4019 replies to this topic

[lostfalco]

Just another fun thing to keep in mind...HDAC Activators. Of course, sometimes this is a good thing. tanstaafl

 

1. Acetyl donors

2. Histone Acetyltransferases (HATs) 

3. HDAC Inhibitors (HDACi)

4. HDAC Activators 

 

http://www.ncbi.nlm....cles/PMC124399/

 

Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8921-6. Epub 2002 Jun 17.

A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression.

Ito K1, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ.

Author information

Abstract

The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDACactivity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes.

 

 

[supernoober]

1. The biggest question for me about enhancing mitochondria is: does it make you reliant on those methods/supplements in terms of downregulation your body's own production and biogenesis? For example, I take LEF's PQQ + Shijat + Ubiquinol supplement, but when I come off it, I feel weaker and lower than baseline mentally and energy-wise for at least several days. I think it is mainly the ubiquinol that leads to downregulating mitochondrial output. Do you guys think PQQ could downregulate biogenesis as well?

 

 

 

2. I'm interested in the LLLT. Does anybody know if it causes downregulation or a rebound affect in some way as well?

 

[lostfalco]

1. The biggest question for me about enhancing mitochondria is: does it make you reliant on those methods/supplements in terms of downregulation your body's own production and biogenesis? For example, I take LEF's PQQ + Shijat + Ubiquinol supplement, but when I come off it, I feel weaker and lower than baseline mentally and energy-wise for at least several days. I think it is mainly the ubiquinol that leads to downregulating mitochondrial output. Do you guys think PQQ could downregulate biogenesis as well?

 

 

 

2. I'm interested in the LLLT. Does anybody know if it causes downregulation or a rebound affect in some way as well?

Hey, supernoober. I haven't seen any evidence in the literature of downregulation with any of those substances or LLLT. Of course, I'm always open to the data. Do you know of any studies showing this?

[lostfalco]

I have finally worked my way through this gigantic thread; Lostfalco & co, you guys are awesome! This month i will be starting my own TULIP experience. However, i am still struggling on what device to get. 

 

http://www.amazon.co...AANG/ref=sr_1_1Light Relief device as recommended by Joe Cohen of Self Hacked

http://www.amazon.co...U/ref=sr_1_cc_2Nitecore CI6 IR Flashlight (850nm / 1500mW)

 

The IR flashlight is higher powered but only uses one LED. Is focused delivery more important vs. area coverage? What are your thoughts on this?

Thanks, neurokwarg! I'd lean towards Joe's recommendation. 

[lostfalco]

 

Acetyl-l-carnitine increases mitochondrial protein acetylation in the aged rat heart.

 

 

Increased mitochondrial protein acetylation - a good, or a bad thing?

 

Hey, rikelme. Ready for a cop-out answer? Here it comes.......sometimes good, sometimes bad. I can easily envisage a situation in which you acetylate histones and open up a corrupted gene to transcription. Other times, you might open up a suite of genes that enhances learning and memory. It's hard to say anything absolute at this point in our knowledge (or my knowledge). This would seem to hold for both mitochondrial and nuclear genes. 

Edited by lostfalco, 10 March 2015 - 10:19 PM.

[lostfalco]

Add one more to the list...HAT Inhibitors. 

 

http://www.ncbi.nlm....les/PMC3931454/

 

F1000Res. 2013 Mar 6;2:78. doi: 10.12688/f1000research.2-78.v1. eCollection 2013.

Anacardic acid, a histone acetyltransferase inhibitor, modulates LPS-induced IL-8 expression in a human alveolar epithelial cell line A549.

Yasutake T1, Wada H1, Higaki M1, Nakamura M1, Honda K1, Watanabe M1, Ishii H1, Kamiya S1, Takizawa H1, Goto H1.

Author information

Abstract

OBJECTIVE AND DESIGN: 

The histone acetylation processes, which are believed to play a critical role in the regulation of many inflammatory genes, are reversible and regulated by histone acetyltransferases (HATs), which promote acetylation, and histone deacetylases (HDACs), which promote deacetylation. We studied the effects of lipopolysaccharide (LPS) on histone acetylation and its role in the regulation of interleukin (IL)-8 expression. 

MATERIAL: 

A human alveolar epithelial cell line A549 was used in vitro.

METHODS: 

Histone H4 acetylation at the IL-8 promoter region was assessed by a chromatin immunoprecipitation (ChIP) assay. The expression and production of IL-8 were evaluated by quantitative polymerase chain reaction and specific immunoassay. Effects of a HDAC inhibitor, trichostatin A (TSA), and a HAT inhibitor, anacardic acid, were assessed.

RESULTS: 

Escherichia coli-derived LPS showed a dose- and time-dependent stimulatory effect on IL-8 protein production and mRNA expression in A549 cells in vitro. LPS showed a significant stimulatory effect on histone H4 acetylation at the IL-8 promoter region by ChIP assay. Pretreatment with TSA showed a dose-dependent stimulatory effect on IL-8 release from A549 cells as compared to LPS alone. Conversely, pretreatment with anacardic acid inhibited IL-8 production and expression in A549 cells. 

CONCLUSION: 

These data suggest that LPS-mediated proinflammatory responses in the lungs might be modulated via changing chromatin remodeling by HAT inhibition.

