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Monthly Archives

May 2018

SAC & Dental Health

By | Dental, Resources, SAC

SAC Therapy and Dental Health

SAC Stimulates Stem Cells to Repair and Rebuild Jaw Bones

SAC in a
Nutshell

SAC (Sigma Antibonding Calcium Carbonate) is the only true ionic calcium delivery system that provides calcium in free ionic state, which is the only physiologically active form of calcium in our body. Normally, calcium from diet and supplements enters our body in the protein-bound form and therefore, cannot trigger the same physiological responses as SAC. Resolving calcium deficiency better than protein-bound calcium, SAC triggers ionic-calcium-sensitive physiological responses that counteract the root cause of diseases and brings natural healing reactions of our body from cellular to the systemic level.

Edentulism -
Age Related
Jaw Bone Loss

Dental health deteriorates with aging and affects our health dramatically and is closely related to the skeletal bone loss (osteoporosis) that comes with hormonal changes and life style changes associated with aging.  As jaw bones shrink, our teeth lose its footing to stay strong.  Edentulism in the elderly population around the world is between 11% and 44%, inversely increasing to socioeconomic status.

The use of implants is considered to be one of the most popular alternatives for its high predictability, durability, and functionality to rehabilitate patients aesthetically and functionally. However, the success of the procedure depends heavily on the supporting dental bone quality. The loss of alveolar bone due to periodontitis is also a signicant concern for all age groups, as it supports not only possible implants, but also natural teeth.  Conclusively, it is the quality and the strength of jaw bones that ultimately determines the success of all  dental procedures.

Periodic increase of calcium ions in our system achieved by SAC Ionic Calcium Therapy, however, can trigger cascade of hormonal responses from pituiatary to thyroid glands that trigger and regulate both TH and PTH to raise bone mineral density (BMD) naturally without side effects. SAC delivers a safe level of calcium ions which in turn regulates bone turnover rates (absorption and resorption rates) to build healthy bones including deteriorating alveola bones of maxilla and mandible.

Age Related
Bone Loss

CAUSES OF AGE RELATED BONE LOSS:

  • Sedentary Lifestyle
  • Lower Sex Hormones
  • Lower Osteocalcin
  • Lower hGH
  • Lower Calmodulin
  • Menopause
  • Poor Absorption of Calcium

Osteoporosis Is Inevitable for Most.
It is Just a Matter of When

Bone is living, growing tissue. Throughout life, our bodies are breaking down old bone cells and rebuilding new bones in a continuous cycle (bone remodeling). This process is necessary to repair damages caused by daily stress on our bones.

When we are younger, we gain more bone than lose. However, after about age 40, this balance is typically reversed, with bone loss occurring at a much faster rate than is replaceable, leaving our bones brittle and leading to osteoporosis with increased risks of fracture, particularly of the hip, spine, wrist and shoulder.

Osteoblasts and osteoclasts are types of cells the human body uses to repair broken bones. Osteoclasts break down old bone tissue allowing osteoblasts to replace it with new material. Together, these cells facilitate bone mending and bone growth. However, as we age osteoblast slows down and bone mineral density continues to decrease, making our bones more susceptible to fracture.

Osteoporosis weakens bones

Losing more than 25% of bone mass is enough for a clinical diagnosis of osteoporosis. In the US, 1/3 of women and 1/4 of men have the disease, with the figure increasing each year. What may be the cause of all this?  Stress, sedentary lifestyle, poor diet, environmental toxins, illnesses, and hormonal change that is a part of aging process.

Stimulating hPDLCs Stem Cells for Repairing and Rebuilding

Periodontal ligament stem cells (PDLSCs), which reside in the perivascular space of the periodontium, possess characteristics of mesenchymal stem cells and are a promising tool for periodontal regeneration by dierentiating into either cementoblasts to synthesize root cementum or osteoblasts to synthesize alveolar bone.

