Vitamin K and Osteoporosis

Vitamin K acts as a coenzyme of carboxylase, catalyzing the carboxylation of several vitamin K dependent proteins. Beyond its well-known effects on blood coagulation, it also exerts relevant effects on bone and the vascular system. In this review, we point out the relevance of an adequate vitamin K intake to obtain sufficient levels of carboxylated (active form) vitamin K dependent proteins (such as Osteocalcin and matrix Gla protein) to prevent bone health. Another bone-related action of Vitamin K is being a ligand of the nuclear steroid and xenobiotic receptor (SXR). We also discuss the recommended intake, deficiency, and assessment of vitamin K. Furthermore, we review the few available studies that have as pre-specified outcome bone fractures, indicating that we need more clinical studies to confirm that vitamin K is a potential therapeutic agent for bone fractures.

Clinical significance of steroid and xenobiotic receptor and its targeted gene CYP3A4 in human prostate cancer,

The steroid and xenobiotic receptor (SXR) regulates cytochromeP450 (CYP) enzymes, which are key inactivators of testosterone inthe liver and prostate. In the present study, we investigated SXRexpression in human prostate tissues. We determined SXR immunoreactivityusing an anti-SXR antibody in benign (n = 78) andcancerous (n = 106) tissues obtained by radical prostatectomy.Stained slides were evaluated for the proportion and stainingintensity of immunoreactive cells. Total immunoreactivity (IR)scores (range: 0–8) were calculated as the sum of the proportionand intensity scores. Associations between the clinicopathologicalfeatures of the patients, SXR status, and CYP3A4 immunoreactivitywere analyzed. Western blot analyses validated the specificity ofthe anti-SXR antibody in 293T cells transfected with pcDNA–FLAG–SXR. Positive (IR score: ‡ 2) nuclear SXR staining was observed in91% (71 ⁄ 78) of benign foci and 47% (50 ⁄ 106) of cancerous lesions.Immunoreactivity scores were significantly lower in the cancerouslesions than in the benign foci (P < 0.0001). Clinicopathologicalanalyses showed that cancer-specific survival in patients with highSXR IR scores (‡4) was significantly increased (P = 0.046). Combineddata of present and previous studies showed that high IRscores for both the SXR and CYP3A4 correlated with significantlybetter cancer-specific survival rates in multivariate regression analyses(hazard ratio: 2.15, 95% confidence interval: 1.25–3.55,P = 0.007). We showed differential SXR expression in human prostatetissues. The high expression of the SXR and CYP3A4 is astrong prognostic indicator of favorable outcomes in prostatecancer, and could be a therapeutic target. (Cancer Sci 2012; 103:176–180)Endocrine therapies for advanced or recurrent prostate cancer(PC) are intended to decrease levels of circulatingandrogens and ⁄ or reduce androgen receptor (AR) activity.(1)Unfortunately, PC frequently develops into castration-resistantprostate cancer (CRPC). In CRPC, AR activity is often preservedby various mechanisms, including changes in intratumorligand concentration, AR gene amplification, AR mutations,changes in regulatory molecules, and ligand-independent ARactivation through kinase cross-talk.(2) Additionally, CRPCresults in high androstenediol levels in PC tissues, even afterandrogen-deprivation therapy.(3) Androstenediol is a morepotent activator of the mutant AR than dihydrotestosterone(DHT) in LNCaP cells, and induces greater cell proliferation.(3)Moreover, cells of a hormone-refractory MDA–PCa-2b subline,which is a metastasis-derived subline generated in vitro frombone, are stimulated by low levels of testosterone.(4) We alsoproposed a possible correlation between PC and intraprostaticandrogen metabolism.(5) In our previous study, decreased cytochromeP450 (CYP)2B6 expression contributed to the progressionof human PC, and transfection of the CYP2B6 geneinhibited proliferation of LNCaP cells.(5) Dihydrotestosterone isinactivated by the enzyme CYP3A4, which is a member of theCYP450 family and is responsible for the hydroxylation of testosteronein the liver and prostate.(6–11) In our previous study,decreased CYP3A4 expression was associated with a higherGleason score (GS) and significantly decreased cancer-specificsurvival in human PC.(12) Therefore, decreased CYP3A4 activitymight contribute to the increased bioavailability of intraprostaticDHT and the subsequent development of PC.Cytochrome P450 3A4 expression is regulated by the steroidand xenobiotic receptor (SXR), also known as the human pregnaneX receptor, which consists of members of the NR1I nuclearreceptor subfamily of ligand-activated transcription factors.(13,14)The SXR is expressed primarily in the liver, intestine, kidney,lung, stomach, peripheral blood monocytes, blood–brain barrier,uterus, ovary, placenta, breast, osteoclasts, heart, adrenal gland,bone marrow, and specific regions of the brain.(13) This wideexpression pattern indicates that the SXR is part of a protectivemechanism for critical cells that are sensitive to aberrant levels ofexogenous or endogenous compounds, such as phenobarbital,dexamethasone (DXM), prednisolone (PSL), androstane, andestrogens.(13) Recent studies have also revealed SXR-activated,signal-regulated proliferation in breast and colon cancer.(15,16)Therefore, we hypothesized that the SXR, which is upstream ofthe CYP3A4 gene, might be associated with PC progression. Inthe present study, we investigated the SXR expression in humanprostate tissues using an anti-SXR antibody.

