Metabolite Of Vitamin Research Articles

Vitamin D decreases silencer methylation to downregulate renin gene expression

Renin, encoded by REN, is an essential enzyme in the renin-angiotensin aldosterone system (RAAS) which is responsible for the maintenance of blood pressure homeostasis. Transcriptional regulation of REN has been linked to enhancer-promoter crosstalk, cAMP response element-binding protein (CREB), the active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), and a less well-characterized intronic silencer element. We hypothesized that in addition to these, differential DNA methylation is linked to REN expression and influenced by 1,25(OH)2D3. REN expressing cells (HEK293) were used to elucidate the effect of 1,25(OH)2D3 on REN methylation and expression as quantified by methylation-sensitive qPCR and RT-qPCR, respectively. In vitro 1,25(OH)2D3 supplementation (10nM) induced significant hypomethylation of the REN silencer (P<0.050), which was linked to a significant reduction in REN expression (P<0.010) but had no effect on enhancer methylation. In addition, 1,25(OH)2D3 increased VDR (P<0.05), as well as TET1 (P<0.05) expression, suggesting an association between 1,25(OH)2D3 and DNA methylation. Thus, it appears that the silencer element, which is controlled by DNA methylation and influenced by 1,25(OH)2D3, plays an essential role in regulating REN expression.

Ultrafine particles altered gut microbial population and metabolic profiles in a sex-specific manner in an obese mouse model

Emerging evidence has highlighted the connection between exposure to air pollution and the increased risk of obesity, metabolic syndrome, and comorbidities. Given the recent interest in studying the effects of ultrafine particle (UFP) on the health of obese individuals, this study examined the effects of gastrointestinal UFP exposure on gut microbial composition and metabolic function using an in vivo murine model of obesity in both sexes. UFPs generated from light-duty diesel engine combustion of petrodiesel (B0) and a petrodiesel/biodiesel fuel blend (80:20 v/v, B20) were administered orally. Multi-omics approaches, including liquid chromatography–mass spectrometry (LC–MS) based targeted metabolomics and 16S rRNA gene sequence analysis, semi-quantitatively compared the effects of 10-day UFP exposures on obese C57B6 mouse gut microbial population, changes in diversity and community function compared to a phosphate buffer solution (PBS) control group. Our results show that sex-specific differences in the gut microbial population in response to UFP exposure can be observed, as UFPs appear to have a differential impact on several bacterial families in males and females. Meanwhile, the alteration of seventy-five metabolites from the gut microbial metabolome varied significantly (ANOVA p < 0.05) across the PBS control, B0, and B20 groups. Multivariate analyses revealed that the fuel-type specific disruption to the microbial metabolome was observed in both sexes, with stronger disruptive effects found in females in comparison to male obese mice. Metabolic signatures of bacterial cellular oxidative stress, such as the decreased concentration of nucleotides and lipids and increased concentrations of carbohydrate, energy, and vitamin metabolites were detected. Furthermore, blood metabolites from the obese mice were differentially affected by the fuel types used to generate the UFPs (B0 vs. B20).

1,25-Dihydroxyvitamin D and S-Klotho Plasma Levels: The Relationship Between Two Renal Antiaging Biomarkers Mediated by Bone Mineral Density in Middle-Aged Sedentary Adults.

