Efficacy and safety of high-dose alfa-lipoic acid in the treatment of diabetic polyneuropathy

BUY ALFA LIPOIC ACID 24ml 600mg amps here

Abstract

OBJECTIVE:

To evaluate the efficacy and safety of high-dose α-lipoic acid in the treatment of diabetic polyneuropathy with regards to sensory symptoms and nerve conduction velocity.

METHODS:

A total of 236 diabetics with symptomatic polyneuropathy were enrolled into this 5-center, randomized, double-blind and placebo-controlled study of α-lipoic acid 1800 mg daily (n = 117) or matching placebo (n = 119) for 12 weeks. The primary outcome was total symptom score (TSS). Secondary end points included nerve conduction velocity, individual symptom score, HbA1c and safety parameters. The above parameters were reviewed and recorded at zero point and after treatment for 2, 4, 8, 12 weeks separately.

RESULTS:

73.27% patients with symptomatic polyneuropathy improved after treatment with α-lipoic acid for 12 weeks versus 18.27% with placebo. TSS declined by 2.6 ± 2.3 with α-lipoic acid. And it was more than 0.7 ± 1.4 versus placebo (P < 0.05). TSS decreased quickly after treatment with α-lipoic acid for 2 weeks (P < 0.05). And it was better than placebo. Individual symptom scores of pain, extremity numbness, burning sensation or resting abnormal sensations were significantly diminished as compared to those before treatment and placebo group (all P < 0.05). Nerve conduction velocity had no change. HbA1c further decreased at the end of trial after α-lipoic acid treatment (P < 0.05). The incidence rates of adverse effects were 25.4% vs 11.8% in the treatment and control groups. The major manifestation was burning sensation from throat to stomach (12.7%).

CONCLUSION:

Oral treatment with high-dose α-lipoic acid for 12 weeks may improve symptoms in patients with diabetic polyneuropathy. Dose of 600 mg thrice daily for 2 weeks has marked effects with a reasonable safety.

PMID:

21092474

[PubMed – indexed for MEDLINE]

Benefits of glutathione GSH (Tationil, Ridutox) in COPD treatment

Benefits:

• It is the major endogenous antioxidant produced by the cells, participating directly in the neutralization of free radicals and reactive oxygen compounds, as well as maintaining exogenous antioxidants such as vitamins C and E in their reduced (active) forms.
• Regulation of the nitric oxide cycle, which is critical for life but can be problematic if unregulated
• Through direct conjugation, it detoxifies many xenobiotics (foreign compounds) and carcinogens, both organic and inorganic. This includes heavy metals such as mercury, lead, and arsenic.
• It is essential for the immune system to exert its full potential, e.g., modulating antigen presentation to lymphocytes, thereby influencing cytokine production and type of response (cellular or humoral) that develops, enhancing proliferation of lymphocytes, thereby increasing magnitude of response, enhancing killing activity of cytotoxic T cells and NK cells, and regulating apoptosis, thereby maintaining control of the immune response.
• It plays a fundamental role in numerous metabolic and biochemical reactions such as DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, and enzyme activation. Thus, every system in the body can be affected by the state of the glutathione system, especially the immune system, the nervous system, the gastrointestinal system and the lungs

Uses:

• Glutathione by Inhalation for COPD
• Glutathione is made in the body and used in every cell, but it is of special importance in lung tissue. It is helpful in emphysema, some asthma and even lung cancer. It can be inhaled as a spray in order to get a higher level directly to the needed lung area.
• A simple home nebulizer allows treatment twice daily for only five to ten minutes and increases the removal of sticky secretions and gives greatly increased lung efficiency. One uses a solution of glutathione in a nebulizer and attaches that to the electric pump. Breathe in as much as you can during the five to ten minute treatment. If you need to stop during the treatment, simply shut off the pump and resume when ready.
• Ophthalmic Drops (Stock #: 15269)
• Glutathione/Vitamin C/DMSO 15ML 1.25/1.25/6.25%
• Glutathione for injection: Glutathione injection is primarily for IV’s for many different oxidative brain disorders, such as: Parkinson’s, MS and Alzheimer’s. According to Dr. Perlmutter’s research, frequent high dose IV’s are very beneficial for “Fire in the Brain.” Watch out for his new book.
• One of the most powerful antioxidants in the body

From: DrWhitaker.com

As I wrote about in the September 2003 issue of Health & Healing, chronic obstructive pulmonary disease (COPD) is a collective term for several diseases of the lungs. COPD most often refers to emphysema, which is almost always caused by smoking. Other ailments falling under the COPD category include chronic obstructive bronchitis and asthmatic bronchitis, which narrow the airways and fill them with mucus.

Conventional medicine holds that there is no remedy for COPD. Yet at the Whitaker Wellness Institute, we recently began utilizing a safe new therapy that has shown great promise: inhaled glutathione. Glutathione is the most efficient free radical scavenger in the airways, and dozens of studies have confirmed that free radical damage is a primary player in COPD. Although not particularly well absorbed when taken orally, the effects of inhaled glutathione are remarkable. (I have attached a medical journal article on this therapy, which includes a list of references.)

This treatment requires a doctor’s prescription. If you or someone you love suffers from chronic lung disease and would like to seek treatment at the Whitaker Wellness Institute, call (800) 488-1500. Or pass along this information and ask your doctor to help you implement these recommendations – and send me a note to tell me how it worked for you.

Protocol for Inhaled Glutathione

Glutathione 300 mg nebulized twice a day (Physicians note: vial = 200 mg/cc, draw 1.5 cc and place in nebulizer)

Treatments take five to ten minutes and may be continued as long as the patient remains symptomatic.

A nebulizer, sometimes called a breathing machine, transforms liquid medications into mists that can be inhaled. To get a nebulizer for home use you will need a prescription from your doctor. Nebulizers cost from $50 to more than $300 and are often covered by insurance. Below is one company that sells nebuliziers. Ask your physician for a referral to other medical equipment companies and for instructions in its use.

• Vitamin C, multiple doses throughout the day, to bowel tolerance (minimum 10 grams per day)
• Magnesium, 500 mg twice a day
• Fish oil, 2 grams three times a day (6 capsules daily)
• Beta-carotene, 300 mg per day (500,000 IU)
• Vitamin A, 20,000 IU per day
• N-acetyl-cysteine, 500 mg three times a day
• Lycopene, 15 mg twice a day
• IV vitamin C

Chronic obstructive pulmonary disease (COPD), a designation which includes emphysema, is a leading cause of death in America. This case study reports on the successful treatment of both acute and chronic emphysema with a novel agent. Much of the tissue damage in emphysema is thought to be mediated by an oxidative down-regulation of the activity of -1-proteinase inhibitor.1 This down-regulation has been shown in vitro to be slowed by glutathione, a sulfhydryl-containing tripeptide known to be a major antioxidant in the lung.2

Glutathione concentrations in bronchoalveolar fluid have been found to be inversely correlated with the degree of inflammatory activity in the lungs of smokers.3 Thiol compounds (i.e., compounds containing an -SH group) like glutathione have a history of use as mucolytics as well.4 Previous clinical trials of nebulized reduced glutathione have demonstrated the bioavailability and safety of up to 600 mg twice daily.5,6 The absorption of oral glutathione remains controversial, with animal studies suggesting significant absorption and some human studies showing little to none.7,8 Based on these findings, it appears inhalation might be the preferred route of administration for respiratory and perhaps systemic effect. We report the case of a man with an acute respiratory crisis due to emphysema and apparent bronchial infection that responded favorably to treatment with nebulized glutathione.