 

 

http://www.ncbi.nlm....pubmed/17876038

 

Mol Cancer Ther. 2007 Sep;6(9):2391-8.

Characterization of novel inhibitors of histone acetyltransferases.

Eliseeva ED1, Valkov V, Jung M, Jung MO.

Author information

Abstract

Modification of proteins by histone acetyltransferases (HAT) or histone deacetylases plays an important role in the control of gene expression, and its dysregulation has been linked to malignant transformation and other diseases. Although histone deacetylase inhibitors have been extensively studied and several are currently in clinical trials, there is little information available on inhibitors of HATs (HATi). Starting from the natural product lead HATi anacardic acid, a series of 28 analogues was synthesized and investigated for HAT-inhibitory properties and effects on cancer cell growth. The compounds inhibited up to 95% HAT activity in vitro, and there was a clear correlation between their inhibitory potency and cytotoxicity toward a broad panel of cancer cells. Interestingly, all tested compounds were relatively nontoxic to nonmalignant human cell lines. Western blot analysis of MCF7 breast carcinoma cells treated with HATi showed significant reduction in acetylation levels of histone H4. To directly show effect of the new compounds on HAT activity in vivo, MCF7 cells were cotransfected with the p21 promoter fused to firefly luciferase and a full-length p300 acetyltransferase, and luciferase activity was determined following treatment with HATi. Significant inhibition of p300 activity was detected after treatment with all tested compounds except one. Effects of the new HATi on protein acetylation and HAT activity in vivo make them a suitable tool for discovery of molecular targets of HATs and, potentially, for development of new anticancer therapeutics.

 

Edited by lostfalco, 11 March 2015 - 12:00 AM.

[BigPapaChakra]

 

Add one more to the list...HAT Inhibitors. 

 

http://www.ncbi.nlm....les/PMC3931454/

 

F1000Res. 2013 Mar 6;2:78. doi: 10.12688/f1000research.2-78.v1. eCollection 2013.

Anacardic acid, a histone acetyltransferase inhibitor, modulates LPS-induced IL-8 expression in a human alveolar epithelial cell line A549.

Yasutake T1, Wada H1, Higaki M1, Nakamura M1, Honda K1, Watanabe M1, Ishii H1, Kamiya S1, Takizawa H1, Goto H1.

Author information

Abstract

OBJECTIVE AND DESIGN: 

The histone acetylation processes, which are believed to play a critical role in the regulation of many inflammatory genes, are reversible and regulated by histone acetyltransferases (HATs), which promote acetylation, and histone deacetylases (HDACs), which promote deacetylation. We studied the effects of lipopolysaccharide (LPS) on histone acetylation and its role in the regulation of interleukin (IL)-8 expression. 

MATERIAL: 

A human alveolar epithelial cell line A549 was used in vitro.

METHODS: 

Histone H4 acetylation at the IL-8 promoter region was assessed by a chromatin immunoprecipitation (ChIP) assay. The expression and production of IL-8 were evaluated by quantitative polymerase chain reaction and specific immunoassay. Effects of a HDAC inhibitor, trichostatin A (TSA), and a HAT inhibitor, anacardic acid, were assessed.

RESULTS: 

Escherichia coli-derived LPS showed a dose- and time-dependent stimulatory effect on IL-8 protein production and mRNA expression in A549 cells in vitro. LPS showed a significant stimulatory effect on histone H4 acetylation at the IL-8 promoter region by ChIP assay. Pretreatment with TSA showed a dose-dependent stimulatory effect on IL-8 release from A549 cells as compared to LPS alone. Conversely, pretreatment with anacardic acid inhibited IL-8 production and expression in A549 cells. 

CONCLUSION: 

These data suggest that LPS-mediated proinflammatory responses in the lungs might be modulated via changing chromatin remodeling by HAT inhibition

 

I wrote a short article or two abour anacardic acid in the past. It, along with other fatty phenols, is present in cashews, cashew nutshell, the cashew leave, and some other sources. I'm having a hard time finding any information on the exact concentration in cashews, though. I may start incorporating them (raw) in my diet, though, as raw nuts have potent prebiotic activity as it is (see: http://aem.asm.org/c...74/14/4264.full(this is of almond seeds; but almond skin, almond oil, etc. have been shown to have similar activities, as have pistachios, cashews, and most other nuts)). 

 

In regards to red light, I've been looking into another form of using it - water filtered infrared-a therapy:

 

  Extreme Whole-Body Hyperthermia with Water-Filtered Infrared-A Radiation 

This is just one simple example of its uses; but there are dozens (perhaps more?) studies on this technique. Some Russian studies indicated it's efficacy for use in nerve and spine issues, and how it impacts axonal proliferation. So, I was actually thinking of using it on my back, neck, and head/face. It can be done DIY rather easily, though probably not as effectively. Incandescent bulbs or heat lamps filtered through water, especially if used with red dye, will produce the desired spectrum of light. Also, see this: 

Halogen light through two inches of water is the way to do light therapy      

[lostfalco]

Ashwagandha and Arc

 

http://www.ncbi.nlm....les/PMC3207967/

 

Trends Neurosci. 2011 Nov;34(11):591-8. doi: 10.1016/j.tins.2011.08.007. Epub 2011 Sep 30.

Arc in synaptic plasticity: from gene to behavior.

Korb E1, Finkbeiner S.

