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176
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Introduction
Dr. Jurutka is an award-winning molecular endocrinologist who applies molecular medicine approaches to elucidate fundamental questions in human health/disease including work on "nutraceuticals", cancer, Alzheimer's disease, irritable bowel syndrome, IBD, rexinoid drug discovery, and neurobiology of vitamin D action in autism/depression.
Additional affiliations
August 2019 - present
August 2018 - present
January 2006 - present
Education
August 1987 - August 1993
January 1983 - May 1987
University of Nevada
Field of study
- Biological Chemistry
Publications
Publications (176)
The actions of 1,25(OH)2D3-VDR that have emerged from recent studies include, but clearly transcend, the bone and calcium/phosphate homeostasis effects originally attributed to vitamin D. This new understanding now encompasses many of the tissues formerly reported to contain vitamin D receptors, but for which no function of the vitamin-derived horm...
To investigate vitamin D-related control of brain-expressed genes, candidate vitamin D responsive elements (VDREs) at -7/-10 kb in human tryptophan hydroxylase (TPH)2 were probed. Both VDREs bound the vitamin D receptor (VDR)-retinoid X receptor (RXR) complex and drove reporter gene transcription in response to 1,25-dihydroxyvitamin D3 (1,25D). Bra...
Development of colorectal adenoma and cancer are associated with low circulating 25-hydroxyvitamin D [25(OH)D] levels. However, less is known regarding colorectal neoplasia risk and variation in CYP27B1 or CYP24A1, genes encoding the enzymes responsible for the synthesis and catabolism of 1α,25-hydroxyvitamin D [1,25(OH)2D]. This study examined ass...
Background/Aims
Irritable bowel syndrome (IBS) is a multifaceted disorder that afflicts millions of individuals worldwide. IBS is currently diagnosed based on the presence/duration of symptoms and systematic exclusion of other conditions. A more direct manner to identify IBS is needed to reduce healthcare costs and the time required for accurate di...
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), binds to the vitamin D receptor (VDR) with high affinity. The VDR then heterodimerizes with the retinoid X receptor (RXR) and associates with vitamin D response elements (VDREs) to regulate the transcription of target genes. Bexarotene (Bex) is an RXR ligand (rexinoid) developed to trea...
Vitamin D hydroxylation in the liver/kidney results in conversion to its physiologically active form of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. 1,25(OH)2D3 controls gene expression through the nuclear vitamin D receptor (VDR) mainly expressed in intestinal epithelial cells. Cytochrome P450 (CYP) 24A1 is a catabolic enzyme expressed in the kidneys....
Bexarotene, a drug approved for treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid by its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous studies...
There is a need to explore combination therapy to improve the efficacy of immunotherapy for colorectal cancer through food probiotics. In this study, extracellular vesicles (EV) derived from Lactobacillus rhamnosus GG (LGG-EV) were successfully isolated. Adjusting the culture temperature to 30 °C led to an elevated LGG-EV yield, and the addition of...
Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demons...
Background:
Observational studies show high pre-diagnosis 25-hydroxyvitamin D is associated with lower mortality after colorectal cancer (CRC) diagnosis. Results from clinical trials suggest vitamin D supplementation may improve outcomes among CRC patients. Most studies included few Black Americans, who typically have lower 25-hydroxyvitamin D. We...
Bexarotene, a drug approved for the treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid due to its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous...
Purpose: Evidence from RCTs suggests vitamin D supplementation may improve colorectal cancer (CRC) outcomes after diagnosis. However, most trials did not include large numbers of Black patients, who typically have lower vitamin D levels. We evaluated associations between vitamin D with all-cause and CRC-specific mortality after CRC diagnosis.
Metho...
Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs a...
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders and affects approximately 4% of the global population. The diagnosis of IBS can be made based on symptoms using the validated Rome criteria and ruling out commonly occurring organic diseases. Although biomarkers exist for “IBS mimickers” such as celiac disease and i...
Vitamin-D receptor (VDR) mRNA is overexpressed in neuroblastoma and carcinomas of lung, pancreas, and ovaries and predicts poor prognoses. VDR antagonists may be able to inhibit tumors that overexpress VDR. However, the current antagonists are arduous to synthesize and are only partial antagonists, limiting their use. Here, we show that the VDR ant...
Altering T cell trafficking to mucosal regions can enhance immune responses towards pathogenic infections and cancers at these sites, leading to better outcomes. All-trans-retinoic acid (ATRA) promotes T cell migration to mucosal surfaces by inducing transcription of the mucosal-homing receptors CCR9 and α4β7 via binding to retinoic acid receptors...
Rexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes. Rexinoids have anti-neoplastic activity in multiple preclinical studies. Bexarotene, used to treat cutaneous T cell lymphoma, is the only FDA-approved rexinoid. Bexarotene has also been evaluated in clinical tri...
Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid—or NEt-4IB—in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), a FDA-approved drug for...
Purpose:
Prior work has shown that higher circulating concentrations of fibroblast growth factor-21 (FGF-21) are associated with an increased likelihood of developing colorectal cancer. We conducted a prospective study to assess the relationship between circulating FGF-21 and odds of developing early neoplastic lesions in the colorectum.
Methods:...
Rexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes. Rexinoids have anti-neoplastic activity in multiple preclinical studies. Bexarotene, used to treat cutaneous T cell lymphoma, is the only FDA-approved rexinoid. Bexarotene has also been evaluated in clinical tri...
There is considerable interest in identifying effective and safe drugs for neurodegenerative disorders. Cell culture and animal model work have demonstrated that modulating gene expression through RXR-mediated pathways may mitigate or reverse cognitive decline. However, because RXR is a dimeric partner for several transcription factors, activating...
The hormonal vitamin D metabolite, 1,25‐dihydroxyvitamin D (1,25D), produced in kidney, acts in numerous end‐organs via the nuclear vitamin D receptor (VDR) to trigger molecular events that orchestrate bone mineral homeostasis. VDR is a ligand‐controlled transcription factor that obligatorily heterodimerizes with retinoid X receptor (RXR) to target...
Mediated by the nuclear vitamin D receptor (VDR), the hormonally active vitamin D metabolite, 1,25-dihydrox-yvitamin D 3 (1,25D), is known to regulate expression of genes impacting calcium and phosphorus metabolism, the immune system, and behavior. Urolithin A, a nutrient metabolite derived from pomegranate, possibly acting through AMP kinase (AMPK...
Certain vitamins directly impact immune cell migration, indicating potential to function as a vaccine adjuvant. We previously showed that all-trans retinoic acid (ATRA), the biologically active form of vitamin A, modifies gut-homing receptor expression on effector T cells upon binding to the retinoic acid receptor (RAR), which joins with the retino...
Bexarotene is an FDA approved anti‐cancer agent, but more recently this drug has been assessed for its potential as a therapeutic for dementia. Bexarotene may reduce amyloid beta (α□) plaques that are thought to play a role in Alzheimer’s disease pathophysiology, although clinical use of bexarotene causes unwanted side‐effects including hyperlipide...
The active vitamin D hormone, 1,25‐dihydroxyvitamin D (1,25D), mediates its biological effects by binding to the nuclear vitamin D receptor (VDR) and promoting heterodimerization with retinoid X receptors (RXRs). Various nutraceuticals, including resveratrol and curcumin, have been postulated to interact with the vitamin D signaling pathway. More r...
Recent studies suggest that the biologically active form of vitamin D, 1,25‐dihydroxyvitamin D (1,25D), plays a role in potentially delaying the aging process, functions as an anti‐carcinogenic agent, and also prevents oxidative damage. 1,25D binding to the vitamin D receptor (VDR) promotes heterodimerization of VDR with the retinoid X receptor (RX...
This study evaluated effect of triterpenoids from edible mushroom Poria cocos on intestinal epithelium integrity and revealed the transcriptional regulatory pathways that underpin restorative mechanisms in the gut. Based on computational docking studies, transcriptional activation experiments, and glucocorticoid receptor (GR) protein immunofluoresc...
Poria cocos is an edible and medicinal fungus that is widely used in Traditional Chinese Medicines (TCM) as well as in modern applications. Retinoid X receptor (RXR) occupies a central place in nuclear receptor signaling and a pharmacological RXR‐dependent pathway is involved in myeloid cell function. Here, structural information for 82 triterpenes...
This chapter outlines the materials, methods, and procedures for the in vitro biological evaluation of retinoid-X-receptor (RXR) agonists including 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN), as well as several NEt-TMN analog compounds recently reported by our group. These methods have general appl...
The methods described in this chapter concern procedures for the design, synthesis, and in vitro biological evaluation of an array of potent retinoid-X-receptor (RXR) agonists employing 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN), and recently reported NEt-TMN analogs, as a case study. These methods...
Vaccines are the most successful defense against infectious diseases. Effective vaccines must target induced immune responses to areas of pathogen entry, a primary site being mucosal surfaces. Certain vitamins can directly impact immune cell migration, indicating potential to function as an adjuvant. We previously showed that all-trans retinoic aci...