Abstract
We present the case of a 95-year-old man with an acute respiratory crisis secondary to emphysema and apparent bronchial infection. Treatment with nebulized glutathione led to a rapid resolution of the crisis, as well as a marked improvement in the chronic course of the disease. This treatment has been used since for a number of patients with emphysema. The safety and bioavailability of this method of delivery have been established in human studies. Preliminary results suggest efficacy for nebulized administration of glutathione in this patient population. We suggest this treatment can be considered an option for acute respiratory crises due to COPD.

Case Report
In 1997, a 95-year-old male with emphysema presented in a wheelchair and using an oxygen tank and mask necessitated by his acute illness. He was alert, responsive, and reported a productive cough with colorless sputum. His breathing was obviously labored.

He refused hospitalization and antibiotic treatment.

We chose to try a single trial dose of 2 ml of a 60 mg/ml glutathione solution (prepared by ApothéCure Pharmacy, Dallas, TX) nebulized and inhaled over a 5-10 minute period.) Due to the obvious immediate benefit, it was decided to continue this treatment with twice-daily administration and close monitoring by his family of his overall condition. He returned to the office in three days without wheelchair or oxygen tank. He showed no signs of respiratory distress, and no adventitious lung sounds were noted on auscultation. The patient reported his breathing was better than it had been in years. He continued daily treatment with glutathione until his death from congestive heart failure over two years later.

Conclusion
While resolution of the acute episode due to a mucolytic effect was the desired outcome of the glutathione treatment, the lasting improvement in breathing was unexpected.

Since we have no serial spirometry data available on this patient, placebo effect cannot be ruled out as an explanation for his marked response.

However, given the progressive nature of his disease, the dramatic and rapid change in physical findings, and the emphatic insistence of the patient for continued treatment, we believe placebo response to be an unlikely explanation. We have subsequently prescribed this preparation for six patients with emphysema, five of whom reported improved breathing after a single in-office application and who later requested to continue treatment. We also have found nebulized glutathione is best administered daily from 4 ml vials. We have also seen improved respiratory function associated with nebulized glutathione treatment in cases of chronic bronchitis and asthma.9 In the case of asthma patients we feel it is advisable to check urinary sulfite excretion to verify proper metabolism of sulfur compounds, as certain individuals appear to experience exacerbation of respiratory symptoms from exogenous sulfur compounds.10 In three cases of non-small cell lung cancer with effusion, the effusion resolved completely. Given the safety and promise of this treatment, combined with the paucity of other effective treatments for emphysema, we suggest this treatment be considered for widespread use.

Melatonin: sleep aid, antioxidant, anti-aging drug & more

Changes in the amount of reduced glutathione and activity of antioxidant enzymes in chosen mouse organs influenced by zymosan and melatonin administration

Reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT)  and glutathione peroxidase (GSHPx) are vital components of the  antioxidative barrier in animal cells. It is suggested more often now  that the effectiveness of the protection of cells against the oxidative stress caused by the inflammation process depends on the  amount of GSH and the activity of SOD, CAT and GSHPx. That is why the  effect of zymosan A (40 mg/kg body mass) and the combined treatment  with zymosan A (at the same dose) and melatonin (50 mg/kg body mass)  on the amount of GSH in the blood and the amount of GSH and activity  of SOD, CAT and GSHPx in the brain, liver and kidneys of male mice was  estimated. Animals (n = 108) were decapitated after 3, 6 and 24 hours  since the moment of the administration of only zymosan A, and combined  zymosan A and after one hour melatonin. After the injection of zymosan  A it was found that the amount of GSH is significantly lower after 3  and 6 hours in the blood and studied organs. The administration of  zymosan A, followed by the administration of melatonin limited the  decrease in the amount of this tripeptide in the same time.  Simultaneously, the decrease in the amount of GSH in the studied  organs was accompanied by a similar decrease in the activity of SOD,
CAT and GSHPx after the injection of only zymosan A and a limited  decrease in the activity after the administration of both zymosan A  and melatonin. It is suggested that a decreased content of GSH and a  decrease in the activity of the studied antioxidative enzymes is  caused by the oxidative stress accompanying the inflammation process.
PMID:21555265

J Neurochem. 2006 Jul;98(1):267-78.

Simultaneous measurement of serotonin and melatonin from the intestine of old mice: the effects of daily melatonin supplementation

Bertrand PP, Bertrand RL, Camello PJ, Pozo MJ. Department of
Physiology, School of Medical Sciences, University of New South Wales,
Sydney, NSW, Australia. dr.p.bertr…@gmail.com

Ageing is associated with important changes in gastrointestinal function and in the levels of intestinal hormones secreted.  Enterochromaffin (EC) cells containing serotonin (5-HT) and melatonin  may play a major role in maintaining gut function during ageing. Our  aim was to characterise the mucosal availability of 5-HT and melatonin  in the ileum and colon of a mouse model of ageing. Female young mice  (2-5 month; n = 6), aged mice (22-24 months; n = 6) and aged mice  treated with melatonin (n = 6; 10 mg/kg/day) were examined.
Electrochemical methods were used to measure 5-HT and melatonin  concentrations near the mucosal surface of ileum and distal colon.  Amperometry studies showed that steady state levels of 5-HT from ileum
and colon were decreased in aged mice treated with melatonin when  compared to aged mice, while compression-evoked 5-HT release was  unchanged. Differential pulse voltammetry studies showed that young
mice had concentrations of 5-HT of 4.8 +/- 0.8 mum in the ileum and  4.9 +/- 1.0 mum in the colon. Concentrations of melatonin were 5.7 +/-  1.4 mum in the ileum and 5.6 +/- 1.9 mum in the colon. Compared to
young mice, the levels of 5-HT and melatonin were increased in aged  mice (combined ileum and colon: 5-HT = 130% and melatonin = 126% of  young mice) and decreased in melatonin-treated mice (5-HT = 94% and
melatonin = 82%). In conclusion, our data show that the availability  of gut 5-HT and melatonin is increased in aged mice and melatonin  treatment suppresses natural gastrointestinal production of 5-HT and
melatonin in the aged mouse intestine. PMID:20374441

Melatonin seems to exert its antioxidant effect in GIS tract by
stimulating SOD and GSH-Px. Selenium also seems to have an antioxidant
contribution on protecting rat gastrointestinal tract I-R injury.
http://www.ncbi.nlm.nih.gov/pubmed/11093033

The higher plasma levels of melatonin in DSS-treated mice might be due
to a stress-induced increase in the production of gastrointestinal
(GIT) melatonin. http://www.ncbi.nlm.nih.gov/pubmed/8609593

Experiments were performed to determine whether diurnal variations in
apoptosis in the mouse small intestine after irradiation with 2.5 Gy
gamma rays depended on the time of day that the mice were irradiated.
http://www.ncbi.nlm.nih.gov/pubmed/9525500

Eksp Klin Farmakol. 2010 Jan;73(1):7-9.

