Calcitriol modifies tight junctions, improves barrier function, and reduces <scp>TNF‐α‐induced</scp> barrier leak in the human <scp>lung‐derived</scp> epithelial cell culture model, <scp>16HBE</scp> 14o‐

Rybakovsky, Elizabeth; DiGuilio, Katherine M; Valenzano, Mary Carmen; Geagan, Sophie; Pham, Kaithlyn; Harty, Ronald N.; Mullin, James M.

doi:10.14814/phy2.15592

Cited by 4 publications

(5 citation statements)

References 80 publications

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“…The fact that naturally occurring-even dietary-compounds are very adept in that regard offers a safety and economic attribution that is very appealing. Although not a flavonoid or polyphenol, vitamin D offers yet another example of a dietary compound that proved clinically useful in COVID-19 and exhibited the ability to modify and improve the barrier function of airway epithelial models (Bae et al, 2022;Rastogi et al, 2022;Gao et al, 2023;Rybakovsky et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

Quercetin improves and protects Calu-3 airway epithelial barrier function

DiGuilio,

Rybakovsky,

Valenzano

et al. 2023

Front. Cell Dev. Biol.

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Introduction: In light of the impact of airway barrier leaks in COVID-19 and the significance of vitamin D in COVID-19 outcomes, including airway barrier protection, we investigated whether the very common dietary flavonoid quercetin could also be efficacious in supporting airway barrier function.Methods: To address this question, we utilized the widely used airway epithelial cell culture model, Calu-3.Results: We observed that treating Calu-3 cell layers with quercetin increased transepithelial electrical resistance while simultaneously reducing transepithelial leaks of 14C-D-mannitol (Jm) and 14C-inulin. The effects of quercetin were concentration-dependent and exhibited a biphasic time course. These effects of quercetin occurred with changes in tight junctional protein composition as well as a partial inhibition of cell replication that resulted in decreased linear junctional density. Both of these effects potentially contribute to improved barrier function. Quercetin was equally effective in reducing the barrier compromise caused by the pro-inflammatory cytokine TNF-α, an action that seemed to derive, in part, from reducing the elevation of ERK 1/2 caused by TNF-α.Discussion: Quercetin improved Calu-3 barrier function and reduced TNF-α-induced barrier compromise, mediated in part by changes in the tight junctional complex.

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Section: Discussionmentioning

confidence: 99%

Quercetin improves and protects Calu-3 airway epithelial barrier function

DiGuilio,

Rybakovsky,

Valenzano

et al. 2023

Front. Cell Dev. Biol.

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“…(Azmi et al 2023 ; Chileshe et al 2022 ; Holick et al 2023 ). Furthermore, calcitriol has been shown to improve the barrier function of 16HBE cell layers based on two independent measures by inhibiting TNF-α-induced barrier leakage of epithelial cells in a human lung culture model (Rybakovsky et al 2023 ).…”

Section: Resultsmentioning

confidence: 99%

Pharmacological evaluation of vitamin D in COVID-19 and long COVID-19: recent studies confirm clinical validation and highlight metformin to improve VDR sensitivity and efficacy

Gomaa,

Abdel-Wadood,

Thabet

et al. 2023

Inflammopharmacol

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Nearly four years after its first appearance, and having gone from pandemic to endemic, the SARS-CoV-2 remains out of control globally. The purpose of this study was to evaluate the clinical efficacy of vitamin D (VD) in COVID-19 and long COVID-19, explain the discrepancy in clinical outcomes and highlight the potential impact of metformin on VD efficacy in recent articles. Articles from January 2022 to August 2023 were selected for this review. The objective of this study was achieved by reviewing, analyzing, and discussing articles demonstrating (1) the mechanism of action of VD (2) observational or randomized clinical trials (RCTs) that support or not the beneficial clinical effects of VD in COVID-19 or long COVID. (3) genetic and non-genetic reasons for the variation in the effects of VD. Articles were collected from electronic databases such as PubMed, Scopus, MEDLINE, Google Scholar, Egyptian Knowledge Bank, Science Direct, and Cochrane Database of Systematic Reviews. Twenty three studies conducted in vitro or in animal models indicated that VD may act in COVID-19 through protecting the respiratory system by antimicrobial peptide cathelicidins, reducing lung inflammation, regulating innate and adaptive immune functions and up regulation of autophagy gene activity. Our review identified 58 clinical studies that met the criteria. The number of publications supporting a beneficial clinical activity of VD in treating COVID-19 was 49 (86%), including 12 meta-analyses. Although the total patients included in all articles was 14,071,273, patients included in publications supporting a beneficial role of VD in COVID-19 were 14,029,411 (99.7%). Collectively, extensive observational studies indicated a decisive relationship between low VD levels and the severity of COVID-19 and mortality outcomes. Importantly, evidence from intervention studies has demonstrated the effectiveness of VD supplements in treating COVID-19. Furthermore, the results of 4 observational studies supported the beneficial role of VD in alleviating symptoms of long COVID-19 disease. However, eight RCTs and one meta-analysis of RCTs may contain low-grade evidence against a beneficial role of VD in COVID-19. Twenty-five articles have addressed the association between VDR and DBP genetic polymorphisms and treatment failure of VD in COVID-19. Impaired VDR signaling may underlie the variability of VD effects as non-genetic mechanisms. Interestingly, in recent studies, metformin has a beneficial therapeutic role in COVID-19 and long COVID-19, possibly by improving AMPK signaling of the VDR and enhancing the efficacy of the VD. In conclusion, evidence has been significantly strengthened over the past 18 months, with several meta-analyses and RCTs reporting conclusive beneficial effects of VD supplementation against COVID-19 and highlighting metformin to improve VDR sensitivity and efficacy in treating COVID-19 and long COVID-19.

