The angiotensin-converting enzyme 2 (ACE2) receptor in the prevention and treatment of COVID-19 are distinctly different paradigms

McLachlan Craig Steven 대한고혈압학회 2020 Clinical Hypertension Vol.26 No.4

There is current debate concerning the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs), for hypertension management, during COVID-19 infection. Specifically, the suggestion has been made that ACE inhibitors or ARBs could theoretically contribute to infection via increasing ACE2 receptor expression and hence increase viral load. The ACE2 receptor is responsible for binding the SAR-CoV2 viral spike and causing COVID-19 infection. What makes the argument somewhat obtuse for ACE inhibitors or ARBs is that ACE2 receptor expression can be increased by compounds that activate or increase the expression of SIRT1. Henceforth common dietary interventions, vitamins and nutrients may directly or indirectly influence the cellular expression of the ACE2 receptor. There are many common compounds that can increase the expression of the ACE2 receptor including Vitamin C, Metformin, Resveratrol, Vitamin B3 and Vitamin D. It is important to acknowledge that down-regulation or blocking the cellular ACE2 receptor will likely be pro-inflammatory and may contribute to end organ pathology and mortality in COVID-19. In conclusion from the perspective of the ACE2 receptor, COVID-19 prevention and treatment are distinctly different. This letter reflects on this current debate and suggests angiotensin-converting enzyme inhibitors and ARBs are likely beneficial during COVID-19 infection for hypertensive and normotensive patients.

운동생리학 : 운동 유형에 따른 선수의 비타민 D 수용체 및 에스트로젠 수용체 유전자 타입과 골밀도와의 상관관계

박정국(JeongGukPark),신영오(YoungOhShin),오재근(JaeKeunOh) 한국체육학회 2005 한국체육학회지 Vol.44 No.5

Previous studies have suggested that variation in the vitamin D receptor (VDR) gene or estrogen receptor (ER) gene are related to bone mineral density (BMD). Our study was aimed to analyze both gene polymorphism and evaluated correlation with BMD by types of exercise in athletes. The subjects were 48 male athletic college students who had not taken hormone replacement. They were divided into two groups; weight bearing exercise group (WB, n=22; hand ball, archery) and non-weight bearing exercise group (NWB, n=26; swim). DNA was extracted from blood and analyzed for restriction fragment length polymorphism with the restriction endonucleases BsmI for vitamin D receptor and XbaI for estrogen receptor. We measured bone mineral density (BMD) of lumbar spine (L2-L4) by using DEXA (Dual energy X-ray absortiometry; Norland, Norway). The results are as follows.BMD in WB is higher significantly than that in NWB (p<.01). There was a significant difference in distribution of VDR genotypes between groups (χ2 test, p<.01; Bb< bb), but not in the case of ER (χ2 test, p >.05; XX<Xx<xx). The subjects with genotype bb in WB had a high level of bone mineral density within group without significance, and between groups (than NWB) with significance (p<.01). The subjects with genotype Xx in WB had a high level of bone mineral density within group and between groups (than NWB) significantly (p<.05, p< .01). In ER, there was significant difference in BMD within NWB group (Xx >xx, p=.049). Three of most frequent cross-genotype were bbxx, bbXx and Bbxx. However, no difference in BMD among three genotypes.In conclusion, there is relationship between vitamin D receptor & estrogen receptor gene polymorphism and bone mineral density in athletes, and moreover, in weight bearing exercise athletes.

Associations of Probiotics with Vitamin D and Leptin Receptors and their Effects on Colon Cancer

Ranji, Peyman,Akbarzadeh, Abolfazl,Rahmati-Yamchi, Mohammad Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.9

Colorectal cancer (CRC) is one of most common causes of cancer-related death worldwide. Recent studies have suggested that microbial and environmental factors including diet and lifestyle can impact on colon cancer development. Vitamin D deficiency and dysfunction of vitamin D receptor (VDR) also correlate with colon cancer. Moreover, leptin, a 16-kDa polypeptide, participates in the regulation of food intake and is associated with other environmental factors affecting colon cancer through the leptin receptor. Altered levels of serum leptin and patterns of expression of its receptor (LPR) may be observed in human colon tumours. Furthermore, the collected data from in vitro and in vivo studies have indicated that consuming probiotic non-pathogenic lactic acid bacteria have beneficial effects on colon cancer. Probiotics, inflammation and vitamin D/VDR have been correlated with leptin and its receptor and are also with colon cancer. Thus, in this paper, we review recent progress on the roles of probiotic, vitamin D/VDR and leptin/LPR in inflammation and colon cancer.

