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Why is nobody looking at boosting NAMPT?

nampt

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#1 Nate-2004

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Posted 02 September 2018 - 08:14 PM


A lot of researchers are looking into inhibiting NAMPT as a way to treat cancer, but why is no one looking at boosting it for otherwise healthy older adults? Wouldn't this be a way around the problems of boosting NAD+ with precursors?

 

Also this: https://www.longecit...ation-with-age/


Edited by Nate-2004, 02 September 2018 - 08:24 PM.

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#2 Phoebus

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Posted 03 September 2018 - 01:07 PM

great question since NAMPT recycles NAM and resolves some of hte issues regarding NR/NMN supplementation increasing NAM levels over time 

 

 

Int J Radiat Oncol Biol Phys. 2016 Nov 1;96(3):538-46. doi: 10.1016/j.ijrobp.2016.06.2442. Epub 2016 Jul 1.

 

Nicotinamide Phosphoribosyltransferase Upregulation by Phenylephrine Reduces Radiation Injury in Submandibular Gland.
 
 
Abstract

 

PURPOSE:

Radiation therapy for head and neck cancer commonly leads to radiation sialadenitis. Emerging evidence has indicated that phenylephrine pretreatment reduces radiosensitivity in the salivary gland; however, the underlying cytoprotective mechanism remains unclear. Nicotinamide phosphoribosyltransferase (NAMPT) is not only a key enzyme for the nicotinamide adenine dinucleotide salvage pathway, but also a cytokine participating in cell survival, metabolism, and longevity, with a broad effect on cellular functions in physiology and pathology. However, the regulatory events of NAMPT in response to the irradiated salivary gland are unknown.

METHODS AND MATERIALS:

The cell viability of primary cultured submandibular gland cells was determined using the PrestoBlue assay. NAMPT expression was measured using reverse transcriptase polymerase chain reaction and Western blotting in vitro and in vivo. Silent information regulator 1 (SIRT1) and phosphorylated Akt protein levels were examined by Western blotting. The cellular locations of NAMPT and SIRT1 were detected by immunohistochemistry. NAMPT promoter activity was assessed using the luciferase reporter gene assay.

RESULTS:

NAMPT was mainly distributed in the cytoplasm of granular convoluted tubule cells and ductal cells in normal submandibular glands. mRNA and protein expression of NAMPT was downregulated after radiation but upregulated with phenylephrine pretreatment both in vivo and in vitro. Moreover, the protein expression of phosphorylated Akt and SIRT1 was decreased in irradiated glands, and phenylephrine pretreatment restored the expression of both. SIRT1 was mainly located in the cell nucleus and cytoplasm in the normal submandibular gland. Phenylephrine dramatically enhanced the expression of SIRT1, which was significantly reduced by radiation. Furthermore, phenylephrine induced a marked increase of NAMPT promoter activity.

CONCLUSIONS:

These findings reveal the regulatory mechanisms of NAMPT expression, which help to understand the mechanism of the cytoprotective role of phenylephrine on irradiated tissues.

 

and 

 

 

 

Phenylephrine is a selective α1-adrenergic receptor agonist of the phenethylamine class used primarily as a decongestant, as an agent to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids. Phenylephrine is marketed as an alternative for the decongestant pseudoephedrine, although clinical trials show phenylephrine, taken orally at the recommended dose, to be no more effective than placebo for allergy relief.[1][2] Phenylephrine can also cause a decrease in heart rate through reflex bradycardia.[3]

 


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#3 Phoebus

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Posted 03 September 2018 - 01:31 PM

 

Given that mitochondrial biogenesis is activated by exercise, we hypothesized that exercise would increase NAMPT expression, as a potential mechanism leading to increased mitochondrial content in muscle. A cross-sectional analysis of human subjects showed that athletes had about a twofold higher skeletal muscle NAMPT protein expression compared with sedentary obese, nonobese, and type 2 diabetic subjects (P < 0.05). NAMPT protein correlated with mitochondrial content as estimated by complex III protein content (R2 = 0.28, P < 0.01), MRS-measured maximal ATP synthesis (R2 = 0.37, P = 0.002), and V̇o2max (R2 = 0.63, P < 0.0001). In an exercise intervention study, NAMPT protein increased by 127% in sedentary nonobese subjects after 3 wk of exercise training (P < 0.01). Treatment of primary human myotubes with forskolin, a cAMP signaling pathway activator, resulted in an ∼2.5-fold increase in NAMPT protein expression, whereas treatment with ionomycin had no effect. Activation of AMPK via AICAR resulted in an ∼3.4-fold increase in NAMPT mRNA (P < 0.05) as well as modest increases in NAMPT protein (P < 0.05) and mitochondrial content (P < 0.05). These results demonstrate that exercise increases skeletal muscle NAMPT expression and that NAMPT correlates with mitochondrial content. 

https://www.physiolo...endo.00318.2009


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#4 tunt01

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Posted 03 September 2018 - 02:23 PM

Long standing problem with no clear solution. 

 

9 years ago, a user on this forum postulated the central role of NAMPT as a key role player in activation of SIRT1.  Read that post.  It was pretty forward thinking.

 

I think a rational person would rather a NAMPT activator than Nicotinamide Riboside or NMN, but where is the readily available solution? 

 

Sign me up for P7C3 or its derivative compound when it's available.