Author information

Abstract

The activity-regulated cytoskeletal (Arc) gene encodes a protein that is critical for memory consolidation. Arc is one of the most tightly regulated molecules known: neuronal activity controls Arc mRNA induction, trafficking and accumulation, and Arc protein production, localization and stability. Arc regulates synaptic strength through multiple mechanisms and is involved in essentially every known form of synaptic plasticity. It also mediates memory formation and is implicated in multiple neurological diseases. In this review, we will discuss how Arc is regulated and used as a tool to study neuronal activity. We will also attempt to clarify how its molecular functions correspond to its requirement in various forms of plasticity, discuss Arc's role in behavior and disease, and highlight critical unresolved questions.

 

"Removal of Arc in knock-out (KO) animals results in an unusual phenotype: short-term learning is normal but lasting memories cannot be formed [17]. Arc, therefore, provides a means to understand the cellular processes of memory consolidation."

 

 

http://www.ncbi.nlm....pubmed/25744565

 

Mol Neurobiol. 2015 Mar 7. [Epub ahead of print]

Alcoholic Extract of Ashwagandha Leaves Protects Against Amnesia by Regulation of Arc Function.

Gautam A1, Kaul SC, Thakur MK.

Author information

Abstract

Our earlier report on scopolamine-induced amnesia and its improvement by pre-treatment with i-Extract (alcoholic extract of Ashwagandha leaf) suggested that the i-Extract mediated nootropic effect may involve neuronal immediate early gene, Arc. With a hypothesis that the i-Extract induced expression of Arc protein may cause augmentation in Arc function, we examined the effect of i-extract on a major function of Arc protein, i.e. F-actin expansion, using Arc antisense oligodeoxynucleotides (ODN). Stereotaxic infusion of Arc antisense ODN in the CA1 region of hippocampus decreased the level of Arc protein as demonstrated by immunoblotting. However, this decrease was attenuated when treated with i-Extract prior to infusion of Arc antisense ODN. We noted a significant decrease in the polymerization of F-actin during scopolamine-induced amnesia as well as Arcantisense ODN infusion that was restored rather enhanced when pre-treated with i-Extract in both the cases. We also compared the corresponding changes between CA1 (the infusion site) and CA3 (neighbouring site of infusion) regions of hippocampus, and found more pronounced effects in CA1 than in the CA3 region. The extent of F-actin polymerization, as revealed by changes in the dendritic spine architecture through Golgi staining, showed that both scopolamine as well as Arc antisense ODN disrupted the spine density and mushroom-shaped morphology that was again regained if pre-treated with i-Extract. In conclusion, the findings reveal that the Arc helps in polymerization of F-actin and subsequent changes in the morphology of dendritic spines after pre-treatment with i-Extract in scopolamine-induced amnesic mice, suggesting an important role of Arc in scopolamine-induced amnesia and its recovery by i-Extract.

 

 

 

 

 

 

Edited by lostfalco, 11 March 2015 - 02:30 PM.

[lostfalco]

PDE5 inhibition is looking pretty good as of late. Get hard, study hard (sorry, I couldn't help myself). PDE5 Inhibitors = sildenafil/Viagra, tadalafil/Cialis, vardenafil/Levitra, etc.

 

 

http://www.ncbi.nlm....pubmed/24285284

 

Int J Impot Res. 2014 Mar-Apr;26(2):76-80. doi: 10.1038/ijir.2013.38. Epub 2013 Nov 28.

Effects of daily low-dose treatment with phosphodiesterase type 5 inhibitor on cognition, depression, somatization and erectile function in patients with erectile dysfunction: a double-blind, placebo-controlled study.

Shim YS1, Pae CU2, Cho KJ3, Kim SW4, Kim JC3, Koh JS3.

Author information

Abstract

Phosphodiesterase type 5 (PDE5) inhibitors have recently been shown to have cognitive-enhancing effects in animal models and in our previous pilot study. To investigate the efficacy of daily low-dose treatment with a PDE5 inhibitor on cognitive function, depression and somatization in patients with erectile dysfunction (ED), 8-week, double-blind, placebo-controlled study enrolled 60 male patients with ED for ≥ 3 months without cognitive impairment. Forty-nine patients completed the study. Patients were randomized to receive either daily low-dose udenafil 50 mg or placebo for 2 months. The International Index of Erectile Function-5 (IIEF-5), the Korean version of the Mini-Mental State Examination (K-MMSE) for general cognitive function and the Seoul Neuropsychological Screening Battery for comprehensive neuropsychological examination, the Physical Health Questionnaire-9 (PHQ-9) for depression and the Physical Health Questionnaire-15 (PHQ-15) for somatization were administered at baseline and at 2 months. The change in the mean IIEF-5 was significantly higher in the udenafil group than the placebo group (6.08 ± 4.72 vs 2.20 ± 3.50, P=0.008). The changes in the PHQ-9 and PHQ-15 were -2.04 ± 3.14 and -2.17 ± 2.87 in the udenafil group, and 1.20 ± 1.63 and 0.56 ± 2.48 in the placebo group (both, P<0.001). The changes in the K-MMSE and Digit Span Forward were 1.25 ± 1.26 and 0.92 ± 1.02 in the udenafil group, and -0.52 ± 1.19 and -0.24 ± 1.13 in the placebo group (both, P<0.001). However, there were no differences in the other neuropsychological tests. Daily dosing with a PDE5 inhibitor seems to improve cognitive function, depression and somatization, as well as erectile function, in patients with ED.

