Mitochondria are the cell's power producers. They convert energy into forms that are usable by the cell. They are the sites of cellular respiration which ultimately generates fuel for the cell's activities. Mitochondrial electron transport is not perfect. Even under ideal conditions, some electrons "leak" from the electron transport chain. These leaking electrons interact with oxygen to produce superoxide radicals.
With mitochondrial dysfunction, leakage of electrons can increase significantly. The close proximity of mtDNA to the flux of superoxide radicals (or hydroxyl radicals), and it's lack of protection and repair mechanisms, leads to free radical-mediated mutations and deletions. Mitochondrial has been proposed as an underlying causes of 1) free-radical stress, 2) degenerative disease and 3) aging.
Evidence is accumulating that mitochondrial dysfunction underlies many common pathologies. Mitochondrial defects have been identified in Parkinson's disease, Alzheimer's disease, heart disease, fatigue syndromes, numerous genetic conditions, and nucleoside therapy for AIDS. Also, many common nutritional deficiences can impair mitochondrial efficiency.
For Mitochondrial disease use: Coenzyme Q10, Carnitine, Alpha Lipoic Acid, Vitamin C, Vitamin B1, B2, Biotin, Vitamin E.
For Lactic Acidosis that effects liver use the drug dichloroacetate along with the above antioxidants.
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NOTE: see details of "Mitochondrial toxicity" on yahoo www.hivforum.org "Metabolic Abnormalities"
Mitochondrial is active in all tissue.
DDI inhibited mitochondrial DNA synthesis and maybe reversible. However, DDI may exert an action against the mitochondrial DNA via some mechanism other than the inhibition of mitochondrial DNA synthesis.
Non-treated HIV have to lesser extent have mitaochondrial problem which can lead to wasting and nephropathy.
Therapeutic options for mitochondrial dysfunction include the following possibilities:
....SUPPORTIVE SUPPLEMENTATION
Thiamine(vitamin B1)
Riboflavin(vitamin B2)
Coenzyme Q
L-carnitine
....FREE RADICAL SCAVENGERS
Vitamin C,E,K
Creatine
...Steriods
...Dichloroacetate(DCA)
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TRYPTOPHAN DEPLETION
"Tryptophan depletion and HIV a infection: a metabolic link to pathogenesis" by Michael F Murray
HIV-1 infected patients have low circulating tryptophan concentrations despite evidence of adequate dietary intake of this essential aminoacid. A chronic increase in inducible tryptophan oxidation is the basis of HIV-1-associated tryptophan depletion. This meatbolic process results in the irretrievable loss of tryptophan molecules from the available pool. Such sustained disruption of normal tryptophan metabolism over time disturbs the many metabolic processes involving this aminoacid, and has been implicated in some features of AIDS pathogenesis. Normal T-cell function is adversely affected by tryptophan depletion, but the extent of the effect in HIV-1-infected patients is still unclear. Attempting to directly supplement tryptophan is not advised given the potential increase in circulating concentrations of neurotoxic intermediates. Although only preliminary data are available, evidence suggests that antiretroviral and nicothinamide treatments can boost plasma tryptophan concentrations in HIV-1-infected patients and impact the secondary effects of tryptophan depletion. Additional study of this metabolism could lead to improved treatment strategies for patients with HIV infection. In this review I focus on the potential links between distrubed tryptophan metabolism and pathogenesis
Lancet Infect Dis 2003; 3:644-652
Localisation of IDO (indolamine 2,3-dioxygenase) activity and increased quinolinic acid in the brain has been associated with HIV dementia.
The possible roles of kynurenines in diabetes. The diabetes that is associated with pregnancy and obesity could result, in part, from the activation of tryptophan metabolism, which produces a reduced plasma tryptophan level and an elevation of kynurenic acid, quinaldic acid and xanthurenic acid levels. Kynurenic aicd blocks the pro-secretory glutamate receptors, whereas quinaldic acid inhibits pro-insulin formation and insulin release. Xanthurenic acid levels are also increased as a result of the tryptophan oxidation, and are further substantially increased when kynureninase activity is suppressed by vitamin B6 deficiency. The resulting complex of xanthurenic aicd with insulin is functionally inactive. IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase.