The main active metabolite of vitamin D, the 1,25-dihydroxyvitamin D (1,25(OH)2D), and the shed form of the α-Klotho gene (S-Klotho) play an important role in aging-related physiological processes and are currently considered powerful antiaging renal biomarkers. We aimed to investigate the relationship between 1,25(OH)2D and S-Klotho plasma levels in middle-aged sedentary healthy adults. We also aimed to study the mediation role of body composition, physical activity levels, dietary parameters, and blood markers in the association between 1,25(OH)2D and S-Klotho plasma levels. A total of 73 middle-aged sedentary adults (53.4% women; 53.7 ± 5.1 years old) were enrolled in this cross-sectional study. The 1,25(OH)2D plasma levels were measured using a DiaSorin Liaison® immunochemiluminometric analyzer. S-Klotho plasma levels were measured using a solid-phase sandwich enzyme-linked immunosorbent assay. Body composition analysis was performed using dual-energy X-ray absorptiometry scanner. A tendency toward a negative association was observed between 1,25(OH)2D and S-Klotho plasma levels (β = -0.222, R2 = 0.049, p = 0.059). The association was attenuated after controlling for age and sex and become significant after controlling for fat mass index. In addition, the association between 1,25(OH)2D and S-Klotho levels was indirectly influenced by bone mineral density (BMD), with a percentage of mediation of 31.40%. Our study shows that 1,25(OH)2D is negatively associated with S-Klotho plasma levels in middle-aged sedentary adults, which is partially mediated by BMD. Clinicaltrial.gov: ID: NCT03334357.

Antiepileptogenic Effect of Retinoic Acid.

Retinoic acid, a metabolite of vitamin A, acts through either genomic or nongenomic actions. The genomic action of retinoids exerts effects on gene transcription through interaction with retinoid receptors such as retinoic acid receptors (RARα, β, and γ) and retinoid X receptors (RXRα, β, and γ) that are primarily concentrated in the amygdala, pre-frontal cortex, and hippocampal areas in the brain. In response to retinoid binding, RAR/RXR heterodimers undergo major conformational changes and orchestrate the transcription of specific gene networks. Previous experimental studies have reported that retinoic acid exerts an antiepileptogenic effect through diverse mechanisms, including the modulation of gap junctions, neurotransmitters, long-term potentiation, calcium channels and some genes. To our knowledge, there are no previous or current clinical trials evaluating the use of retinoic acid for seizure control.

All-trans-retinoic acid ameliorates atherosclerosis, promotes perivascular adipose tissue browning, and increases adiponectin production in Apo-E mice

All-trans-retinoic acid (atRA), an active metabolite of vitamin A, exerts a potential role in the prevention of cardiovascular diseases. It has been shown that atRA ameliorates atherosclerosis while the exact mechanism underlying this protection remains unknown. This study investigated the influence of atRA on insulin resistance (IR), atherosclerosis, and the process of perivascular adipose tissue (PVAT) browning. Moreover, syntheses of adiponectin, adipokine with anti-atherogenic effects, and tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine, were determined in PVAT. Apolipoprotein E-deficient mice (Apo-E) and control C57BL/6J wild-type mice were treated with atRA (5 mg/kg/day) or vehicle (corn oil) by plastic feeding tubes for 8 weeks. Long-term atRA treatment in Apo-E mice did not affect insulin resistance. AtRa administration ameliorated atherosclerosis, induced PVAT browning, and increased adiponectin production in PVAT in Apo-E mice. Furthermore, atRA increased nitric oxide (NO) level but did not affect adiponectin concentration in the aorta of Apo-E mice. These results indicate that atRA ameliorates atherosclerosis in Apo-E mice. We also observed the browning of PVAT. Besides, atRA increased the synthesis of adiponectin in PVAT and augmented NO level in the aorta in ApoE mice.

The effects of all-trans retinoic acid on immune cells and its formulation design for vaccines.

As one of the most important metabolites of vitamin A, all-trans retinoic acid (RA) plays a crucial role in regulating immune responses. RA has been shown to promote the differentiation of naïve T and B cells and perform diverse functions in the presence of different cytokines. RA also induces gut tropic lymphocytes through upregulating the expression of chemokine (C-C motif) receptor 9 (CCR9) and α4β7 integrin. In addition, RA promotes the expression of the enzyme retinal dehydrogenase (RALDH) on dendritic cells, which in turn strengthens the ability to synthesize RA. Due to the insolubility of RA, proper formulation design can maximize its ability to improve immune responses for vaccines. Recent studies have developed some formulations co-loading RA and antigen, which can effectively imprint lymphocytes gut homing properties and induce intestine immune responses as well as systemic responses through parenteral administration, providing a promising direction for the protection against mucosal infections. Here, we review the mechanism and effects of RA on lymphocyte differentiation and gut homing, and recent progress of RA delivery systems to improve mucosal immune responses.

