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time will come when medicine will organize itself into an
undercover dictatorship.   To restrict the art of healing to
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the Bastille of medical science.  All such laws are
un-American and despotic
Dr. Benjamin Rush
Signer of the Declaration of Independence
Cystic Fibrosis
Curcumin, a major constituent of turmeric, corrects cystic fibrosis
defects.
Egan ME, Pearson M, Weiner SA, Rajendran V, Rubin D, Glöckner-Pagel J, Canny S, Du K, Lukacs GL,
Caplan MJ.

Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, Post Office Box
208026, New Haven, CT 06520-8026, USA.
1: Science. 2004 Apr 23;304(5670):600-2.Click here to read   PMID: 16086935
Turmeric  may help correct defective CFTR gene in Cystic Fibrosis
Full Citation: "Cystic fibrosis is caused by mutations in the gene encoding the
cystic fibrosis transmembrane conductance regulator (CFTR). The most common
mutation, DeltaF508, results in the production of a misfolded CFTR protein that is
retained in the endoplasmic reticulum and targeted for degradation. Curcumin is
a nontoxic Ca-adenosine triphosphatase pump inhibitor that can be administered
to humans safely. Oral administration of curcumin to homozygous DeltaF508
CFTR mice in doses comparable, on a weight-per-weight basis, to those well
tolerated by humans corrected these animals' characteristic nasal potential
difference defect. These effects were not observed in mice homozygous for a
complete knockout of the CFTR gene. Curcumin also induced the functional
appearance of DeltaF508 CFTR protein in the plasma membranes of transfected
baby hamster kidney cells. Thus, curcumin treatment may be able to correct
defects associated with the homozygous expression of DeltaF508 CFTR."
Genistein may help correct defective CFTR gene in Cystic Fibrosis
Genistein potentiates wild-type and delta F508-CFTR channel activity.
Berger AL, Randak CO, Ostedgaard LS, Karp PH, Vermeer DW, Welsh MJ.

Hwang TC, Wang F, Yang IC, Reenstra WW.

Department of Physiology, Dalton Cardiovascular Research Center, University of Missouri-Columbia
65211, USA.
1: Am J Physiol. 1997 Sep;273(3 Pt 1):C988-98. PMID: 9316420
View all 6 of Turmeric/Cystic Fibrosis Citations Here
Full Citation: "Effects of genistein on wild-type (wt) and delta F508-cystic fibrosis
transmembrane conductance regulator (CFTR) were studied in NIH/3T3 cells
stably transfected with wt or mutant CFTR cDNA. As measured by I- efflux,
half-maximal concentration of agonist (K1/2) for forskolin-dependent activation
was greater for delta F508-CFTR than wt-CFTR. Genistein decreased the K1/2
for both forms of the channel and increased the maximal activity of delta
F508-CFTR by 3.7-fold. In cell-attached patches, 10 microM forskolin induced
minimal delta F508-CFTR activity with characteristic prolonged closed times
(estimated time constant, > 30 s). Genistein increased the forskolin-induced
macroscopic currents of wt-CFTR and delta F508-CFTR by 3- and 19-fold,
respectively. Variance analysis suggested that in the presence of forskolin and
genistein the open probabilities (Po) of wt- and delta F508-CFTR were identical.
In single-channel studies, at maximal adenosine 3',5'-cyclic monophosphate
(cAMP) stimulation, genistein increased the Po of wt-CFTR by prolonging the
open time, but, at submaximal cAMP stimulation, the Po was increased by
prolonging the open time and shortening the closed time. In excised patches with
CFTR channels preactivated in the cell-attached mode, genistein increased
ATP-dependent wt- and delta F508-CFTR current about twofold by prolonging
the open time. Our results thus suggest that phosphorylation-dependent
activation of delta F508-CFTR is defective and that genistein corrects this
defect at least in part by binding to the CFTR protein."
View all 4 of the GenisteinCystic Fibrosis Citations Here
Ginseng may help combat  lung infection from P. aeruginosa in Cystic Fibrosis
Ginseng treatment enhances bacterial clearance and decreases lung
pathology in athymic rats with chronic P. aeruginosa pneumonia.
Song ZJ, Johansen HK, Faber V, Høiby N.
Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Denmark.

