Up-Regulated Vitamin D Receptor by Pelargonium sidoides Extract EPs® 7630 Contributes to Rhinovirus Defense in Bronchial Epithelial Cells

Roth, Michael; Sun, Qingzhu; Tamm, Michael

doi:10.3390/ph14020172

Cited by 15 publications

(23 citation statements)

References 40 publications

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“…The fractions generated by ultrafiltration were analyzed using HPLC-UV, gel permeation chromatography (GPC), and NMR spectroscopy. HPLC analysis was used to monitor the purine derivatives and benzopyranones in the fractions according to the LC-MS assignment reported by Roth et al ( Roth et al, 2021 ). Polymeric and oligomeric prodelphinidins appeared as broad signals in HPLC analysis, whereas carbohydrates were not detectable due to the absence of chromophores.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, whereas the 1–3 kDa fraction comprises mainly monomeric gallocatechin and prodelphinidin dimers to tetramers with proven effects in virus entry, the <1 kDa fraction contains highly substituted benzopyranones like umckalin and other small molecules. Although little is known about the antiviral effect of these compounds, umckalin and other benzopyranones were shown to modulate immune responses and affect antiviral defense mechanisms ( Robertson et al, 2016 ; Roth et al, 2021 ). Considering the TMPRSS2-independent entry inhibition that we observed in Vero cells, it appears likely that umckalin and other small molecules contributed to the inhibition of SARS-CoV-2 entry in our study.…”

Section: Discussionmentioning

confidence: 99%

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Antiviral and Immunomodulatory Effects of Pelargonium sidoides DC. Root Extract EPs® 7630 in SARS-CoV-2-Infected Human Lung Cells

Papies¹,

Emanuel²,

Heinemann³

et al. 2021

Front. Pharmacol.

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Treatment options for COVID-19 are currently limited. Drugs reducing both viral loads and SARS-CoV-2-induced inflammatory responses would be ideal candidates for COVID-19 therapeutics. Previous in vitro and clinical studies suggest that the proprietary Pelargonium sidoides DC. root extract EPs 7630 has antiviral and immunomodulatory properties, limiting symptom severity and disease duration of infections with several upper respiratory viruses. Here we assessed if EPs 7630 affects SARS-CoV-2 propagation and the innate immune response in the human lung cell line Calu-3. In direct comparison to other highly pathogenic CoV (SARS-CoV, MERS-CoV), SARS-CoV-2 growth was most efficiently inhibited at a non-toxic concentration with an IC50 of 1.61 μg/ml. Particularly, the cellular entry step of SARS-CoV-2 was significantly reduced by EPs 7630 pretreatment (10–100 μg/ml) as shown by spike protein-carrying pseudovirus particles and infectious SARS-CoV-2. Using sequential ultrafiltration, EPs 7630 was separated into fractions containing either prodelphinidins of different oligomerization degrees or small molecule constituents like benzopyranones and purine derivatives. Prodelphinidins with a low oligomerization degree and small molecule constituents were most efficient in inhibiting SARS-CoV-2 entry already at 10 μg/ml and had comparable effects on immune gene regulation as EPs 7630. Downregulation of multiple pro-inflammatory genes (CCL5, IL6, IL1B) was accompanied by upregulation of anti-inflammatory TNFAIP3 at 48 h post-infection. At high concentrations (100 μg/ml) moderately oligomerized prodelphinidins reduced SARS-CoV-2 propagation most efficiently and exhibited pronounced immune gene modulation. Assessment of cytokine secretion in EPs 7630-treated and SARS-CoV-2-coinfected Calu-3 cells showed that pro-inflammatory cytokines IL-1β and IL-6 were elevated whereas multiple other COVID-19-associated cytokines (IL-8, IL-13, TNF-α), chemokines (CXCL9, CXCL10), and growth factors (PDGF, VEGF-A, CD40L) were significantly reduced by EPs 7630. SARS-CoV-2 entry inhibition and the differential immunomodulatory functions of EPs 7630 against SARS-CoV-2 encourage further in vivo studies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antiviral and Immunomodulatory Effects of Pelargonium sidoides DC. Root Extract EPs® 7630 in SARS-CoV-2-Infected Human Lung Cells

Papies¹,

Emanuel²,

Heinemann³

et al. 2021

Front. Pharmacol.

