Just thought I would drop you all a note letting you know about:
transient receptor potential vanilloid subfamily member 1 (TRPV1). If the initial research on this pans out it could be the BIGTIME.
Research is still preliminary at best and needs validation but it seems pretty amazing. Might want to read up on it.
Cheers,
Spook
Full Version: TRPV1
In what area ? fat-loss ?
Activation of Transient Receptor Potential Vanilloid Type-1 Channel Prevents Adipogenesis and Obesity
http://circres.ahajournals.org/cgi/content/full/100/7/1063
Activation of Transient Receptor Potential Vanilloid Type-1 Channel Prevents Adipogenesis and Obesity
http://circres.ahajournals.org/cgi/content/full/100/7/1063
Interesting, from the link above:
QUOTE
The oral administration of capsaicin for 120 days prevented obesity in male wild type mice but not in TRPV1 knockout mice assigned to high fat diet. We conclude that the activation of TRPV1 channels by capsaicin prevented adipogenesis and obesity.
Novel gating and sensitizing mechanism of capsaicin receptor (TRPV1): Tonic inhibitory regulation of extracellular sodium through the external protonation sites on TRPV1.
Ohta T, Imagawa T, Ito S.
Lab. Pharmacol., Dept. Biomed. Sci.,, Grad. Sch. Vet. Med., Hokkaido Univ., Sapporo 0600818.
Transient receptor potential V1 (TRPV1) is a nonselective cation channel expressed in nociceptors and activated by capsaicin. TRPV1 detects diverse stimuli, including acid, heat and endogenous vanilloids, and functions as a molecular integrator of pain perception. Herein we demonstrate a novel regulatory role of extracellular Na(+) ([Na(+)](o)) on TRPV1 function. In human embryonic kidney (HEK) 293 cells expressing porcine TRPV1, low [Na(+)](o) evoked increases of [Ca(2+)](i) that were suppressed by TRPV1 antagonists and facilitated responses to capsaicin, protons, heat and an endovanilloid. [Na(+)](o) removal simultaneously elicited a [Ca(2+)](i) increase and outward-rectified current with a reversal potential similar to those of capsaicin. Neutralization of the two acidic residues, which confer the proton-sensitivity to TRPV1, resulted in a reduction of low [Na(+)](o)-induced responses. In primary culture of porcine sensory neurons, the removal of [Na(+)](o) produced a [Ca(2+)](i) increase and current responses only in the cells responding to capsaicin. Low [Na(+)](o) evoked a [Ca(2+)](i) increase in sensory neurons of wild type mice, but not TRPV1-null mice, and in HEK293 cells expressing human TRPV1. The present results suggest that [Na(+)](o) negatively regulates the gating and polymodal sensitization of the TRPV1 channel. [Na(+)](o) surrounding several proton-sensitive sites on the extracellular side of the pore-forming loop of the TRPV1 channel may play an important role as a brake to suppress the excessive activity of this channel under physiological conditions.
Ohta T, Imagawa T, Ito S.
Lab. Pharmacol., Dept. Biomed. Sci.,, Grad. Sch. Vet. Med., Hokkaido Univ., Sapporo 0600818.
Transient receptor potential V1 (TRPV1) is a nonselective cation channel expressed in nociceptors and activated by capsaicin. TRPV1 detects diverse stimuli, including acid, heat and endogenous vanilloids, and functions as a molecular integrator of pain perception. Herein we demonstrate a novel regulatory role of extracellular Na(+) ([Na(+)](o)) on TRPV1 function. In human embryonic kidney (HEK) 293 cells expressing porcine TRPV1, low [Na(+)](o) evoked increases of [Ca(2+)](i) that were suppressed by TRPV1 antagonists and facilitated responses to capsaicin, protons, heat and an endovanilloid. [Na(+)](o) removal simultaneously elicited a [Ca(2+)](i) increase and outward-rectified current with a reversal potential similar to those of capsaicin. Neutralization of the two acidic residues, which confer the proton-sensitivity to TRPV1, resulted in a reduction of low [Na(+)](o)-induced responses. In primary culture of porcine sensory neurons, the removal of [Na(+)](o) produced a [Ca(2+)](i) increase and current responses only in the cells responding to capsaicin. Low [Na(+)](o) evoked a [Ca(2+)](i) increase in sensory neurons of wild type mice, but not TRPV1-null mice, and in HEK293 cells expressing human TRPV1. The present results suggest that [Na(+)](o) negatively regulates the gating and polymodal sensitization of the TRPV1 channel. [Na(+)](o) surrounding several proton-sensitive sites on the extracellular side of the pore-forming loop of the TRPV1 channel may play an important role as a brake to suppress the excessive activity of this channel under physiological conditions.
The seek of neuroprotection: introducing cannabinoids.
Martínez-Orgado J, Fernández-López D, Lizasoain I, Romero J.
