Epigallocatechin-3-Gallate Prevents Autoimmune-Associated Down- Regulation of p21 in Salivary Gland Cells Through a p53-Independent Pathway

Abstract

The submandibular salivary glands of non-obese diabetic (NOD) mice, a model for Sjogren’s syndrome and type-1 diabetes, show an elevated level of proliferating cell nuclear antigen (PCNA), a protein involved in cell proliferation and repair of DNA damage. We reported previously that epigallocatechin-3-gallate (EGCG), the most abundant green tea catechin, normalizes the PCNA level. PCNA’s activity can be regulated by the cyclin-dependent kinase inhibitor p21, which is also important for epithelial cell differentiation. In turn, expression of p21 and PCNA are partially regulated by Rb phosphorylation levels. EGCG was found to modulate p21 expression in epithelial cells, suggesting that EGCG-induced p21 could be associated with down-regulation of PCNA in vivo. The current study examined the protein levels of p21 and p53 (which can up-regulate p21) in NOD mice fed with either water or EGCG, and the effect of EGCG on p21 and p53 in cell line models with either normal or defective Rb. In NOD mice, the p21 level was low, and EGCG normalized it. In contrast to HSG cells with functional Rb, negligible expression of p21 in NS-SV-AC cells that lack Rb was not altered by EGCG treatment. Inhibition of p53 by siRNA demonstrated that p21 and p53 were induced independently in HSG cells by a physiological concentration range of EGCG, suggesting p53 could be an important but not conditional factor associated with p21 expression. In conclusion, PCNA and p21 levels are altered inversely in the NOD model for SS and in HSG cells, and warrant further study as candidate new markers for salivary dysfunction associated with xerostomia. Induction of p21 by EGCG could provide clinically useful normalization of salivary glands by promoting differentiation and reducing PCNA levels.

Evaluation of Novel Nasal Mucoadhesive Nanoformulations Containing Lipid-Soluble EGCG for Long COVID Treatment

“…In autoimmune animal studies, we found that EGCG significantly reduced lymphocyte infiltration and serum autoantibody levels, and protects human cells from TNF-αinduced cytotoxicity [17,18]. Interestingly, our animal studies showed that EGCG modulates the antioxidant defense enzymes to protect cells from free radical-induced damage [19] and stabilizes p21 expression and reduces DNA damage from inflammation-induced reactive oxygen species [20]. Also, it has been widely reported that EGCG provides neuroprotective effects in preclinical studies and clinical trials [21][22][23].…”

The effects of flavonoids, green tea polyphenols and coffee on DMBA induced LINE-1 DNA hypomethylation

“…On the other hand, the regulatory role and pathological significance of the LINE-1 methylation pattern is indicated by the fact, that in patients with hypomethylated LINE-1 and with cyclin-dependent kinase-6 (CDK6) amplified esophageal squamous cell carcinoma the expression of P21 decreased [56]. This can be related to the antitumor effect of EGCG as well, as EGCG increases the expression of P21 tumor suppressor gene in vivo through hypomethylation of the promoter region of P21, irrespective of the P53 tumor suppressor-induced signaling pathway [30,57]-and P21 inhibits DNMT1 [30].…”

Evaluation of Novel Nasal Mucoadhesive Nanoformulations Containing Lipid-Soluble EGCG for Long COVID Treatment

“…In autoimmune animal studies, we found that EGCG significantly reduces lymphocyte infiltration and serum autoantibody levels and protects human cells from TNF-α-induced cytotoxicity [ 20 , 21 ]. Interestingly, our animal studies showed that EGCG modulates the antioxidant defense enzymes to protect cells from free-radical-induced damage [ 22 ], stabilizes p21 expression, and reduces DNA damage from inflammation-induced reactive oxygen species [ 23 ]. Also, it has been widely reported in preclinical studies and clinical trials that EGCG provides neuroprotective effects [ 24 , 25 , 26 ].…”