Clinical Implications of Serum 25-Hydroxyvitamin D Status after 5-Year Adjuvant Endocrine Therapy for Late Recurrence of Hormone Receptor-positive Breast Cancer

임승택,전예원,곽홍기,서영진 한국유방암학회 2020 Journal of breast cancer Vol.23 No.5

Purpose: The prognostic implications of serum vitamin D status after a 5-year adjuvant endocrine therapy on the risk of late recurrence among hormone receptor (HR)-positive breast cancer patients remain unclear. Hence, we investigated this among Korean HR-positive breast cancer patients. Methods: A total of 455 patients with HR-positive stage I–III invasive breast cancer who underwent curative surgery at St. Vincent's Hospital between February 2004 and April 2012 were included in this retrospective study. Patients were categorized based on their serum 25-hydroxyvitamin D (25(OH)D) levels after the 5-year adjuvant endocrine therapy. Initial recurrence sites were categorized. The primary clinical outcome was late recurrence-free survival (LRFS). Results: Among the 455 patients, 242 and 213 were included in the 25(OH)D-deficient group and 25(OH)D-sufficient group, respectively. Forty-eight patients experienced late recurrence. Across all recurrence sites, the 25(OH)D-deficient group showed significantly worse LRFS rates than the 25(OH)D-sufficient group (hazard ratio [HR], 2.284; 95% confidence interval [CI], 1.155–4.515; p = 0.018). After patient subgrouping based on recurrence site, the 25(OH)D-deficient group also showed significantly worse LRFS rates in terms of regional lymph node (LN) (HR, 17.453; 95% CI, 2.46–128.83; p = 0.005), bone (HR, 2.394; 95% CI, 1.024–5.599; p = 0.044), and visceral (HR, 2.735; 95% CI, 1.182–6.328; p = 0.019) recurrence. However, there was no significant difference between the 2 groups in terms of local recurrence (p = 0.611). Conclusions: We found that 25(OH)D deficiency after the 5-year adjuvant endocrine therapy was associated with worse LRFS among HR-positive breast cancer patients, particularly with respect to regional LN, bone, and visceral recurrence.

Association between Circulating Vitamin D, the Taq1 Vitamin D Receptor Gene Polymorphism and Colorectal Cancer Risk among Jordanians

Atoum, Manar Fayiz,Tchoporyan, Melya Nizar Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.17

Background: The physiological role of vitamin D extends beyond bone health and calcium-phosphate homeostasis to effects on cancer risk, mainly for colorectal cancer. Vitamin D may have an anticancer effect in colorectal cancer mediated by binding of the active form $1,25(OH)_2D$ to the vitamin D receptor (VDR). The Taq1 VDR gene polymorphism, a C-to-T base substitution (rs731236) in exon 9 may influence its expression and function. The aim of this study wass to determine the 25(OH)D vitamin D level and to investigate the association between circulating vitamin D level and Taq1VDR gene polymorphism among Jordanian colorectal cancer patients. Materials and Methods: This case control study enrolled ninety-three patients and one hundred and two healthy Jordanian volunteers from AL-Basheer Hospital/Amman (2012-2013). Ethical approval and signed consent forms were obtained from all participants before sample collection. 25(OH)D levels were determined by competitive immunoassay Elecsys (Roche Diagnostic, France). DNA was extracted (Promega, USA) and amplified by PCR followed by VDR Taq1 restriction enzyme digestion. The genotype distribution was evaluated by paired t-test and chi-square. Comparison between vitamin D levels among CRC and control were assessed by odds ratio with 95% confidence interval. Results: The vitamin D serum level was significantly lower among colorectal cancer patients (8.34 ng/ml) compared to the healthy control group (21.02ng/ml). Patients deficient in vitamin D (less than 10.0 ng/ml) had increased colorectal cancer risk 19.2 fold compared to control. Only 2.2% of CRC patients had optimal vitamin D compared to 23.5% among healthy control. TT, Tt and tt Taq1 genotype frequencies among CRC cases was 35.5%, 50.5% and 14% compared to 43.1%, 41.2% and 15.7% among healthy control; respectively. CRC patients had lower mean vitamin D level among TT ($8.91{\pm}4.31$) and Tt ($9.15{\pm}5.25$) genotypes compared to control ($21.3{\pm}8.31$) and ($19.3{\pm}7.68$); respectively. Conclusions: There is significant association between low 25(OH)D serum level and colorectal cancer risk. The VDRTaq1 polymorphism was associated with increased colorectal cancer risk among patient with VDRTaq1 TT and Tt genotypes. Understanding the functional mechanism of VDRTaq1 TT and Tt may provide a strategy for colorectal cancer prevention and treatment.