Non-Coding RNAs in Retinoic Acid as Differentiation and Disease Drivers.

All-trans retinoic acid (RA) is the most active metabolite of vitamin A. Several studies have described a pivotal role for RA signalling in different biological processes such as cell growth and differentiation, embryonic development and organogenesis. Since RA signalling is highly dose-dependent, a fine-tuning regulatory mechanism is required. Thus, RA signalling deregulation has a major impact, both in development and disease, related in many cases to oncogenic processes. In this review, we focus on the impact of ncRNA post-transcriptional regulatory mechanisms, especially those of microRNAs and lncRNAs, in RA signalling pathways during differentiation and disease.

Genome-wide genetic marker analysis and genotyping of Escherichia fergusonii strain OTSVEF-60.

Poultry originated Escherichia fergusonii (POEF), an emerging bacterial pathogen, causes a wide range of intestinal and extra-intestinal infections in the poultry industry which incurred significant economic losses worldwide. Chromosomal co-existence of antibiotics and metal resistance genes has recently been the focal point of POEF isolates besides its pathogenic potentials. This study reports the complete genome analysis of POEF strain OTSVEF-60 from the poultry originated samples of Bangladesh. The assembled draft genome of the strain was 4.2 Mbp containing 4503 coding sequences, 120 RNA (rRNA = 34, tRNA = 79, ncRNA = 7), and three intact phage signature regions. Forty-one broad range antibiotic resistance genes (ARGs) including dfrA12, qnrS1, blaTEM-1, aadA2, tet(A), and sul-2 along with multiple efflux pump genes were detected, which translated to phenotypic resistant patterns of the pathogen to trimethoprim, fluoroquinolones, β-lactams, aminoglycoside, tetracycline, and sulfonamides. Moreover, 22 metal resistance genes were found co-existing within the genome of the POEF strain, and numerous virulence genes (VGs) coding for cit (AB), feo (AB), fep (ABCG), csg (ABCDEFG), fliC, ompA, gadA, ecpD, etc. were also identified throughout the genome. In addition, we detected a class I integron gene cassette harboring dfrA12, ant (3″)-I, and qacEΔ-sul2 genes; 42 copies of insertion sequence (IS) elements; and two CRISPR arrays. The genomic functional analysis predicted several metabolic pathways related to motility, flagellar assembly, epithelial cell invasion, quorum sensing, biofilm formation, and biosynthesis of vitamin, co-factors, and secondary metabolites. We herein for the first time detected multiple ARGs, VGs, mobile genetic elements, and some metabolic functional genes in the complete genome of POEF strain OTSVEF-60, which might be associated with the pathogenesis, spreading of ARGs and VGs, and subsequent treatment failure against this emerging avian pathogen with currently available antimicrobials.

Nutritional composition of Apis mellifera adansonii L. (Hymenoptera: Apidae) from three ecological zones of Nigeria

The honey bee is an important economic and domesticated insect. This insect has been gaining attention as a potential nutritional source in different parts of the world. This study therefore evaluated the nutritional and anti-nutritional composition of the tissue of honey bees, Apis mellifera adansonii, from the rainforest, guinea savannah and derived savannah zones of Nigeria. Honey bee samples were collected from fully colonised colonies of two different apiaries each from the rainforest, guinea and derived savannah zones of Nigeria for chemical analyses. Proximate, minerals composition, vitamin and secondary metabolites composition were estimated using standard methods. The levels of proximate compositions (fat, ash, crude fibre, crude protein and carbohydrate contents), minerals, vitamins and secondary metabolites recorded in the honey bees from the three ecological zones were not significantly different. Potassium, chloride and calcium respectively were higher in the honey bee tissue than the other minerals tested. However, the level of phytate was higher in the honey bee samples than the regulatory safe level. Based on the results of this study, honey bees from the studied ecological zones of Nigeria are equally nutritious.