Area de Pediatría y Neonatología, Fundación Hospital Alcorcón; Budapest, 1; 28922-Alcorcón Madrid, Spain. jamartinezo@fhalcorcon.es
The cannabinoid system is constituted by some endogenous ligands (endocannabinoids), usually arachydonic acid derivatives, and their specific receptors. The endogenous cannabinoid system (ECS) is involved in the control of synaptic transmission, modulating memory, motivation, movement, nociception, appetite and thermoregulation. ECS also exert extraneural effects, mainly immunomodulation and vasodilation. Two cannabinoid receptors have been cloned so far: CB(1) receptors are expressed in the central nervous system (CNS) but can also be found in glial cells and in peripheral tissues; CB(1) receptors are Gi/o protein coupled receptors that modulate the activity of several plasma membrane proteins and intracellular signaling pathways. CB(2) receptors are also Gi/o protein-coupled receptors; although it is accepted that CB(2) receptors are not expressed in forebrain neurons, they have been described in activated glia. Some of the cannabinoids activate other receptors, for instance vanilloid receptors (TRPV1). Lately, the ECS is emerging as a natural system of neuroprotection. This consideration is based on some properties of cannabinoids as their vasodilatory effect, the inhibition of the release of excitotoxic amino acids and cytokines, and the modulation of oxidative stress and toxic production of nitric oxide. Such effects have been demonstrated in adult and newborn animal models of acute and chronic neurodegenerative conditions, and postulate cannabinoids as valuable neuroprotective agents. Patents related to cannabinoid receptors are also discussed.
PMID: 18221224 [PubMed - in process]
Martínez-Orgado J, Fernández-López D, Lizasoain I, Romero J.
Area de Pediatría y Neonatología, Fundación Hospital Alcorcón; Budapest, 1; 28922-Alcorcón Madrid, Spain. jamartinezo@fhalcorcon.es
The cannabinoid system is constituted by some endogenous ligands (endocannabinoids), usually arachydonic acid derivatives, and their specific receptors. The endogenous cannabinoid system (ECS) is involved in the control of synaptic transmission, modulating memory, motivation, movement, nociception, appetite and thermoregulation. ECS also exert extraneural effects, mainly immunomodulation and vasodilation. Two cannabinoid receptors have been cloned so far: CB(1) receptors are expressed in the central nervous system (CNS) but can also be found in glial cells and in peripheral tissues; CB(1) receptors are Gi/o protein coupled receptors that modulate the activity of several plasma membrane proteins and intracellular signaling pathways. CB(2) receptors are also Gi/o protein-coupled receptors; although it is accepted that CB(2) receptors are not expressed in forebrain neurons, they have been described in activated glia. Some of the cannabinoids activate other receptors, for instance vanilloid receptors (TRPV1). Lately, the ECS is emerging as a natural system of neuroprotection. This consideration is based on some properties of cannabinoids as their vasodilatory effect, the inhibition of the release of excitotoxic amino acids and cytokines, and the modulation of oxidative stress and toxic production of nitric oxide. Such effects have been demonstrated in adult and newborn animal models of acute and chronic neurodegenerative conditions, and postulate cannabinoids as valuable neuroprotective agents. Patents related to cannabinoid receptors are also discussed.
PMID: 18221224 [PubMed - in process]
I've been following this also, just a few things that its manipulation could prove beneficial: pain, weight, (sodium induced) hypertension, plasma GH/IGF-1, hair growth, skin plasticity, thermogenesis, digestion
Best of all, potent VR1 agonists are available legally and cheap
Best of all, potent VR1 agonists are available legally and cheap
Bummer
Transient receptor potential vanilloid 1 agonists cause endoplasmic reticulum stress and cell death in human lung cells.
Thomas KC, Sabnis AS, Johansen ME, Lanza DL, Moos PJ, Yost GS, Reilly CA.
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
Transient receptor potential vanilloid 1 (TRPV1) is a calcium-selective ion channel expressed in human lung cells. We show that activation of the intracellular subpopulation of TRPV1 causes endoplasmic reticulum (ER) stress and cell death in human bronchial epithelial and alveolar cells. TRPV1 agonist (nonivamide) treatment caused calcium release from the ER and altered the transcription of growth arrest- and DNA damage-inducible transcript 3 (GADD153), GADD45alpha, GRP78/BiP, ATF3, CCND1, and CCNG2) in a manner comparable with prototypical ER stress-inducing agents. The TRPV1 antagonist N-(4-tert-butylbenzyl)-N'-(1-[3-fluoro-4-(methylsulfonylamino)-phenyl]ethyl)thiourea (LJO-328) inhibited mRNA responses and cytotoxicity. EGTA and ruthenium red inhibited cell surface TRPV1 activity, but they did not prevent ER stress gene responses or cytotoxicity. Cytotoxicity paralleled eukaryotic translation initiation factor 2, subunit 1 (EIF2alpha) phosphorylation and the induction of GADD153 mRNA and protein. Transient overexpression of GADD153 caused cell death independent of agonist treatment, and cells selected for stable overexpression of a GADD153 dominant-negative mutant exhibited reduced sensitivity. Salubrinal, an inhibitor of ER stress-induced cytotoxicity via the EIF2alphaK3/EIF2alpha pathway, or stable overexpression of the EIF2alpha-S52A dominant-negative mutant also inhibited cell death. Treatment of the TRPV1-null human embryonic kidney 293 cell line with TRPV1 agonists did not initiate ER stress responses. Likewise, n-benzylnonanamide, an inactive analog of nonivamide, failed to cause ER calcium release, an increase in GADD153 expression, and cytotoxicity. We conclude that activation of ER-bound TRPV1 and stimulation of GADD153 expression via the EIF2alphaK3/EIF2alpha pathway represents a common mechanism for cytotoxicity by cell-permeable TRPV1 agonists. These findings are significant within the context of lung inflammatory diseases where elevated concentrations of endogenous TRPV1 agonists are probably produced in sufficient quantities to cause TRPV1 activation and lung cell death.