 

http://www.ncbi.nlm....pubmed/21544084

 

Int J Impot Res. 2011 May-Jun;23(3):109-14. doi: 10.1038/ijir.2011.13. Epub 2011 May 5.

Effects of repeated dosing with Udenafil (Zydena) on cognition, somatization and erection in patients with erectile dysfunction: a pilot study.

Shim YS1, Pae CU, Kim SW, Kim HW, Kim JC, Koh JS.

Author information

Abstract

The PDE5 inhibitors have recently been found to have cognitive-enhancing effects in animal models. To investigate the efficacy of repeated dosing with a PDE5 inhibitor on cognitive function and somatization in patients with erectile dysfunction, 27 patients with erectile dysfunction received udenafil (100 mg) at 3-day intervals for 2 months. The international index of erectile function-5 (IIEF-5), a cognitive battery (the Korean version of mini-mental state examination (K-MMSE), the frontal assessment battery (K-FAB), the Seoul verbal learning test) and a physical health questionnaire-15 (PHQ-15) were performed at baseline and at 2 months, following the administration of udenafil. The patients were divided on the basis of their IIEF-5 score into responders (change>7) and non-responders. The mean IIEF-5 score was significantly increased after treatment (7.92 ± 3.83 to 16.33 ± 4.75, P<0.001). The scores of K-MMSE (27.03 ± 1.58 to 28.07 ± 1.57, P=0.001), K-FAB (13.65 ± 1.96 to 15.41 ± 1.85, P<0.001) and PHQ-15 (18.92 ± 4.96 to 17.63 ± 4.75, P=0.003) were significantly improved after treatment. In addition, the responders (n=16) had more improved cognitive function (r=0.603, P=0.001) and somatization (r=-0.402, P=0.038) than non-responders (n=11). Repeated dosing with a PDE5 inhibitor seems to improve cognitive function and somatization, as well as erectile function in patients with erectile dysfunction.

 

http://www.ncbi.nlm....pubmed/24284467

 

NeuroRehabilitation. 2014;34(1):101-11. doi: 10.3233/NRE-131022.

Phosphodiesterase inhibition facilitates cognitive restoration in rodent models of age-related memory decline.

Devan BD1, Pistell PJ1, Duffy KB2, Kelley-Bell B3, Spangler EL2, Ingram DK2.

Author information

Abstract

BACKGROUND: 

Previous studies have shown that cyclic nucleotide phosphodiesterase type 5 (PDE5) inhibition with the drugs sildenafil and vardenafil can enhance spatial performance and object recognition in rodent models of learning and memory.

OBJECTIVE: 

We review recent studies on PDE5 inhibition and report novel data that specifically tests the systemic effects of both pharmacological agents in aged rats using two different spatial learning/memory paradigms.

METHODS: 

The 14-unit T-maze was used as a test of egocentric spatial processing that requires rats to learn a series of left/right turns to avoid mild footshock. The Morris water maze is a test of allocentric spatial learning that requires the acquisition of place information to localize a hidden platform relative to distal room cues.

RESULTS: 

In both cases, acquisition (i.e., learning performance) was not improved, however after a one week drug washout period, aged animals demonstrated improved spatial memory retention compared to aged controls, ruling out simple performance effects.

CONCLUSIONS: 

These findings are discussed in relation to recent reports on the use of PDE inhibitors to treat Alzheimer's disease (AD) dementia and age-related memory impairments. While some report promising pre-clinical results, others note that PDE5 may not be an appropriate target in AD due to a lack of localization within critical brain structures where therapeutic activity is needed. Despite these limitations, PDE5 inhibition may produce beneficial effects via several mechanisms that target predisposing risk factors leading to increased incidence of memory impairment in aged individuals and influence memory consolidation mechanisms that preserve long-term retention of cognitive information.

 

http://www.ncbi.nlm....les/PMC3764028/

 

PLoS One. 2013 Sep 5;8(9):e73664. doi: 10.1371/journal.pone.0073664. eCollection 2013.

Regulation of hippocampal cGMP levels as a candidate to treat cognitive deficits in Huntington's disease.

Saavedra A1, Giralt A, Arumí H, Alberch J, Pérez-Navarro E.

Author information

Abstract

Huntington's disease (HD) patients and mouse models show learning and memory impairment associated with hippocampal dysfunction. The neuronal nitric oxide synthase/3',5'-cyclic guanosine monophosphate (nNOS/cGMP) pathway is implicated in synaptic plasticity, and in learning and memory processes. Here, we examined the nNOS/cGMP pathway in the hippocampus of HD mice to determine whether it can be a good therapeutic target for cognitive improvement in HD. We analyzed hippocampal nNOS and phosphodiesterase (PDE) 5 and 9 levels in R6/1 mice, and cGMP levels in the hippocampus of R6/1, R6/2 and Hdh(Q7/Q111) mice, and of HD patients. We also investigated whether sildenafil, a PDE5 inhibitor, could improve cognitive deficits in R6/1 mice. We found that hippocampal cGMP levels were 3-fold lower in 12-week-old R6/1 mice, when they show deficits in object recognition memory and in passive avoidance learning. Consistent with hippocampal cGMP levels, nNOS levels were down-regulated, while there were no changes in the levels of PDE5 and PDE9 in R6/1 mice. A single intraperitoneal injection of sildenafil (3 mg/Kg) immediately after training increased cGMP levels, and improved memory in R6/1 mice, as assessed by using the novel object recognition and the passive avoidance test. Importantly, cGMP levels were also reduced in R6/2 mouse and human HD hippocampus. Therefore, the regulation of hippocampal cGMP levels can be a suitable treatment for cognitive impairment in HD.