Concise Synthesis of (S)-δ-CEHC, a Metabolite of Vitamin E.

Carboxyethyl hydroxychromans (CEHCs) are natural metabolites of vitamin E (VE). Their urinary levels can serve as useful biomarkers for the nutritional assessment of VE. Moreover, specific biological activities of CEHCs deserve further investigation. Here, we report a concise method to build up a chiral 6-hydroxychroman scaffold of VE and CEHCs. The first total synthesis of (S)-δ-CEHC was accomplished in 40% overall yield and 97% ee using a chiral synthon derived from naturally occurring (−)-linalool.

Altered vitamin A metabolism in human liver slices corresponds to fibrogenesis.

All‐trans‐retinoic acid (atRA), the active metabolite of vitamin A, has antifibrogenic properties in vitro and in animal models. Liver vitamin A homeostasis is maintained by cell‐specific enzymatic activities including storage in hepatic stellate cells (HSCs), secretion into circulation from hepatocytes, and formation and clearance of atRA. During chronic liver injury, HSC activation is associated with a decrease in liver retinyl esters and retinol concentrations. atRA is synthesized through two enzymatic steps from retinol, but it is unknown if the loss of retinoid stores is associated with changes in atRA formation and which cell types contribute to the metabolic changes. The aim of this study was to determine if the vitamin A metabolic flux is perturbed in acute liver injury, and if changes in atRA concentrations are associated with HSC activation and collagen expression. At basal levels, HSC and Kupffer cells expressed key genes involved in vitamin A metabolism, whereas after acute liver injury, complex changes to the metabolic flux were observed in liver slices. These changes include a reproducible spike in atRA tissue concentrations, decreased retinyl ester and atRA formation rate, and time‐dependent changes to the expression of metabolizing enzymes. Kinetic simulations suggested that oxidoreductases are important in determining retinoid metabolic flux after liver injury. These early changes precede HSC activation and upregulation of profibrogenic gene expression, which were inversely correlated with atRA tissue concentrations, suggesting that HSC and Kupffer cells are key cells involved in changes to vitamin A metabolic flux and signaling after liver injury. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Vitamin A is metabolized in the liver for storage as retinyl esters in hepatic stellate cell (HSCs) or to all‐trans‐retinoic acid (atRA), an active metabolite with antifibrogenic properties. Following chronic liver injury, vitamin A metabolic flux is perturbed, and HSC activation leads to diminished retinoid stores. WHAT QUESTION DID THIS STUDY ADDRESS? Do changes in the expression of vitamin A metabolizing enzymes explain changes in atRA concentrations and the regulation of fibrosis following acute liver injury? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? In healthy liver, both HSC and Kupffer cells may mediate vitamin A homeostasis. Following acute liver injury, complex changes in metabolizing enzyme expression/activity alter the metabolic flux of retinoids, resulting in a transient peak in atRA concentrations. The atRA concentrations are inversely correlated with profibrogenic gene expression, HSC activation, and collagen deposition. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Improved understanding of altered vitamin A metabolic flux in acute liver injury may provide insight into cell‐specific contributions to vitamin A loss and lead to novel interventions in liver fibrosis.

The role of the retinoid receptor, RAR/RXR heterodimer, in liver physiology

Activated by retinoids, metabolites of vitamin A, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs) play important roles in a wide variety of biological processes, including embryo development, homeostasis, cell proliferation, differentiation and death. In this review, we summarized the functional roles of nuclear receptor RAR/RXR heterodimers in liver physiology. Specifically, RAR/RXR modulate the synthesis and metabolism of lipids and bile acids in hepatocytes, regulate cholesterol transport in macrophages, and repress fibrogenesis in hepatic stellate cells. We have also listed the specific genes that carry these functions and how RAR/RXR regulate their expression in liver cells, providing a mechanistic view of their roles in liver physiology. Meanwhile, we pointed out many questions regarding the detailed signaling of RAR/RXR in regulating the expression of liver genes, and hope future studies will address these issues.