The Levels of Vitamin D, Vitamin D Receptor, Homocysteine and Complex B Vitamin in Children with Autism Spectrum Disorders

Hatice Altun,Ergül Belge Kurutaş,Nilfer Şahin,Olcay Güngör,Ebru Fındıklı 대한정신약물학회 2018 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.16 No.4

Objective: Autism spectrum disorder (ASD) is a complex neurodevelopmental syndrome with an increasingly prevalent etiology, yet not fully understood. It has been thought that vitamin D, complex B vitamin levels and homocysteine are associated with environmental factors and are important in ASD. The aim of this study was to examine serum vitamin D, vitamin D receptor (VDR), homocysteine, vitamin B6, vitamin B12 and folate levels in ASD. Methods: In this study, serum vitamin D and VDR, homocysteine, vitamins B6, B12 and folate levels were determined in 60 patients with ASD (aged 3 to 12 years) and in 45 age-gender matched healthy controls. In addition, calcium, phosphorus and alkaline phosphatase, which are associated with vitamin D metabolism, were measured from serum in both groups. ASD severity was evaluted by the Childhood Autism Rating Scale (CARS). Results: Serum vitamin D and VDR were substantially reduced in patients with ASD in comparision to control group. However, homocysteine level was significantly higher and vitamin B6, vitamin B12 and folate were also reduced in patients with ASD. Total CARS score showed a positive association with homocysteine and a negative correlation with vitamins D,B6, B12, folate and VDR. Conclusion: This comprehensive study, which examines many parameters has shown that low serum levels of vitamins D, B6, B12, folate and VDR as well as high homocysteine are important in the etiopathogenesis of ASD. However, further studies are required to define the precise mechanism(s) of these parameters and their contributions to the etiology and treatment of ASD.

한국인 폐경여성에서 비타민 D 수용체, 에스트로겐 수용체, Transforming Growth Factor -β1 및 Interleukin-6 유전자 다형성과 골밀도와의 연관성

권동진 ( Kwon Dong Jin ),유영옥 ( Yu Yeong Og ),김대훈 ( Kim Dae Hun ),조현희 ( Jo Hyeon Hui ),박원종 ( Park Won Jong ),김장흡 ( Kim Jang Heub ),임용택 ( Im Yong Taeg ),김은중 ( Kim Eun Jung ),이진우 ( Lee Jin U ),김진홍 ( Kim Jin 대한산부인과학회 2003 Obstetrics & Gynecology Science Vol.46 No.5

