Educational Forum with Clinical Studies Current Science and Research

February 13, 2016

CIRCADIAN SKIN IS A REALITY : The secrets of skin repair in wound healing and anti-aging


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CIRCADIAN SKIN IS A REALITY : The secrets of skin repair in wound healing and anti-aging

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Historically, work on peripheral circadian clocks has been focused on organs and tissues that have prominent metabolic functions, such as the liver, fat, and muscle. In recent years, skin has emerged as a model for studying circadian clock regulation of cell proliferation, stem cell functions, tissue regeneration, aging, etc. Morphologically, skin is complex, containing multiple cell types and structures, and there is evidence for a functional circadian clock in most, if not all, of its cell types. Despite the complexity, skin stem cell populations are well defined, experimentally tractable, and exhibit prominent daily cell proliferation cycles. Healing is the interaction of a complex cascade of cellular hemostasis, inflammation, proliferation and migration, followed by scar tissue remodeling. All these events are based on the same cell communications that trascend aging. Due to the accessibility of skin, in vivo imaging techniques can be readily applied to study the circadian clock and its outputs in real time, even at the single-cell level. Skin provides the first line of defense against many environmental and stress factors that exhibit dramatic diurnal variations such as solar ultraviolet (UV) radiation and temperature. Studies have already linked the circadian clock to the control of UVB-induced DNA damage and skin cancers. Due to the important role that skin plays in the defense against microorganisms, it also represents a promising model system to further explore the role of the clock in the regulation of the body’s immune functions. To that end, recent studies have already linked the circadian clock to psoriasis, one of the most common immune-mediated skin disorders. Hand in hand with skin circadian clocks is the extensive signalling within and between cells. We believe that the two are linked and work together.   In the signaling arena, we observe that healing is much slower with age due to aberrant cell communications leaving the body with inappropriate levels of Growth factors and connexins resulting in hypo or hyperproliferation or sustained inflammation. Unbalanced levels of hormonal signal, RBC’s aggregation leading to insufficient oxygen and cell’s inability to sustain nutrients are additional determining factors of wounds and aging. Diabetic ulcers are associated with reduced supply of oxygen and other nutrients, prolonged inflammation, impaired neovascularization, decreased synthesis of collagen, increased level of proteinases and defective macrophage function. Keloids involve increased activity of fibrogenic cytokines such as TGF b1, IGF01 and interleukin-1 and mutations in regulatory genes such as p53. The same unbalanced processes are observed in aging. Keratonicytes, fibroblasts and vascular endothelial cells display a reduced proliferative response in the aged as a result of reduced signaling. Re-epithelization and collagen synthesis exhibit a delay again due to deficient signaling. There is a general decrease in the number and size of dermal fibroblasts. Aged fibroblasts exhibit a diminished response to growth factors, in other words, their aging process is related to diminished hormonal signaling.

Research in wound healing demonstrate that keratinocytes adopt a migratory phenotype as they start to crawl across the wound bed to close the epidermal breach an event that is interrelated with activities in specific signaling pathways. Again via signaling mechanisms, wound healing brings together cells from distant positions and involves processes such as DNA synthesis and cell proliferation.   Growth Factors Signaling is necessary for cell movement into wounds. Transforming growth factors (TGF) b1, b2 be, transforming factor a, Fibroblast growth factors (FGF), vascular endothelial growth factos VEGF), platelet-derived growth factors (PDGF) AB and BB, insulin growth factor (IGF-1) and Keratinocyte Growth Factor (KGF) TGF b1, FGF and PDGF are proinflammatory agents and have proven successful in promoting different aspects of wound healing such a cell proliferation and migration. Proteinases signaling are necessary for cell movement into wounds, urokinase-type plasminogen activator (uPA), matrix matelloproteinases (MMPs) such as collagenase 1, gelatinase A, collagenase 3, and tissue plasminogen activator (t-A)