Peretinoin, an Acyclic Retinoid, for the Secondary Prevention of Hepatocellular Carcinoma.

The high rates of hepatocellular carcinoma (HCC) recurrence after initially successful curative therapy emphasize ongoing unmet needs to prevent or reduce HCC recurrence. Retinoid acid (RA), a metabolite of vitamin A and its related analogues (termed retinoids) has been suggested as a promising chemotherapeutic agent in cancer treatment. The synthetic oral retinoid peretinoin is the only agent for the secondary chemoprevention of HCC after curative therapy that is currently well applied into clinical development. Here we present an updated summary of the molecular pathogenesis of HCC and of preclinical and clinical findings with peretinoin, including its clinical characteristics, safety and tolerability profile and future perspectives for clinical use.

The Relative Expression of ERα Isoforms ERα66 and ERα36 Controls the Cellular Response to 24R,25-Dihydroxyvitamin D3 in Breast Cancer.

Vitamin D3 and its metabolites have antitumorigenic properties in vitro and in vivo; however, clinical trials and retrospective studies on the effectiveness of vitamin D3 oral supplementation against cancer have been inconclusive. One reason for this may be that clinical trials ignore the complex vitamin D metabolome and the many active vitamin D3 metabolites present in the body. Recent work by our lab showed that 24R,25(OH)2D3, a vitamin D3 metabolite that is active in chondrocyte proliferation and differentiation, has antitumorigenic properties in estrogen receptor alpha-66 (ERα66)-positive (ER+) breast cancer, but not in ERα66-negative (ER-) breast cancer. Here we show that 24R,25(OH)2D3 is protumorigenic in an in vivo mouse model (NOD.Cg-PrkdcscidIl2rgtm1Wjl /SzJ (NSG) mice) of ER- breast cancer, causing greater tumor growth than in mice treated with vehicle alone. In vitro results indicate that the effect of 24R,25(OH)2D3 is via a membrane-associated mechanism involving ERs and phospholipase D. 24R,25(OH)2D3 increased proliferation and reduced apoptosis in ERα66-negative HCC38 breast cancer cells, and stimulated expression of metastatic markers. Overexpressing ESRI, which encodes ERα66, ERα46, and ERα36, reduced the proapoptotic response of ERα66- cells to 24R,25(OH)2D3, possibly by upregulating ERα66. Silencing ESR1 in ERα66+ cells increased apoptosis. This suggests 24R,25(OH)2D3 is differentially tumorigenic in cancers with different ERα isoform profiles. Antiapoptotic actions of 24R,25(OH)2D3 require ERα36 and proapoptotic actions require ERα66. IMPLICATIONS: These results suggest that 24R,25(OH)2D3, which is a major circulating metabolite of vitamin D, is functionally active in breast cancer and that the regulatory properties of 24R,25(OH)2D3 are dependent upon the relative expression of ERα66 and ERα36.

All-trans retinoic acid regulating angiopoietins-1 and alleviating extracellular matrix accumulation in interstitial fibrosis rats

All-trans retinoic acid (ATRA) is one of essentially active metabolite of vitamin A, and plays an important role in diverse physiological processes, such as cellular growth and function. Renal interstitial fibrosis (RIF) is a common pathological characteristic of chronic renal disease causing end-stage renal disease currently lacking effective treatment. Low level of Angiopoietins-1 (Angpt-1) is associated with extracellular matrix accumulation and fibrosis diseases. This study was performed to assess the association of ATRA with Angpt-1 in RIF disease. Rats were divided into three groups: group of sham (SHO group), group of unilateral ureteral obstruction group (UUO group), UUO mice administrated daily at the dose of ATRA (ATRA group). Masson-staining was used to detect the histologic lesion. Immunohistochemistry and Western-blot were applied to determine the targeted proteins. RIF score was significantly increased in UUO rats when compared with that of SHO group, and the fibrosis score was notably reduced in ATRA group. Transforming growth factor-β1 (TGF-β1), collagen IV (Col-IV) and fibronectin (FN) expressions in UUO group were significantly up-regulated, whereas Angpt-1 expression was significantly down-regulated compared with the SHO group. ATRA treatment reduced TGF-β1, Col-IV and FN expressions and improved Angpt-1 expression compared with the UUO group. The protein expression of Angpt-1 in kidney tissue of UUO group was negatively correlated with RIF index and protein expressions of Col-IV, FN and TGF-β1. In conclusion, low expression of Angpt-1 was associated with the RIF disease and ATRA treatment can increase the Angpt-1 and alleviate the RIF lesion in UUO rats.