Publication Types:
* Research Support, N.I.H., Extramural
PMID: 17332266 [PubMed - indexed for MEDLINE]
Transient receptor potential vanilloid 1 agonists cause endoplasmic reticulum stress and cell death in human lung cells.
Thomas KC, Sabnis AS, Johansen ME, Lanza DL, Moos PJ, Yost GS, Reilly CA.
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
Transient receptor potential vanilloid 1 (TRPV1) is a calcium-selective ion channel expressed in human lung cells. We show that activation of the intracellular subpopulation of TRPV1 causes endoplasmic reticulum (ER) stress and cell death in human bronchial epithelial and alveolar cells. TRPV1 agonist (nonivamide) treatment caused calcium release from the ER and altered the transcription of growth arrest- and DNA damage-inducible transcript 3 (GADD153), GADD45alpha, GRP78/BiP, ATF3, CCND1, and CCNG2) in a manner comparable with prototypical ER stress-inducing agents. The TRPV1 antagonist N-(4-tert-butylbenzyl)-N'-(1-[3-fluoro-4-(methylsulfonylamino)-phenyl]ethyl)thiourea (LJO-328) inhibited mRNA responses and cytotoxicity. EGTA and ruthenium red inhibited cell surface TRPV1 activity, but they did not prevent ER stress gene responses or cytotoxicity. Cytotoxicity paralleled eukaryotic translation initiation factor 2, subunit 1 (EIF2alpha) phosphorylation and the induction of GADD153 mRNA and protein. Transient overexpression of GADD153 caused cell death independent of agonist treatment, and cells selected for stable overexpression of a GADD153 dominant-negative mutant exhibited reduced sensitivity. Salubrinal, an inhibitor of ER stress-induced cytotoxicity via the EIF2alphaK3/EIF2alpha pathway, or stable overexpression of the EIF2alpha-S52A dominant-negative mutant also inhibited cell death. Treatment of the TRPV1-null human embryonic kidney 293 cell line with TRPV1 agonists did not initiate ER stress responses. Likewise, n-benzylnonanamide, an inactive analog of nonivamide, failed to cause ER calcium release, an increase in GADD153 expression, and cytotoxicity. We conclude that activation of ER-bound TRPV1 and stimulation of GADD153 expression via the EIF2alphaK3/EIF2alpha pathway represents a common mechanism for cytotoxicity by cell-permeable TRPV1 agonists. These findings are significant within the context of lung inflammatory diseases where elevated concentrations of endogenous TRPV1 agonists are probably produced in sufficient quantities to cause TRPV1 activation and lung cell death.
Publication Types:
* Research Support, N.I.H., Extramural
PMID: 17332266 [PubMed - indexed for MEDLINE]
Probably the most important discovery
1: Trends Pharmacol Sci. 2008 Jan;29(1):29-36. Epub 2007 Dec 4. Links
The emerging role of TRPV1 in diabetes and obesity.
Suri A, Szallasi A.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Immunology and Inflammation Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
The capsaicin receptor transient receptor potential vanilloid subfamily member 1 (TRPV1) is highly expressed on sensory nerve fibers innervating the pancreas. Indeed, the role of TRPV1 in mediating pain during pancreatitis is well established. The initial excitation of these nerves by capsaicin is followed by a reversible refractory state (desensitization) or, under certain conditions such as neonatal treatment, neurotoxicity. Interestingly, ablation of TRPV1-positive fibers by subcutaneous capsaicin treatment not only ameliorates pancreatitis pain but also diminishes aging-associated weight gain and improves glucose tolerance both in mice on a high-fat diet and in rat models of type 2 diabetes. New evidence implies an unexpected, pivotal role for TRPV1 in type 1 (autoimmune) diabetes. Non-obese diabetic (NOD) mice carry a hypofunctional TRPV1 mutant. Ablation of nerves carrying this mutant TRPV1 by capsaicin prevents immune-mediated destruction of islet beta cells despite the persistence of diabetogenic T cells. Collectively, these findings establish a crucial link among sensory nerves, obesity and diabetes and identify pharmacological TRPV1 blockade as a novel therapeutic approach for diabetes prevention and weight control.
PMID: 18055025 [PubMed - in process]
Can't seem to find a place to upload the text in this forum.
1: Trends Pharmacol Sci. 2008 Jan;29(1):29-36. Epub 2007 Dec 4. Links
The emerging role of TRPV1 in diabetes and obesity.
Suri A, Szallasi A.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Immunology and Inflammation Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
The capsaicin receptor transient receptor potential vanilloid subfamily member 1 (TRPV1) is highly expressed on sensory nerve fibers innervating the pancreas. Indeed, the role of TRPV1 in mediating pain during pancreatitis is well established. The initial excitation of these nerves by capsaicin is followed by a reversible refractory state (desensitization) or, under certain conditions such as neonatal treatment, neurotoxicity. Interestingly, ablation of TRPV1-positive fibers by subcutaneous capsaicin treatment not only ameliorates pancreatitis pain but also diminishes aging-associated weight gain and improves glucose tolerance both in mice on a high-fat diet and in rat models of type 2 diabetes. New evidence implies an unexpected, pivotal role for TRPV1 in type 1 (autoimmune) diabetes. Non-obese diabetic (NOD) mice carry a hypofunctional TRPV1 mutant. Ablation of nerves carrying this mutant TRPV1 by capsaicin prevents immune-mediated destruction of islet beta cells despite the persistence of diabetogenic T cells. Collectively, these findings establish a crucial link among sensory nerves, obesity and diabetes and identify pharmacological TRPV1 blockade as a novel therapeutic approach for diabetes prevention and weight control.
