A tip by DIM has got me interested in DHEA and pregnenolone:
1: Growth Horm IGF Res. 2004 Jun;14 Suppl A:S18-33. Links
Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination.Schumacher M, Guennoun R, Robert F, Carelli C, Gago N, Ghoumari A, Gonzalez Deniselle MC, Gonzalez SL, Ibanez C, Labombarda F, Coirini H, Baulieu EE, De Nicola AF.
Inserm U488, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France. firstname.lastname@example.org
Progesterone (PROG) is synthesized in the brain, spinal cord and peripheral nerves. Its direct precursor pregnenolone is either derived from the circulation or from local de novo synthesis as cytochrome P450scc, which converts cholesterol to pregnenolone, is expressed in the nervous system. Pregnenolone is converted to PROG by 3beta-hydroxysteroid dehydrogenase (3beta-HSD). In situ hybridization studies have shown that this enzyme is expressed throughout the rat brain, spinal cord and dorsal root ganglia (DRG) mainly by neurons. Macroglial cells, including astrocytes, oligodendroglial cells and Schwann cells, also have the capacity to synthesize PROG, but expression and activity of 3beta-HSD in these cells are regulated by cellular interactions. Thus, Schwann cells convert pregnenolone to PROG in response to a neuronal signal. There is now strong evidence that P450scc and 3beta-HSD are expressed in the human nervous system, where PROG synthesis also takes place. Although there are only a few studies addressing the biological significance of PROG synthesis in the brain, the autocrine/paracrine actions of locally synthesized PROG are likely to play an important role in the viability of neurons and in the formation of myelin sheaths. The neuroprotective effects of PROG have recently been documented in a murine model of spinal cord motoneuron degeneration, the Wobbler mouse. The treatment of symptomatic Wobbler mice with PROG for 15 days attenuated the neuropathological changes in spinal motoneurons and had beneficial effects on muscle strength and the survival rate of the animals. PROG may exert its neuroprotective effects by regulating expression of specific genes in neurons and glial cells, which may become hormone-sensitive after injury. The promyelinating effects of PROG were first documented in the mouse sciatic nerve and in co-cultures of sensory neurons and Schwann cells. PROG also promotes myelination in the brain, as shown in vitro in explant cultures of cerebellar slices and in vivo in the cerebellar peduncle of aged rats after toxin-induced demyelination. Local synthesis of PROG in the brain and the neuroprotective and promyelinating effects of this neurosteroid offer interesting therapeutic possibilities for the prevention and treatment of neurodegenerative diseases, for accelerating regenerative processes and for preserving cognitive functions during aging.
PMID: 15135772 [PubMed - indexed for MEDLINE]
1: Microsurgery. 2003;23(1):49-55. Links
Effect of subepineurial dehydroepiandrosterone treatment on healing of transected nerves repaired with the epineurial sleeve technique.Ayhan S, Markal N, Siemionow K, Araneo B, Siemionow M.
Department of Plastic and Reconstructive Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
The epineurial sleeve technique for nerve repair is designed in part to protect a healing nerve from external humoral influences, but research suggests that the external factor dehydroepiandrosterone (DHEA) may actually improve nerve healing in crush injuries. To test the effect of DHEA, we injected it into the epineurial chambers created to repair transected rat sciatic nerves. In 18 control rats, the nerve was transected and repaired without DHEA treatment. Eighteen animals received subepineurial injections of propylene glycol vehicle, and 18 received subepineurial injections of about 0.2 ml DHEA. Walking-track analysis and toe-contracture measurements showed no significant differences among the three groups. At 12 weeks, the gastrocnemius muscles in the DHEA group were significantly heavier than those of untreated controls. At 6 and 12 weeks, DHEA-treated nerves had significantly more myelinated axons, larger average fiber diameter, and greater axonal cross-sectional areas in the proximal, middle, and distal sections. Myelin thickness did not differ between groups, except at 6 weeks between the DHEA and vehicle-treated groups. We conclude that subepineurial dehydroepiandrosterone treatment reduced the extent of denervation atrophy and induced an earlier onset of axonal regeneration. Copyright 2003 Wiley-Liss, Inc.
1: J Immunol. 2001 Dec 15;167(12):7094-101. Links
Administration of dehydroepiandrosterone suppresses experimental allergic encephalomyelitis in SJL/J mice.Du C, Khalil MW, Sriram S.
Department of Neurology, Multiple Sclerosis Research Center, Vanderbilt University Medical Center, Nashville, TN 37212, USA. email@example.com
Experimental allergic encephalomyelitis (EAE) is a Th1-mediated inflammatory demyelinating disease in the CNS, an animal model of multiple sclerosis. We have examined the effect of dehydroepiandrosterone (DHEA) on the development of EAE in mice. The addition of DHEA to cultures of myelin basic protein-primed splenocytes resulted in a significant decrease in T cell proliferation and secretion of (pro)inflammatory cytokines (IFN-gamma, IL-12 p40, and TNF-alpha) and NO in response to myelin basic protein. These effects were associated with a decrease in activation and translocation of NF-kappaB. In vivo administration of DHEA significantly reduced the severity and incidence of acute EAE, along with a decrease in demyelination/inflammation and expressions of (pro)inflammatory cytokines in the CNS. These studies suggest that DHEA has potent anti-inflammatory properties, which at least are in part mediated by its inhibition of NF-kappaB activation.