Vitamin D Metabolism and Guidelines for Vitamin D Supplementation.

Vitamin D is essential for bone health and is known to be involved in immunomodulation and cell proliferation. Vitamin D status remains a significant health issue worldwide. However, there has been no clear consensus on vitamin D deficiency and its measurement in serum, and clinical practice of vitamin D deficiency treatment remains inconsistent. The major circulating metabolite of vitamin D, 25-hydroxyvitamin D (25(OH)D), is widely used as a biomarker of vitamin D status. Other metabolic pathways are recognised as important to vitamin D function and measurement of other metabolites may become important in the future. The utility of free 25(OH)D rather than total 25(OH)D needs further assessment. Data used to estimate the vitamin D intake required to achieve a serum 25(OH)D concentration were drawn from individual studies which reported dose-response data. The studies differ in their choice of subjects, dose of vitamin D, frequency of dosing regimen and methods used for the measurement of 25(OH)D concentration. Baseline 25(OH)D, body mass index, ethnicity, type of vitamin D (D2 or D3) and genetics affect the response of serum 25(OH)D to vitamin D supplementation. The diversity of opinions that exist on this topic are reflected in the guidelines. Government and scientific societies have published their recommendations for vitamin D intake which vary from 400-1000 IU/d (10-25 μg/d) for an average adult. It was not possible to establish a range of serum 25(OH)D concentrations associated with selected non-musculoskeletal health outcomes. To recommend treatment targets, future studies need to be on infants, children, pregnant and lactating women.

Pillar[6]arene acts as a biosensor for quantitative detection of a vitamin metabolite in crude biological samples

Metabolic syndrome is associated with obesity, hypertension, and dyslipidemia, and increased cardiovascular risk. Therefore, quick and accurate measurements of specific metabolites are critical for diagnosis; however, detection methods are limited. Here we describe the synthesis of pillar[n]arenes to target 1-methylnicotinamide (1-MNA), which is one metabolite of vitamin B3 (nicotinamide) produced by the cancer-associated nicotinamide N-methyltransferase (NNMT). We found that water-soluble pillar[5]arene (P5A) forms host–guest complexes with both 1-MNA and nicotinamide, and water-soluble pillar[6]arene (P6A) selectively binds to 1-MNA at the micromolar level. P6A can be used as a “turn-off sensor” by photoinduced electron transfer (detection limit is 4.38 × 10−6 M). In our cell-free reaction, P6A is used to quantitatively monitor the activity of NNMT. Moreover, studies using NNMT-deficient mice reveal that P6A exclusively binds to 1-MNA in crude urinary samples. Our findings demonstrate that P6A can be used as a biosensor to quantify 1-MNA in crude biological samples.

Dietary vitamin A supplementation prevents early obesogenic diet-induced microbiota, neuronal and cognitive alterations.