Comparative experimental study of the psychotropic and chronotropic
activity of adaptogenic phytopreparations and melaxen.

Arushanian EB, Naumov SS.

Adaptogenic drugs of plant origin (complex phytopreparation tonizid,
Ginkgo biloba extract bilobil) and hormonal origin (melaxen or
melatonin) exhibit similar spectra ofpsychotropic activity in rats,
which are manifested by improved memory, increased locomotion and
investigation activity, and decreased anxiety. At the same time, these
drugs had different chronotropic properties, depending on the schedule
(acute vs. repeated) and daytime (morning vs. evening) of
administration. PMID:20184280

Eksp Klin Farmakol. 2009 Jul-Aug;72(4):3-5.

Dependence of atropin-induced amnesia fluctuations on the state of
pineal gland.

Arushanian EB, Beĭer EV, skorniakoc AA.

Atropin produces weakening of the memory on the model of passive
avoidance reaction in rats, the effect being more pronounced in
evening hours. The drug effect is increased in pinealectomized animals
and attenuated by the pineal hormone melatonin, also differently in
daytime. PMID:19803360

Eksp Klin Farmakol. 2006 Nov-Dec;69(6):17-9.

Effects of melatonin and motherwort tincture on the emotional state
and visual functions in anxious subjects.

Ovanesov KB, Ovanesova IM, Arushanian EB.

The chronic administration of melatonin (0.75 mg at night, 10 days)
led to a significant decrease in the thresholds of retinal brightness
sensitivity and improved the emotional state in anxious young
subjects. Analogous changes were less pronounced after the treatment
with common motherwort (Leonurus cardiaca) tincture. It is suggested
that there is a relation between the limitation of anxiety and the
improvement of visual function (sensitivity). PMID:17209457

Eksp Klin Farmakol. 2006 Nov-Dec;69(6):13-6.

Comparative study of the effects of melatonin and epitalon on the
protracted memory under the shuttle labyrinth test conditions in rats
in the course of aging.

Vinogradova IA.

The influence of the chronic administration of melatonin (epiphyseal
hormone) and epitalon (a synthetic tetrapeptide increasing melatonin
production) on the learning process and the protracted memory has been
studied in LIO rats in the course of aging for 2 years under standard
illumination regime (12L :12D). The daily administration of melatonin
(Sigma, USA) with drinking water (in 10 mg/liter dose at night) in
rats beginning with the age of 4 months did not influence the learning
processes in young and adult animals but it was found to contribute to
optimization of the brain cognitive function in rats in the course of
aging, by improving the protracted memory process. Epitalon
administered in a daily dose of 0.1 microg per animal beginning with
the age of 4 months showed mnemotropic properties (decreasing the
extent of memory disorders) in old rats under conditions of the
shuttle labyrinth test. PMID:17209456

Enhanced mental and physical performance with Rhodiola rosea

Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity

Panossian A, Wikman G.

Source

Swedish Herbal Institute Research and Development, Spårvägen 2, SE-43296 Askloster, Sweden. alexander.panossian@shi.se

Abstract

The aim of this review article is to assess the level of scientific evidence presented by clinical trials of adaptogens in fatigue, and to provide a rationale at the molecular level for verified effects. Strong scientific evidence is available for Rhodiola rosea SHR-5 extract, which improved attention, cognitive function and mental performance in fatigue and in chronic fatigue syndrome. Good scientific evidence has been documented in trails in which Schisandra chinensis and Eleutherococcus senticosus increased endurance and mental performance in patients with mild fatigue and weakness. Based on their efficacy in clinical studies, adaptogens can be defined as a pharmacological group of herbal preparations that increase tolerance to mental exhaustion and enhance attention and mental endurance in situations of decreased performance. The beneficial stress-protective effect of adaptogens is related to regulation of homeostasis via several mechanisms of action associated with the hypothalamic-pituitary-adrenal axis and the control of key mediators of stress response such as molecular chaperons (e.g. Hsp70), stress-activated c-Jun N-terminal protein kinase (JNK1), Forkhead Box O transcription factor DAF-16, cortisol and nitric oxide (NO). The key point of action of phytoadaptogens appears to be their up-regulating and stress-mimetic effects on the “stress-sensor” protein Hsp70, which plays an important role in cell survival and apoptosis. Hsp70 inhibits the expression of NO synthase II gene and interacts with glucocorticoid receptors directly and via the JNK pathway, thus affecting the levels of circulating cortisol and NO. Prevention of stress-induced increase in NO, and the associated decrease in ATP production, results in increased performance and endurance. Adaptogen-induced up-regulation of Hsp70 triggers stress-induced JNK-1 and DAF-16-mediated pathways regulating the resistance to stress and resulting in enhanced mental and physical performance and, possibly, increased longevity.

PMID:

19500070

[PubMed – indexed for MEDLINE]

Dark chocolate for performance enhancement

The effect of acute pre-exercise dark chocolate consumption on plasma antioxidant status, oxidative stress and immunoendocrine responses to prolonged exercise.

Davison G, Callister R, Williamson G, Cooper KA, Gleeson M.

Source

Department of Sport and Exercise Science, Aberystwyth University, Ceredigion, Aberystwyth, SY23 3FD, UK, gdd@aber.ac.uk.

Abstract

PURPOSE:

Acute antioxidant supplementation may modulate oxidative stress and some immune perturbations that typically occur following prolonged exercise. The aims of the present study were to examine the effects of acutely consuming dark chocolate (high polyphenol content) on plasma antioxidant capacity, markers of oxidative stress and immunoendocrine responses to prolonged exercise.

METHODS:

Fourteen healthy men cycled for 2.5 h at ~60% maximal oxygen uptake 2 h after consuming 100 g dark chocolate (DC), an isomacronutrient control bar (CC) or neither (BL) in a randomised-counterbalanced design.