Many researches investigated the effects of extracellular calcium on cell proliferation and osteogenic differentiation of human periodontal ligament cells (hPDLCs). In the human PDLSC line they examined, calcium treatment increased the expression of genes of bone-related molecules such as BMP-2, OCN, OPN, and RUNX2, and also resulted in mineralization. These genes are found to facilitate the periodontal ligament cells and regulated by RUNX2.

SAC releases physiologically active calcium ions to stimulate stem cells to restore the physiological function of teeth by rebuilding periodontal supporting tissues including alveolar bone, gingiva, periodontal ligaments (PDL), and the cementum.

Periodontal ligament stem cells (PDLSCs), which reside in the perivascular space of the periodontium, possess characteristics of mesenchymal stem cells and are a promising tool for periodontal regeneration by dierentiating into either cementoblasts to synthesize root cementum or osteoblasts to synthesize alveolar bone.

Many researches investigated the effects of extracellular calcium on cell proliferation and osteogenic differentiation of human periodontal ligament cells (hPDLCs). In the human PDLSC line they examined, calcium treatment increased the expression of genes of bone-related molecules such as BMP-2, OCN, OPN, and RUNX2, and also resulted in mineralization. These genes are found to facilitate the periodontal ligament cells and regulated by RUNX2.

SAC releases physiologically active calcium ions to stimulate stem cells to restore the physiological function of teeth by rebuilding periodontal supporting tissues including alveolar bone, gingiva, periodontal ligaments (PDL), and the cementum.

SAC Restores Calcium Homeostasis for Optimum Stem Cell Functions

SAC Ionic Calcium Therapy for Dentistry

Synthetic bone replacement is used to fill and restore alveolar bone, and a number of bone-lling materials containing calcium (Ca2+) and phosphate (P) ions have been also used in the repair of periodontal bone defects. However, the effects that local release of Ca2+ and P ions have on biological reactions are not fully understood. To make bone graft materials work better, targeting the underlying condition of calcium and hormone imbalance is essential.  SAC delivers physiologically active calcium ions that trigger the systemic regulation of hormones and restores calcium homeostasis which revives the core metabolism.

Application of SAC for Dentistry

  • Edentulous (Bone Loss)
  • Periodontitis / Gingivitis /Gum Tissue
  • Periodontal Ligament / LooseTeeth
  • Bone Graft Assist / Implant Osseointegration

Sample Clinical Case of SAC Therapy in Dentistry

Generally lower jaw is harder to build than upper jaw bone. SAC calcium therefore promotes cementogenesis for the formation of cementum.

The x-ray images of a 58 year old Asian male who conducted molar tooth extraction show signicant dental bone growth after treating with SAC for 7 months without any co-treatments

Effects of Ionic Calcium for Dentistry

  • Helps restore and maintain your oral health
  • Creates strong jaw bones to support the teeth
  • Great for patients undergoing dental implants
  • Significantly promotes cementogenesis,the formation of cementum

Periodontal gum line recedes with age as the aveolar bone underneath is lost to edentulism.  When strong osteoblast in initiated with SAC Ionic Therapy, aveolar bone in strengthened again to support loose teeth.  Restored calcium homeostasis triggers dormant hPDLC stem cells to proliferate and repair the damaged ligaments.

“My dentist extracted my molar tooth with cavity 6 months ago. He recommended that I do an implant after bone graft. I then remembered hearing about DentiGen and told him that I would come back after increasing my jaw bone density. The dentist said that there is simply no way to increase jaw bone density and that he would eat his hat if my bone density increased. For a few months I took DentiGen faithfully and visited the dentist. He could not believe what he saw in xrays! He did not end up eating his hat but confirmed that now implant is doable due to increased jaw bone density. Wow!”

Soonok Chung – Age 47, Female

SAC Triggers Bone Repair & Rebuilding

SAC is the world’s first calcium-ion-delivery-system, which safely and effectively elevates the level of calcium-ion concentration in our blood. By utilizing a very weak chemical bonding, namely sigma antibonding, to calcium carbonate molecules, Calcium & Bone Health Institute of Canada (CBHI) invented new calcium carbonate, which maintains loosely held calcium ion to its carbonate group.