1: J Soc Biol. 1999;193(3):285-92.Links
[Neurosteroids: trophic effects in the nervous system][Article in French]
Schumacher M, Robert F, Baulieu EE.
U488 INSERM, Le Kremlin-Bicêtre, France. firstname.lastname@example.org
Some steroids, named "neurosteroïds", can be synthesized from cholesterol within both the central and peripheral nervous systems. Thus, pregnenolone and progesterone persist in the brain and in peripheral nerves long after removal of the steroidogenic endocrine glands by castration and adrenalectomy. The role of neurosteroids during the development of the nervous system is not well known, although they are synthesized by glial cells and some populations of neurons already during embryonic life. Cell culture experiments suggest that neurosteroids may influence the survival and differentiation of neurons and glial cells. In the adult nervous system, neurosteroids play an important role during regeneration. Progesterone is indeed synthesized by Schwann cells in peripheral nerves, where it plays an important role in the formation of new myelin sheaths after lesion. This is the first demonstration of a vital role for a neurosteroid in the nervous system.
1: Hum Reprod. 2000 Jun;15 Suppl 1:1-13.Links
Hum Reprod. 2001 Aug;16(8):1542.
Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination.Baulieu EE, Schumacher M.
INSERM U 488, Le Kremlin-Bicetre, France.
Some steroids are synthesized within the central and peripheral nervous system, mostly by glial cells. These are known as neurosteroids. In the brain, certain neurosteroids have been shown to act directly on the function of membrane receptors for neurotransmitters. For example, progesterone inhibits the neuronal nicotinic acetylcholine receptor, whereas its 3alpha,5alpha-reduced metabolite 3alpha,5alpha-tetrahydroprogesterone (allopregnanolone) activates the gamma-aminobutyric acid receptor complex A (GABA-R(A)). Besides these effects, neurosteroids also regulate important glial functions such as the synthesis of myelin proteins. Thus, in cultures of glial cells prepared from neonatal rat brain, progesterone increases the number of oligodendrocytes expressing the myelin basic protein (MBP) and the 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase). An important role for neurosteroids in myelin repair has been demonstrated in the rodent sciatic nerve, where progesterone and its direct precursor pregnenolone are synthesized by Schwann cells. After cryolesion of the male mouse sciatic nerve, blocking the local synthesis or action of progesterone impairs remyelination of the regenerating axons, whereas administration of progesterone to the lesion site promotes the formation of new myelin sheaths.
Praise the lord for PubMed! Or rather praise the humans who put it together!!!!!
Bloody hayfever! It's driving me bananas. At 5:30 am 11/6/08 after a fairly miserable night even with the surgical mask on I take a zirtek. This seems to have no effect on the hayfever and I sneeze a lot until about 8:50 when the sneezing calms down. Whether the 2g of ganoderma lucidum I took at 8:10 and washed down with hot tea had anything to do with this is moot as I suppose the pollen count could have suddenly dropped. I still feel rubbish with my glands in the throat all sore. Judging by the attack of hayfever that started last night in a late night drive through london the ganoderma lucidum doesn't have an effect since I had 2g immediately before a meal about an hour before the drive. However they do say that the herbs need to be taken with hot tea about an hour before a meal....ho hum. I hate the summer!
My right index wasn't painful this am.
My bad right leg was quite stiff but not too bad.
I feel like I have flu. My leg is always seems to be stiffer after I take any ganoderma lucidum and it was this morning after the 8am 2g dose and when I awoke. I think and taking into account an example of how it seems to work below I'm just going to forgo the ganoderma lucidum anti-hayfever strategy.
1: Iran J Immunol. 2007 Dec;4(4):220-6.Links
Effect of Ganoderma lucidum on cytokine release by peritoneal macrophages.Ahmadi K, Riazipour M.
Department of Immunology, Research Center of Molecular Biology, Baqiyatallah University of Medical Sciences, Tehran, Iran. email@example.com
BACKGROUND: The water-soluble extract of Ganoderma lucidum (Reishi) has been used as an immunomodulator to stimulate spleen cells proliferation and cytokine expression. OBJECTIVES: To investigate the effect of Ganoderma lucidum (G. lucidum) on cytokine production by mice peritoneal macrophages. METHODS: Mice peritoneal macrophages were prepared by intra-peritoneal injection of 5 ml cold PBS. Peritoneal macrophages were plated out at 1X10(6) cell/well in 1ml RPMI 1640 medium supplemented with 10%FCS, 50 microg streptomycin and 50U penicillin. Cells were incubated in the presence or absence of different concentrations of G. lucidum at 37 degrees C and 5% CO2 for 48 hours. Cell free medium was removed and used for cytokine assay by ELISA method (Bender med system). RESULTS: The results showed no significant differences in cell viability at concentrations ranged from 0-40 microg/ml compared with control group. G. lucidum enhanced IL-1beta, TNF-alpha and NO production in a concentration dependent manner. However, it is not clear if the enhancement of NO release is due to direct effect of G. lucidum on NO synthesis or by indirect endogenous modulation via cytokines. IL-12 release by peritoneal macrophages was also increased in response to different concentrations of G. lucidum, but maximum enhancement was induced in response to 5 microg/ml of G. lucidum (P<0.001). CONCLUSION: Our results indicate that G. lucidum at concentrations used has a positive effect on cytokine release and NO production by peritoneal macrophages. Therefore, it is concluded that G. lucidum at moderate concentrations improves macrophage function through cytokine and NO release.