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Niacinamide is found to increase tryptophan 40%
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LACTOFERRIN
E-mail from Joel Kehler
http://www.freepatentsonline.com/EP0559425.html
The studies at the end of this patent application are new to me. The use of bLF to treat stomatitis in cats is well established by at least one other study. However, this (Example 5) is the first clinical use of a transferrin I have seen to sucessfully treat URI in FIV+ cats. (There are in vitro studies of inhibition of feline herpes and calici virus.) I am somewhat at a loss to understand why ovotransferrin was used in the study rather than lactoferrin. The former does not even seem to be commercially available. I did some reading up. Lactoferrin, serum transferrin, and ovotransferrin are closely related over a wider ph range. Often the three are lumped together, although I did find one study of a virus I never heard of which was better inhibited by hen ovotransferrin than by lactoferrin.
Example 4
The most frequent opportunistic infections encountered in feline immunodeficiency virus (FIV) infected cats are stomatitis, gingivitis and chronic infection of the upper air way (upper respiratory tract). FIV-positive cats taken to domestic animal hospitals were orally treated with lactoferrin (20 mg/kg, daily). The lactoferrin used was bovine native lactoferrin with 85% purity and 25% ferric iron saturation. After it was dissolved in distilled water, the solution was sprayed over ulcers and aphthac in the oral cavity of cats with stomatitis and gingivitis caused by FIV and dental calculus. The treatment periods were from 7 days to several months, and the amounts of saliva and stench from the mouth were observed. Among a total of 11 cases, 4 cases were remarkably improved by lactoferrin treatment and 3 cases were partially improved during the treatment period. It was unclear whether or not the treatment afforded the beneficial effects in the remaining 4 cases. The two cases out of 4 where lactoferrin treatment greatly improved the stomatitis and gingivitis were FIV-positive, where very severe gingivitis and stomatitis were observed and the animals lost appetite dues to the pain before the treatment. However, the appetite much increased 7-10 days after the lactoferrin treatment as the pain ameliorated, and resulted in disappearance of the stench from the mouth. Much driveling was again observed after cessation of lactoferrin treatment.
Example 5
A total of 9 adult cats positive with FIV (complicated with upper bronchial infection) were randomly allocated into 2 groups as they were taken to domestic animal hospitals. The first group was treated with ovo-transferrin and the others with controls. The experimental perlod was 8 weeks, and the daily dose of ovo-transferrin was 20 mg/kg that was given to the animals as an admixture of canned fish or animal meats. The controls died due to pneumonia 8, 11, and 34 days after the beginning of the study and only one survied throughout the experimental peroid, while all animals survived 8 weeks after the study in the ovo-transferrin group. Therefore it is evident that ovo-transferrin is both preventative and curative against chronic upper bronchial infections in FIV-positive cats.
I also came across (in another patent application) this succinct explanation of why the antiviral activity of transferrins is independent of their iron-binding activity, which is central to their antibacterial action:
Recently, an antiviral function of lactoferrin has been demonstracted, a glycoprotein able to bind 2 atoms of Fe3+ per molecule. The antiviral function of lactoferrin, firstly attributed to its iron deprivation capability, may be, on the contrary, due to a specific binding with the host surface in its N-terminus in a region distince from the iron binding sites. In fact, it has been demonstracted that lactoferrin (human and bovine) specifically binds to heparin sulfate, a ubiquitous proteoglycan, multifunctional constituent of mammalian cell membranes and of extracellular matrix. This component and other glyosaminoglycans may act as receptors for some enveloped viruses, including HSV1 and HIV. It can be inferred that lactoferrin is able to selectively inhibit the early interactions HSV1-host cell and, consequently, is able to inhibit the internalization of the virus.