Early consumption of obesogenic diets, rich in saturated fat and added sugar, is associated with a plethora of biological dysfunctions, at both peripheral and brain levels. Obesity is also linked to decreased vitamin A bioavailability, an essential molecule for brain plasticity and memory function. Here we investigated in mice whether dietary vitamin A supplementation (VAS) could prevent some of the metabolic, microbiota, neuronal and cognitive alterations induced by obesogenic, high-fat and high-sugar diet (HFSD) exposure from weaning to adulthood, i.e. covering periadolescent period. As expected, VAS was effective in enhancing peripheral vitamin A levels as well as hippocampal retinoic acid levels, the active metabolite of vitamin A, regardless of the diet. VAS attenuated HFSD-induced excessive weight gain, without affecting metabolic changes, and prevented alterations of gut microbiota α-diversity. In HFSD-fed mice, VAS prevented recognition memory deficits but had no effect on aversive memory enhancement. Interestingly, VAS alleviated both HFSD-induced higher neuronal activation and lower glucocorticoid receptor phosphorylation in the hippocampus after training. Dietary VAS was protective against the deleterious effects of early obesogenic diet consumption on hippocampal function, possibly through modulation of the gut-brain axis.

Calcitriol Suppresses HIF-1 and HIF-2 Transcriptional Activity by Reducing HIF-1/2α Protein Levels via a VDR-Independent Mechanism.

Hypoxia-inducible transcription factors 1 and 2 (HIFs) are major mediators of cancer development and progression and validated targets for cancer therapy. Although calcitriol, the biologically active metabolite of vitamin D, was attributed with anticancer properties, there is little information on the effect of calcitriol on HIFs and the mechanism underling this activity. Here, we demonstrate the negative effect of calcitriol on HIF-1/2α protein levels and HIF-1/2 transcriptional activity and elucidate the molecular mechanism of calcitriol action. We also reveal that the suppression of vitamin D receptor (VDR) expression by siRNA does not abrogate the negative regulation of HIF-1α and HIF-2α protein levels and HIF-1/2 transcriptional activity by calcitriol, thus testifying that the mechanism of these actions is VDR independent. At the same time, calcitriol significantly reduces the phosphorylation of Akt protein kinase and its downstream targets and suppresses HIF-1/2α protein synthesis by inhibiting HIF1A and EPAS1 (Endothelial PAS domain-containing protein 1) mRNA translation, without affecting their mRNA levels. On the basis of the acquired data, it can be proposed that calcitriol reduces HIF-1α and HIF-2α protein levels and inhibits HIF-1 and HIF-2 transcriptional activity by a VDR-independent, nongenomic mechanism that involves inhibition of PI3K/Akt signaling pathway and suppression of HIF1A and EPAS1 mRNA translation.

All-trans retinoic acid has renoprotective effects on Cisplatin-induced acute kidney injury in rats.

All-trans retinoic acid (ATRA) is the active metabolites of vitamin A; it has antioxidant effects, and can regulate apoptosis. This study aims to observe the effects of ATRA on cisplatin-induced acute kidney injury, where a total of 96 Sprague-Dawley rats (180–220 g) were divided into four groups; (24 rats in each); normal group, DMSO group, cisplatin group, and cisplatin with retinoic acid group. Eight rats were sacrificed on days 3, 7, and 11 in each group. Serum creatinine, blood urea nitrogen and MAU levels were assayed, the activities of Catalase (CAT), glutathione reductase (GSH) and malondialdehyde (MDA) were tested in kidney tissue, expressions of nuclear factor- kB (NF- kB), Caspase-3, and TGFβ1 were determined by real time PCR, also Histopathological changes in kidney tissue were determined. Our study found that the levels of serum creatinine, BUN, MAU, and MDA in cisplatin group were significantly increased, while the activities of CAT and GSH were significantly decreased, as well as, the expression levels of caspase-3, NF-kB, and TGFβ1 were significantly increased in cisplatin group. In contrast, ATRA group showed lower levels of serum creatinine, BUN, MAU and MDA (p < 0.05), and increased levels of CAT and GSH (p < 0.05), which reached the highest levels at day 11, also the expression levels of caspase-3, NF-kB and TGFβ1 decreased significantly in ATRA group (P< 0.05). Our study concluded that, ATRA has a protective effect on cisplatin-induced acute kidney injury in rats, and it is associated with inhibition of lipid peroxidation, lower inflammation and lower apoptosis.