Definitely don't want upregulation of NFKappaB below:
1: Int Immunopharmacol. 2007 Jun;7(6):864-70. Epub 2007 Mar 13. Links
Enhancement of IL-2 and IFN-gamma expression and NK cells activity involved in the anti-tumor effect of ganoderic acid Me in vivo.Wang G, Zhao J, Liu J, Huang Y, Zhong JJ, Tang W.
State Key Laboratory of Bioreactor Engineering and School of Pharmacy, East China University of Science and Technology, Shanghai, China.
Ganoderic acid Me (GA-Me) is a lanostane triterpenoid purified from Ganoderma lucidum mycelia, one of the most widely used herbs for cancer treatment and prevention in east Asia. In the present study, it was demonstrated that GA-Me could inhibit both tumor growth and lung metastasis of Lewis lung carcinoma in C57BL/6 mice. Compared with the control group, Natural Killer (NK) cells activity was significantly enhanced by intraperitoneal administration of GA-Me (28 mg/kg). Results of ELISA assay and RT-PCR showed that the expressions of Interleukin-2 (IL-2) and Interferon-gamma (IFN-gamma) were also increased (p<0.05). Additionally, the expression of Nuclear Factor-kappaB (NF-kappaB) was up-regulated after the treatment of GA-Me, which might be involved in the production of IL-2. In conclusion, the findings of this study implied that GA-Me could effectively inhibit tumor growth and lung metastasis through increasing immune function.
However here it seems to downregulate NF-kappaB
1: Mol Cell Biochem. 2007 Jul;301(1-2):173-9. Epub 2007 Jan 12. Links
Ganoderma lucidum polysaccharide peptide reduced the production of proinflammatory cytokines in activated rheumatoid synovial fibroblast.Ho YW, Yeung JS, Chiu PK, Tang WM, Lin ZB, Man RY, Lau CS.
Department of Pharmacology, University of Hong Kong, Hong Kong SAR, Hong Kong.
The aim of the current study was to elucidate the potential therapeutic effect of Ganoderma lucidum polysaccharide peptide (GL-PP) in rheumatoid arthritis (RA). The effects of GL-PP on cell proliferation and cytokine production were studied in RA synovial fibroblasts (RASF). GL-PP significantly inhibited the proliferation of RASF. Following the incubation with GL-PP, production of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 in RASF were significantly increased as expressed as percentage change from basal values. However, the actual effects were minimal due to the low basal values. When RASF were activated by IL-1beta or lipopolysaccharides, IL-8 and MCP-1 production increased many folds. GL-PP significantly suppressed their productions. The inhibitory effects of GL-PP on cytokine production in RASF were at least in part, by inhibiting the nuclear factor-kappa B (NF-kappaB) transcription pathway. Our results demonstrated that GL-PP had the unique ability to modulate cytokine production in RASF and warrants further investigation into its mechanism of action.
On balance though there seems to be more articles about upregulation of NF-kappaB than downregulation:
1: J Ethnopharmacol. 2006 Jan 16;103(2):217-22. Epub 2005 Sep 15. Links
Ganoderma lucidum mycelia enhance innate immunity by activating NF-kappaB.Kuo MC, Weng CY, Ha CL, Wu MJ.
Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan 717, Taiwan, ROC.
Ganoderma lucidum is a popular medicinal mushroom in China and Japan for its immunomodulatory and antitumor effects. The goal of this research is to investigate the effect of dried mycelia of Ganoderma lucidum produced by submerged cultivation on the enhancement of innate immune response. We found that Ganoderma lucidum mycelia (0.2-1.6 mg/ml) stimulated TNF-alpha and IL-6 production after 8h treatment in human whole blood. IFN-gamma release from human whole blood was also enhanced after 3 day-culture with Ganoderma lucidum mycelia (0.2-1.0mg/ml). However, Ganoderma lucidum mycelia did not potentiate nitric oxide production in RAW264.7 cells. To better understand the possible immuno-enhancement mechanisms involved, we focused on nuclear factor (NF)-kappaB activation. Electrophoretic mobility shift assay revealed that the Ganoderma lucidum mycelia (1.6 mg/ml) activated kappaB DNA binding activity in RAW264.7 cells. These results provide supporting evidences for the immunomodulatory effect of Ganoderma lucidum mycelia
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,