골밀도가 감소하는 질환인 골다공증의 발생에는 여러 가지 다양한 요인들이 관여하는 것으로 지금까지 알려져 왔다. 특히 폐경기 여성에서 골다공증의 발생에는 파골세포에 의한 골흡수가 증가하여 발생하는데 비타민 D, 에스토겐, TGF-β와 IL-6 유전자가 중요한 역할을 한다. 이에 저자들은 가톨릭대학교 의과대학 산부인과 폐경기 크리닉을 방문한 161명의 자연 폐경여성을 대상으로 요추, 대퇴골경부, Ward 삼각주, 대퇴돌기의 골밀도를 측정하여 정상군, 골감소증군과 골다공증군으로 분류하고 골다공증 발생에 있어서 중요한 역할을 하는 것으로 알려진 비타민 D 수용체 Fok Ⅰ, 에스트로겐 수용체 Pvu Ⅱ, TGF-β1 T_(869)C 및 IL-6 G_(174)C 유전자의 다형성을 관찰하고, 이러한 유전자들의 단독 또는 복합적인 다형성이 골밀도와 어떤 연관성이 있는가를 알아보고자 본 연구를 시도하였다. 저자들의 연구 결과에서 대상 폐경기 여성의 유전자형 분포 양상은 비타민 D 수용체가 FF 32.9%, Ff 50.9%, ff 16.2% ; 에스트로겐 수용체가 PP 13.6%, Pp 48.4%, pp 38.0% ; TGF-β1은 T/T 74.1%, T/C 12.4%, C/C 13.1% ; IL-6 유전자는 G/G 99.4%, G/C 0.6%를 보였고, 정상군에 비해 골감소증군과 골다공증군에서 FF 유전자형의 빈도는 유의하게 낮은 분포 양상을 보였으나, 에스트로겐 수용체와 TGF-β1 유전자형에서는 세 군간에 차이가 없었다. IL-6 유전자는 골감소증군에서 G/C 유전자형이 1예만 관찰되었다. 단일 유전자형과 골밀도 관계에서 비타민 D 수용체 유전자의 FF 유전자형은 Ff와 ff 유전자형보다 모든 부위에서 골밀도가 유의하게 높았으나 에스트로겐 수용체와 TGF-β1 유전자의 단일 유전자형과 골밀도간에는 통계적으로 유의한 차이는 없었다. 복합 교차유전자형과 골밀도 관계에서 비타민 D 수용체와 에스트로겐 수용체 유전자의 FFPp 유전자형은 FfPp, Ffpp와 ffpp 유전자형보다 요추, 대퇴골경부 및 Ward 삼각주 부위에서 골밀도가 유의하게 높았으며 비타민 D 수용체와 TGF-β1 유전자의 FFTT 유전자형은 FfTT와 ffTT 유전자형보다 대퇴골경부 및 Ward 삼각주 부위에서 골밀도가 유의하게 높았다. 이상의 결과로 한국인 폐경여성에서 비타민 D 수용체 Fok Ⅰ 다형성은 단독 또는 에스트로겐 수용체 RvuⅡ, TGF-β1 T_(869)C 다형성과 복합적으로 골밀도에 중요한 역할을 하는 것을 알 수 있었다. Objective : To evaluate the relationship between vitamin D receptor (VDR), estrogen receptor (ER), transforming growth factor-β1 (TGF-β1) and interleukin-6 (IL-6) gene polymorphism, and bone mineral density (BMD). Materials and Methods : Restriction fragment length polymorphisms at the VDR Fok I, ER Pvu Ⅱ, TGF-β1 T_(869)C and IL-6 G_(174)C gene sites, and BMD at the lumbar spine, proximal femur were analyzed in 161 postmenopausal Korean women. The subjects were divided in normal, osteopenic, and osteoporotic on the basis of the T-score values according to the classification of the World Health Organization (WHO). Results : The genotype distribution of VDR, ER, TGF-β1 and IL-6 gene polymorphism was as follows : FF 32.9%, Ff 50.9%, ff 16.2% ; PP 13.6%, Pp 48.4%, pp 38.0% ; T/T 74.1%, T/C 12.4%, C/C 13.1% ; G/G 99.4%, G/C 0.6%. Significant differences in the distribution of FF genotype among normal, ostemopenic and osteoporotic group were observed. No significant differences in the distribution of ER and TGF-β1 genotypes among three groups were observed. BMD at all sites in the FF genotype was significantly higher than in the Ff and ff genotypes. There was no relationship between ER and TGF-β1 gene polymorphism, and BMD. By combining VDR, ER and TGF-1 genotypes, BMD at lumbar spine, femur neck and ward triangle in the FFPp genotype was significantly higher than in the FfPp, Ffpp and ffpp genotypes, and BMD at femur neck and ward triangle in the FFTT genotype was significantly higher than in the FfTT and ffTT genotypes. Conclusion : The results suggest that VDR Fok I polymorphisms, singly and in relation to ER Pvu Ⅱ and TGF-β1 T_(869)C polymorphism, may influence bone mass in postmenopausal Korean women.

Vitamin D Receptor Gene, Matrix Metalloproteinase 3 Polymorphisms and the Risk of Intervertebral Disc Degeneration Susceptibility: Meta-Analysis

Luming Nong,Yongjing Huang,Shujie Zhao,Nanwei Xu 대한척추외과학회 2016 Asian Spine Journal Vol.10 No.5

Several studies have evaluated the association between vitamin D receptor, matrix metalloproteinase 3 (MMP-3) polymorphisms and the risk of intervertebral disc degeneration susceptibility. The findings were inconsistent. This meta-analysis aimed to systematically assess the association between vitamin D receptor, MMP-3 polymorphisms and the risk of intervertebral disc degeneration susceptibility. A search of various databases was done covering all papers published until December 31th, 2014. Eight, 4, 3 studies were finally included that addressed the risk of intervertebral disc degeneration susceptibility and vitamin D receptor FokI (rs2228570), ApaI (rs7975232), and MMP-3 (rs731236) polymorphisms, respectively. FokI (f vs. F: summary odds ratio [OR], 1.13; 95% confidence interval [CI], 0.76–1.69; ff vs. FF: OR, 1.02; 95% CI, 0.59–1.77; ff vs. Ff/FF: OR, 1.05; 95% CI, 0.70–1.58), ApaI (a vs. A: OR, 0.73; 95% CI, 0.45–1.19; aa vs. AA: OR, 0.53; 95% CI, 0.22–1.25 p =0.14; aa vs. AA/Aa: OR, 0.69; 95% CI, 0.53–0.89) in the vitamin D receptor gene and MMP3 polymorphisms (5A vs. 6A: OR, 1.92; 95% CI, 0.77–4.80; 5A5A vs. 6A6A: OR, 2.17; 95% CI, 0.75–6.24; 5A5A vs. 5A6A/6A6A: OR, 1.58; 95% CI, 0.72–3.44) were not obviously associated with risk of intervertebral disc degeneration susceptibility. FokI, ApaI polymorphisms in the vitamin D receptor gene and MMP-3 polymorphism are not obvious risk factors for intervertebral disc degeneration susceptibility.

