Oregano compound activates Oocytes, kills Glioblastoma cells, and enhances immune cells: AMPK links the creation of all human life, cancer, and HIV-1

    

Hey Blogger fam, take a look at my recent LinkedIn post detailing a pretty striking example of the "shock and live approach" from my most recent publication. Carvacrol, a compound that is found in Oregano, has been shown by Harvard researchers to be capable of activating mouse oocytes (a model for human oocytes) by activating a heat channel present on oocytes.  Interestingly, the oregano compound activates oocytes similar to a compound called strontium. Strontium has been used to activate human oocytes during in vitro fertilization procedures and produce normal, healthy children. The oregano compound is known to induce a warming sensation when placed on the tongue as well, indicating that the induction of heat stress is a method through which this compound exerts its beneficial effects. Capsaicin, a compound found in chilli peppers, also works by the same method. Interestingly, activation of this heat channel increases calcium in the oocyte, a process that mimics how human sperm activates oocytes (an increase in oocyte calcium as well). Not surprisingly, as T cell activation is also dependent on an increase in calcium, the oregano compound (and capsaicin) also enhances T cell activation. What's really surprising though is that the oregano compound also kills glioblastoma (brain cancer) cells by increasing calcium levels as well. In fact, the oregano compound stimulates the same pathway in oocytes, T cells, and brain cancer cells, leading to the activation of oocytes and T cells, but "stressing" cancer cells to death. AMPK sits at the helm of this pathway. The activation of this pathway through the induction of a "shock" or a "stressor" is responsible for the creation of all human life, immune system activation and HIV-1 eradication (through a "shock and kill approach"), and, in my opinion, the eradication of deadly cancers through an analogous "shock and kill approach". As AMPK is indeed critical for the beginning of all human life, are there other unanswered biological mysteries that point to this pathway? Is the activation (and thus fertilization capability) of sperm dependent on this pathway? Could consciousness itself be linked to this pathway?? If this turns out to be true..............:-)        

Oregano compound activates Oocytes, kills Glioblastoma cells, and enhances immune cells: AMPK links the creation of all human life, cancer, and HIV-1.

The following provides an excerpt from my recent publication “Oocyte activation and latent HIV-1 reactivation: AMPK as a common mechanism of action linking the beginnings of life and the potential eradication of HIV-1”, highlighting a recent study by Harvard researchers published in the Journal Cell Reports in December of 2013 strikingly demonstrating that carvacrol, a compound found in the essential oil of Origanum vulgare (oregano), induces activation of mouse oocytes (a model for human oocytes) via a similar mechanism as strontium chloride, a compound that induces parthenogenetic activation of human oocytes that has resulted in successful term pregnancies and the birth of normal children. Because carvacrol has also been shown to activate AMPK in vivo, enhance signaling mechanisms that are critical for T cell activation, and induce cell death in glioblastoma cells, AMPK activation likely represents a central node that links the creation of all human life ("The Shock and Live Approach"), the potential eradication of HIV-1 through T cell activation-induced latent HIV-1 reactivation ("The Shock and Kill Approach"), and the possible elimination of cancers as deadly as brain tumors. 

“An illustrative example that underscores the potential common mechanism of action linking alterations in energy metabolism and AMPK activation is oocyte activation and potentiation of T cell activation via stimulation of transient receptor potential channels (TRP) by carvacrol and capsaicin.  Carvacrol, a monoterpenoid phenol found in the essential oil of Origanum vulgare (oregano), is a potent activator of the transient receptor potential cation channel, subfamily V, member 3 (TRPV3), a nonselective cation channel that functions in vasoregulation and temperature sensation and is activated between the temperatures of 22 and 40 degrees Celsius [1,2].  The TRPV3 channel, which is also directly activated by the natural compounds thymol (Thymus vulgaris) and eugenol (heavily concentrated in Syzygium aromaticum), has been shown to associate with and form heteromeric channels with the Ca2+-permeable TRPV1 channel, another nonselective cation channel that is also regulated by temperature sensation and is activated by both physical and chemical stimuli, including temperatures greater than 43 degrees Celsius as well as the natural compound capsaicin (an active component of chili peppers from the genus Capsicum) [2-4].  