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“…2 ). Most recently, EPs®7630, a herbal drug preparation from the roots of Pelargonium sidoides , which is efficacious against respiratory tract infections, was found to increase host defense against RV by upregulating the VDR in human bronchial epithelial cells [ 80 ].…”

Section: D Signaling Boosts Antiviral Immunitymentioning

confidence: 99%

Vitamin D, infections and immunity

Ismailova

White

2021

Rev Endocr Metab Disord

173

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Vitamin D, best known for its role in skeletal health, has emerged as a key regulator of innate immune responses to microbial threat. In immune cells such as macrophages, expression of CYP27B1, the 25-hydroxyvitamin D 1α-hydroxylase, is induced by immune-specific inputs, leading to local production of hormonal 1,25-dihydroxyvitamin D (1,25D) at sites of infection, which in turn directly induces the expression of genes encoding antimicrobial peptides. Vitamin D signaling is active upstream and downstream of pattern recognition receptors, which promote front-line innate immune responses. Moreover, 1,25D stimulates autophagy, which has emerged as a mechanism critical for control of intracellular pathogens such as M. tuberculosis. Strong laboratory and epidemiological evidence links vitamin D deficiency to increased rates of conditions such as dental caries, as well as inflammatory bowel diseases arising from dysregulation of innate immune handling intestinal flora. 1,25D is also active in signaling cascades that promote antiviral innate immunity; 1,25D-induced expression of the antimicrobial peptide CAMP/LL37, originally characterized for its antibacterial properties, is a key component of antiviral responses. Poor vitamin D status is associated with greater susceptibility to viral infections, including those of the respiratory tract. Although the severity of the COVID-19 pandemic has been alleviated in some areas by the arrival of vaccines, it remains important to identify therapeutic interventions that reduce disease severity and mortality, and accelerate recovery. This review outlines of our current knowledge of the mechanisms of action of vitamin D signaling in the innate immune system. It also provides an assessment of the therapeutic potential of vitamin D supplementation in infectious diseases, including an up-to-date analysis of the putative benefits of vitamin D supplementation in the ongoing COVID-19 crisis.

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“…A possible role for VDR in maintaining pulmonary barrier integrity has been described because Vdr −/− mice present alterations in adherent junctions in the lungs [24]. In addition, previous studies have demonstrated the presence and functionality of VDR in bronchial epithelial cells and alveolar macrophages [24][25][26]. Interestingly, low lung VDR expression has been found in patients with acute lung damage, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis.…”

Section: Of 12mentioning

confidence: 99%

Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel Activity

Olivencia,

Villegas-Esguevillas,

Sancho

et al. 2023

IJMS

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Recent evidence suggests that vitamin D is involved in the development of pulmonary arterial hypertension (PAH). The aim of this study was to analyze the electrophysiological and contractile properties of pulmonary arteries (PAs) in vitamin D receptor knockout mice (Vdr−/−). PAs were dissected and mounted in a wire myograph. Potassium membrane currents were recorded in freshly isolated PA smooth muscle cells (PASMCs) using the conventional whole-cell configuration of the patch-clamp technique. Potential vitamin D response elements (VDREs) in Kv7 channels coding genes were studied, and their protein expression was analyzed. Vdr−/− mice did not show a pulmonary hypertensive phenotype, as neither right ventricular hypertrophy nor endothelial dysfunction was apparent. However, resistance PA from these mice exhibited increased response to retigabine, a Kv7 activator, compared to controls and heterozygous mice. Furthermore, the current sensitive to XE991, a Kv7 inhibitor, was also higher in PASMCs from knockout mice. A possible VDRE was found in the gene coding for KCNE4, the regulatory subunit of Kv7.4. Accordingly, Vdr−/− mice showed an increased expression of KCNE4 in the lungs, with no changes in Kv7.1 and Kv7.4. These results indicate that the absence of Vdr in mice, as occurred with vitamin D deficient rats, is not sufficient to induce PAH. However, the contribution of Kv7 channel currents to the regulation of PA tone is increased in Vdr−/− mice, resembling animals and humans suffering from PAH.

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Up-Regulated Vitamin D Receptor by Pelargonium sidoides Extract EPs® 7630 Contributes to Rhinovirus Defense in Bronchial Epithelial Cells

Cited by 15 publications

References 40 publications

Antiviral and Immunomodulatory Effects of Pelargonium sidoides DC. Root Extract EPs® 7630 in SARS-CoV-2-Infected Human Lung Cells

Antiviral and Immunomodulatory Effects of Pelargonium sidoides DC. Root Extract EPs® 7630 in SARS-CoV-2-Infected Human Lung Cells

Vitamin D, infections and immunity

Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel Activity

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