Because of the weak chemical bonding of SAC, calcium ion is easily detached and passively absorbed into our system through stomach lining as ions via diffusion and osmotic pressure, not requiring digestion, vitamin D, nor peptides for absorption.  This is called passive transport.

Because of our body’s natural sensitivity to fluctuations of serum plasma ionic calcium level, a minimal elevation of ionic calcium concentration achieved by SAC can trigger hormonal responses, such as the release of TSH and calcitonin to trigger bone-building osteoblasts. SAC therapy utilizes ionic calcium as a signaling agent to trigger our body’s natural responses to increase bone turnover rate in repairing and building healthy bones.  SAC’s healing pathway is genuinely unique without side effects experienced in prescription drugs.

The 4 Functions of SAC Calcium

SAC as Hormone Regulator

Bone metabolism is controlled by the interaction of a number of hormones.

Hormonal imbalance can wreak havoc on bone metabolism. SAC helps triggering hormones to maintain bone metabolic balance, by signaling pituitary hormones to trigger the release of thyroid and parathyroid hormones.

SAC as Calcium Navigator

Inactive calcium molecules such as protein-bound calcium do not know where to go.

SAC navigates calcium to reach its ultimate destination – the bone. SAC calcium will not be deposited in the wrong places such as the kidneys or blood vessels.

SAC as Calcium Activator

About 50% of calcium in our blood is inactive.

SAC’s ionization process activates inactive calcium molecules to be used in bone building by stimulating the secretion of thyroid hormone (TH), which is responsible for depositing minerals in our bones.

SAC as Bone Mineral Builder

Without any side effects, SAC calcium considerably aids in the prevention and treatment of osteoporosis, thereby reducing fracture risks by significantly improving bone mineral density.

Within a relatively shorter period of time, SAC helps to deposit other essential minerals from one’s diet into the bone along with calcium for healthier bones.

SAC Therapy Builds Bones Naturally & Effectively

Physiological Effects of SAC

After intake, SAC’s effect lasts about four hours in our body, initially raising the serum ionic calcium concentration to a higher yet safe level to trigger various physiological functions before bringing down the serum ionic calcium concentration down to the average physiological level.

While ionic calcium level is elevated, bone-building osteoblast with osteoclastic activity is triggered to raise the bone turnover rate, repairing and rebuilding bones. This process also activates idle protein-bound calcium, releasing both ionic calcium and protein, further fueling bone-building and clearing body-wide calcification. Ionic calcium also aids cellular metabolism, releasing more ATP (adenosine triphosphate) and raising body temperature. As kidneys try to excrete excess ionic calcium through urination, an urge to urinate within an hour of taking SAC is experienced, which is both healthy and normal, indicating that SAC is working.

STRONGER BONES LEAD TO A HEALTHIER LIFE

A long term, follow up study done in Denmark for 35,000 people revealed that the people with strong bones in their 50’s lived 11.6 years longer.
YET, in Canada, 49% of infants are born with calcium deficiency. Only 70% recover after breastfeeding. Calcium deficiency during pregnancy and infancy leads to serious health issues.

Bone Loss Leads to 150+ Degenerative Diseases

Bone health is directly related to our overall health. Emptier bone characterized by osteoporosis or osteopenia indicates not only a higher risk of fracture but also a greater chance of developing degenerative diseases. Why? Because emptying bones cause calcification in both cellular and systemic levels, causing cellular communications mayhem by disrupting calcium signaling.

Promising Animal Clinical Trials

Calcium ions in the blood are so vital that the body cannot permit it to fluctuate. Therefore, even a slight increase in the concentration of ionized calcium in the blood triggers the bone building process to take excess calcium into bones. Utilizing this process is by far the most effective and safe way to support strong bones since it follows the body’s natural bone building mechanism. This amazing effect of SAC was observed in this animal clinical trial through the bone break test where SAC ‘treated’ bone displayed almost 100x bone building power compared to regular calcium carbonate.