RESULTS:

DC enhanced pre-exercise antioxidant status (P = 0.003) and reduced by trend (P = 0.088) 1 h post-exercise plasma free [F(2)-isoprostane] compared with CC (also, [F(2)-isoprostane] increased post-exercise in CC and BL but not DC trials). Plasma insulin concentration was significantly higher pre-exercise (P = 0.012) and 1 h post-exercise (P = 0.026) in the DC compared with the CC trial. There was a better maintenance of plasma glucose concentration on the DC trial (2-way ANOVA trial × time interaction P = 0.001), which decreased post-exercise in all trials but was significantly higher 1 h post-exercise (P = 0.039) in the DC trial. There were no between trial differences in the temporal responses (trial × time interactions all P > 0.05) of hypothalamic-pituitary-adrenal axis stress hormones, plasma interleukin-6, the magnitude of leukocytosis and neutrophilia and changes in neutrophil function.

CONCLUSION:

Acute DC consumption may affect insulin, glucose, antioxidant status and oxidative stress responses, but has minimal effects on immunoendocrine responses, to prolonged exercise.

Turmeric (curcumin, curcuma longa): anti-diabetic, AMPK activating, anti-inflammatory properties

Curcumin activates AMPK and suppresses gluconeogenic gene expression in hepatoma cells.
Kim T, Davis J, Zhang AJ, He X, Mathews ST.
Source

Department of Nutrition and Food Science, Boshell Diabetes and Metabolic Diseases, Research Program, Auburn University, Auburn, AL 36849, USA.
Abstract

Curcumin, the bioactive component of curry spice turmeric, and its related structures possess potent anti-oxidant and anti-inflammatory properties. Several lines of evidence suggest that curcumin may play a beneficial role in animal models of diabetes, both by lowering blood glucose levels and by ameliorating the long-term complications of diabetes. However, current understanding of the mechanism of curcumin action is rudimentary and is limited to its anti-oxidant and anti-inflammatory effects. In this study we examine potential anti-diabetic mechanisms of curcumin, curcumin C3 complex), and tetrahydrocurcuminoids (THC). Curcuminoids did not exert a direct effect on receptor tyrosine kinase activity, 2-deoxy glucose uptake in L6-GLUT4myc cells, or intestinal glucose metabolism measured by DPP4/alpha-glucosidase inhibitory activity. We demonstrate that curcuminoids effectively suppressed dexamethasone-induced phosphoenol pyruvate carboxy kinase (PEPCK) and glucose6-phosphatase (G6Pase) in H4IIE rat hepatoma and Hep3B human hepatoma cells. Furthermore, curcuminoids increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase (ACC) in H4IIE and Hep3B cells with 400 times (curcumin) to 100,000 times (THC) the potency of metformin. These results suggest that AMPK mediated suppression of hepatic gluconeogenesis may be a potential mechanism mediating glucose-lowering effects of curcuminoids.

PMID:
19665995
[PubMed – indexed for MEDLINE]

Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa).
Chainani-Wu N.
Source

Department of Stomatology, University of California, San Francisco, CA 94143-0658, USA. nitacwu@itsa.ucsf.edu
Abstract
INTRODUCTION:

Tumeric is a spice that comes from the root Curcuma longa, a member of the ginger family, Zingaberaceae. In Ayurveda (Indian traditional medicine), tumeric has been used for its medicinal properties for various indications and through different routes of administration, including topically, orally, and by inhalation. Curcuminoids are components of tumeric, which include mainly curcumin (diferuloyl methane), demethoxycurcumin, and bisdemethoxycurcmin.
OBJECTIVES:

The goal of this systematic review of the literature was to summarize the literature on the safety and anti-inflammatory activity of curcumin.
METHODS:

A search of the computerized database MEDLINE (1966 to January 2002), a manual search of bibliographies of papers identified through MEDLINE, and an Internet search using multiple search engines for references on this topic was conducted. The PDR for Herbal Medicines, and four textbooks on herbal medicine and their bibliographies were also searched.
RESULTS:

A large number of studies on curcumin were identified. These included studies on the antioxidant, anti-inflammatory, antiviral, and antifungal properties of curcuminoids. Studies on the toxicity and anti-inflammatory properties of curcumin have included in vitro, animal, and human studies. A phase 1 human trial with 25 subjects using up to 8000 mg of curcumin per day for 3 months found no toxicity from curcumin. Five other human trials using 1125-2500 mg of curcumin per day have also found it to be safe. These human studies have found some evidence of anti-inflammatory activity of curcumin. The laboratory studies have identified a number of different molecules involved in inflammation that are inhibited by curcumin including phospholipase, lipooxygenase, cyclooxygenase 2, leukotrienes, thromboxane, prostaglandins, nitric oxide, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1 (MCP-1), interferon-inducible protein, tumor necrosis factor (TNF), and interleukin-12 (IL-12).
CONCLUSIONS:

Curcumin has been demonstrated to be safe in six human trials and has demonstrated anti-inflammatory activity. It may exert its anti-inflammatory activity by inhibition of a number of different molecules that play a role in inflammation.

PMID:
12676044
[PubMed – indexed for MEDLINE]

>GSH glutathione, the master antioxidant (Tationil, TAD600, Ridutox)

>
GSH glutathione, the master antioxidant (Tationil, TAD600, Ridutox) – skin smoothing-glowing-whitening, cellular rejuvenation

1. it is a protein (amino acid) molecule which is important as our body antioxidant, immune system booster and detoxifier
2. it presents in every cell to promote normal function as maintaining the immune system
3. one of the master antioxidant that mostly found in liver
4. it eliminates toxic compound (such as Paracetamol) in liver
5. it reconstitutes vitamin C and E which is being oxidized
6. combine taking with vitamin c injection greatly enhance your immunity, reduces tiredness, more youthful skin and stay healthy
7. fights against the cancer, heart disease, premature aging, autoimmune disease and chronic illness

Interaction: No known interaction, individual with liver malfunction is supposed to take this product. Pregnant and lactating women are not supposed to take the injection and other same kind of supplementary.

Dosage and method: 1-3 ampoules weekly by intravenous or intramuscular method.

Frequently Asked Questions:

1. What is glutathione? It is an important chemical that acts as a powerful antioxidant to preserve and protect the brain and other body tissues by protecting them from the damage of free radicals. It also acts to recycle vitamin C & E which also reduce free radicals.

2. What studies prove it work or are there any studies that prove it works?
The landmark study was done by the Department of Neurology, University of Sassari, Italy in 1996. In this study all patients improved significantly after glutathione therapy with a 42% decline in disability.

3. What is glutathione used for? It has been used to treat all symptoms of neurodegenerative diseases such as Parkinson’s, Alzheimer’s, multiple sclerosis, stroke, ALS, irritable bowel, and chronic fatigue.

4. What improvement in symptoms can one expect? Many patients have had profound improvements with respect to reduction of rigidity, increased mobility, improved ability to speak, less depression, and decreased tremor. Glutathione has the added benefit of protecting the brain from free radical damage, thus possibly slowing the progression of the underlying illness.