PMID: 18055025 [PubMed - in process]
Can't seem to find a place to upload the text in this forum.
Not to rain on anybody's parade here but I have become highly suspicious of rodent obesity research and wonder if the differences between a rodent's digestive optimization and a human's is the reason so many things that seem to work to reduce or control obesity in rodents do not pan out in people.
QUOTE(avantgarde @ Feb 13 2008, 12:11 PM) [snapback]457159[/snapback]
In what area ? fat-loss ?
Just in the general scientific sense. The recent discovery of receptor specific antagonists for the vanilaoid family are showing some rather amazing things. Specifically the link between autoimune diseases, nervous tissue, and metabolic disturbances.
The studies on TRPV1 are interesting in and of themselves but what is really exciting is interpreting these new findings in light of all of the research on capsacin which is a non specific agonist.
It also makes me think about the research on HISS. Seeing how one can severe a single nerve bundle to the liver and abolish most insulin action. Seems related to the data on oral capsacin stimulation of intestinal and vagal nerves and the effects that causes.
Just one example is how capsacin activates intestinal nerve bundles conected to the liver which results in vasoconstriction to visceral fat pads. Thus preferentially shifting fat distribution to peripheral stores which is optimal.
No definitive unifying theory on all this but it just seems to be connected as very few commonly ingested food stuffs directly act on nervous tissue. Thus it seems to me all of these things are related in some fashion.
interesting. any other nutrigenomic/epigenetic tips on your plate or radar now?
QUOTE(Benson @ Feb 13 2008, 09:30 PM) [snapback]457419[/snapback]
Not to rain on anybody's parade here but I have become highly suspicious of rodent obesity research and wonder if the differences between a rodent's digestive optimization and a human's is the reason so many things that seem to work to reduce or control obesity in rodents do not pan out in people.
Sodium Tungstate comes to mind...
http://www.sciencedaily.com/releases/2008/...80313125347.htm
activation of TPRV1 receptors can trigger long-term depression
http://www.sciencedaily.com/releases/2008/...80312141250.htm
"The researchers found that they could block LTD in the brain slices using drugs that block TRPV1. Also, they could induce LTD (long-term depression) using the TRPV1-activating compound capsaicin."
Bummer
activation of TPRV1 receptors can trigger long-term depression
http://www.sciencedaily.com/releases/2008/...80312141250.htm
"The researchers found that they could block LTD in the brain slices using drugs that block TRPV1. Also, they could induce LTD (long-term depression) using the TRPV1-activating compound capsaicin."
Bummer
yeah, we'd all be ripped like jesus if half this stuff actually crossed over to humans.
Cool.
Biol Psychiatry. 2008 Apr 9 [Epub ahead of print]
Related Articles, Links
Click here to read
Antistress Effect of TRPV1 Channel on Synaptic Plasticity and Spatial Memory.
Li HB, Mao RR, Zhang JC, Yang Y, Cao J, Xu L.
Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases.
BACKGROUND: Stress is believed to exacerbate neuropsychiatric and cognitive disorders. In particular, the hippocampus, which plays critical roles in certain types of memory, including spatial memory, is exquisitely sensitive to stress. Certain types of memory are believed to depend on activity-dependent hippocampal synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), but stress suppresses LTP and facilitates LTD in the hippocampus and impairs spatial memory. Although the transient receptor potential vanilloid 1 (TRPV1 or VR1) is widely expressed in the hippocampus, it remains unknown whether the TRPV1 channel antagonizes the stress effects on hippocampal function. METHODS: Using the TRPV1 agonists capsaicin and resiniferatoxin and selective antagonists capsazepine and SB366791, we examined the effect of TRPV1 activation on LTP and LTD in hippocampal CA1 slices of juvenile rats. Furthermore, we examined whether the effects of acute stress on synaptic plasticity and spatial memory could be prevented by intrahippocampal or intragastric infusion of a TRPV1 agonist. RESULTS: The TRPV1 agonists capsaicin and resiniferatoxin facilitated LTP but suppressed LTD. Alterations were mediated by TRPV1 because the TRPV1 selective antagonists capsazepine and SB366791 blocked the actions of capsaicin. Acute stress suppressed LTP and enabled LTD, but the TRPV1 agonist capsaicin effectively prevented this effect. When capsaicin was intrahippocampally or intragastrically infused, the acute stress effect on impairing spatial memory retrieval was completely prevented. CONCLUSIONS: The TRPV1 channel is a potential target to facilitate LTP and suppress LTD, in turn protecting hippocampal synaptic plasticity and spatial memory retrieval from the influence of acute stress.
PMID: 18405883 [PubMed - as supplied by publisher]
Biol Psychiatry. 2008 Apr 9 [Epub ahead of print]
Related Articles, Links
Click here to read
Antistress Effect of TRPV1 Channel on Synaptic Plasticity and Spatial Memory.