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Down-regulation of CXCR-4 and CCR-5 expression by interferon-gamma is associated with inhbition of chemotaxis and human immunodeficiency virus (HIV) replication but not HIV entry into human monocytes by Creery D, Weiss W, etc
Alterations in the expression of CXCR4 and CCR5, the co-receptors for HIV entry, may be associated with susceptiblity of monocytic cells to HIV infection. Interferon (IFN)-gamma has been shown to inhibit HIV replication in monocytic cells. etc These results suggest that although IFN-gamma-induced down inhibition of SDF-1-/MIP-1alpha-mediated chemotaxis IFN-gamma-induced inhibition of HIV replication may be mediated at levels subsequent to the virus entry.
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The OLVG/Dutch management protocol for HIV lactic acidosis calls for:
Interuption of NRTIs
Intravenous fluid support
Vitamin supplementation
.....Vitamin B complex forte(4 ml bid includes 20 mg of riboflavin bid and 100 mg of thiamin bid)
.....L-carntine (1000 mg bid) Continue treatment until lactatic levels are normal
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L-carnitine/Acetyl-L-carnitine Study
Eleven asymptomatic HIV-infected individuals who were not receiving any antiviral treatment, received daily infusion of six grams L-carnitine for four months. Prior to the study they all had been experiencing steady CD4 count declines for 12 months. At day 150, mean CD4 counts were significantly elevated and a positinve trend was observed for increases in CD8 counts. Two sugjects had a doubling of their CD4 count, two had a more than 50-perent increase, three had approximately 30-percent increases, and threee had no significant increase over baseline. The researchers also saw a significant drop in apoptotic cell death in both CD4 and CD8 cells for both values. Ceramide levels were significantly higher than in HIV-negative individuals, and dropped significantly over the course of the trial. HIV-1 viremia increased slihtly over the 150-day period. There was no toxicity related to the L-carnitine therapy.
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ALPHA LIPOIC ACID
When sugar is metabolized in the production of energy, it is converted into pyruvic acid. The pyruvate is broken down by an enzyme complex that contains lipoic acid, niacin and thiamin (vitamin B1). The principal uses of alpha lipoic acid are in the treatment of diabetes and HIV/AIDS.
During HIV infection, key cells of the immune system called CD lymphocytes lose their ability to make and to transport glutathione. Antioxidants such as glutathione prevent HIV viral replication while reactive oxidants tend to stimulate the virus. Glutathione is a major cellular antioxidant, and thus, the CD lymphocytes are exposed to excess oxidative stress and this contributes to immune system failure. Alpha lipoic acid is a powerful antioxidant and facilitator of glutathione production. A strong antioxidant defense system can help prevent this oxidative damage and help keep the immune system strong.
Lipoic acid protects a complex called Nuclear Factor kappa-B and prevents it from activating the HIV virus that enhances the level of replication. The long terminal repeat (LTR) region of HIV proviral DNA contains binding sites for nuclear factor kappa B (NF-kappa B), and this transcriptional activator appears to regulate HIV activation. Recent findings suggest an involvement of reactive oxygen species (ROS) in signal transduction pathways leading to NF-kappa B activation. A study was based on reports that antioxidants which elimate ROS should block the activation of NF-kappa B and subsequently HIV transcription, and thus antioxidants can be used as therapertic agents for AIDS.
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Hi Arthur,
How are you? Hope all is well..I was wondering if you knew of any mineral deficiencies or imbalances that is associated with FIV in cats?
I know of this person that has a kitty that keeps licking and eating dirt...I pected perhaps he's attracted to fertilizers but then I also wondered that perhaps the cat was lacking in something and his body is trying to substitute whats missing with minerals in the dirt... any answers? ...............
I have heard of some cats eating dirt, just as some cats eat wool. My own cats eat grass.
FIV cat do have mineral deficiencies. The most common is selenium. Others are zinc, copper, iron. One of the problems in FIV or HIV is Mitochondria which dysfunctions with this disease.
There is a progressive decline of selenium levels in HIV patients. This is a significant predictor of survival since decline of selenium parallels the progress of the disease.
Selenium is in the ground-dirt. But I don't think the other cats that eat dirt have FIV. Dietary selenium can be found in meats, fish and a variety of grains. It is also found in brewer's yeast.
Brewer's yeast is a good idea to feed a FIV cat. It contains vitamin B complex which is helpful.