1: APMIS. 1997 Jun;105(6):438-44.Links   PMID: 9236860
Full Citation: "Our findings indicate that ginseng treatment increases the
resistance of the athymic rats to P. aeruginosa lung infection. We therefore think
that ginseng has promising potential as a natural medicine for stimulation of the
immune system in CF patients with chronic P. aeruginosa lung infections."
DHA may down-regulate Linolenic Acid metabolism in CF. (Note:
reduction in LA metabolism would reduce inflammation via
prostaglandin pathways)
A mechanism accounting for the low cellular level of linoleic acid in
cystic fibrosis and its reversal by DHA.
Al-Turkmani MR, Andersson C, Alturkmani R, Katrangi W, Cluette-Brown JE, Freedman SD, Laposata M.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
02114.

1: J Lipid Res. 2008 Sep;49(9):1946-54. Epub 2008 May 14  PMID: 18480495
Excerpt: "The metabolic conversion of LA to n-6 metabolites, including 18:3n-6
and arachidonic acid, was upregulated in CF cells, indicating increased flux
through the n-6 pathway. Supplementing CF cells with DHA inhibited the
production of LA metabolites and corrected the n-6 fatty acid defect. In
conclusion, the evidence suggests that low LA level in cultured CF cells is due to
its increased metabolism, and this increased LA metabolism is corrected by DHA
supplementation."
Capsaican may help correct defective CFTR gene in Cystic Fibrosis
Capsaicin potentiates wild-type and mutant cystic fibrosis
transmembrane conductance regulator chloride-channel currents.
Ai T, Bompadre SG, Wang X, Hu S, Li M, Hwang TC.

Department of Medical Pharmacology and Physiology, Dalton Cardiovascular Research Center,
University of Missouri-Columbia School of Medicine, Columbia, Missouri 65211, USA.
1: Mol Pharmacol. 2004 Jun;65(6):1415-26. PMID: 15155835
Excerpt: "In whole-cell experiments, capsaicin potentiates cAMP-stimulated
wild-type CFTR currents expressed in NIH 3T3 cells or Chinese hamster ovary
cells in a dose-dependent manner with a maximal response approximately 60% of
that with genistein and an apparent Kd of 48.4 +/- 6.8 microM. In cell-attached
recordings, capsaicin alone fails to activate CFTR in cells that show negligible
basal CFTR activity, indicating that capsaicin does not stimulate the cAMP
cascade. The magnitude of potentiation with capsaicin depends on the channel
activity before drug application; the lower the prestimulated Po, the higher the
potentiation. Single-channel kinetic analysis shows that capsaicin potentiates
CFTR by increasing the opening rate and decreasing the closing rate of the
channel."
Feverfew may down-regulate inflammation in Cystic Fibrosis
Parthenolide inhibits IkappaB kinase, NF-kappaB activation, and
inflammatory response in cystic fibrosis cells and mice.
Saadane A, Masters S, DiDonato J, Li J, Berger M.

Department of Pediatrics, Rainbow Babies and Childrens' Hospital, Case Western Reserve University
School of Medicine, Cleveland, Ohio 44106, USA.

1: Am J Respir Cell Mol Biol. 2007 Jun;36(6):728-36. Epub 2007 Feb 1. PMID:
17272824
Excerpt: "We thus conclude that parthenolide inhibits IkappaB kinase, resulting
in stabilization of cytoplasmic IkappaBalpha, which in turn leads to inhibition of
NF-kappaB translocation and attenuation of subsequent inflammatory responses.
IkappaB kinase may be a good target, and parthenolide and/or feverfew might be
promising treatments for the excessive inflammation in CF."
Evening Primrose Oil may correct the theoretical
delta-6-desaturase abberation in Cystic Fibrosis.
Reduced levels of prostaglandin precursors in the blood of atopic
patients: defective delta-6-desaturase function as a biochemical basis
for atopy.
Manku MS, Horrobin DF, Morse N, Kyte V, Jenkins K, Wright S, Burton JL.