5. How long can a person take glutathione and how long will the effect last after I stop using it? It can be taken permanently. In the 1996 Italian study the therapeutic effect lasted 2-4 months after therapy was stopped.

6. How long has this treatment been used. Physicians have been using glutathione infusions for at least 30 years, probably longer.

7. How is the treatment given? It is given intravenously in the arm by IV push over 10 to 15 minutes usually three times a week in a physician’s office.

>The wonderful world of VITAMIIN C (ascorbic acid)

>Vitamin C, 500 mg/5 ml amp $4 each superhumangear@gmail.com

Vitamin C, or ascorbic is acid is a truly wonderful substance. It can work as an anti-oxidant, as pro-oxidant by releasing hydrogen peroxide in the body, it boosts collagen synthesis, lightens skin, fights tumors, diseases, flu’s and so on.

Vitamin C: The Ultimate Anti-Aging Vitamin

Remember when vitamin C was hailed as the best, and maybe only, cold remedy? Then it became the Rodney Dangerfield of vitamins: It didn’t get any respect. The nutrient’s glory days of curing scurvy-riddled sailors via juicy citrus fruit seemed to be the only thing keeping its reputation afloat, particularly after a massive research review found C to be virtually useless for fighting colds. But don’t believe it. The truth is that scientists have taken a fresh look at C—and have found lots of new ways it can help you stay healthy and look and feel younger. Here’s the latest on what C can really do for you.

Prevent wrinkles
You can’t pick up a beauty product these days without the label touting its antioxidants. There’s a good reason: Antioxidants—like vitamin C—help turn back the clock. An October 2007 study published in the American Journal of Clinical Nutrition found that people who ate foods rich in vitamin C had fewer wrinkles and less age-related dry skin than those whose diets contained only small amounts of the vitamin. C helps form collagen, which smooths fine lines and wrinkles, according to Patricia Farris, MD, clinical assistant professor of dermatology at Tulane University in New Orleans.

The key seems to be C’s ability to fight free radicals, a by-product of cell metabolism in your body. Free radicals are thought to attack proteins, fats, and DNA—and break down collagen. C also seems to guard against ultraviolet rays from the sun, which can lead to freckles and a mottled complexion. “Vitamin C does some repair and firming on the skin,” Farris says.

What to do now: Use a topical vitamin C treatment daily after you wash your face and before you slather on moisturizer or sunscreen so it penetrates the skin. Farris recommends La Roche-Posay Active C facial moisturizer or SkinCeuticals C E Ferulic topical antioxidant treatment.

Protect your heart
Experts continue to argue about whether antioxidants like vitamin C can prevent heart disease. But some of the evidence is highly persuasive. When Finnish researchers looked at studies involving nearly 300,000 people over 10 years, they found that taking more than 700 milligrams of C supplements daily reduced the risk of cardiovascular disease by 25 percent. And a recent study from Harvard Uni-versity researchers hints that women who take a combo of 500 milligrams of vitamin C daily and 600 IU of vitamin E (another antioxidant) can cut their risk of stroke by 30 percent. It’s possible that people who take vitamin supplements simply have healthier lifestyles than those who don’t, which could explain this finding. It’s also possible, experts say, that C enhances the functioning of endothelial cells (which line the inside of all blood vessels), slowing artery clogging and lowering blood pressure.
Keep cancer at bay
A diet full of vitamin C–rich fruits and vegetables isn’t just good for your heart, it may also lower your risks of bladder, esophagus, stomach, and lung cancers. Even though more research is needed to find out which compounds in fruits and veggies do the trick, researchers say the association is strong. Someday, C may also be used to treat cancer. High levels of C given intravenously seem to be toxic to cancer cells (studies on vitamin C taken orally showed no effect on cancerous cells). Intravenous C appears to trigger the formation of hydrogen peroxide, which kills some cancer cells while leaving healthy cells unharmed, says lead study author Mark Levine, MD, chief of the molecular and clinical nutrition section and senior staff physician at the National Institutes of Health. Levine says doctors at the University of Kansas Medical School and Jefferson Medical College in Philadelphia are trying this therapy on cancer patients.

What to do now: “Strive for five or more fruits and vegetables daily, in a rainbow of colors,” Levine says. “It’s where the most benefit is.

Boost brain power
Pairing vitamins C and E is smart for another reason: It may lessen your Alzheimer’s risks by as much as 64 percent, according to research in the Archives of Neurology. Just 500 milligrams of C and 400 IU of E appear to be enough. The brain’s high fat content makes it especially vulnerable to free radicals, but these antioxidants may act as shields, says study author Peter Zandi, PhD, an assistant professor at Johns Hopkins University Bloomberg School of Public Health. “Some studies suggest that vitamin E does its job reducing free radicals in the body, but then its capacity is depleted,” Zandi says. “Vitamin C may recharge E.”

What to do now: Try taking C and E supplements, and talk to your doc about your risks for Alzheimer’s and dementia.

Save your eyesight
Vitamin C can’t prevent the need for reading glasses around age 45. But anti-oxidants, including C, help prevent one of the leading causes of blindness: age-related macular degeneration (AMD). More than 3.5 million Americans are thought to be in the early stages, and the disease strikes more women than men. A major clinical trial sponsored by the National Eye Institute showed that a daily supplement of 500 milligrams of vitamin C, 400 IU of vitamin E, 15 milligrams of beta-carotene, 80 milligrams of zinc, and 2 milligrams of copper reduced the risk of moderate or severe AMD-related vision loss by up to 25 percent. The antioxidants neutralize damage to the retina caused by, you guessed it, free radicals.

What to do now: If you’re at high risk for AMD (you’re overweight or have a family history), check to see if your multi-vitamin contains the study’s amounts of C, E, beta-carotene/vitamin A, zinc, and copper. Chances are, its C and E levels fall short, but additional supplements will do the job. (Caveat: Don’t follow this advice if you smoke; this level of beta-carotene may up your lung-cancer risks.)

Help you live longer
You’ve probably heard that green tea boosts the body’s defenses against toxins. That’s important because toxins are thought to contribute to cancer, heart attack, stroke, and lots of other maladies. In fact, one to two cups a day may reduce a woman’s risk of dying by about 20 percent, Japanese researchers say. What’s the vitamin C connection? Citrus juices (lemon, lime, orange) may supercharge the immunity-boosting power of green tea. A new Purdue University study found that mixing citrus juice with green tea allowed 80 percent of the tea’s anti-oxidants to stick around after simulated digestion, making the pairing healthier than thought, says study author Mario G. Ferruzzi, PhD, assistant professor in Purdue’s department of food and nutrition.