Li HB, Mao RR, Zhang JC, Yang Y, Cao J, Xu L.
Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases.
BACKGROUND: Stress is believed to exacerbate neuropsychiatric and cognitive disorders. In particular, the hippocampus, which plays critical roles in certain types of memory, including spatial memory, is exquisitely sensitive to stress. Certain types of memory are believed to depend on activity-dependent hippocampal synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), but stress suppresses LTP and facilitates LTD in the hippocampus and impairs spatial memory. Although the transient receptor potential vanilloid 1 (TRPV1 or VR1) is widely expressed in the hippocampus, it remains unknown whether the TRPV1 channel antagonizes the stress effects on hippocampal function. METHODS: Using the TRPV1 agonists capsaicin and resiniferatoxin and selective antagonists capsazepine and SB366791, we examined the effect of TRPV1 activation on LTP and LTD in hippocampal CA1 slices of juvenile rats. Furthermore, we examined whether the effects of acute stress on synaptic plasticity and spatial memory could be prevented by intrahippocampal or intragastric infusion of a TRPV1 agonist. RESULTS: The TRPV1 agonists capsaicin and resiniferatoxin facilitated LTP but suppressed LTD. Alterations were mediated by TRPV1 because the TRPV1 selective antagonists capsazepine and SB366791 blocked the actions of capsaicin. Acute stress suppressed LTP and enabled LTD, but the TRPV1 agonist capsaicin effectively prevented this effect. When capsaicin was intrahippocampally or intragastrically infused, the acute stress effect on impairing spatial memory retrieval was completely prevented. CONCLUSIONS: The TRPV1 channel is a potential target to facilitate LTP and suppress LTD, in turn protecting hippocampal synaptic plasticity and spatial memory retrieval from the influence of acute stress.
PMID: 18405883 [PubMed - as supplied by publisher]
QUOTE
Effect of topical application of raspberry ketone on dermal production of insulin-like growth factor-I in mice and on hair growth and skin elasticity in humans.
Harada N, Okajima K, Narimatsu N, Kurihara H, Nakagata N.
Department of Translational Medical Science Research, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
Sensory neurons release calcitonin gene-related peptide (CGRP) on activation. We recently reported that topical application of capsaicin increases facial skin elasticity and promotes hair growth by increasing dermal insulin-like growth factor-I (IGF-I) production through activation of sensory neurons in mice and humans.Raspberry ketone (RK), a major aromatic compound contained in red raspberries (Rubus idaeus), has a structure similar to that of capsaicin. Thus, it is possible that RK activates sensory neurons, thereby increasing skin elasticity and promoting hair growth by increasing dermal IGF-I production. In the present study, we examined this possibility in mice and humans. RK, at concentrations higher than 1muM, significantly increased CGRP release from dorsal root ganglion neurons (DRG) isolated from wild-type (WT) mice and this increase was completely reversed by capsazepine, an inhibitor of vanilloid receptor-1 activation. Topical application of 0.01% RK increased dermal IGF-I levels at 30min after application in WT mice, but not in CGRP-knockout mice. Topical application of 0.01% RK increased immunohistochemical expression of IGF-I at dermal papillae in hair follicles and promoted hair re-growth in WT mice at 4 weeks after the application. When applied topically to the scalp and facial skin, 0.01% RK promoted hair growth in 50.0% of humans with alopecia (n=10) at 5 months after application and increased cheek skin elasticity at 2 weeks after application in 5 females (p<0.04). These observations strongly suggest that RK might increase dermal IGF-I production through sensory neuron activation, thereby promoting hair growth and increasing skin elasticity.
Harada N, Okajima K, Narimatsu N, Kurihara H, Nakagata N.
Department of Translational Medical Science Research, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
Sensory neurons release calcitonin gene-related peptide (CGRP) on activation. We recently reported that topical application of capsaicin increases facial skin elasticity and promotes hair growth by increasing dermal insulin-like growth factor-I (IGF-I) production through activation of sensory neurons in mice and humans.Raspberry ketone (RK), a major aromatic compound contained in red raspberries (Rubus idaeus), has a structure similar to that of capsaicin. Thus, it is possible that RK activates sensory neurons, thereby increasing skin elasticity and promoting hair growth by increasing dermal IGF-I production. In the present study, we examined this possibility in mice and humans. RK, at concentrations higher than 1muM, significantly increased CGRP release from dorsal root ganglion neurons (DRG) isolated from wild-type (WT) mice and this increase was completely reversed by capsazepine, an inhibitor of vanilloid receptor-1 activation. Topical application of 0.01% RK increased dermal IGF-I levels at 30min after application in WT mice, but not in CGRP-knockout mice. Topical application of 0.01% RK increased immunohistochemical expression of IGF-I at dermal papillae in hair follicles and promoted hair re-growth in WT mice at 4 weeks after the application. When applied topically to the scalp and facial skin, 0.01% RK promoted hair growth in 50.0% of humans with alopecia (n=10) at 5 months after application and increased cheek skin elasticity at 2 weeks after application in 5 females (p<0.04). These observations strongly suggest that RK might increase dermal IGF-I production through sensory neuron activation, thereby promoting hair growth and increasing skin elasticity.
Very interesting. Shows that both RK is a TRPV1 agonist, and that it induces hair growth in human males (which fitnecise mentioned previously).