 

[mettmett]

Haha. Very interesting findings falco. How hard did you look to find these.

[lostfalco]

I think we may have a winner here. Inhibit PDE5, increase cGMP, activate c-GKI, phosphorylate CREB, enhance CRE mediated transcription, enhance the consolidation phase of LTP.  

 

Tadalafil/Cialis looks especially promising since it has an 18 hour half-life and has been used chronically in humans. 

 

Found this research liquid (no affiliation)...and, of course, I am not endorsing the use of research chemicals.  http://www.superiorp...e.com/tadalafil

 

http://www.ncbi.nlm....pubmed/20171263

 

Neurosci Lett. 2010 Apr 5;473(2):82-6. doi: 10.1016/j.neulet.2010.02.020. Epub 2010 Feb 18.

cGMP-dependent protein kinase type I promotes CREB/CRE-mediated gene expression in neurons of the lateral amygdala.

Paul C1, Stratil C, Hofmann F, Kleppisch T.

Author information

Abstract

The process transforming newly learned information into stable long-term memory is called memory consolidation and, like the underlying long-term synaptic plasticity, critically depends on de novo RNA and protein synthesis. We have shown recently that the cGMP-dependent protein kinase Type I (cGKI) plays an important role for the consolidation of amygdala-dependent fear memory and long-term potentiation (LTP) in the lateral amygdala. Signalling downstream of cGKI at the level of transcriptional regulation remained unclear. A transcription factor of major importance for learning and memory is the cAMP-response element binding protein (CREB). The representation of fear memory in the lateral amygdala strikingly depends on the activity of CREB in individual neurons. Moreover, findings from in vitro experiments demonstrate CREB phosphorylation by cGK. In the hippocampus, CREB phosphorylation increases following activation of NO/cGMP signalling contributing to the late phase of LTP. To demonstrate a link from cGKI to activation of CREB and CREB-dependent transcription in neurons of the lateral amygdala as a possible mechanism for cGKI-mediated fear memory consolidation, we examined the effect of cGMP on activation of CREB/CRE using immunohistochemical staining specific for phospho-CREB and a reporter gene in control and cGKI-deficient mice, respectively. Supporting our hypothesis, marked CREB phosphorylation and CRE-mediated transcription was induced by cGMP in the lateral amygdala of control mice, but not in cGKI-deficient mice. It has been proposed that activation of cGKI is followed by its nuclear translocation that would allow direct phosphorylation of CREB. Therefore, we examined the cellular localisation of cGKI in neurons of the lateral amygdala in the presence of cGMP by double staining for cGKI and a nuclear marker in sections from areas showing prominent CREB phosphorylation, and did not observe prominent nuclear translocation of the enzyme. In summary, we provide evidence that cytosolic cGKI can support fear memory consolidation and LTP in neurons of the lateral amygdala via activation of CREB and CRE-dependent transcription.

 

Edited by lostfalco, 11 March 2015 - 11:32 PM.

[lostfalco]

Haha. Very interesting findings falco. How hard did you look to find these.

haha I see what you did there, mettmett. 

[supernoober]

 

1. The biggest question for me about enhancing mitochondria is: does it make you reliant on those methods/supplements in terms of downregulation your body's own production and biogenesis? For example, I take LEF's PQQ + Shijat + Ubiquinol supplement, but when I come off it, I feel weaker and lower than baseline mentally and energy-wise for at least several days. I think it is mainly the ubiquinol that leads to downregulating mitochondrial output. Do you guys think PQQ could downregulate biogenesis as well?

 

 

 

2. I'm interested in the LLLT. Does anybody know if it causes downregulation or a rebound affect in some way as well?

Hey, supernoober. I haven't seen any evidence in the literature of downregulation with any of those substances or LLLT. Of course, I'm always open to the data. Do you know of any studies showing this?

 

 

Just Anecdotally for discontinuing coq10 or ubiquinol. John Brisson, who is coming out with a about mitochondria talks about this. I've personally experienced the rebound fatigue, tiredness and muscle weakness. I can't speak for LLLT though. Do you cycle NADH or D-ribose, and do they have to be taken together?

Can LLLT be used over the eyelids? I had eyelid surgery in the past and there is residual scar tissue internally that I'm hoping it can help.

[kentolpad]

i don't know if it would help your scar but i have been using it a few times on my eyes (sinusitis and the led are too big) and never noticed problems at least.

[mettmett]

On my phone - this study says we should be weary about using tadalafil BC it isn't pde5 specific. It also acts on pde11 which can cause back pains and change sperm quality

"Tadalafil, compared to the baseline, caused a statistically significant decrease of spermatozoa with rapid progressive motility (12.3%plusminus2.2 vs 9%plusminus1.9 (P<0.05)).4"

http://www.nature.co...l/3901304a.html

Ok apparently it's not so cut and dry: http://www.ncbi.nlm....pubmed/16079899

Still something to keep in mind though

Edited by mettmett, 12 March 2015 - 07:15 PM.

