AHR

Humans are keenly aware of their mortality. Given a limited time what we do with our life is a reflection of knowledge of our mortality. In 2009 the Nobel prize in medicine to Jack W Szostak, Elizabeth Blackburn, Carol W Greider for their work on Telomerase and scientific research exploded in this area. Telomere protect chromosome ends the Telomerase enzyme maintains Teleomere length. This activity of Telomerase is essential in aging and stem cells and achieving longer life spans. Telomerase is expressed in 85% of human cancer cell lines, but its enzymatic activity is not detectable in most human somatic cells which constitute the vast majority of the cells in the human body. There is a need for increased telomerase activity in stem cells for use in the treatment of therapies where there is an active role for telomerase. Umbilical Cord Blood (UCB) provides an attractive source of stem cells for research and therapeutic uses. Work shown here characterizes the gene expression changes from Umbilical cord cells differentiate toward telomerase on treatment with Metadichol ®. Metadichol ® is a nanoemulsion of long-chain alcohols that is nontoxic. It is a mixture of long-chain alcohols derived from food. The work presented here is about the effect of Metadichol ® on Telomerase expression profile in Umbilical cord cells. Our results using q-RT-PCR show increases of mRNA telomerase expression by Sixteen-fold at one picogram but down-regulates expression at higher concentrations of 100 pg, 1 ng, 100 ng and one microgram per ml concentration. Western blot studies showed expression of Telomerase protein which is slightly higher than control at one picogram, i.e., Telomerase protein expression continues at replacement level. Since it is devoid of toxic effects, it can be directly tested on humans and is in use today as an immune boosting supplement. Metadichol ® increases expression of Klotho an anti-aging gene expression in cancer cell lines by Four to Tenfold , and Klotho gene has been documented to inhibits the growth of cancer cells. Metadichol ® also inhibits TNF, ICAM1, CCL2, and BCAT1 which that is associated with proliferation in yeast and increased metastatic potential in human cancers. It paves the way for safe clinical testing and research and study of Telomerase biology and its use in humans.

Metadichol ® is a nano formulation of long-chain lipid alcohols derived from food It is a inverse agonist of Vitamin
D receptor (VDR), Aryl hydrocarbon receptor (AHR), and ROR gamma (RORC) that could have beneficial effects on
skin diseases. We now present case studies of patients with various skin diseases who has symptoms mitigated on
treatment with Metadichol. The proposed mechanism is that Metadichol by its actions on the above mentioned
nuclear receptors affects Th1, TH2,Th 17, IL 17 and IL22 and IL 23 pathways that exacerbate many Skin diseases.
Metadichol is the first molecule to successfully navigate around the problems involved with promiscuous ligands
and targets. It fulfills the goals of the emerging field of Polypharmacology i.e a single drug is able to bind to multiple
targets beyond the "one drug, one target" concept. We show how Metadichol is an innovative treatment for treating
multiple skin diseases like eczema, acne, diabetic wounds viral and bacterial infection and also improving skin
texture. Metadichol ® is a safe non toxic low cost solution and is an alternative to numerous clinical candidates in
combating over 3000 skin diseases.

In recent years, the health effects associated with air pollution have been intensively studied. Most studies focus on air pollution effects on the lung and the cardiovascular system. More recently, however, epidemiological and mechanistic studies suggest that air pollution is also affecting skin integrity. This state-of-the-art review focuses on this latter aspect; it was developed with the collaboration of European and Chinese board of experts with specific interests in environmental health, clinical and basic research in dermatology and cosmetic dermatology. A literature review limited to pollution and health effects and (sensitive) skin was performed using PubMed. Review and original articles were chosen. We summarize the existing scientific evidence that air pollution exerts detrimental effects on human skin, discuss potential clinical implications and suggest specific and unspecific cosmetic protective measures.

reased risk of psoriatic arthritis, lymphomas, cardiovascular disease, and Crohn’s disease. Psoriasis treatments
today include steroid and vitamin D3 cream, ultraviolet light, and immune systemsuppressing medications such as
methotrexate.
The T cells responsible for psoriasis are Th1 and Th l7 cells. IL-22, produced by Th17 cells, is crucial for the
proliferation of keratinocytes. IL-22 with the help of IL-17 can induce the critical events of psoriasis. To maintain
Th17 cells, IL-23 is required, and it is released from tumor necrosis factor-alpha (TNF-alpha) induced pathways. The
pathophysiology of psoriasis involves RORC (retinoic acid receptor-related orphan nuclear receptor gamma) as a
critical transcription factor for the development of Th17 cells. FDA has approved an antibody Secukinumab® targeting
TNF-α for the treatment of psoriasis. Other FDA approved drugs are Tremfya® targeting IL23 for treatment of moderate
to severe plaque psoriasis and Taltz® that blocks IL17 for treatment of plaque psoriasis.
Metadichol® a nanoformulation of long-chain lipid alcohols derived from food is a TNF-alpha inhibitor and also
binds to Vitamin D receptor (VDR) that could have beneficial effects on Psoriasis. VDR modulates Th1-mediated
inflammatory disease like psoriasis. We now present evidence that Metadichol is an inverse agonist of RORγt and
AHR (Aryl Hydrocarbon Receptor) thus controlling Th17, IL17 and IL22. Being a TNF-alpha inhibitor, it can control IL23
thus blocking the significant pathways that exacerbate psoriasis. We present case studies of 7 patients afflicted with
psoriasis and skin related conditions and how treatment with Metadichol resolved the underlying disease. Metadichol®
has properties that allow its use as a safe nontoxic, toxic solution to combating the growing number of psoriasis cases.