In free radical scavenging system the following enzymes are used: superoxide dismutase, catalase, glutathione.
Superoxide dismutase is of two types: copper/zinc SOD and manganese SOD. Along with glutathione reduce the rate of cell destruction.
I made an addition to my webpage giving a section to MITOCHONDRIA. I did not give much of an explanation of a subject that can run into many pages. Only one page giving a short summary. It is the basis for using antioxidants to treat AIDS. There are a lot of basic knowledge gaps on this subject.
Well so much for the subject of dirt.
Arthur Gitleman
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The following maybe of interest:
On Yahoo access "www.vitatime.com" BOSTON BUYER'S CLUB
Fact Sheets and Information
Selection from DR Lark Land's book Positively Well: Living with HIV
I noted, "As to the use of glutathione itself, old research had led to questions about how well glutathione absorbs orally. However, later research countered that, showing that it is effective to take it by mouth. Thus although most research is still centered on the use of NAC to raise glutathione, the far better approach is to use the combination of all the nutrients important for glutathione synthesis and recylcing, including NAC, oral glutathione, vitamin C, alpha-lipoic acid, and L-glutamine."
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Massive Loss of Sulfur Seen in HIV Positive Patients
German study notes loss of sulfur in patients who were on and off HAART
by Jeff Getty.. Survive AIDS Writers' Pool
On March 21, Reuters News Service published a story entitled "HIV Infection Results in Massive Loss of Sulfur." This short report that mentioned recent research findings from Germany immediately created a buzz among AIDS activists in the US. As with so much mainstream media reporting on AIDS, the headline was misleading. Should PWAs now start ingesting lumps of sulfur? Here's what we found out.
A group of German doctors from the Krebsforschungszentrum (don't even try to pronounce it) in Heidelberg, Germany published a report in the February 2000 edition of AIDS Human Retroviruses called "Massive Loss of Sulfur in HIV Infection." The abstract of the report states that the German scientists (a well-respected group) measured the sulfate concentrations in arterial venous blood from the lower extremities of 16 HIV positive patients and 16 HIV negative controls. The findings showed that the HIV positive patients' peripheral tissue released large amounts of sulfate, regardless of whether or not they were using HAART (highly active antiretroviral therapy).
A previous study showed that HIV positive patients have increased plasma levels of sulfate, thioredoxin and interleukin 6. Another study comparing 19 HIV positive patients to 22 healthy HIV negative subjects showed that the HIV positive patients were losing massive amounts of sulfur in their urine. This loss of sulfur was not changed by use of HAART. A normal body excretes about 3 grams of cysteine (a sulfur-containing amino acid). The HIV positive patients were excreting more than 3 times that amount (about 10 grams daily).
The scientists concluded that these findings show that HIV positive patients suffer loss of glutathione, an essential amino acid known to help in cell metabolism. Anyone who has been following AIDS research over the years has probably heard about this before. The glutathione connection has been intensely studied since the late 1980's, but with little progress in determining why this deficiency occurs, or more importantly, why replacing the sulfur or glutathione does not seem to be an easy answer. Many long-term AIDS patients remember N-acetylcysteine (NAC), a popular supplement taken by thousands of PWAs in the period 1994-1997. At the time there were anecdotal reports of NAC users experiencing increased weight and energy. However, a Stanford University study carried out by the Herzenberg Lab revealed no significant benefit for patients taking NAC compared to patients on placebo.
One of the researchers who worked on the NAC study under Leonard and Lenora Herzenberg was Dr. Steve De Rosa said that the initial study was completed in 1995. There were a total of 60 patients studied for 8 weeks. Half the patients received NAC and the other half got a placebo. "The study showed that taking NAC replenished glutathione as measured in the lymph and red blood cells," he said. But the study was too short, and De Rosa's opinion is that longer-term use of NAC might have shown some clinical benefit. The study found no changes in absolute CD4 counts and no change in HIV viral load. After the study was published, NAC use declined significantly. However, some HIV positive individuals still use NAC, and they claim that it has beneficial effects.