[BieraK]

Cordyceps/Cordycepin was proposed by Jeoshua in the CILTEP thread for an increase the cGMP.

http://www.longecity...ced-ltp/page-77
and for PDE5 inhibition Icariin is the herbal option

PDE4 inhibition+Cordycelps+TULIP could be a interesting stack...or Icariin or Taldanafil+TULIP

[Razor444]

'Proof-of-Concept Randomized Controlled Study of Cognition Effects of the Proprietary Extract Sceletium tortuosum (Zembrin) Targeting Phosphodiesterase-4 in Cognitively Healthy Subjects: Implications for Alzheimer's Dementia'

 

 

Converging evidence suggests that PDE-4 (phosphodiesterase subtype 4) plays a crucial role in regulating cognition via the PDE-4-cAMP cascade signaling involving phosphorylated cAMP response element binding protein (CREB).

 

This is an old (2014) study. It was originally on reddit, but don't think it got much play on here.

 

Anecdotally, zembrin definitely improves memory; all day (at least for me). It did cause a little stomach upset, but nothing major. I tested it after trying hesperitin, which is a minor PDE4 inhibitor. Even though zembrin has been talked about with CILTeP, it may be worth trying it alone.

 

Having tested icariin, I'm of the opinion that it's moderate for memory improvements. There seems to be health benefit to taking it, regardless of targeting cognitive prowess, though.

[Razor444]

Have you tried NSI-189 Lostfalco?15mg with 480mg ginkgo phytosome and 200mg caffeine is decent for analytical work.

[ceridwen]

I saw an article on Science Daily yesterday that worried me about every one on this thread. Unfortunately I then lost the article but I copied much of the article into my notebook. Those jottings I now transfer here because I believe you should know what it said asap. Ok here are the notes. Normal non-genetically modified neurons can be activated by heat generated by pulses of infrared light but this method lacks specifity and can damage cells! To improve the technique they focused on gold nano particles spheres only 20 nanoparticles in diameter more than 300 times smaller than a human blood cell. When stimulated with visible light,spherical gold nanoparticles absorb and convert energy into heat. This heating effect which is most effective using GREEN light,can activate unmodified neurons. However nanoparticles must be extremely close to a cell to produce any effect since the nanoparticles diffuse quickly,or get washed away in a neuron's immediate environment their efficacy is short lived.
To get nanoparticles to stick Benzanilla and his team coupled them to a synthetic molecule based on Ts1 a scorpion neurotoxin,which binds to sodium channels without breaking them.Neurons treated with Ts1 coupled nanoparticles were readily activated by light.Untreated neurons were non responsive. Treated neurons could still be stimulated even after being continually washed for 30 minutes,indicating that nanoparticles were tightly bound to the cell surface. They also minmised potentially harmful elevated temperatures as excess nanoparticles were washed away.
Neurons treated with Ts1 coupled nanoparticles could be stimulated repeatedly with no evidence of cell damage.Some individual neurons produced more than 3000 actionals over a span of 30 minutes with no reduction in efficacy.
The technique is easy to implement and elicits neuronal activity using light pulses.Therefore stimulating electrodes are not required. With differently shaped nanoparticles it can work in near infrared as well as visible wavelengths which has many practical advantages in living animals.Thus far most optogenetic tools have been limited to visible wavelengths.

[ceridwen]

Well what I thought about the above is Scorpion neurotoxin is safer than what we do now! What we do must be quite risky and I thought it was safe! The next question is how can we translate this safely into current practice. Should we take colloidal gold does that contain gold nanoparticles? The scorpion venom sounds dangerous what can be done to move LLT to the next level should we just combine this with colloidal gold and experiment with green light until more is known. Hopefully there will be some feedback on methodology.

[lostfalco]

I saw an article on Science Daily yesterday that worried me about every one on this thread. Unfortunately I then lost the article but I copied much of the article into my notebook. Those jottings I now transfer here because I believe you should know what it said asap. Ok here are the notes. Normal non-genetically modified neurons can be activated by heat generated by pulses of infrared light but this method lacks specifity and can damage cells! To improve the technique they focused on gold nano particles spheres only 20 nanoparticles in diameter more than 300 times smaller than a human blood cell. When stimulated with visible light,spherical gold nanoparticles absorb and convert energy into heat. This heating effect which is most effective using GREEN light,can activate unmodified neurons. However nanoparticles must be extremely close to a cell to produce any effect since the nanoparticles diffuse quickly,or get washed away in a neuron's immediate environment their efficacy is short lived.
To get nanoparticles to stick Benzanilla and his team coupled them to a synthetic molecule based on Ts1 a scorpion neurotoxin,which binds to sodium channels without breaking them.Neurons treated with Ts1 coupled nanoparticles were readily activated by light.Untreated neurons were non responsive. Treated neurons could still be stimulated even after being continually washed for 30 minutes,indicating that nanoparticles were tightly bound to the cell surface. They also minmised potentially harmful elevated temperatures as excess nanoparticles were washed away.
Neurons treated with Ts1 coupled nanoparticles could be stimulated repeatedly with no evidence of cell damage.Some individual neurons produced more than 3000 actionals over a span of 30 minutes with no reduction in efficacy.
The technique is easy to implement and elicits neuronal activity using light pulses.Therefore stimulating electrodes are not required. With differently shaped nanoparticles it can work in near infrared as well as visible wavelengths which has many practical advantages in living animals.Thus far most optogenetic tools have been limited to visible wavelengths.