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“…Using COVID-19 as an example, it is instructive to consider the now-demonstrated utility of the micronutrient vitamin D3 in this disease's severity [46][47][48]. The clinical picture here is well-supported by vitamin D's reported ability to improve airway barrier function, as well as reduce the airway barrier compromise caused by proinflammatory TNF-α in in vitro studies [29,45]. It is interesting to consider whether a widespread use of a Vitamin D supplement at the height of the COVID-19 pandemic would have supported SARS-CoV-2-compromised airway barrier function and measurably reduced the disease's toll on health care systems worldwide.…”

Section: Micronutrient Reduction Of Barrier Leakmentioning

confidence: 96%

“…Many excellent reviews have been written on the subject and it currently seems a well-established fact that micronutrients can improve basal epithelial barrier function [ 24 , 40 , 41 , 42 ]. In addition, micronutrients have demonstrated efficacy in reducing the barrier compromise caused by disease agents and modifiers [ 43 , 44 , 45 ]. In doing this, they have shown the promise of clinical value as both preventatives and therapeutics in various disease scenarios.…”

Section: Micronutrient Reduction Of Barrier Leakmentioning

confidence: 99%

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Micronutrients at Supplemental Levels, Tight Junctions and Epithelial Barrier Function: A Narrative Review

DiGuilio,

Del Rio,

Harty

et al. 2024

IJMS

Self Cite

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Disease modifiers, whether from cancer, sepsis, systemic inflammation, or microbial pathogens, all appear to induce epithelial barrier leak, with induced changes of the Tight Junctional (TJ) complex being pivotal to the process. This leak—and the ensuant breakdown of compartmentation—plays a central role in disease morbidity on many levels. Accumulation of lung water in the luminal compartment of airways was a major driver of morbidity and mortality in COVID-19 and is an excellent example of the phenomenon. Increasing awareness of the ability of micronutrients to improve basal barrier function and reduce barrier compromise in pathophysiology may prove to be a low-cost, safe, and easily administered prophylactic and/or therapeutic option amenable to large populations. The growing appreciation of the clinical utility of supplemental doses of Vitamin D in COVID-19 is but one example. This narrative review is intended to propose a general theory on how and why micronutrients—at levels above normal dietary intake—successfully remodel TJs and improve barrier function. It discusses the key difference between dietary/Recommended Daily Allowance (RDA) levels of micronutrients versus supplemental levels, and why the latter are needed in disease situations. It advances a hypothesis for why signal transduction regulation of barrier function may require these higher supplemental doses to achieve the TJ remodeling and other barrier element changes that are clinically beneficial.

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Calcitriol modifies tight junctions, improves barrier function, and reduces TNF‐α‐induced barrier leak in the human lung‐derived epithelial cell culture model, 16HBE 14o‐

Cited by 4 publications

References 80 publications

Quercetin improves and protects Calu-3 airway epithelial barrier function

Quercetin improves and protects Calu-3 airway epithelial barrier function

Pharmacological evaluation of vitamin D in COVID-19 and long COVID-19: recent studies confirm clinical validation and highlight metformin to improve VDR sensitivity and efficacy

Micronutrients at Supplemental Levels, Tight Junctions and Epithelial Barrier Function: A Narrative Review

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