Salivary markers and coronavirus disease 2019: insights from cross-talk between the oral microbiome and pulmonary and systemic low-grade inflammation and implications for vascular complications.

To date, coronavirus disease 2019 (COVID-19) has affected over 6.2 million individuals worldwide, including 1.46 million deaths. COVID-19 complications are mainly induced by low-grade inflammation-causing vascular degeneration. There is an increasing body of evidence that suggests that oral dysbiotic taxa are associated with worse prognosis in COVID-19 patients, especially the Prevotella genus, which was retrieved from nasopharyngeal and bronchoalveolar lavage samples in affected patients. Oral dysbiosis may act by increasing the likelihood of vascular complications through low-grade inflammation, as well as impairing respiratory mucosal barrier mechanisms against SARS-CoV-2. Salivary markers can be used to reflect this oral dysbiosis and its subsequent damaging effects on and the lungs and vasculature. Salivary sampling can be self-collected, and is less costly and less invasive, and thus may be a superior option to serum markers in risk stratification of COVID-19 patients. Prospective studies are needed to confirm such hypothesis. Video Abstract: http://links.lww.com/CAEN/A28.

Hypoxia-inducible factor (HIF): The link between obesity and COVID-19.

The COVID-19 death toll has involved to date more than 1 million confirmed deaths. The death rate is even higher in the obese COVID-19 patients, as a result of hypoxia, due to the interplay between adipose tissue hypoxia and obstructive sleep apnea. The discrepancy of manifestations seen in COVID-19 seems to be mediated by a differential immune response rather than a differential viral load. One of the key players of the immune response is HIF. HIF-1ß is a stable constitutively expressed protein in the nucleus; and under hypoxic changes, its activity is unaffected, whereas the HIF-α subunit has a short half-life and because of its degradation by an enzyme known as propyl hydroxylase; under hypoxic conditions, propyl hydroxylase gets deactivated thus leading to the stabilization of HIF-1α. As mentioned before, HIF-1α expression is triggered by hypoxic states, this crippling condition will aggravate the pro-inflammatory characteristics of HIF-1α. The vast majority of decompensated COVID19 cases manifest with drastic lung injury and severe viral pneumonia, the infection-induced hypoxia will the existing hypoxia in obesity. This will additionally augment HIF-1α levels that will provoke the already existing cytokines' storm to fulminant. Consequently, this will directly correlate the effect of a hypoxic environment with the increase of HIF-1α level. HIFɑ exists in two main isoforms HIF-1α and HIF-2α. HIF-1α and HIF-2α act in distinct ways in how they work on different target genes. For example, HIF-2α may act on hemopoietin genes (heme-regulating genes); while HIF-1α acts on EPO. HIF-1α release seems to be markedly augmented in obesity due to adipose tissue hypoxia and obstructive sleep apnea resulting in cyclic hypoxia. HIF-1α can also be secreted by direct viral proteolytic effects. Whereas, HIF-2α is stimulated by chronic hypoxia. HIF-1α exerts detrimental effects on the immune system, characterized by unopposed pro-inflammation at the macrophages, dendritic cells, T cells, and complement levels resulting in cytokines' storm, which is linked to the poor outcomes of COVID-19. On the other hand, HIF-2α role is regulatory and largely opposes the actions mediated by HIF-1α. In view of this, inhibiting HIF-1α release or switching its production to HIF-2α by natural products such as resveratrol or by synthetic drugs, offer a good therapeutic strategy that can prevent COVID-19 worst outcome in infected patients. The approach of breaking the vicious circle between lung damage-induced hypoxia and HIF-1α pro-inflammatory stimulant through drugs is considered to be extremely promising as a therapeutic manner to combat further deterioration of COVID19 cases.

The Dental Pulp Stem/Progenitor Cells-Mediated Inflammatory-Regenerative Axis.

Relying on their ease of isolation and remarkable tissue reparative/regenerative potential, dental pulp stem/progenitor cells (DPSCs) gained pronounced importance in the field of regenerative dentistry. Though inflammation is classically considered the reason for the damage of the dentin-pulpal complex, it continues to be an essential stage of any dentin-pulpal tissue repair or regeneration procedures. During their performance of a pulpal tissue repair or regeneration actions, DPSCs interact with their inflammatory microenvironment locally, possibly influencing their fate and the result of any DPSCs-mediated dentin-pulpal reparative/regenerative endeavor. Hence, this review aims at comprehensively elaborating on these complex interactions of DPSCs with their local pulpal inflammatory microenvironment, particularizing on the inflammatory aspects, affecting DPSCs' stemness, homing/migration, proliferation, differentiation as well as immunomodulation characteristics, and the potentially fundamental intracellular processes involved and their anticipated association with the noncanonical as well as canonical Wnt/ß-Catenin intracellular signaling. Impact Statement This review particularizes on the current state of knowledge on the complex interrelation between dental pulp stem/progenitor cells and their pulpal inflammatory microenvironment; elaborates on inflammation aspects affecting their stemness, proliferation, migration/homing, differentiation and immunomodulation characteristics, and the fundamental intracellular processes involved and their anticipated association with the canonical and noncanonical Wnt pathways. All these aspects could significantly affect the dento-pulpal regenerative therapeutic approaches in vivo.