Hey ceridwen, thanks for your concern. We are using Low Level Laser Therapy which is also known as 'cold laser' therapy. The wavelengths and doses we use cause extremely minimal heating (if at all) and do not damage cells. The dose makes the poison. Check out the human studies I posted at the beginning of this thread for more info. =)  http://www.longecity...ts/#entry582938 

[Joe Cohen]

Hey lostfalco and TULIPers.  Hope all is fantastic.

 

I'd like to report based on my N=1 that I've found a hack better than LLLT, PQQ and pregnenolone for conditions such as fatigue and related issues that people on this forum/thread are dealing with.  It's certainly not a cure, but nothing is for that matter and I've gotten better results with it relative to LLLT- even though I still use LLLT (thanks to Lostfalco).  I think it can be used as an enhancement as well, but I'd like for people without any history with fatigue use it and report back, such as none other than Lostfalco.

 

http://selfhacked.co...-upgraded-pemf/

 

MitoQ is also quite useful, but you'd want to check if you've got the SOD2 mutation like I do and a very large percentage of my brain fog clients.  Brain fog is caused by superoxide in the hypothalamus and perhaps more specifically in the mitochondria.  That mutation means you break down superoxide signifcantly less well.  MitoQ breaks down superoxide in the mitochondria.  I need to take 20mg for it to have a very noticeable effect. 

 

"The SOD2 mutation causes a 33% decrease of the enzyme (MnSOD) that breaks down superoxide in the mitochondria.  Superoxide production is the most significant cause of brain fog.

In 2014, two studies found that the level of genes expression of SOD2 (MnSOD) is strongly correlated with cognitive performance. (R, R2)

The main SOD2 gene (rs4880(C;C)) is extremely common in my brain fog clientele and there’s a lot of scientific research on it.

Three other SOD2 genes are also heavily overrepresented in my clientele and include: rs2758331 (AA), rs2758339 (CC), rs10370 (AA).  Although little science has been done on these and the most important gene is rs4880(C;C)."

http://selfhacked.co...e-of-brain-fog/

I'm working on many posts regarding genetic data.

P.S. The Molecular Hydrogen is good, but I feel it's very subtle and is more a prevention tool rather than something you'll notice very acute effects from.

Edited by Joe Cohen, 14 March 2015 - 12:15 AM.

[xls]

Gonna keep looking into this and maybe start saving up to eventually buy it! Thanks Joe, love your work.

[kentolpad]

WOW so many interesting things popping up as of late !

[lostfalco]

Hey lostfalco and TULIPers.  Hope all is fantastic.

 

I'd like to report based on my N=1 that I've found a hack better than LLLT, PQQ and pregnenolone for conditions such as fatigue and related issues that people on this forum/thread are dealing with.  It's certainly not a cure, but nothing is for that matter and I've gotten better results with it relative to LLLT- even though I still use LLLT (thanks to Lostfalco).  I think it can be used as an enhancement as well, but I'd like for people without any history with fatigue use it and report back, such as none other than Lostfalco.

 

http://selfhacked.co...-upgraded-pemf/

 

MitoQ is also quite useful, but you'd want to check if you've got the SOD2 mutation like I do and a very large percentage of my brain fog clients.  Brain fog is caused by superoxide in the hypothalamus and perhaps more specifically in the mitochondria.  That mutation means you break down superoxide signifcantly less well.  MitoQ breaks down superoxide in the mitochondria.  I need to take 20mg for it to have a very noticeable effect. 

 

"The SOD2 mutation causes a 33% decrease of the enzyme (MnSOD) that breaks down superoxide in the mitochondria.  Superoxide production is the most significant cause of brain fog.

In 2014, two studies found that the level of genes expression of SOD2 (MnSOD) is strongly correlated with cognitive performance. (R, R2)

The main SOD2 gene (rs4880(C;C)) is extremely common in my brain fog clientele and there’s a lot of scientific research on it.

Three other SOD2 genes are also heavily overrepresented in my clientele and include: rs2758331 (AA), rs2758339 (CC), rs10370 (AA).  Although little science has been done on these and the most important gene is rs4880(C;C)."

http://selfhacked.co...e-of-brain-fog/

I'm working on many posts regarding genetic data.

P.S. The Molecular Hydrogen is good, but I feel it's very subtle and is more a prevention tool rather than something you'll notice very acute effects from.

Hey, what's up Joe? Thanks for the heads up man! I've been looking at PEMF for a couple of years now but none of the available technologies seemed all that effective. Let me do a little research on this new device before I drop $400+ on it. It looks VERY interesting though. I'll get back to you in a few days.  

[lostfalco]

Have you tried NSI-189 Lostfalco?15mg with 480mg ginkgo phytosome and 200mg caffeine is decent for analytical work.