Interestingly, Carvacho et al. demonstrated that the TRPV3 channel is differentially expressed in mouse oocytes during maturation and reaches peak density and activity at metaphase II, the stage at which oocytes develop the competency to initiate Ca2+ oscillations in response to fertilization [5].  The authors also showed that strontium chloride (SrCl2), a compound that induces parthenogenetic activation of mammalian oocytes and has resulted in successful term pregnancies and the birth of normal children, promotes Ca2+ oscillations and induces oocyte activation via TRPV3-mediated Sr2+ influx, as TRPV3 deletion in oocytes (TrpV3−/−) failed to respond to Sr2+-induced activation [5,6].  As the TRPV3 channel is Ca2+ permeable and SrCl2-induced oocyte activation is thought to occur via mimicking Ca2+ by sensitizing and potentiating IP3 receptors, the authors also showed that application of the TRPV3 agonist carvacrol in heterozygous oocytes (TrpV3+/−) led to a substantial increase in intracellular Ca2+ levels as well as parthenogenesis in both TrpV3+/− and wild-type oocytes (TrpV3+/+) (as measured by pronuclear formation and cleavage to the 2-cell stage), whereas TRPV3-deficient oocytes failed to respond [5]. 

Furthermore, the phorbol ester PMA, which has been shown to induce parthenogenetic activation of mouse oocytes when combined with ionomycin and reactivate latent HIV-1, has also been shown to potentiate TRPV3 channel activation in a PKC-dependent manner, while PIP2 hydrolysis potentiates TRPV3 voltage-independent current, causing thermal activation at cooler temperatures, suggesting the involvement of the PLC/PIP2/IP3/Ca2+/DAG/PKC pathway in the regulation of the TRPV3 channel [7-10].  Indeed, carvacrol was shown to induce intracellular Ca2+ mobilization and the phosphorylation of PLCγ1 in human dermal fibroblasts [11]. As CaMKK2 and PLCγ1 are also present in oocytes and T cells and PLCγ1 activation is essential for TCR-stimulated T cell activation and T cell activation-induced latent HIV-1 reactivation, a common mechanism of action potentially characterized by a Ca2+-induced stress signal is implicated, wherein activation of the PLC/Ca2+/CaMKK2/AMPK pathway is likely critical for both oocyte activation and T cell activation.  

Moreover, both carvacrol and the TRPV1 channel agonist capsaicin have been shown to activate AMPK and potentiate T cell activation [12,13].  Chan et al. demonstrated that in both Jurkat T cells and THP-1 monocytic cells, carvacrol administration triggered intracellular Ca2+ mobilization as well as selective activation of the mitogen-activated protein kinases JNK in THP-1 monocytic cells and ERK in Jurkat T cells [14].  Because studies have also shown that latent HIV-1 reactivation by phorbol esters such as prostratin involve the activation of both ERK and JNK and T cell activation leads to the phosphorylation and activation of ERK, carvacrol may indeed be effective in modulating the activities of immuno-responsive cells, particularly T cell activation [15,16,20].”  

Similar to the AMPK activator Metformin, several studies have also demonstrated that carvacrol is also capable of suppressing the proliferation, migration, and invasion of glioblastoma cells, an aggressive and incurable brain tumor type that is invariably associated with devastating consequences [17,18,21]. Strikingly, as an increase in intracellular Ca2+ concentrations is critical for the activation of oocytes and T cells (and thus T cell activation-induced latent HIV-1 reactivation), Liang et al. also demonstrated that carvacrol induced apoptosis (i.e. programmed cell death) in human glioblastoma cells by increasing intracellular levels of Ca2+ in a concentration-dependent manner that was abolished via inhibition of PLC and PKC [19]. Carvacrol also induced a concentration-dependent increase in cellular ROS levels, leading the researchers to conclude that carvacrol-induced cell death of human glioblastoma cells is mediated by an increase in intracellular Ca2+ levels via inducing the PLC/Ca2+/PKC pathway [19]. 

This pathway is nearly identical to the pathway that characterizes the activation of both oocytes and T cells, namely the PLC/PIP2/IP3/Ca2+/DAG/PKC pathway (see Figure below). Because CaMKK2 is also present in oocytes and T cells, is activated by increases in intracellular Ca2+ levels, and functions as an upstream activator of AMPK, the augmentation of the aforementioned pathway, producing the PLC/PIP2/IP3/Ca2+/CaMKK2/AMPK/DAG/PKC pathway, likely plays an essential role in oocyte activation, latent HIV-1 activation, and cancer cell apoptosis.  Indeed, if evidence continues to accrue implicating AMPK activation as a central mediator in the creation of all human life and the potential eradication of diseases thought to be incurable (e.g. HIV-1 and glioblastoma), a paradigm shift in the assessment of disease etiology and treatment is inevitable.

https://www.linkedin.com/pulse/oregano-compound-activates-oocytes-kills-glioblastoma-finley?published=u 

References:

           

1. Xu H, Ramsey IS, Kotecha SA, et al. TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature. 2002 Jul 11;418(6894):181-6. 