Connexins are also crucial in wound healing. C 43 increases in blood vessels in and around the site of injury.   Downregulation of Cx43 by Antisense has the effect of speeding the migration or keratinocytes and fibroblasts which results in closing the wound and forming the granulation tissue considerably faster. It also results in reducing negative effects such as inflammation. Cx26 has been associated with hyperproliferative conditions delaying remodeling and recovery. Clearly the appropriate levels of connexin expression are crucial for normal healing to take place. Clinically, we have tried to enhance signaling related to wound healing by a device that combines circadian timings with signaling specifications known to enhance fibroblast secretion, collagenase 1 and 3, Keratinocyte growth factors and certain pro-inflammatory agents. Results of single study studies have been encouraging as shown by the before and after pictures provided
Research is now focused on collagen receptors and signaling pathways in relationship to wound healing. Collagen receptors such as DDR1 are not essential for wound healing. However, the collagen receptor DDR2 is crucial for wound healing. Statistical Analysis using the Fisher exact test showed that there was a mild but significant difference(p<0.05) between controls and experimental subjects whereas up-regulating the JNK (c-Jun NH2-terminal kinases) signaling pathway increases wound healing and down-regulating the JNK signaling pathway slows down wound healing. Recent research (Suh 2002) demonstrated that aging is associated with a molecular signaling defect in the JNK pathway that impairs the balance between cell survival and apoptosis. While increased apoptosis could lead to cell loss, loss of apoptosis competence results in the an increase of cancer incidence. Again, the key is a balance between apoptosis and cell survival. Researchers such as Wang et al (2003) introduce the JNK signaling pathway as a genetic determinant of aging. They demonstrate that the JNK functions at the center of a signal transduction network that coordinates the induction of protective genes in response to oxidative challenge. JNK signaling activity thus alleviates the toxic effects of reactive oxygen species (ROS)

In conclusion, we propose a combination of signaling and timing as an aspect of circadian rhythms as well as circadian clocks to be instrumental in wound healing as well as the aging process.   Any aberrant communication between cells and their surrounding ECM delay or obstruct wound healing. Aberrant communications between cells and their surrounding ECM also leads to aging or desease. A number of studies examining protein to protein interactions in aged and young subjects demonstrated that Aging is the result of disorganized protein to protein interactions. Correct timing and meaningful signals sent and received by cells during their whole existence are essential for the harmonious development, maintenance and survival of tissues, organs and bodies. Timing and Signaling also govern movement, thought and behavior of cellular «microsocieties» whose proper functioning requires a precise coordination of emission and reception of signals. This perspective combines timing, circadian rhythms and signalling communications in an organized complex that could serve as the cornerstone of Anti-aging, Regenerative and Preventive Medicine


June 17, 2011

Wnt signalling in stem cells and cancer. Xanya Sofra Weiss

The canonical Wnt cascade has emerged as a critical regulator of stem cells. In many tissues, activation of Wnt signalling has also been associated with cancer. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signalling in stem and progenitor cells is subverted in cancer cells to allow malignant proliferation. Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals.

Stem cells are cells that have the unique ability to self- renew as well as to generate more differentiated progeny. The most primitive stem cell is the embryonic stem cell, which is derived from the inner cell mass of the blasto- cyst. This cell is pluripotent and can thus generate all the tissues of the body. Following the pioneering work on haemato- poietic stem cells over the last five decades, a multitude of recent studies have indicated that most other adult tissues also harbour stem cells. These adult stem cells are normally involved in homeo- static self-renewal processes but can also be rapidly recruited to repair tissues upon injury. With the study of adult stem cell biology, recurring roles of a limited set of signalling cascades are rapidly being uncovered. One of these is the canonical Wnt cascade. Notably, in many of the same tissues where the Wnt cascade controls stem cells, cancer ensues upon dysregulated activation of this pathway. Conceptually, this indicates that an efficient road to cancer involves the hijacking of physiological regulators of stem cell function in these particular tissues. Below, we first outline the canonical Wnt cascade, and then describe its mirror image roles in the biology of stem cells and cancer.

vertebrate genome encodes four highly similar Tcf/Lef proteins. In the absence of a Wnt signal, Tcf/Lef proteins repress target genes through a direct association with co-repressors such as Groucho. The interaction with b-catenin transiently converts Tcf/Lef factors into transcriptional activators. Drosophila genetics has recently identified two additional nuclear components, Pygopus and Bcl9 (also known as legless), conserved in vertebrates. Pygopus is essential for transcriptional activation of Tcf/Lef target genes, whereas Bcl9 seems to bridge Pygopus to Tcf-bound b-catenin. In sum, the canonical pathway translates a Wnt signal into the transient transcription of a Tcf/Lef target gene programme.

Xanya Sofra Weiss

Xanya Sofra Weiss

February 27, 2011


The action of dopamine was evaluated in the nucleus accumbens of acutely prepared rabbits. It was found that the effect of iontophoretically applied dopamine depended upon the frequency of stimulation of an afferent pathway; in this case the ipsilateral fimbria. Dopamine had a marked suppressive effect on field responses evoked by fimbria stimulation at 0.5 Hz, but not those responses evoked at 6.0 Hz. Dopamine was also effective in activating adenylate cyclase. Both the physiological and the biochemical effects of dopamine could be blocked by appropriate antagonists, suggesting that the phenomena observed were receptor mediated. It is suggested that dopamine serves to enhance information arriving from the hippocampal formation within the theta range by the suppression of competing non-theta activity.