>Alpha-lipoic acid (thioctic acid) the magic antioxidant and much more

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Summary

• Alpha-lipoic acid (LA), also known as thioctic acid, is a naturally occurring compound that is synthesized in small amounts by humans. More information
• Endogenously synthesized LA is bound to protein and functions as a cofactor for several important mitochondrial enzymes. More information
• Supplementation with high doses of LA transiently increases plasma and cellular levels of free LA. More information
• Although LA is a potent antioxidant in the test tube, LA supplementation may affect health by stimulating glutathione synthesis, enhancing insulin signaling and modulating the activity of other cell signaling molecules and transcription factors. More information
• Overall, the available research indicates that treatment with 600 mg/day of intravenous racemic LA for 3 weeks significantly reduces the symptoms of diabetic peripheral neuropathy. More information
• Although the benefit of long-term oral LA supplementation for diabetic peripheral neuropathy is less clear, there is some evidence that oral supplementation with at least 600 mg/day of racemic LA may be beneficial. More information
• It is not yet known whether LA supplementation is beneficial in the treatment of multiple sclerosis or neurodegenerative diseases, such as Alzheimer’s disease. More information
• If you choose to take LA supplements, the Linus Pauling Institute recommends a daily dose of 200-400 mg/day of racemic LA for generally healthy people.

Introduction

Alpha-lipoic acid (LA), also known as thioctic acid, is a naturally occurring compound that is synthesized in small amounts by plants and animals, including humans (1, 2). Endogenously synthesized LA is covalently bound to specific proteins, which function as cofactors for several important mitochondrial enzyme complexes (see Biological Activities below). In addition to the physiological functions of protein-bound LA, there is increasing scientific and medical interest in potential therapeutic uses of pharmacological doses of free LA (3). LA contains two thiol (sulfur) groups, which may be oxidized or reduced (Figure). The reduced form is known as dihydrolipoic acid (DHLA), while the oxidized form is known as LA (4). LA also contains an asymmetric carbon, meaning there are two possible optical isomers that are mirror images of each other (R-LA and S-LA). Only the R– isomer is endogenously synthesized and bound to protein. Free LA supplements may contain either R-LA or a 50/50 (racemic) mixture of R-LA and S-LA (see Supplements below).

Metabolism and Bioavailability

Endogenous Biosynthesis

LA is synthesized de novo from an 8-carbon fatty acid (octanoic acid) in mitochondria, where protein-bound LA functions as an enzyme cofactor. Recent evidence suggests that LA can be synthesized “on site” from octanoic acid that is already covalently bound to LA-dependent enzymes (5, 6). The final step in LA synthesis is the insertion of two sulfur atoms into octanoic acid. This reaction is catalyzed by lipoyl synthase, an enzyme that contains iron-sulfur clusters, which are thought to act as sulfur donors to LA (7, 8). The gene for lipoyl synthase has recently been cloned, and research is underway to learn more about its regulation (9).

Dietary and Supplemental Alpha-Lipoic Acid

Exogenous LA from the diet can be activated with ATP or GTP by lipoate activating enzyme, and transferred to LA-dependent enzymes by lipoyl transferase (10, 11). Consumption of LA from foods has not yet been found to result in detectable increases of free LA in human plasma or cells (3, 12). In contrast, high oral doses of free LA (50 mg or more) result in significant but transient increases in free LA in plasma and cells. Pharmacokinetic studies in humans have found that about 30-40% of an oral dose of racemic LA is absorbed (12, 13). Oral LA supplements are better absorbed on an empty stomach than with food. Taking racemic LA with food decreased peak plasma LA concentrations by about 30% and total plasma LA concentrations by about 20% compared to fasting (14). After oral dosing with racemic LA, peak plasma concentrations of R-LA were found to be 40-50% higher than S-LA, suggesting R-LA is better absorbed than S-LA (12, 14, 15). Both isomers are rapidly metabolized and excreted. Plasma LA concentrations generally peak in one hour or less and decline rapidly (12, 13, 15, 16). In cells, LA is quickly reduced to DHLA, and studies in vitro indicate that DHLA is rapidly exported from cells (3).

Biological Activities

Protein-Bound Alpha-Lipoic Acid

Enzyme Cofactor

R-LA is an essential cofactor for several mitochondrial enzyme complexes that catalyze critical reactions related to energy production and the catabolism (breakdown) of alpha-keto acids and amino acids (17). In each case, R-LA is covalently bound to a specific lysine residue in one of the proteins in the enzyme complex. The pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-coenzyme A (CoA), an important substrate for energy production via the citric acid cycle. The alpha-ketoglutarate dehydrogenase complex catalyzes the conversion of alpha-ketoglutarate to succinyl CoA, another important citric acid cycle intermediate. The activity of the branched-chain ketoacid dehydrogenase complex results in the catabolism of the branched-chain amino acids, leucine, isoleucine and valine (18). The glycine cleavage system is a multi-enzyme complex that catalyzes the oxidation of glycine to form 5,10 methylene tetrahydrofolate, an important cofactor in nucleic acid synthesis (19).

Free Alpha-Lipoic Acid

When considering the biological activities of supplemental free LA, it is important to keep in mind the limited and transient nature of the increases in plasma and tissue LA (see Metabolism and Bioavailability above) (3).

Antioxidant Activities

Scavenging Reactive Oxygen and Nitrogen Species: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive compounds with the potential to damage DNA, proteins and lipids (fats) in cell membranes. Both LA and DHLA can directly scavenge (neutralize) physiologically relevant ROS and RNS in the test tube [reviewed in (3)]. However, it is not clear whether LA acts directly to scavenge ROS and RNS in vivo. The highest tissue concentrations of free LA likely to be achieved through oral supplementation are at least 10 times lower than those of other intracellular antioxidants, such as vitamin C and glutathione. Moreover, free LA is rapidly eliminated from cells, so any increases in direct radical scavenging activity are unlikely to be sustained.

Regeneration of Other Antioxidants: When an antioxidant scavenges a free radical, it becomes oxidized itself and is not able to scavenge additional ROS or RNS until it has been reduced. DHLA is a potent reducing agent with the capacity to reduce the oxidized forms of several important antioxidants, including vitamin C and glutathione (20). DHLA may also reduce the oxidized form of alpha-tocopherol (the alpha-tocopheroxyl radical) directly or indirectly, by reducing the oxidized form of vitamin C (dehydroascorbate), which is able to reduce the alpha-tocopheroxyl radical (21). Coenzyme Q₁₀ is an important component of the mitochondrial electron transport chain that also has antioxidant activity. DHLA can also reduce oxidized forms of coenzyme Q₁₀ (22), which may also reduce the alpha-tocopheroxyl radical (23). Although DHLA has been found to regenerate oxidized antioxidants in the test tube, it is not known whether DHLA effectively regenerates other antioxidants under physiological conditions (3).