1:1: Prostaglandins Leukot Med. 1982 Dec;9(6):615-28.PMID: 6961468
Excerpt: "That the observed biochemical deficit plays a causative role in the
manifestations of atopy was indicated by the fact that in a double-blind,
placebo-controlled crossover trial, gamma-linolenic acid in the form of evening
primrose oil (Efamol), partially corrected both the biochemical abnormalities and
the clinical state.."
Flavonoids may improve CFTR gene function in Cystic Fibrosis.
Flavonoids stimulate Cl conductance of human airway epithelium in
vitro and in vivo.
Illek B, Fischer H.

Research Institute, Children's Hospital Oakland, Oakland, California 94609, USA.

1: Am J Physiol. 1998 Nov;275(5 Pt 1):L902-10.  PMID: 9815107
Excerpt: "The ability of the flavonoids genistein, apigenin, kaempferol, and
quercetin to activate cystic fibrosis transmembrane conductance
regulator-mediated Cl currents in human airway epithelium was investigated...All
flavonoids stimulated Cl currents in transepithelial experiments dose dependently.
"
Flavonoids may improve CFTR gene function in Cystic Fibrosis.
Modulation of deltaF508 cystic fibrosis transmembrane regulator
trafficking and function with 4-phenylbutyrate and flavonoids.
Lim M, McKenzie K, Floyd AD, Kwon E, Zeitlin PL.

Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287,
USA.
1: Am J Respir Cell Mol Biol. 2004 Sep;31(3):351-7. Epub 2004 Jun 10.Click here to read   PMID:
15191910
Excerpt: "Over 70% of patients with cystic fibrosis have the DeltaF508 mutation.
This protein is a partially functional chloride (Cl-) channel that is prematurely
degraded in the endoplasmic reticulum. Specific members of the flavonoid class
of compounds have been shown to increase Cl- conductance of wild-type and
DeltaF508 cystic fibrosis transmembrane regulator (CFTR)...Thus, a
combination of chronic treatment with 4-PBA or select flavonoids, followed
by acute flavonoid exposure, may be beneficial in cystic fibrosis."
Plant Lipase may provide ideal acid-stable adjunct to pancreatin
derived enzymes.
Plant sources of acid stable lipases: potential therapy for cystic fibrosis.
Tursi JM, Phair PG, Barnes GL.