The function of the aryl hydrocarbon receptor (AhR) in mediating the biological effect to environmental pollutants is well established. However, accumulated evidence indicates a wide range of physiological and pathological functions mediated by the AhR, suggesting the existence of endogenous AhR ligand(s). The nature of an AhR ligand remain elusive; however, it is known that the AhR is activated by several compounds, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin or the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole. In this study, we show that physiological concentrations of tryptamine (TA) lead to induction of cytochrome P4501A1 transcription through an AhR-dependent mechanism. In addition, we show that activation of the AhR by TA requires a functional monoamino oxidase system, suggesting that TA acts as an AhR proligand possibly by converting to a high-affinity AhR ligand. Taken together, we show a possible mechanism, through which AhR signaling is activated by endogenous conversion of TA involving monoamine oxidases.

Nonasthmatic eosinophilic bronchitis (EB) has emerged as a useful tool to study the structural and inflammatory mechanisms of airway hyperresponsiveness (AHR) in asthma. We have previously shown that vascular remodeling and reticular basement membrane (RBM) thickening are present in EB. However, it is not known whether other features of structural remodeling including increased airway smooth muscle (ASM) mass, matrix deposition, and glandular hyperplasia are also present in EB.We sought to determine whether structural remodeling occurs in EB and is associated with AHR and airflow limitation.Forty-two patients with asthma, 21 patients with EB, and 19 healthy volunteers were recruited. ASM area, RBM thickness, collagen 3 deposition, glandular area, mast cells, and granulocytes were assessed in bronchial biopsy samples.Nonasthmatic eosinophilic bronchitis and asthma were associated with a significant increase in ASM mass and RBM thickness compared with healthy subjects. In contrast, we did not observe any significant differences in collagen 3 deposition in the lamina propria and ASM or the % area of glands in the lamina propria. Univariate analysis demonstrated that mast cell numbers in the ASM were the only feature of remodeling associated with AHR (β = –0.51; P = .004). Stepwise linear regression revealed that a combination of mast cell numbers in the ASM (β = –0.43) and disease duration (β = –0.25; model-adjusted R2 = 0.26; P = .027) best modeled AHR.Mast cell localization to the ASM bundle, but not structural remodeling of the airway wall, is associated with AHR in asthma.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant known to exhibit toxic effects on the male reproductive system, including the epididymus and spermatozoa. However, the mechanism(s) that mediate dioxin toxicity in spermatozoa remain unclear. The aim of the present study was to investigate whether exposure to TCDD would cause a loss in mitochondrial membrane potential (Deltapsi(m)) in spermatozoa and whether such an effect is mediated by the Ah receptor (AhR). Exposure of C57BL/6 male mice to TCDD at concentrations of 0.1-50 microg/kg for 24 h caused a dose-dependent loss of Deltapsi(m) in epididymal spermatozoa compared to spermatozoa from vehicle-treated mice. However, this effect was not apparent in spermatozoa from AhR knockout (KO) mice. Exposure of spermatozoa from C57BL/6 mice to 1 nM or 5 nM TCDD in vitro also induced loss of Deltapsi(m). TCDD-exposed C57BL/6 mice failed to exhibit changes in the morphology of testes and epididymus, and did not show a...

PURPOSE: We sought to study the possible association between parental age and autism spectrum disorder (ASD) by using both a cohort design and a sibling design.
METHODS: Our cohort included all singleton births in Denmark from January 1, 1980, through December 31, 2003, a total of 1,311,736 children. Cases of ASDs were obtained from the Danish National Psychiatric Register using International Classification of Diseases (ICD)-8 and ICD-10.
RESULTS: A total of 9556 children were diagnosed with an ASD. Both maternal and paternal age were associated with a greater risk of ASD in the offspring (hazard ratios ranging from 1.21 (1.10–1.34) to 1.65 (1.09–2.48) depending on combinations of parental age categories; <35, 35–39, and 40+ years). For
mothers younger than 35 years, the risk of ASD increased with increasing father’s age group. For fathers younger than 35 years, the risk of ASD increased with increasing maternal age.
CONCLUSIONS: We found an association between parental age and ASD in the cohort study, but the combined underlying mechanisms through which paternal and maternal age impact ASD risk do not seem to act synergistically. The results of the sibling analysis suggest that the association between parental age and ASD found in the cohort study cannot be accounted for by common genetic and environmental factors.