Metal Chelation: Redox-active metal ions, such as free iron and copper, can induce oxidative damage by catalyzing reactions that generate highly reactive free radicals (24). Compounds that chelate (bind) free metal ions in a way that prevents them from generating free radicals offer promise in the treatment of neurodegenerative and other chronic diseases, in which metal-induced oxidative damage may play a role (25). Both LA and DHLA have been found to inhibit copper- and iron-mediated oxidative damage in the test tube (26, 27), and to inhibit excess iron and copper accumulation in animal models (28, 29).

Induction of Glutathione Synthesis: Glutathione is an important intracellular antioxidant that also plays a role in the detoxification and elimination of potential carcinogens and toxins. Studies in animals have found that glutathione synthesis and tissue glutathione levels are significantly lower in aged animals than in younger animals, leading to decreased ability of aged animals to respond to oxidative stress or toxin exposure (30). LA has been found to increase glutathione synthesis in cultured cells and in the tissues of aged animals fed LA. Recent research suggests that LA may increase glutathione synthesis in aged animals by increasing the expression of gamma-glutamylcysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis (31) and by increasing cellular uptake of cysteine, an amino acid required for glutathione synthesis (32).

Modulating Signal Transduction

Insulin Signaling: The binding of insulin to the insulin receptor (IR) triggers the autophosporylation of several tyrosine residues on the IR. Activation of the IR in this manner stimulates a cascade of protein phosphorylations, resulting in the translocation of glucose transporters (GLUT4) to the cell membrane and increased cellular glucose uptake (3, 33). LA has been found to increase GLUT4 translocation to cell membranes and to increase glucose uptake in cultured adipose (fat) and muscle cells (34, 35). Although LA does not appear to bind to the IR like insulin, it can activate the insulin signaling cascade in cultured cells, possibly by acting as a mild oxidizing agent (3, 33).

PKB/Akt-dependent Signaling: In addition to insulin signaling, phosphorylation and dephosphorylation of other cell signaling molecules affect a variety of cellular processes, including metabolism, stress responses, proliferation and survival (3). One such molecule is protein kinase B also known as Akt (PKB/Akt). The addition of LA to cultured cells has been found to activate PKB/Akt-dependent signaling resulting in increased survival of neurons (36). LA administration improved nitric oxide-dependent vasodilation in aged rats by increasing PKB/Akt-dependent phosphorylation of endothelial nitric oxide synthase (eNOS), which increases eNOS catalyzed production of nitric oxide (37).

Redox-Sensitive Transcription Factors: Transcription factors are proteins that bind to specific sequences of DNA and promote or repress the transcription of selected genes. Some transcription factors are sequestered outside the nucleus until some sort of signal induces their translocation to the nucleus. Oxidative stress or changes in the balance between oxidation and reduction (redox status) in a cell can trigger the translocation of redox-sensitive transcription factors to the nucleus. One such family of redox-sensitive transcription factors, known as nuclear factor-kappa B (NF-KB), regulates a number of genes related to inflammation and cell cycle control, which are involved in the pathology of diabetes, atherosclerosis and cancer (19). Physiologically relevant concentrations of LA added to cultured cells have been found to inhibit NF-KB nuclear translocation (38). Another redox-sensitive transcription factor known as Nrf2 enhances the transcription of genes that contain specific DNA sequences known as antioxidant response elements (AREs). LA has been found to enhance the nuclear translocation of Nrf2 and the transcription of genes containing AREs in vivo, including genes for GCL, the rate-limiting enzyme in glutathione synthesis (31).

Deficiency

LA deficiency has not been described, suggesting that humans are able to synthesize enough to meet their needs for enzyme cofactors (39).

Disease Treatment

Diabetes Mellitus

Chronically elevated blood glucose levels are the hallmark of diabetes mellitus (DM). In type 1 DM, insulin production is insufficient due to autoimmune destruction of the insulin-producing beta-cells of the pancreas. Type 1 DM is also known as insulin-dependent DM, because exogenous insulin is required to maintain normal blood glucose levels. In contrast, impaired cellular glucose uptake in response to insulin (insulin resistance) plays a key role in the development of type 2 DM (40). Although individuals with type 2 DM may eventually require insulin, type 2 DM is also known as noninsulin-dependent DM because interventions that enhance insulin sensitivity may be used to maintain normal blood glucose levels.

Glucose Utilization

There is limited evidence that high doses of LA can improve glucose utilization in individuals with type 2 DM. A small clinical trial in 13 patients with type 2 DM found that a single intravenous infusion of 1000 mg of racemic LA improved insulin-stimulated glucose disposal (insulin sensitivity) by 50% compared to a placebo infusion (41). In an uncontrolled pilot study of 20 patients with type 2 DM, intravenous infusion of 500 mg/day of racemic LA for 10 days also improved insulin sensitivity measured 24 hours after the last infusion (42). A placebo-controlled study of 72 patients with type 2 DM found that oral administration of racemic LA at doses of 600 mg/day, 1200 mg/day or 1800 mg/day improved insulin sensitivity by 25% after 4 weeks of treatment (43). There were no significant differences among the three doses of LA, suggesting that 600 mg/day may be the maximum effective dose (40). Data from animal studies suggests that the R-isomer of LA may be more effective in improving insulin sensitivity than the S-isomer (35, 44), but this possibility has not been tested in any published human trials.

The effect of LA supplementation on long-term blood glucose (glycemic) control has not been well-studied. In an uncontrolled pilot study of a controlled-release form of oral racemic LA, 15 patients with type 2 DM took 900 mg/day for 6 weeks and 1200 mg/day for another 6 weeks in addition to their current medications (16). At the end of 12 weeks, plasma fructosamineglycosylated hemoglobin (HbA1c) levels did not change. Plasma fructosamine levels reflect blood glucose control over the past 2-3 weeks, while HbA1c values reflect blood glucose control over the past 2-4 months. At present, it is not clear whether oral or intravenous LA therapy improves long-term glycemic control in individuals with type 2 DM. concentrations decreased by about 10%, but

Vascular Disease

The inner lining of blood vessels, known as the endothelium, plays an important role in preventing vascular disease. Endothelial function is often impaired in diabetic patients, who are at high risk for vascular disease (45). Intra-arterial infusion of racemic LA improved endothelium-dependent vasodilation in 39 diabetic patients, but not in 11 healthy controls (46). Endothelial function can be assessed noninvasively by using ultrasound to measure flow-mediated vasodilation, which is endothelium-dependent (47). A randomized controlled trial assessed the effect of oral LA supplementation on flow-mediated vasodilation in 58 patients diagnosed with the metabolic syndrome, a condition of abnormal glucose and lipid (fat) metabolism (48). Oral supplementation with 300 mg/day of LA for 4 weeks improved flow-mediated vasodilation by 44% compared to placebo. Diabetic patients are also at high risk of microvascular disease, which may contribute to diabetic neuropathy (40). In an uncontrolled study, oral supplementation with 1200 mg/day of racemic LA for 6 weeks improved a measure of capillary perfusion in the fingers of 8 diabetic patients with peripheral neuropathy (49). While these results are encouraging, long-term randomized controlled trials are needed to determine whether LA supplementation can reduce the risk of vascular complications in individuals with diabetes.