Additionally, it is interesting that this relationship with IGF-I goes both ways; there have been previous reports that IGF-I increase expression of TRPV1 and its permeability, and this shows that agonism of TRPV1 increases IGF-I (which seems like some sort of positive feedback system - weird). I wonder what effects systemic administration of TRPV1 agonists might have on IGF-I levels... Answer:
QUOTE
Plasma levels of IGF-I were significantly increased from baseline levels in 31 volunteers with alopecia at 5 months after [daily] oral administration of capsaicin (6 mg/day) and isoflavone (75 mg/day) (p < 0.01), while they were not increased in 17 volunteers with alopecia administered placebo. The number of volunteers with alopecia who showed promotion of hair growth at 5 months after administration was significantly higher among volunteers administered capsaicin and isoflavone (20/31: 64.5%) than among those administered placebo (2/17: 11.8%) (p < 0.01). (Here)
It appears that oral TRPV1 agonists are effective at both: (1) increasing plasma IGF-I levels, and (2) promoting hair growth in a whopping 64.5% of the subjects. Hot Damn!
Some image-y goodness showing how significant some of the improvement was:
"Effect of oral administration of capsaicin and isoflavone on hair growth in 4 volunteers with alopecia. Hair growth was observed at 5 months after administration of capsaicin and isoflavone in a male volunteer with AGA (54 y.o.) (a), in a male volunteer with AT (29 y.o.) (b), in a female volunteer with AGA (39 y.o.) (c ), and in a female volunteer with AA (40 y.o.) (d)."
Also, from the full text of the study mentioned by avantgarde, we get:
QUOTE
Previous studies indicated that adipogenesis is regulated by calcium. Shi et al reported that elevated calcium markedly suppressed adipogenesis with a decrease in triglyceride accumulation and a substantial inhibition in PPAR-{gamma} expression. In the present study adipogenesis was induced in 3T3-L1-preadipocytes using 3-isobutyl-1-methylxanthine, dexamethasone, and insulin. We showed that capsaicin-induced elevation of cytosolic calcium reduced intracellular lipid droplets, reduced triglyceride levels, reduced expression of PPAR-{gamma} and reduced fatty acid synthase in stimulated preadipocytes, whereas administration of the TRPV1 antagonist capsazepine did not prevent adipogenesis. Furthermore, after TRPV1 knockdown the administration of capsaicin did not prevent adipogenesis in TRPV1 knockdown 3T3-L1-preadipocytes. Hence we confirmed that increased calcium after administration of capsaicin significantly blocked adipogenesis in stimulated 3T3-L1-preadipocytes. (Here)
Which is excellent, and exactly what we want. Vanilloid receptors are expressed in adipose tissues (this was shown in humans as well as mice in this study) and the agonism of them removes the triglycerides from their droplets (not wholly verified in humans, yet).
QUOTE (Mr.Kite @ Apr 16 2008, 11:57 PM) 
Very interesting. Shows that both RK is a TRPV1 agonist, and that it (and capsaicin) induces hair growth in blading human males (which fitnecise mentioned previously). Someone make a cream with RK, Evodiamine, and other TRPV1 agonists.
Additionally, it is interesting that this relationship with IGF-I goes both ways; there have been previous reports that IGF-I increase expression of TRPV1 and its permeability, and this shows that agonism of TRPV1 increases IGF-I (which seems like some sort of positive feedback system - weird). I wonder what effects systemic administration of TRPV1 agonists might have on IGF-I levels.
Additionally, it is interesting that this relationship with IGF-I goes both ways; there have been previous reports that IGF-I increase expression of TRPV1 and its permeability, and this shows that agonism of TRPV1 increases IGF-I (which seems like some sort of positive feedback system - weird). I wonder what effects systemic administration of TRPV1 agonists might have on IGF-I levels.
In the cap study: "Plasma levels of IGF-I were significantly increased from baseline levels in 31 volunteers with alopecia at 5 months after oral administration of capsaicin (6 mg/day) and isoflavone (75 mg/day) (p < 0.01), while they were not increased in 17 volunteers with alopecia administered placebo"
edit: I see you just edited and added
We are actually considering these exact ingredients among others, and I think I have a way to get around pain issues, but I need to refresh on the etiologies of hairloss as I recall there was a possible problem of acceleration depending on cause. Will get the project going again, thanks for the motivation.
Excellent news fitnecise. Additionally, it seems that Cocoa blocks CGRP release by blocking Ca2+ ion channels:
Granted, this is in sensory nerves in the face, but it is something to consider when taking your chocamine with your raspberry ketones and evodiamine.
On the other hand, migraine sufferers beware:
It appears that TRPV1 and its release of CGRP are involved in migraines, so that could be a factor that one might want to consider when looking into these TRPV1 agonists.
Interesting...
More...
It seems that the mechanism for the (significant) sensitization caused by the TRPV1 agonists is being discovered. It is unsurprising that CaMKIIa is implicated, because it has significant roles in the phosphorylation of NMDA receptors in LTP.
QUOTE
Our results demonstrate that Theobroma cacao extract can repress stimulated CGRP release by a mechanism that likely involves blockage of calcium channel activity. Furthermore, our findings suggest that the beneficial effects of diets rich in cocoa may include suppression of sensory trigeminal nerve activation. (Here)
Granted, this is in sensory nerves in the face, but it is something to consider when taking your chocamine with your raspberry ketones and evodiamine.