Therapeutic targets of vitamin D receptor ligands and their pharmacokinetic effects by modulation of transporters and metabolic enzymes

최민식,김유철,맹한주 한국약제학회 2020 Journal of Pharmaceutical Investigation Vol.50 No.1

Vitamin D is involved in retaining the balance of several minerals in the body, such as calcium and phosphate, which are crucial for the bone formation and development. These physiological effects of vitamin D are mediated by activation of the transcription factor vitamin D receptor (VDR). Moreover, vitamin D is closely related to several pathological conditions including osteoporosis, secondary hyperparathyroidism, cancer, psoriasis and autoimmune diseases, which is not only due to calcemic but also non-calcemic effects of vitamin D such as cell proliferation, differentiation, and immunomodulation. These various abilities of vitamin D have made VDR an attractive therapeutic target. Already, numerous vitamin D analogs have been developed and studied in in vitro disease models or animal models, and some have been in clinical trials or approved for the treatment of certain diseases. In addition, the transcriptional and/or post-transcriptional regulation by VDR activation also affects the genes involved in drug metabolism and disposition, possibly leading to pharmacokinetic changes of several drugs in clinical use. This review provides a detailed summary of therapeutic targets of VDR ligands, and their effects on the transporters and metabolic enzymes, causing in vitro and in vivo pharmacokinetic changes of several drugs. The clinical research is further required for the confirming the clinical relevance of pharmacokinetic drug interactions by VDR ligands.

Upregulation of the Vitamin D Receptor in the Nasal Mucosa of Patients With Allergic Rhinitis

김현근,Da Bin Lee,Tae Hoon Lee,최보윤,한문수,이상학,김태훈 대한비과학회 2021 Journal of rhinology Vol.28 No.3

Background and Objectives: Vitamin D modulates immunity, including that of allergic diseases, and plays its roles through contact with vitamin D receptors (VDR). Recent studies have shown that patients with allergic rhinitis have low systemic serum vitamin D level. However, the expression of VDR in local tissue such as human nasal mucosa has not been investigated. Our study demonstrated that, in nasal mucosa of normal controls and patients with allergic rhinitis. Materials and Methods: Nasal mucosa were harvested from twenty-five patients who had normal nasal mucosa and twenty-five patients with allergic rhinitis. After the total RNA isolation, we performed reverse transcriptase-polymerase chain reaction, immunohistochemical staining and western blot analysis. Results: VDR were expressed in submucosal glands and the superficial layer of epithelial cell, and that inflammatory cells are expressed more highly in the nasal mucosa of patients with allergic rhinitis compared to those without. In the mucosa of patients with allergic rhinitis, VDR expression level was upregulated compared to that in normal nasal mucosa. Conclusion: This findings suggest that VDR plays a role in the pathogenesis of allergic rhinitis. Additional research is needed to determine the mechanism and consequences of VDR upregulation. Background and Objectives: Vitamin D modulates immunity, including that of allergic diseases, and plays its roles through contact with vitamin D receptors (VDR). Recent studies have shown that patients with allergic rhinitis have low systemic serum vitamin D level. However, the expression of VDR in local tissue such as human nasal mucosa has not been investigated. Our study demonstrated that, in nasal mucosa of normal controls and patients with allergic rhinitis.Materials and Methods: Nasal mucosa were harvested from twenty-five patients who had normal nasal mucosa and twenty-five patients with allergic rhinitis. After the total RNA isolation, we performed reverse transcriptase-polymerase chain reaction, immunohistochemical staining and western blot analysis.Results: VDR were expressed in submucosal glands and the superficial layer of epithelial cell, and that inflammatory cells are expressed more highly in the nasal mucosa of patients with allergic rhinitis compared to those without. In the mucosa of patients with allergic rhinitis, VDR expression level was upregulated compared to that in normal nasal mucosa.Conclusion: This findings suggest that VDR plays a role in the pathogenesis of allergic rhinitis. Additional research is needed to determine the mechanism and consequences of VDR upregulation.