Rexinoids, selective ligands for retinoid X receptors (RXR), have shown promise in preventing many types of cancer. However, the limited efficacy and undesirable lipidemic side-effects of the only clinically approved rexinoid, bexarotene, drive the search for new and better rexinoids. Here we report the evaluation of novel pyrimidinyl (Py) analogue...
This article presents the experimental data supporting analysis of differential gene expression of human cutaneous T cell lymphoma (CTCL) cell culture cells (Hut78) treated with bexarotene or a variety of rexinoids, in conjunction with “A Novel Gene Expression Analytics-based Approach to Structure Aided Design of Rexinoids for Development as Next-G...
Background
Diminished brain levels of two neurohormones, 5-hydroxytryptamine (5-HT; serotonin) and 1,25-dihydroxyvitamin D3 (1,25D; active vitamin D metabolite), are proposed to play a role in the atypical social behaviors associated with psychological conditions including autism spectrum disorders and depression. We reported previously that 1,25D...
Non-melanoma skin cancers (NMSCs) are the leading cause of skin cancer-related morbidity and mortality. Effective strategies are needed to control NMSC occurrence and progression. Non-toxic, plant-derived extracts have been shown to exert multiple anti-cancer effects. Graviola (Annona muricata), a tropical fruit-bearing plant, has been used in trad...
Non-melanoma skin cancers (NMSCs) are the leading cause of skin cancer-related morbidity and mortality. Effective strategies are needed to control NMSC occurrence and progression. Non-toxic, plant-derived extracts have been shown to exert multiple anti-cancer effects. Graviola (Annona muricata), a tropical fruit-bearing plant, has been used in trad...
Vaccines are the most effective defense against infectious diseases. To be most successful, vaccines must target the induced immune response to chief sites of pathogen entry: epithelial and mucosal surfaces. We have previously shown that the biologically active form of Vitamin A, all-trans retinoic acid (ATRA), can directly modulate the expression...
Rexinoids are powerful ligands that bind to retinoid-X-receptors (RXRs) and show great promise as therapeutics for a wide range of diseases, including cancer. However, only one rexinoid, bexarotene (Targretin TM) has been successfully transitioned from the bench to the clinic and used to treat cutaneous T-cell lymphoma (CTCL). Our goal is to develo...
The Klotho gene has been closely associated with delayed onset of aging. Inhibition of the klotho protein promotes aging‐like phenotypes, while its overexpression has been found to extend lifespan in mice. The single‐pass transmembrane isoform of klotho (m‐klotho) forms a receptor complex with the fibroblast growth factor (FGF) receptor to create a...
Antagonists are chemical compounds that bind to receptors without eliciting activation of signaling, therefore the biochemical response to the receptor ligand can be blocked or significantly decreased. Receptor antagonists display varying levels of binding affinity but do not produce the agonist‐mediated response upon binding. The vitamin D recepto...
The active form of vitamin D ³ , 1,25‐dihydroxyvitamin D (1,25D), and serotonin (5‐HT) are postulated to play significant roles in abnormal social behavior associated with psychological conditions including autism spectrum disorders (ASDs) and depression. Moreover, we have observed that 1,25D regulates synthesis of two isoforms of tryptophan hydrox...
Treatment with 1,25-dihydroxyvitamin D₃ (1,25D) improves psoriasis symptoms, possibly by inducing the expression of late cornified envelope (LCE)3 genes involved in skin repair. In psoriasis patients, the majority of whom harbor genomic deletion of LCE3B and LCE3C (LCE3C_LCE3B-del), we propose that certain dietary analogues of 1,25D activate the ex...
The hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), binds to the vitamin D receptor (VDR) and promotes heterodimerization of VDR with a retinoid-X-receptor (RXR) to genomically regulate diverse cellular processes. Herein, it is revealed for the first time that VDR is post-translationally acetylated, and that VDR immunoprecipitat...
Background:
Previous studies rarely evaluated the associations between vitamin D binding protein and free vitamin D with colorectal cancer (CRC) risk. We assessed these biomarkers and total 25-hydroxyvitamin D in relation to CRC risk in a sample of African Americans.
Methods:
Cases comprised 224 African American participants of the Southern Comm...
Background:
Several lifestyle factors targeted by the American Cancer Society (ACS) Nutrition and Physical Activity Cancer Prevention Guidelines are also associated with circulating concentrations of vitamin D metabolites. This suggests that greater adherence to the ACS guidelines may be related to better vitamin D status.
Objective:
We examined...
1,25-Dihydroxyvitamin D3 (1,25D) is the endocrine metabolite of vitamin D that signals through binding to the vitamin D receptor (VDR). The ligand–receptor complex transcriptionally regulates genes that encode factors promoting intestinal calcium and phosphate absorption plus bone remodeling, maintaining a skeleton with reduced risk of age-related...