Diabetic Neuropathy

Intravenous and oral LA are approved for the treatment of diabetic neuropathy in Germany (4). More than 20% of diabetic patients develop peripheral neuropathy, a type of nerve damage that may result in pain, loss of sensation and weakness, particularly in the lower extremities (40). In addition to the pain and disability caused by diabetic neuropathy, it is a leading cause of lower limb amputation in diabetic patients (50). The results of several large randomized controlled trials indicate that maintaining blood glucose at near normal levels is the most important step in decreasing the risk of diabetic neuropathy (51, 52). However, such intensive blood glucose control may not be achievable in all diabetic patients. A meta-analysis that combined the results of four randomized controlled trials, including 1258 diabetic patients, found that treatment with 600 mg/day of intravenous racemic LA for 3 weeks significantly reduced the symptoms of diabetic neuropathy to a clinically meaningful degree (53).

The efficacy of oral LA in the treatment of diabetic neuropathy is less clear. A short-term study of 24 patients with type 2 DM found that the symptoms of peripheral neuropathy were improved in those who took 1800 mg/day of oral racemic LA for 3 weeks compared to those who took a placebo (54). A much larger clinical trial randomly assigned more than 500 patients with type 2 DM and symptomatic peripheral neuropathy to one of the following treatments: 1) 600 mg/day of intravenous racemic LA for 3 weeks followed by 1800 mg/day of oral racemic LA for 6 months, 2) 600 mg/day of intravenous racemic LA for 3 weeks followed by oral placebo for 6 months, or 3) intravenous placebo for 3 weeks followed by oral placebo for 6 months (55). Although symptom scores did not differ significantly from baseline in any of the groups, assessments of sensory and motor deficits by physicians improved significantly after 3 weeks of intravenous LA therapy. Motor and sensory deficits were also somewhat improved at the end of 6 months of oral LA therapy, but the trend did not reach statistical significance. In the longest controlled trial of oral LA therapy, 299 patients with diabetic peripheral neuropathy were randomly assigned to treatment with 1200 mg/day of racemic LA, 600 mg/day of racemic LA or a placebo (56). However, after 2 years of treatment, only 65 of the original participants were included in the final analysis. In that subgroup, those who took either 1200 mg/day or 600 mg/day of LA showed significant improvement in electrophysiological tests of nerve conduction compared to those who took the placebo.

Another neuropathic complication of diabetes is cardiovascular autonomic neuropathy, which occurs in as many as 25% of diabetic patients (40). Cardiovascular autonomic neuropathy is characterized by reduced heart rate variability, and is associated with increased risk of mortality in diabetic patients. In a randomized controlled trial of 72 patients with type 2 DM and reduced heart rate variability, oral supplementation with 800 mg/day of racemic LA for 4 months resulted in significant improvement in 2 out of 4 measures of heart rate variability compared to placebo (57).

Overall, the available research suggests that treatment with 600 mg/day of intravenous LA for 3 weeks significantly reduces the symptoms of diabetic peripheral neuropathy. Although the benefit of long-term oral LA supplementation is less clear, there is some evidence to suggest that oral LA may be beneficial in the treatment of diabetic peripheral neuropathy (600-1800 mg/day) and cardiovascular autonomic neuropathy (800 mg/day).

Multiple Sclerosis

Feeding high doses of LA to mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), has been found to slow disease progression (58, 59). In these animals, LA feeding appeared to inhibit the migration of inflammatory T cells into the brain and spinal cord, possibly by inhibiting the activity of an enzyme known as matrix metalloproteinase (MMP)-9. A small pilot study designed to evaluate the safety of LA in 30 people with relapsing or progressive MS found that treatment with 1200-2400 mg/day of oral LA for 2 weeks was generally well-tolerated (see Safety), and that higher peak serum levels of LA were associated with greater decreases in serum MMP-9 levels (60). However, this pilot study was not designed to assess the clinical benefit of LA. Larger, long-term clinical trials are needed to assess the safety and efficacy of LA in the treatment of MS (61).

Cognitive Decline and Dementia

LA alone or in combination with other antioxidants or L-carnitine has been found to improve measures of memory in animal models of age-associated cognitive decline, including rats (62, 63), mice (64) and dogs (65). However, it is not clear whether oral LA supplementation can slow cognitive decline related to aging or other pathology in humans. An uncontrolled, open-label trial in 9 patients with Alzheimer’s disease and related dementias, who were also taking acetylcholinesterase inhibitors, reported that oral supplementation with 600 mg/day of racemic LA appeared to stabilize cognitive function over a one-year period (66). However, the significance of these findings is difficult to assess without a control group for comparison. A randomized controlled trial found that oral supplementation with 1200 mg/day of racemic LA for 10 weeks was of no benefit in treating HIV-associated cognitive impairment (67). Although studies in animals suggest that LA may be helpful in slowing age-related cognitive decline, randomized controlled trials are needed to determine whether LA supplementation is effective in preventing or slowing cognitive decline associated with age or neurodegenerative disease.

>Curcumin is an AMPK activator and induces glutathione synthesis – no need for AICAR?

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Curcumin stimulates glucose uptake through AMPK-p38 MAPK pathways in L6 myotube cells
Ji Hae Kim 1, Ji Man Park 2, Eung-Kyun Kim 2, Jung Ok Lee 1, Soo Kyung Lee 1, Jin Hee Jung 1, Ga Young You 1, Sun Hwa Park 1, Pann-Ghill Suh 2 *, Hyeon Soo Kim 1 *
1Department of Anatomy, Korea University College of Medicine, Seoul, South Korea
2Division of Molecular and Life Science, POSTECH (Pohang University Science and Technology), Pohang, South Korea

Abstract
Curcumin has been shown to exert a variety of beneficial human health effects. However, mechanisms by which curcumin acts are poorly understood. In this study, we report that curcumin activated AMP-activated protein kinase (AMPK) and increased glucose uptake in rat L6 myotubes. In addition, curcumin activated the mitogen-activated protein kinase kinase (MEK)3/6-p38 mitogen-activated protein kinase (MAPK) signaling pathways in the downstream of the AMPK cascade. Moreover, inhibition of either AMPK or p38 MAPK resulted in blockage of curcumin-induced glucose uptake. Furthermore, the administration of curcumin to mice increased AMPK phosphorylation in the skeletal muscles. Taken together, these results indicate that the beneficial health effect of curcumin can be explained by its ability to activate AMPK-p38 MAPK pathways in skeletal muscles. J. Cell. Physiol. 223:771-778, 2010. © 2010 Wiley-Liss, Inc.