Importance of SAC therapy goes beyond the stronger bone-building.  Although most of our body’s calcium is stored in bone, the tiny amount that circulates in your bloodstream is disproportionately vital to good health. About half of this circulating serum calcium (50%) is “ionized”, which means it carries electrical charges and this calcium ions (Ca2+) are the only physiologically active form that can be recognized by our body and responsible for numerous functions of our body such as the firing of muscle and nerve cells, promoting blood clotting, preventing the depletion of bone mass, securing proper cellular functions by preserving calcium signaling, etc.  As we age, this vital ionic calcium homeostasis is disrupted as our bone breaks down and calcifies trillions of cells.  SAC therapy can restore this fragile calcium homeostasis and gives our body a chance to fight back the onset of 150+ degenerative diseases  that are thought to be caused by calcium displacement.

Osteoporosis Reversed under SAC Therapy

(Lab Anim Res 2011: 27(4), 301-307, 2011)

Group
BMD
Sham (Control)
0.2276 ± 0.011 a
OVX (Osteoporosis)
0.1965 ± 0.012 b
OVX + SAC
0.2276 ± 0.012 a
  • Control: sham operation
  • OVX: no treatment after ovariectomy
  • OVX+SAC: SAC treatment after ovariectomy.

The effects of Sigma Anti-bonding Molecule Calcium Carbonate on bone turnover and calcium balance in ovariectomized rats are studied. The study revealed that the induced osteoporosis was completely reversed with SAC therapy. Osteocalcin, estradiol, eosinophil, CTx and BMD level were elevated with SAC, indicating that optimal bone health is indeed restored.

Values are mean ± SD for 5 rats. Means with different superscript letters are significantly different at p<0.05 by Duncan’s multiple range tests.

Before & After Bone Density Trial Results

Over 90% of Volunteers at CBHI Experienced Significant Increase in BMD

"I have taken MegaGen since I was diagnosed with severe osteoporosis with T-score of -3.7. After taking 17 bottles of Megagen, my bone density is back to the normal range. Incredible!!"

M. S. PARK – Age 55, Male

Human Bone Density Clinical Case under SAC

(CBHI Canada Conducted BMD Increase Trial for +1000 Patients under SAC Therapy.)

CBHI (Calcium & Bone Health Institute of Canada) utilized FDA approved ultrasound bone densitometer by BeamMed in measuring and comparing BMD data of more than a thousand patients.  Over 90% of the patients experienced increased bone density.

Fracture Healing Effects of SAC Therapy

Steroid Induced Osteoporosis, auto fracture (Male, 52, Indonesia)

Dosage: MaraGen 2x /day for first 2 months and then only 1x. Able to walk normally again.

Decalcification Effects of SAC Therapy

Removing Calcification from Cellular to Systemic Level is a Key to Recovery

Conditions Commonly Treated with SAC Therapy

Cellular Recovery Helps to Restore Mitochondrial Function & Reduce Oxidative Stress

  • Autoimmune disease (Lupus, Vitiligo, Hashimoto’s, Crohn’s, Celiac disease, eczema, MS, rheumatoid, etc.)
  • Lyme disease, HIV, Shingles and other viral infections
  • Parkinson’s, ALS, Alzheimer’s and
    other neurodegenerative diseases
  • Arthritis, Gout, CPPD, Inflammations
  • Mitochondrial Disease
  • Cancer (carcinoma, sarcoma,
    lymphoma, leukemia, multiple
    myeloma)
  • Arrhythmia, Heart palpitation, Mitral Valve Prolapse,
  • Diabetes, Metabolic Syndrome
  • Thrombosis, Hemolytic Anemia
  • Autism Spectrum Disorder,
  • ADHD, Epilepsy
  • Asthma, COPD
  • Glaucoma, Cataract, Intermittent Exotropia, Retinal Vein Occlusion
  • Menier’s Disease, Aurora Migraine
    Disease, Tinnitus, Vertigo
  • Osteoporosis, Bone Necrosis
  • Chromosome 8 syndrome
  • Chronic Kidney Disease
  • Gum disease, Loose teeth
  • Calcification (joints and tissues),
    Calcific tendonitis, Fibrosis, Kidney
    and Gall Bladder Stones
  • Dysmenorrhea, infertility