What's up, Razor? I haven't tried NSI yet. I have tried ginkgo and caffeine though. =)

[lostfalco]

'Proof-of-Concept Randomized Controlled Study of Cognition Effects of the Proprietary Extract Sceletium tortuosum (Zembrin) Targeting Phosphodiesterase-4 in Cognitively Healthy Subjects: Implications for Alzheimer's Dementia'

 

 

Converging evidence suggests that PDE-4 (phosphodiesterase subtype 4) plays a crucial role in regulating cognition via the PDE-4-cAMP cascade signaling involving phosphorylated cAMP response element binding protein (CREB).

 

This is an old (2014) study. It was originally on reddit, but don't think it got much play on here.

 

Anecdotally, zembrin definitely improves memory; all day (at least for me). It did cause a little stomach upset, but nothing major. I tested it after trying hesperitin, which is a minor PDE4 inhibitor. Even though zembrin has been talked about with CILTeP, it may be worth trying it alone.

 

Having tested icariin, I'm of the opinion that it's moderate for memory improvements. There seems to be health benefit to taking it, regardless of targeting cognitive prowess, though.

Thanks for this study, Razor! I may try a little dual PDE4 and PDE5 inhibition with Zembrin and Cialis. I've only been testing Cialis for about 4 days now but anecdotally it seems very promising for memory enhancement...and it definitely works for other "enhancement" as well. Anyway, my Anki studying on Cialis has been extremely fruitful...but, of course, this is just my 4 day anecdote so take it for what it is. 

 

I have also tested icariin and didn't notice much. 

 

 

[lostfalco]

Cordyceps/Cordycepin was proposed by Jeoshua in the CILTEP thread for an increase the cGMP.

http://www.longecity...ced-ltp/page-77
and for PDE5 inhibition Icariin is the herbal option

PDE4 inhibition+Cordycelps+TULIP could be a interesting stack...or Icariin or Taldanafil+TULIP

Very cool, BieraK. Do you know if anyone tested out that combo?

 

I think you're exactly right about TULIP synergies. Theoretically they should go extremely well together but experiment always has the ultimate say. 

[lostfalco]

On my phone - this study says we should be weary about using tadalafil BC it isn't pde5 specific. It also acts on pde11 which can cause back pains and change sperm quality

"Tadalafil, compared to the baseline, caused a statistically significant decrease of spermatozoa with rapid progressive motility (12.3%plusminus2.2 vs 9%plusminus1.9 (P<0.05)).4"

http://www.nature.co...l/3901304a.html

Ok apparently it's not so cut and dry: http://www.ncbi.nlm....pubmed/16079899

Still something to keep in mind though

These are great points, mettmett. Tadalafil isn't a pure PDE5 inhibitor but simply inhibits PDE5 much more effectively than other PDEs. 

 

The sperm issue is definitely not cut and dried...just as you said. =)

 

Here's a study on acute tadalafil administration. 

 

http://www.ncbi.nlm....pubmed/23581543

 

Andrologia. 2014 May;46(4):417-22. doi: 10.1111/and.12097. Epub 2013 Apr 14.

Effect of acute tadalafil on sperm motility and acrosome reaction: in vitro and in vivo studies.

Yang Y1, Ma Y, Yang H, Jin Y, Hu K, Wang HX, Wang YX, Huang YR, Chen B.

Author information

Abstract

Effects of acute tadalafil on sperm motility and acrosome reaction were investigated, both in vitro and in vivo. Twenty asthenozoospermic and 20 normozoospermic patients as control were randomly enrolled. For in vitro part, 0.5 ml tadalafil solutions with different concentrations were added (0.2, 0.1, 0.05 and 0.025 μg ml(-1) , respectively) into semen samples. In both groups, samples treated with 0.2 μg ml(-1) tadalafil had significant increase in sperm motility after 2 h incubation. For in vivo part, oral administration of tadalafil (20 mg) or sildenafil (100 mg) was given. In both groups, computer-assisted semen analysis parameters showed no significant difference. After the administration of tadalafil (2 h) and sildenafil (1 h), there was no significant difference observed in premature acrosome reaction incidence rate. Taking both in vitro and in vivo results into consideration, acute on-demand administration of tadalafil would have no adverse effect on semen parameters.

[lostfalco]

 

I wrote a short article or two abour anacardic acid in the past. It, along with other fatty phenols, is present in cashews, cashew nutshell, the cashew leave, and some other sources. I'm having a hard time finding any information on the exact concentration in cashews, though. I may start incorporating them (raw) in my diet, though, as raw nuts have potent prebiotic activity as it is (see: http://aem.asm.org/c...74/14/4264.full(this is of almond seeds; but almond skin, almond oil, etc. have been shown to have similar activities, as have pistachios, cashews, and most other nuts)). 

 

In regards to red light, I've been looking into another form of using it - water filtered infrared-a therapy:

 

  Extreme Whole-Body Hyperthermia with Water-Filtered Infrared-A Radiation 

This is just one simple example of its uses; but there are dozens (perhaps more?) studies on this technique. Some Russian studies indicated it's efficacy for use in nerve and spine issues, and how it impacts axonal proliferation. So, I was actually thinking of using it on my back, neck, and head/face. It can be done DIY rather easily, though probably not as effectively. Incandescent bulbs or heat lamps filtered through water, especially if used with red dye, will produce the desired spectrum of light. Also, see this: 

Halogen light through two inches of water is the way to do light therapy      

 

Thanks for the links, Papa! Have you tested this out yet? I know Zawy has used a similar method in the past.