A36 THE ROLE OF MICROBIAL INDOLE METABOLITES IN CONTROLLING INFLAMMATORY RESPONSES AND HEALING IN RESPONSE TO DSS-INDUCED COLITIS

Background Failure to resolve inflammation is often associate with the complications of Crohn’s Disease (CD). The pregnane X receptor (PXR), a xenobiotic receptor, is recognized for its role in suppressing inflammation and has recently been shown to influence fibrogenesis in the liver. In the intestine, PXR-signaling can be influenced by the microbial tryptophan metabolite indole-3- propionic acid (IPA), which can modulate intestinal inflammation, in turn influencing fibrogenesis, resolution and healing. This suggests that the gut microbiota could modulate mucosal homeostasis and resolution of inflammation via microbial metabolites Aims To understand and characterize the interplay between microbial complexity and the regulation of host inflammatory and healing responses, specifically focusing on the PXR and its microbial metabolite ligand IPA. Methods Intestinal inflammation was induced using DSS (1%, 1.5%, 2% and 3.5%) for 5 days followed by healing for 25 days in C57Bl/6 stably derived moderately diverse mouse microbiota 2 (sDMDMm2) colonized gnotobiotic and C57Bl/6 specific pathogen free (SPF) mice. Inflammation, architectural changes and fibrosis were assessed using Haemotoxylin and Eosin and Masson-Trichrome histological stains. Weight was recorded daily for the first 10 days and every other day after for 25 days, for a total of 30 days. Fecal lipocalin was quantified in samples collected throughout the study to assess inflammation. Innate immune cell influx was measured by flow cytometry, and the microbiota assessed via 16S rRNA sequencing. Results The gnotobiotic sDMDMm2 mice were exquisitely sensitive to DSS-induced colitis, exhibiting significantly increased mortality and morbidity at 2% and 3.5% w/v DSS compared to the SPF group. To elicit the same degree of disease to assess recovery, sDMDMm2 mice were exposed to 1.5% DSS and SPF mice to 3.5% DSS. Following 25 days recovery, sDMDMm2 colonized mice showed increased levels of fecal lipocalin 2, as compared to the SPF mice. DSS-treated sDMDMm2 mice supplemented with IPA during their recovery presented lower levels of fecal lipocalin, similar to colitic SPF mice. IPA supplemented sDMDMm2 mice also exhibited greater overall survival, with no significant differences in neutrophil count compared to mice given H20 during recovery. Conclusions A model system with a less complex microbiota (sDMDMm2) has a higher susceptibility to acute inflammation and a diminished capacity to resolve said inflammation. Addition of the microbial metabolite IPA normalized the recovery of the sDMDMm2 colonized mice, to a response indistinguishable from SPF mice, while also increasing survival. These data highlight the importance of microbial complexity in the regulation of intestinal mucosal homeostasis. Funding Agencies CAG, CCC, CIHR

Ameliorative effects of resveratrol against cadmium-induced nephrotoxicity via modulating nuclear xenobiotic receptor response and PINK1/Parkin-mediated Mitophagy

Resveratrol is shown to alleviate Cd-induced histopathological lesions of the kidney, mitigating Cd-induced oxidative stress by activating NXRs (CAR/PXR/AHR/Nrf2) response and phase II detoxification system.