SAC for Calcium Signalling (Book)

By | books, SAC

SAC for Calcium Signalling

CBHI Canada

Through many academic pieces of literature, books, and media, people are well-informed that calcium is an essential mineral to maintain our bone health. As there are many calcium supplements available in the market, calcium is aggressively advertised for its positive effects on our bodies. As many pieces of research have shown, calcium plays a critical role in treating osteoporosis, which is one of the most prevalent aging-related chronic degenerative diseases. Moreover, as the demand for calcium is increasing, many medical scientists are focusing on the effects of intracellular calcium ion on our health. While cell health translates to our overall health, calcium is closely related to the mitochondrial function, which is the key to treating aging-related chronic degenerative diseases as well as cancers. Nevertheless, even though we had already established that balancing intracellular calcium ion is crucial for cell health and offers immense potency to treat the diseases that we have not yet eradicated, there were no particular calcium treatments that could directly affect the cellular calcium homeostasis.

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Switching p53 states by calcium: dynamics and interaction of stress systems

By | DNA Repair

Switching p53 states by calcium: dynamics and interaction of stress systems

Md. Jahoor Alam, Gurumayum Reenaroy Devi, Ravins, Romana Ishrat, Subhash M. Agarwal and R. K. Brojen Singh

The integration of calcium and a p53–Mdm2 oscillator model is studied using a deterministic as well as a stochastic approach, to investigate the impact of a calcium wave on single cell dynamics and on the inter-oscillator interaction. The high dose of calcium in the system activates the nitric oxide synthase, synthesizing nitric oxide which then downregulates Mdm2 and influences drastically the p53–Mdm2 network regulation, lifting the system from a normal to a stressed state. The increase in calcium level switches the system to different states, as identified by the different behaviours of the p53 temporal dynamics, i.e. oscillation death to sustain the oscillation state via a mixed state of dampened and oscillation death states. Further increase of the calcium dose in the system switches the system from sustained to oscillation death state again, while an excess of calcium shifts the cell to an apoptotic state. Another important property of the calcium ion is its ability to behave as a synchronizing agent among the interacting systems. The time evolution of the p53 dynamics of the two diffusively coupled systems at stress condition via Ca2+ shows synchronization between the two systems. The noise contained in the system interestingly helps the system to maintain its stabilized state (normal condition). However, noise has the tendency to destruct the synchronization effect, which means that it tries to restrict the system from external signals to maintain its normal condition. However, at the stress condition, the synchronization rate is found to be faster.

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Proteins of the S100 family regulate the oligomerization of p53 tumor suppressor

By | DNA Repair

Proteins of the S100 family regulate the oligomerization of p53 tumor suppressor

Maria Rosario Fernandez-Fernandez, Dmitry B. Veprintsev, and Alan R. Fersht

S100B protein is elevated in the brains of patients with early stages of Alzheimer’s disease and Down’s syndrome. S100A4 is correlated with the development of metastasis. Both proteins bind to p53 tumor suppressor. We found that both S100B and S100A4 bind to the tetramerization domain of p53 (residues 325–355) only when exposed in lower oligomerization states and so they disrupt the tetramerization of p53. In addition, S100B binds to the negative regulatory and nuclear localization domains, which results in a very tight binding to p53 protein sequences that exposed the tetramer- ization domain in their C terminus. Because the trafficking of p53 depends on its oligomerization state, we suggest that S100B and S100A4 could regulate the subcellular localization of p53. But, the differences in the way these proteins bind to p53 could result in S100B and S1004 having different effects on p53 function in cell-cycle control.