Xanya Sofra Weiss

Xanya Sofra Weiss

Multiple Sclerosis: Low-Frequency Temporal Blood Oxygen Level– Dependent Fluctuations Indicate Reduced Functional Connectivity —Initial Results

PURPOSE: To study the correlation of low-frequency blood oxygenation level– dependent (BOLD) fluctuations on magnetic resonance (MR) images obtained of the left- and right-hemisphere primary motor regions in healthy control subjects and patients with multiple sclerosis (MS). MATERIALS AND METHODS: Sixteen healthy volunteers and 20 patients with MS underwent MR imaging with a 1.5-T imager by using a protocol designed to monitor low-frequency BOLD fluctuations. Data for low-frequency BOLD fluctuations were
acquired with subjects at rest and during continuous performance of a bilateral fingertapping task. These data were low-pass filtered (<0.08 Hz), and cross correlations of all acquired pixels to a region of interest in the left precentral gyrus were calculated. Confidence levels were calculated from the cross correlations. The fraction of pixels in the right precentral gyrus above a confidence level of 95% for correlation with the precentral gyrus was calculated for each subject. RESULTS: A plot of the fraction of the right precentral gyrus with high correlation with the left precentral gyrus for the finger-tapping state versus the resting state showed a clear discrimination between patients with MS and control subjects. Compared with control subjects, patients with MS generally had a smaller fraction of the pixels in the right precentral gyrus above the confidence level. This finding indicates that our method results in greater than 60% sensitivity and 100% specificity for discriminating patients with MS from control subjects. No significant correlation was found between clinical measures of MS disease and correlations of low-frequency BOLD fluctuations between left and right precentral gyri. CONCLUSION: On the basis of the connectivity measure of low-frequency BOLD fluctuations, patients with MS exhibited lower functional connectivity between rightand left-hemisphere primary motor cortices when compared with that in control subjects.

Xanya Sofra Weiss

Xanya Sofra Weiss

February 26, 2011

Bioimpedance Neuronal Microstimulation. Xanya Sofra Weiss

Bioimpendance Neuronal Micro-stimulation (BNM) was engineered to treat sports injury and muscle atrophy, as well as promote lipolysis and muscle hypertrophy. A clinical study with individuals presenting abnormally clumped RBCs was completed in February 2009 with the Ion Magnum. Results indicate that this technology rapidly and efficiently leads to normalized erythrocytes’ separation at the microscopic level. Red Blood Cells’(RBCs) separation is crucial for the timely transport of hormones,antibodies, oxygen and nutrients to the cells and waste products to the kidneys. Therefore, blood separation is crucial in a number of biological processes including cellular cleansing, nourishment and oxygenation, endocrine and immune functioning. Ion Magnum’s (IM) dynamic, multi-sine, analogue waveform was originally tested at the cellular level by Dr. Donald Gilbert (1992), a molecular biologist, and was electronically composed by the Co-Inventor of the first Pacemaker (2008) to resonate at the motor nerve the signal of strenuous exercise normally emitted by the brain. Due to its resonance with the biological signal, the Ion Magnum signal spreads throughout the CNS ultimately triggering hormonal secretion such as Growth Hormone (GF), Thyroxine (T4) and Triiodothyronine (T3) for lipolysis and Insulin Growth Factor (IGF-1) for muscle hypertrophy. Power detox is an additional benefit of Ion Magnum’s induced effortless and painless isometric and isotonic muscle contractions. Sever al devices stimulate the muscles such asTENS Muscle Stimulators. However, TENS devices deplete ATP. Besides, muscle stimulation does not automatically release hormones. Neuronal synapses activated out of sync with the other inputs to the neuron stands out as odd and are eliminated. Neuronal synapses that are activated in sync with other inputs to the neuron are strengthened. The signal of a device must be in sync with the biological choreography in order to spread via the spinal cord and reach the brain. In sync, or resonance, has been touted by a number of approximate hit-ormiss techniques involving magnetic and electrical fields with dubious inconsistent results. But no technology has ever achieved nerve signaling that is biologically comparable to physical exercise. What the Co-Inventor of the first Pacemaker has accomplished, first in London University and then in the EU funded Research Center for Innovations Science, UK, is a full force, high-speed workout without actual movement, side effects or pain, that enhances hormonal secretion. Lipolysis and muscle hypertrophy following IM treatments has been reported by a number single subject design clinical studies.

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