cancer. Pre-but not post-application of NF-κB inhibitor, significantly blocks overexpression of Il6 and prostaglandin H synthases 2 (Ptgs2), and reverses miR-21, miR-155, miR-99a phenotypes, supporting its early bile-induced pro-inflammatory effect. We thus provide novel evidence that topical administration of a pharmacological NF-κB inhibitor, either before or after acidic bile exposure can successfully prevent its oncogenic mRNA and miRNA phenotypes in HM, supporting the observation that coadministration of NF-κB inhibitor may not be essential in preventing early bile-related oncogenic events and encouraging a capacity for further translational exploration.

Laryngopharyngeal reflux, a variant of gastroesophageal reflux disease, has been considered a risk factor in the development of hypopharyngeal cancer. Bile acids are frequently present in the gastroesophageal refluxate and their effect has been associated with inflammatory and neoplastic changes in the upper aerodigestive tract. Recent in vitro and in vivo studies have provided direct evidence of the role of acidic bile refluxate in hypopharyngeal carcinogenesis and documented the crucial role of NF-κB as a key mediator of early oncogenic molecular events in this process and also suggested a contribution of STAT3. Acidic bile can cause premalignant changes and invasive squamous cell cancer in the affected hypopharynx accompanied by DNA damage, elevated p53 expression and oncogenic mRNA and microRNA alterations, previously linked to head and neck cancer. Weakly acidic bile can also increase the risk for hypopharyngeal carcinogenesis by inducing DNA damage, exerting anti-apoptotic effects and causing precancerous lesions. The most important findings that strongly support bile reflux as an independent risk factor for hypopharyngeal cancer are presented in the current review and the underlying mechanisms are provided.