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Possible role of NF-kB and p53 in the glutamate-induced pro-apoptotic neuronal pathway

By | DNA Repair

Possible role of NF-kB and p53 in the glutamate-induced pro-apoptotic neuronal pathway

Mariagrazia Grilli and Maurizio Memo

Apoptosis is now recognized as an important component in many progressive and acute neurodegenerative diseases. Extracellular signals and intracellular mechanisms triggering and regulating apoptosis in neuronal cells are still a matter of investigation. Here we review data from our and other laboratories with the aim to elucidate the nature of some proteins which are known to be involved in cell cycle regulation as well as in promoting degeneration and apoptosis of neurons. The following molecules will be taken into consideration: NF-kB, p53, p21 and MSH2. These proteins are activated by neurotoxic experimental conditions which involve the stimulation of selective receptors for the excitatory aminoacid glutamate. Thus, we hypothesize their contribution to an intracellular pathway responsible for the glutamate- induced neuronal death. Identification of such mechanisms could be relevant for understanding the apoptosis associated with various neurodegenerative diseases as well as for developing novel strategies of pharmacological intervention.

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PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kB, MAPkinase and p53 pathways

By | DNA Repair

PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells
and regulates survival and chemoresistance via NF-kB, MAPkinase and p53 pathways

VL Grandage, RE Gale, DC Linch and A Khwaja

The phosphoinositide 3-kinase (PI3-kinase) signalling pathway plays a key role in the regulation of cell survival and proliferation. We show that the PI3-kinase/Akt pathway is constitutively active in primary acute myeloid leukaemia (AML) cells and that blockade by the selective inhibitor LY294002 reduces survival of the total blast population (mean 52%). The ERK/MAPK module is also constitutively active and treatment with the MAPKK inhibitor U0126 reduces cell survival by 22%. In 10 of 18 samples, PI3-kinase contributes to MAPK activation as incubation with LY294002 leads to a marked reduction in its phosphorylation. PI3-kinase inhibition reduces survival of the CD34 þ 38 AML progenitor subset by 44%, whereas MAPKK inhibition has little effect. Reporter assays in primary AML cells show that blocking PI3-kinase leads to a marked reduction of constitutive NF-kB activity and promotes p53-mediated transcription. This is associated with a synergis- tic interaction between LY294002 and Ara-C. An inducible activated form of Akt protects normal myeloid cells from Ara- C and etoposide-mediated apoptosis. These results show that blocking PI3-kinase has direct antileukaemic effects and potentiates the response to conventional cytotoxics via a number of targets including NF-kB, p53 and MAPK. Inhibitors of PI3-kinase and Akt may be useful in the treatment of AML.

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Effects of Sigma Anti-bonding Calcium on Bone Turnover (Animal Trial)

By | Osteoporosis, SAC

Effects of Sigma Anti-bonding Molecule Calcium Carbonate on bone turnover and calcium balance in ovariectomized rats

So-Young Choi, Dongsun Park, Goeun Yang, Sun Hee Lee, Dae Kwon Bae, Seock-Yeon Hwang, Paul K Lee, Yun-Bae Kim, Ill-Hwa Kim, Hyun-Gu Kang

This study was conducted to evaluate the effect of Sigma Anti-bonding Molecule Calcium Carbonate (SAC) as therapy for ovariectomy-induced osteoporosis in rats. Three weeks after surgery, fifteen ovariectomized Sprague-Dawley rats were divided randomly into 3 groups: sham-operated group (sham), ovariectomized group (OVX) and SAC-treatment group (OVX+SAC). The OVX+SAC group was given drinking water containing 0.0012% SAC for 12 weeks. Bone breaking force and mineralization as well as blood parameters related to the bone metabolism were analyzed. In OVX animals, blood concentration of 17β- estradiol decreased significantly, while osteocalcin and type I collagen C-terminal telopeptides (CTx) increased. Breaking force, bone mineral density (BMD), calcium and phosphorus in femurs, as well as uterine and vaginal weights, decreased significantly following OVX. However, SAC treatment (0.0012% in drinking water) not only remarkably restored the decreased 17β-estradiol and increased osteocalcin and CTx concentrations, but also recovered decreased femoral breaking force, BMD, calcium and phosphorus, although it did not reversed reproductive organ weights. It is suggested that SAC effectively improve bone density by preventing bone turnover mediated osteocalcin, CTx and minerals, and that it could be a potential candidate for therapy or prevention of menopausal osteoporosis.