On the other hand, migraine sufferers beware:
QUOTE
Although knowledge on the main molecular players is still incomplete, recent preclinical and clinical findings indicate that there is a clear correlation between migraine-associated headache and the release of the neuropeptide calcitonin gene-related peptide (CGRP). BIBN4096 was the first CGRP antagonist to be tested in clinical trials for the treatment of migraine. The proven efficacy of this agent, and also the CGRP antagonist MK-0974, to alleviate acute migraine headache provided significant support for the hypothesis that CGRP has an important role in migraine pathophysiology. (Here)
It appears that TRPV1 and its release of CGRP are involved in migraines, so that could be a factor that one might want to consider when looking into these TRPV1 agonists.
Interesting...
QUOTE
High sodium [diet] upregulates mesenteric TRPV1 expression, and increases NADA-induced CGRP release in vitro and in vivo. (Here)
More...
QUOTE
CAP also stimulated a significant approximately 50% increase in autophosphorylation of CaMKIIalpha at Thr286/287. Immunocytochemistry for phospho-CaMKIIalpha indicated that this effect specifically occurred in TRPV1-positive TG neurons. These findings indicate that phopho-CaMKIIalpha is likely to play a role in presynaptic primary afferents in animal models of nociceptive hypersensitivity and provide support for CaMKIIalpha modulation of TRPV1 activity in sensory neurons. (Here)
It seems that the mechanism for the (significant) sensitization caused by the TRPV1 agonists is being discovered. It is unsurprising that CaMKIIa is implicated, because it has significant roles in the phosphorylation of NMDA receptors in LTP.
So this is why you hardly ever see naturally balding mexican/latino. jalapeños!
Edit: sorry to dumb down the thread
Edit: sorry to dumb down the thread
QUOTE (Mr.Kite @ Apr 17 2008, 01:22 PM)
Excellent news fitnecise. Additionally, it seems that Cocoa blocks CGRP release by blocking Ca2+ ion channels:
Granted, this is in sensory nerves in the face, but it is something to consider when taking your chocamine with your raspberry ketones and evodiamine.
On the other hand, migraine sufferers beware:
It appears that TRPV1 and its release of CGRP are involved in migraines, so that could be a factor that one might want to consider when looking into these TRPV1 agonists.
Interesting...
More...
It seems that the mechanism for the (significant) sensitization caused by the TRPV1 agonists is being discovered. It is unsurprising that CaMKIIa is implicated, because it has significant roles in the phosphorylation of NMDA receptors in LTP.
Granted, this is in sensory nerves in the face, but it is something to consider when taking your chocamine with your raspberry ketones and evodiamine.
On the other hand, migraine sufferers beware:
It appears that TRPV1 and its release of CGRP are involved in migraines, so that could be a factor that one might want to consider when looking into these TRPV1 agonists.
Interesting...
More...
It seems that the mechanism for the (significant) sensitization caused by the TRPV1 agonists is being discovered. It is unsurprising that CaMKIIa is implicated, because it has significant roles in the phosphorylation of NMDA receptors in LTP.
Nice find wrt. to LTP.
I had some problems with migraines when I tested capsacian awhile back, although it did curb hunger. Not worth the trouble IME.
QUOTE (Mr.Kite @ Apr 16 2008, 11:57 PM)
Very interesting. Shows that both RK is a TRPV1 agonist, and that it induces hair growth in human males (which fitnecise mentioned previously).
Additionally, it is interesting that this relationship with IGF-I goes both ways; there have been previous reports that IGF-I increase expression of TRPV1 and its permeability, and this shows that agonism of TRPV1 increases IGF-I (which seems like some sort of positive feedback system - weird). I wonder what effects systemic administration of TRPV1 agonists might have on IGF-I levels... Answer:
It appears that oral TRPV1 agonists are effective at both: (1) increasing plasma IGF-I levels, and (2) promoting hair growth in a whopping 64.5% of the subjects. Hot Damn!
Some image-y goodness showing how significant some of the improvement was:
"Effect of oral administration of capsaicin and isoflavone on hair growth in 4 volunteers with alopecia. Hair growth was observed at 5 months after administration of capsaicin and isoflavone in a male volunteer with AGA (54 y.o.) (a), in a male volunteer with AT (29 y.o.) (
, in a female volunteer with AGA (39 y.o.) (c ), and in a female volunteer with AA (40 y.o.) (d)."
Also, from the full text of the study mentioned by avantgarde, we get:
Which is excellent, and exactly what we want. Vanilloid receptors are expressed in adipose tissues (this was shown in humans as well as mice in this study) and the agonism of them removes the triglycerides from their droplets (not wholly verified in humans, yet).
Additionally, it is interesting that this relationship with IGF-I goes both ways; there have been previous reports that IGF-I increase expression of TRPV1 and its permeability, and this shows that agonism of TRPV1 increases IGF-I (which seems like some sort of positive feedback system - weird). I wonder what effects systemic administration of TRPV1 agonists might have on IGF-I levels... Answer:
It appears that oral TRPV1 agonists are effective at both: (1) increasing plasma IGF-I levels, and (2) promoting hair growth in a whopping 64.5% of the subjects. Hot Damn!