So why did replacing lost cysteine through NAC or glutathione not work in a controlled study? Nobody seems to know for sure. Dr Catherine Mulligan, a University of California researcher, is intrigued by the recent German findings. "I still think there is something more to learn about NAC." she said. Mulligan studies the process in metabolism that lead to AIDS-related wasting. She also criticized the German report. "There are a number of things that worry me about this article - "massive loss of sulfur" sounds too alarming." she said. When asked whether or not patients should experiment with sulfur supplements, she seemed worried that the Reuter's article might start a new treatment fad. "I definitely encourage people not to rush out and buy sulfur. The kind of sulfur that comes from taking sulfur tablets is not going to fix the sulfur loss," she remarked.
Sulfur that can be metabolized by humans appears in the body as cysteine. Cysteine is then converted or taken up by a larger amino chain, glutathione. Experience tells us that pouring in more raw ingredients such as sulfur is probably not as beneficial as adding a compound closer to the metabolized amino acid. Cysteine in NAC would be the logical and best way to introduce the correct type of sulfur into the body. Herzenberg's group still believes that NAC is going to prove beneficial one day. The Herzenbergs are trying to find ways to fund a much larger and longer study. "The problem with commonly available NAC is that no pharmaceutical company will fund a study since it cannot have a patent on the product," De Rosa said. The group is working with at least one interested party in reformulating NAC so that it can get some type of patent and then possibly apply for FDA approval.
Clearly, sulfur loss reveals another missing link in our understanding of AIDS. Why did patients on or off HAART both have "massive" sulfur loss? If the viral load is undetectable, then why the continued perturbation? And other abnormalities in the body such as immune dysfunction continue even after effective HIV suppression. De Rosa and others believe that we have not gotten very far in our understanding of AIDS. "Glutathione and sulfur is telling us that HAART not the answer, but merely a first step. We need to find moreanswers," he remarked. Mulligan agrees. She said that people taking indinavir are already getting plenty of sulfur from that drug. Mulligan also wishes to revisit the potential benefits of using NAC. but the question of why the sulfur loss is happening in the first place remains unanswered.
For years, AIDS buyers clubs have been selling sulfur (in the form of NAC). There are anecdotal reports that it has prolonged the lives of late stage AIDS patients. Unfortunately, most of these clubs have shut down because of lost business to conventional pharmaceuticals and competing health food stores. NAC can still be found at health food stores, but De Rosa cautions that not all NACs may be beneficial. He worries that some over-the-counter NAC is heavily oxidated. "Too much oxidation could cause damage." he said. So PWAs need to be sure that any NAC they buy is of good quality. This can be problematic since most makers claim their product is "low-oxidative." De Rosa does not believe their claims.
Most patients who use NAC take 1-2 grams per day. There are no documented side effects to taking NAC. The Herzenberg study used a very high dose (8 grams per day) and still did not see any significant side effects. Of course, taking NAC could be a waste of time and money, but replenishing missing amino acids through a harmless supplement may be a reasonable approach for now. But the mystery remains--why are HIV-infected patients losing sulfur in the first place? "If you knew the answer to that and other questions about HIV, you would win a Nobel prize." quipped De Rosa.
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NAC N-acetl-cysteine
J Mol Med 2000;78(1):55-62 (ISSN: 0946-2716)
Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials
Breitkreutz R; Pittack N; Nebe CT; Schuster D; Brust J; Beichert M; Hack V; Edler I; Droge W
Deutsches Krdbsforschungszentrum, Division of Immunochemistry, Heidelberg, Germany.
To determine the therapeutic effect of sulfur amino acid supplementation in HIV infection we randomized 40 patients with antiretroviral therapy (ART; study 1) and 29 patients without ART (study 2) to treatment for 7 months with N-acetyl-cysteine or placebo at an individually adjusted dose according to a defined scheme. The main outcome measures were the change in immunological parameters including natural killer (NK) cell and T cell functions and the viral load. Both studies showed consistently that N-acetyl-cysteine causes a marked increase in immunological functions and plasma albumin concentrations. The effect of N-acetyl-cysteine on the viral load, in contrast, was not consistent and may warrant further studies. Our findings suggest that the impairment of immune reconstitution is a widely accepted aim of HIV treatment, N-acetyl-cysteine treatment may be recommended for patients with and without ART. Our previous report on the massive loss of sulfur in HIV-infected subjects and the present demonstration of the immunoreconstituting effect of cysteine supplementation indicate that the HIV-induced cysteine depletion is a novel mechanism by which a virus destroys the immune defense of the host and escapes immune elimination.