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p53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent manner

By | DNA Repair

p53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent manner

Carlotta Giorgi, Massimo Bonora, Giovanni Sorrentino, Sonia Missiroli, Federica Poletti, Jan M. Suski, Fabian Galindo Ramirez, Rosario Rizzuto, Francesco Di Virgilio, Ester Zito, Pier Paolo Pandolfi, Mariusz R. Wieckowski, Fabio Mammano, Giannino Del Sal, and Paolo Pinton

The tumor suppressor p53 is a key protein in preventing cell transformation and tumor progression. Activated by a variety of stimuli, p53 regulates cell-cycle arrest and apoptosis. Along with its well-documented transcriptional control over cell-death pro- grams within the nucleus, p53 exerts crucial although still poorly understood functions in the cytoplasm, directly modulating the apoptotic response at the mitochondrial level. Calcium (Ca2+) transfer between the endoplasmic reticulum (ER) and mitochondria represents a critical signal in the induction of apoptosis. However, the mechanism controlling this flux in response to stress stimuli remains largely unknown. Here we show that, in the cytoplasm, WT p53 localizes at the ER and at specialized contact domains be- tween the ER and mitochondria (mitochondria-associated mem- branes). We demonstrate that, upon stress stimuli, WT p53 accumu- lates at these sites and modulates Ca2+ homeostasis. Mechanistically, upon activation, WT p53 directly binds to the sarco/ER Ca2+-ATPase (SERCA) pump at the ER, changing its oxidative state and thus leading to an increased Ca2+ load, followed by an enhanced transfer to mi- tochondria. The consequent mitochondrial Ca2+ overload causes in turn alterations in the morphology of this organelle and induction of apoptosis. Pharmacological inactivation of WT p53 or naturally occurring p53 missense mutants inhibits SERCA pump activity at the ER, leading to a reduction of the Ca2+ signaling from the ER to mitochondria. These findings define a critical nonnuclear function of p53 in regulating Ca2+ signal-dependent apoptosis.

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p53: Good Cop/Bad Cop

By | DNA Repair

p53: Good Cop/Bad Cop

Norman E. Sharpless and Ronald A. DePinho

Activation of the p53 transcription factor in response to a variety of cellular stresses, including DNA damage and oncogene activation, initiates a program of gene expression that blocks the proliferative expansion of damaged cells. While the beneficial impact of the anti- cancer function of p53 is well established, several re- cent papers suggest that p53 activation may in some circumstances act in a manner detrimental to the long- term homeostasis of the organism. Here, we discuss the significant participation of p53 in three non-mutu- ally exclusive theories of human aging involving DNA damage, telomere shortening, and oxidative stress. These “good cop/bad cop” functions of p53 appear to place it at the nexus of two opposing forces, cancer and aging. By extension, this relationship implies that therapies aimed to reduce cancer and postpone aging, and thereby increase longevity, will necessarily work either upstream or downstream, but not on the level of, p53.

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Role of the calcium-sensing receptor in parathyroid gland physiology

By | Osteoporosis

Role of the calcium-sensing receptor in parathyroid gland physiology

Randolph A. Chen and William G. Goodman

The calcium-sensing receptor (CaSR) represents the molecular mechanism by which parathyroid cells detect changes in blood ionized calcium concentration and modulate parathyroid hormone (PTH) secretion to maintain serum calcium levels within a narrow physiological range. Much has been learned in recent years about the diversity of signal transduction through the CaSR and the various factors that affect receptor expression. Beyond its classic role as a determinant of calcium-regulated PTH secretion, signaling through the CaSR also influences both gene transcription and cell proliferation in parathyroid cells. The CaSR thus serves a broad physiological role by integrating several distinct aspects of parathyroid gland function. The current review summarizes recent developments that enhance our understanding of the CaSR and its fundamental importance in parathyroid gland physiology.

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