 

 

 


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#5 Nate-2004

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Posted 03 September 2018 - 03:14 PM

Long standing problem with no clear solution. 

 

9 years ago, a user on this forum postulated the central role of NAMPT as a key role player in activation of SIRT1.  Read that post.  It was pretty forward thinking.

 

I think a rational person would rather a NAMPT activator than Nicotinamide Riboside or NMN, but where is the readily available solution? 

 

Sign me up for P7C3 or its derivative compound when it's available.

 

Sounds like Google's company is on top of this one.



#6 tunt01

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Posted 03 September 2018 - 03:52 PM

Sounds like Google's company is on top of this one.

 

If I recall correctly, the backdrop of that discussion I mentioned was resveratrol and the SIRT1 resveratrol craze at the time.  That discussion around that time by niner, geddarkstorm and others prompted evaluation of AMPK activators as a way to increase NAMPT, increase NAD+ and improve sirtuins.

 

Example thread

Example thread

  

 

PMC4220583_JNME2014-239750.006.png

 

 

The best solution is to upregulate AMPK through what we know are obvious approaches:  periodic fasting and exercise (in a fasted state).  But the first drug/supplement that came to my mind then... and still does today is AICAR.

 

AICAR --> AMPK --> Nampt/NAD --> Sirt1/3 activation

 

I'm still kind of amazed there was never a group buy for AICAR and a lack of interest in it, given all the purchases that have gone on in this forum over the years.  I may be making this too simplistic, but to me, AICAR is basically an injectable form (peptide) of aerobic exercise.  Maybe I'm missing something very basic about it or alternatives like bitter melon extract or metformin were just easily obtainable and not some injectable drug.


Edited by tunt01, 03 September 2018 - 03:58 PM.

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#7 Phoebus

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Posted 03 September 2018 - 04:32 PM

 

 

AICAR --> AMPK --> Nampt/NAD --> Sirt1/3 activation

 

I'm still kind of amazed there was never a group buy for AICAR and a lack of interest in it, given all the purchases that have gone on in this forum over the years.  I may be making this too simplistic, but to me, AICAR is basically an injectable form (peptide) of aerobic exercise.  Maybe I'm missing something very basic about it or alternatives like bitter melon extract or metformin were just easily obtainable and not some injectable drug.

 

 

aicar also upregulates Nitric oxide, Nitric oxide donors  increase mitochondrial biogenesis

 

also aicar is extremely expensive 

 

 

Paradoxically, we found that the AMPK-activating compound, AICAR, induced NO release from L6 myotubes, and that AICAR-induced upregulation of PGC-1α mRNA was prevented by inhibition of NOS with NG-nitro-l-arginine methyl ester (l-NAME, 1 mm). Additionally, incubation of isolated mouse extensor digitorum longus (EDL) muscles with 2 mm AICAR for 20 min or electrical stimulation (10 Hz, 13 V) for 10 min induced phosphorylation of AMPKα (P < 0.05), which was completely prevented by pre-treatment with the NOS inhibitor, l-NG-monomethyl arginine (l-NMMA, 1 mm). These data identify the AMPKα1 isoform as the mediator of NO-induced effects in skeletal muscle cells. Further, this study supports a proposed model of synergistic interaction between AMPK and NOS that is critical for maintenance of metabolic function in skeletal muscle cells

 

https://physoc.onlin...iol.2010.194035


Edited by Phoebus, 03 September 2018 - 04:51 PM.

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#8 Nate-2004

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Posted 04 September 2018 - 04:13 AM

Well, metformin activates AMPK... I assume that would upregulate NAMPT? 



#9 Nate-2004

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Posted 05 September 2018 - 04:10 PM

Does sulforaphane upregulate NAMPT? I can only find one suggestion that it does with a Google search but the guy isn't citing or linking to his sources.



#10 Phoebus

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Posted 08 February 2019 - 03:13 AM

 

Cell. 2014 Sep 11; 158(6): 1324–1334.

PMCID: PMC4163014
NIHMSID: NIHMS619251
PMID: 25215490

P7C3 Neuroprotective Chemicals Function by Activating the Rate-limiting Enzyme in NAD Salvage

 

 

The P7C3 class of aminopropyl carbazole chemicals fosters the survival of neurons in a variety of rodent models of neurodegeneration or nerve cell injury. To uncover its mechanism of action, an active derivative of P7C3 was modified to contain both a benzophenone for photo-crosslinking and an alkyne for CLICK chemistry. This derivative was found to bind nicotinamide phosphoribosyltransferase (NAMPT), the rate limiting enzyme involved in the conversion of nicotinamide into nicotinamide adenine dinucleotide (NAD). Administration of active P7C3 chemicals to cells treated with doxorubicin, which induces NAD depletion, led to a rebound in intracellular levels of NAD and concomitant protection from doxorubicin-mediated toxicity. Active P7C3 variants likewise enhanced the activity of the purified NAMPT enzyme, providing further evidence that they act by increasing NAD levels through its NAMPT-mediated salvage.

 

https://www.ncbi.nlm...les/PMC4163014/

 

 


Edited by Phoebus, 08 February 2019 - 03:14 AM.


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#11 MikeDC

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Posted 21 February 2019 - 02:20 PM

NAMPT outside cells is inflammatory.
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