2. Xu H, Delling M, Jun JC, Clapham DE. Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels. Nat Neurosci. 2006 May;9(5):628-35. 

3. Cheng W, Yang F, Liu S, et al. Heteromeric heat-sensitive transient receptor potential channels exhibit distinct temperature and chemical response. J Biol Chem. 2012 Mar 2;287(10):7279-88. 

4. Tominaga M, Tominaga T. Structure and function of TRPV1. Pflugers Arch. 2005 Oct;451(1):143-50. 

5. Carvacho I, Lee HC, Fissore RA, Clapham DE. TRPV3 channels mediate strontium-induced mouse-egg activation. Cell Rep. 2013 Dec 12;5(5):1375-86. 

6. Kyono K, Kumagai S, Nishinaka C, et al. Birth and follow-up of babies born following ICSI using SrCl2 oocyte activation. Reprod Biomed Online. 2008 Jul;17(1):53-8. 

7. Uranga JA, Pedersen RA, Arechaga J. Parthenogenetic activation of mouse oocytes using calcium ionophores and protein kinase C stimulators. Int J Dev Biol. 1996 Apr;40(2):515-9. 

8. Hu HZ, Xiao R, Wang C, et al. Potentiation of TRPV3 channel function by unsaturated fatty acids. J Cell Physiol. 2006 Jul;208(1):201-12. 

9. Doerner JF, Hatt H, Ramsey IS. Voltage- and temperature-dependent activation of TRPV3 channels is potentiated by receptor-mediated PI(4,5)P2 hydrolysis. J Gen Physiol. 2011 Mar;137(3):271-88. 

10. Spina CA, Anderson J, Archin NM, et al. An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathog. 2013;9(12):e1003834. 

11. Lee J, Jung E, Yu H, et al. Mechanisms of carvacrol-induced expression of type I collagen gene. J Dermatol Sci. 2008 Dec;52(3):160-9. 

12. Kim E, Choi Y, Jang J, Park T. Carvacrol Protects against Hepatic Steatosis in Mice Fed a High-Fat Diet by Enhancing SIRT1-AMPK Signaling. Evid Based Complement Alternat Med. 2013;2013:290104. 

13. Lee GR, Jang SH, Kim CJ, et al. Capsaicin suppresses the migration of cholangiocarcinoma cells by down-regulating matrix metalloproteinase-9 expression via the AMPK-NF-κB signaling pathway. Clin Exp Metastasis. 2014 Dec;31(8):897-907.   

14. Chan AS, Pang H, Yip EC, Tam YK, Wong YH.  Carvacrol and eugenol differentially stimulate intracellular Ca2+ mobilization and mitogen-activated protein kinases in Jurkat T-cells and monocytic THP-1 cells. Planta Med. 2005 Jul;71(7):634-9.

15. Na BR, Kim HR, Kwon MS, et al. Aplotaxene blocks T cell activation by modulation of protein kinase C-θ-dependent pathway. Food Chem Toxicol. 2013 Dec;62:23-31. 

16. Márquez N, Calzado MA, Sánchez-Duffhues G, et al. Differential effects of phorbol-13-monoesters on human immunodeficiency virus reactivation. Biochem Pharmacol. 2008 Mar 15;75(6):1370-80. 

17. Chen WL, Barszczyk A, Turlova E, et al. Inhibition of TRPM7 by carvacrol suppresses glioblastoma cell proliferation, migration and invasion. Oncotarget. 2015 Jun 30;6(18):16321-40. 

18. Chen WL, Turlova E, Sun CL, et al. Xyloketal B suppresses glioblastoma cell proliferation and migration in vitro through inhibiting TRPM7-regulated PI3K/Akt and MEK/ERK signaling pathways. Mar Drugs. 2015 Apr 22;13(4):2505-25. 

19. Liang WZ, Lu CH. Carvacrol-induced [Ca2+]i rise and apoptosis in human glioblastoma cells. Life Sci. 2012 May 15;90(17-18):703-11. 

20. Finley J. Oocyte activation and latent HIV-1 reactivation: AMPK as a common mechanism of action linking the beginnings of life and the potential eradication of HIV-1. Med Hypotheses. 2016 Aug;93: 34-47.
21. Seliger C, Meyer AL, Renner K, et al. Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-β2. Cell Cycle. 2016 May 10:1-12.