Some image-y goodness showing how significant some of the improvement was:
"Effect of oral administration of capsaicin and isoflavone on hair growth in 4 volunteers with alopecia. Hair growth was observed at 5 months after administration of capsaicin and isoflavone in a male volunteer with AGA (54 y.o.) (a), in a male volunteer with AT (29 y.o.) (
, in a female volunteer with AGA (39 y.o.) (c ), and in a female volunteer with AA (40 y.o.) (d)."Also, from the full text of the study mentioned by avantgarde, we get:
Which is excellent, and exactly what we want. Vanilloid receptors are expressed in adipose tissues (this was shown in humans as well as mice in this study) and the agonism of them removes the triglycerides from their droplets (not wholly verified in humans, yet).
Look at those pictures! Nice.
Yeah posted the Cap+ Isoflavone=hair study in another thread. Could someone please help me find products with these ingredients without other stuff ?
And yeah no products with caffeine in them.
Also the study used 6 mg Cap - every product I find are Cayenne Pepper extracts - listing Heat Units - how do I translate the dose ?
Same with Isoflavone - what product ?
And yeah no products with caffeine in them.
Also the study used 6 mg Cap - every product I find are Cayenne Pepper extracts - listing Heat Units - how do I translate the dose ?
Same with Isoflavone - what product ?
I want to start cataloging all the known TRPV1 agonists, so that those who can either: (1) source them or (2) make products with them have a list available.
Here are the agonists that I am currently aware of:
(with the format: Name (comments & analogs; plant found in) - common uses/effects.)
Capsaicin (Dihydrocapsaicin, Olvanil, Arvanil, Capsiate; red pepper) - Analgesic, fat loss, hair regrowth.
Resiniferatoxin (ultra potent capsaicin analog; euphorbia resinifera) - Analgesic, this one is so potent that it can easily induce cell death.
Raspberry Ketones (raspberry) - Fat loss.
Evodiamine (evodiae fructus) - Fat loss.
Curcumin (turmeric) - Antioxidant, anticancer.
Piperine (aka Bioperine; black pepper) - Increasing nutrient bioavailability (especially curcumin), roughly as potent as capsaicin at TRPV1 receptor.
Gingerol (Zingerone, Paradol; ginger) - Control blood sugar levels, and increase nutrient bioavailability.
Allyl Isothiocyanate (mustard oil, horseradish, wasabi) - Antibacterial.
Cinnamaldehyde (cinnamon) - Control blood sugar levels, and Antifungal (also inexpensive).
Eugenol (clove, nutmeg) - Analgesic, antiseptic.
Catechins (EGCG, etc.; green tea, black tea) - These have been found to by synergistic with TRPV1 agonists.
Vinpocetine (Vincamine; periwinkle) - A PDE-1 inhibitor that results in increases in cGMP. Increases in cGMP are linked to increases in CGRP, the primary product of TRPV1 agonism (see here for related discussion). Thus, it appears that Vinpocetine should be synergistic with TRPV1 agonists.
I think that many of the compounds listed above are currently under-explored & under-utilized, and someone should do something about that.
Here are the agonists that I am currently aware of:
(with the format: Name (comments & analogs; plant found in) - common uses/effects.)
Capsaicin (Dihydrocapsaicin, Olvanil, Arvanil, Capsiate; red pepper) - Analgesic, fat loss, hair regrowth.
Resiniferatoxin (ultra potent capsaicin analog; euphorbia resinifera) - Analgesic, this one is so potent that it can easily induce cell death.
Raspberry Ketones (raspberry) - Fat loss.
Evodiamine (evodiae fructus) - Fat loss.
Curcumin (turmeric) - Antioxidant, anticancer.
Piperine (aka Bioperine; black pepper) - Increasing nutrient bioavailability (especially curcumin), roughly as potent as capsaicin at TRPV1 receptor.
Gingerol (Zingerone, Paradol; ginger) - Control blood sugar levels, and increase nutrient bioavailability.
Allyl Isothiocyanate (mustard oil, horseradish, wasabi) - Antibacterial.
Cinnamaldehyde (cinnamon) - Control blood sugar levels, and Antifungal (also inexpensive).
Eugenol (clove, nutmeg) - Analgesic, antiseptic.
Catechins (EGCG, etc.; green tea, black tea) - These have been found to by synergistic with TRPV1 agonists.
Vinpocetine (Vincamine; periwinkle) - A PDE-1 inhibitor that results in increases in cGMP. Increases in cGMP are linked to increases in CGRP, the primary product of TRPV1 agonism (see here for related discussion). Thus, it appears that Vinpocetine should be synergistic with TRPV1 agonists.
I think that many of the compounds listed above are currently under-explored & under-utilized, and someone should do something about that.
An interesting little blip I came across when perusing a full text on Resiniferatoxin (RTX):
Might want to try and avoid Propranolol if you are looking to use TRPV1 agonists for fat loss.
QUOTE
Then, we examined the effects of capsaicin desensitization, pretreatment with vanilloid antagonists ruthenium red and capsazepine, adrenal demedullation, and pretreatment with the β-blocker propranolol on the RTX-induced responses in the thermoregulatory system.
...
The late and long-lasting thermogenesis after the RTX injection was blocked by pretreatment with propranolol
...
The late and long-lasting thermogenesis after the RTX injection was blocked by pretreatment with propranolol
Might want to try and avoid Propranolol if you are looking to use TRPV1 agonists for fat loss.
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