MEDLINE Life Sci 2000;67(2):147-54
Oral N-acetyl-cysteome increases the production of anti HIV chemokines in peripheral blood mononuclear cells.
Cavallini L, Alexandre A
Department of Biological Chemistry, C.N.R. Centro di Studio delle Biomembrane, University of Padova, Italy.
The C-C chemokines MIP-1alpha, MIP-1beta and RANTES are specific and powerful inhibitors of HIV infectivity. They appear to work by blocking the interaction of the virus with the receptor (CCR5). The latter is utilized as a coreceptor for cell penetration by macrophage-tropic (R5) HIV strains responsible for the majority of HIV transmissions. A natural high capability to release such chemokines has been proposed as a protection factor against HIV infection in exposed uninfected individuals. We report that oral administration of N-acetl-cysteine (NAC) to healthy volunteers increases the capability of their peripheral blood mononuclear cells (PBMC) to release such anti HIV chemokines upon stimulation. The data reported may explain at least in part the mechanism of action of NAC as an anti HIV therapeutic agent: By potentiating chemokine production NAC decrease susceptibility to infection.
JVet Med Sci 1998 Nov;60(11):1187-93 (ISSN: 0916-7250)
Inhibition of apoptosis and virus replication in feline immunodeficiency virus-infected cells by N-acetylcysteine and ascorbic acid.
Mortola E; Okuda M; Ohno K; Watare T; Tsujimoto H; Hasegawa A
Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, University of Tokyo, Japan.
Infection of feline immunodeficiency virus (FIV) has been shown to induce apoptosis that might be associated with the lymphocyte depletion in the infected cats. To investigate the inhibitory effect of antioxidants on FIV-induced apoptosis, we examined the effect of N-acetylcysteine (NAC) and ascorbic acid (AA) on apoptosis and virus replication in feline lymphoblastoid (Fel-039) and fibroblastoid (CRFK) cell lines infected with FIV. The treatment with NAC or AA induced a significant inhibition of viral replication and apoptosis in Fel-039 cells and tumor necrosis factor alpha (TNF-alpha)-treated CRFK cells infected with FIV. Both cell lines in the presence of noncytotoxic concentrations of NAC or AA showed in increase of intracellular glutathione (GSH) level, which might protect the cells against oxidative stresses exerted by FIV infection and TNF-alpha treatment. On the basis of these in vitro results, we suggest that antioxidant therapies aimed at restoring depleted GSH level might be effective for inhibition of viral replication and cell death associated with the development of immunodeficiency.
NOTE In another study:
"Mitochondria alterations and dramatic tendency to undergo apoptosis in peripheral blood lymphocytes during acute HIV syndrome"
Antioxidants tested: N-acetyl-cysteine (NAC), or nicotinamide (NAM), or L-acetyl-carnitine (LAC) seems to rescue cells through a protective effect on mitochondria.
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MITOCHONDRIAL TOXICITY
Is related to the inhibition of human DNA polymerase gamma activity may be the possible mechanism by which NRTIs exerted a toxic effect. Long-term toxicities (central nervous system, hepatic, lipid metabolism) of NRTI-based regimens are not fully defined.
Just writing to let you know my cat (Fido) has had FIV for almost 5 years now. She is regularly on prednisone and an antiboitic. I also put pedialyte in her water to keep her hydrated. The antibiotic has changed from various kinds to various strengths. Occasionally she has had serious bouts of sickness, and at that time she usually stays at the vets, and gets the needed iv drugs, whatever else, and lots of hydration. I'm sorry to hear about Blackie. I just thought I'd let you know about our success because you seemed concerned, and in case your other cat happened to show up positive.
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