Sulphonic acid analogs of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1)—or bexarotene—as well as seven novel and two reported analogs of 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN) were synthesized and assessed for selective retinoid-X-receptor (RXR) agonism. Com...
Since the isolation and identification of the retinoid X receptor (RXR) as a member of the nuclear receptor (NR) superfamily in 1990, its analysis has ushered in a new understanding of physiological regulation by nuclear receptors, and novel methods to identify other unknown and orphan receptors. Expression of one or more of the three isoforms of R...
While hydrophobic bile acids have been demonstrated to exhibit cytotoxic and carcinogenic effects in the colorectum, ursodeoxycholic acid (UDCA) has been investigated as a potential chemopreventive agent. Vitamin D has been shown to play a role in both bile acid metabolism and in the development of colorectal neoplasia. Employing a cross-sectional...
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with chronic abdominal pain along with recurrent diarrhea, constipation, or both that afflicts millions of people worldwide. Currently, the etiological foundation of the disorder remains enigmatic. However, there is mounting evidence suggesting that serotonin may pl...
The two compounds, 1,25‐dihydroxyvitamin D (1,25D, vitamin D) and 5‐hydroxytryptamine (5‐HT, serotonin), have been proposed to play a significant role in abnormal social behavior associated with psychological conditions including autism spectrum disorders (ASDs) and depression; however, the mechanism underlying these associations has yet to be eluc...
Vitamin D, Klotho, and FOXO3 have all been linked to have anti-aging and anti-cancerous effects as separate pathways. Specifically, mice with knockout Klotho in their genes have displayed signs of premature aging, humans who are vitamin D deficient have been shown to develop cardiovascular disease and cognitive impairments, and those who have displ...
The human klotho gene encodes a protein that can generate two isoforms: a single‐pass transmembrane protein (mKlotho) or a secreted peptide (sKlotho) formed from the cleavage of the former. The two isoforms likely possess physiologically unique roles, as mKlotho is known to serve as a membrane‐bound coreceptor for FGF23, while sKlotho may function...
Over the past two decades, the question of whether vitamin D has a role in cancer incidence, progression, and mortality has been studied in detail. Colorectal, breast, and prostate cancers have been a particular area of focus; together, these three malignancies account for approximately 35% of cancer cases and 20% of cancer deaths in the United Sta...
1,25-Dihydroxyvitamin D3 (1,25D) is the renal metabolite of vitamin D that signals through binding to the nuclear vitamin D receptor (VDR). The ligand-receptor complex transcriptionally regulates genes encoding factors stimulating calcium and phosphate absorption plus bone remodeling, maintaining a skeleton with reduced risk of age-related osteopor...
In addition to the synergistic interaction between calcium and vitamin D observed in many previous studies, a recent study found that magnesium may also modify the association between serum 25-hydroxyvitamin D (25D) and risk colorectal cancer mortality. However, the study was unable to include the biologically active form of vitamin D, 1α,25-dihydr...
In a closed endocrine loop, 1,25-dihydroxyvitamin D3 (1,25D) induces the expression of fibroblast growth factor-23 (FGF23) in bone, with the phosphaturic peptide in turn acting at kidney to feedback repress CYP27B1 and induce CYP24A1 to limit the levels of 1,25D. In 3T3-L1 differentiated adipocytes, 1,25D represses FGF23 and leptin expression, whil...
In order to determine the feasibility of utilizing novel rexinoids for chemotherapeutics and as potential treatments for neurological conditions, we undertook an assessment of the side effect profile of select rexinoid X receptor (RXR) analogs that we reported previously. We assessed pharmacokinetic profiles, lipid and thyroid-stimulating hormone (...
The 1,25-dihydroxyvitamin D3 (1,25D) hormone is derived from vitamin D generated in skin or obtained from the diet, and binds to and activates the vitamin D receptor (VDR) in target tissues including kidney, colon/small intestine, and bone/muscle. We tested resveratrol for its ability to modulate VDR signaling, using vitamin D responsive element (V...
Aim:
Few epidemiological studies have investigated the association between circulating concentrations of the active vitamin D metabolite 1,25(OH)2D and metabolic syndrome. We sought to determine whether blood levels of 1,25(OH)2D are associated with metabolic syndrome and its individual components, including waist circumference, triglycerides, blo...
Cellular-level studies demonstrate that the availability of the secosteroid hormone 1α,25-dihydroxyvitamin D [1,25(OH)2D] to colon cells promotes anti-carcinogenic activities. Although epidemiological data are relatively sparse, suggestive inverse trends have been reported between circulating 1,25(OH)2D concentration and colorectal neoplasia. We th...