Department of Gastroenterology, Royal Children's Hospital, Parkville, Victoria, Australia.
1: J Paediatr Child Health. 1994 Dec;30(6):539-43. PMID: 7865271
Excerpt: "Exogenous lipase used in the treatment of pancreatic insufficiency may
be destroyed by stomach acid...If simple methods of enzyme purification and
concentration can be developed, oats [and other plant sourced enzaymes) may
prove to be a practical source of acid stable lipase for use in the treatment of
patients with pancreatic insufficiency, especially those who have cystic fibrosis."
Bovine lactoferrin inhibits the efficiency of invasion of respiratory A549
cells of different iron-regulated morphological forms of Pseudomonas
aeruginosa and Burkholderia cenocepacia.
1: Int J Immunopathol Pharmacol. 2008 Jan-Mar;21(1):51-9.
PMID: 18336731
Lactoferrin inhibits Pseudomonas aeruginosa and Burkholderia cenocepia,
two infectious organisms found in Cystic Fibrosis patients.
Full Citation: "Pseudomonas aeruginosa and Burkholderia cenocepacia are two important
opportunistic respiratory pathogens of cystic fibrosis (CF) patients. Infections caused by these
microorganisms are particularly difficult to eradicate because they are usually highly resistant to
several currently available broad-spectrum antibiotics. Lactoferrin (Lf), a glycoprotein found in
physiological fluids of mammals and present at high concentrations in infected and inflamed
tissues, plays an important role in the natural defence mechanism against pathogens and in
immune regulation. In the present study, we evaluate the ability of bovine lactoferrin (bLf) to
influence P. aeruginosa PAO1 and B. cenocepacia PV1 adhesiveness and invasiveness, using the
A549 human bronchial cell line. Three different iron-induced morphological forms of bacteria
(free-living, aggregates and biofilm) were assayed. The addition of bLf to cells just before infection
had little influence on adhesion efficiency for all three of the morphological forms of B. cenocepacia
PV1, while a slight increase in adhesion efficiency by P. aeruginosa PAO1 was noticed.
Conversely, invasion of all three morphological forms of both P. aeruginosa and B.
cenocepacia was strongly inhibited by the presence of bLf, independently of its degree of
iron-binding activity. This is the first report demonstrating an anti-invasive property of bLf
for strains of P. aeruginosa and B. cenocepacia.."
Choline-related supplements improve abnormal plasma
methionine-homocysteine metabolites and glutathione status in
children with cystic fibrosis.
1: Am J Clin Nutr. 2007 Mar;85(3):702-8.  PMID: 17344490
Choline-related supplements may improve status of children with Cystic
Fibrosis
Full Citation: "BACKGROUND: Liver triacylglycerol accumulation and oxidative stress
are common in cystic fibrosis (CF) and also occur in choline deficiency. Previously, we
showed an association between elevated plasma homocysteine, reduced ratios of
S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH) and of
phosphatidylcholine to phosphatidylethanolamine, and phospholipid malabsorption in
children with CF. OBJECTIVE: The objective was to address a possible relation between
altered methionine-homocysteine metabolism and choline metabolism in children with
CF. DESIGN: Children with CF were assigned without bias to supplementation with 2 g
lecithin/d (n = 13), 2 g choline/d (n = 12), or 3 g betaine/d (n = 10) for 14 d. Plasma
concentrations of methionine, adenosine, cysteine, cysteinyl-glycine, glutathione,
glutathione disulfide (GSSG), and fatty acids; SAM:SAH; and red blood cell
phospholipids were measured within each group of children with CF before and after
supplementation. Plasma from healthy children without CF (n = 15) was analyzed to
obtain reference data. RESULTS: Children with CF had higher plasma homocysteine,
SAH, and adenosine and lower methionine, SAM:SAH, and glutathione:GSSG than did
children without CF. Supplementation with lecithin, choline, or betaine resulted in a
significant increase in plasma methionine, SAM, SAM:SAH, and glutathione:GSSG and a
decrease in SAH (n = 35). Supplementation with choline or betaine was associated with
a significant decrease in plasma SAH and an increase in SAM:SAH, methionine, and
glutathione:GSSG. Supplementation with lecithin or choline also increased plasma
methionine and SAM. CONCLUSION: We showed that dietary supplementation with
choline-related compounds improves the low SAM:SAH and glutathione redox
balance in children with CF."
Ginseng treatment reduces bacterial load and lung pathology in chronic
Pseudomonas aeruginosa pneumonia in rats.


1: Antimicrob Agents Chemother. 1997 May;41(5):961-4.   PMID: 9145852
Full Citation: "The predominant pathogen in patients with cystic fibrosis (CF) is
Pseudomonas aeruginosa, which results in a chronic lung infection associated
with progressive pulmonary insufficiency. In a rat model of chronic P. aeruginosa
pneumonia mimicking that in patients with CF, we studied whether the
inflammation and antibody responses could be changed by treatment with the
Chinese herbal medicine ginseng. An aqueous extract of ginseng was injected
subcutaneously, and cortisone and saline were used as controls. Two weeks
after challenge with P. aeruginosa, the ginseng-treated group showed a
significantly improved bacterial clearance from the lungs (P < 0.04), less severe
lung pathology (P = 0.05), lower lung abscess incidence (P < 0.01), and fewer
mast cell numbers in the lung foci (P < 0.005). Furthermore, lower total
immunoglobulin G (IgG) levels (P < 0.01) and higher IgG2a levels (P < 0.025) in
serum against P. aeruginosa sonicate and a shift from an acute type to a chronic
type of lung inflammation compared to those in the control and cortisone-treated
groups were observed. These findings indicate that ginseng treatment of an
experimental P. aeruginosa pneumonia in rats promotes a cellular response
resembling a TH1-like response. On the basis of these results it is suggested
that ginseng may have the potential to be a promising natural medicine, in
conjunction with other forms of treatment, for CF patients with chronic P.
aeruginosa lung infection."
Vitamin C controls the cystic fibrosis transmembrane conductance
regulator chloride channel.
1: Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3691-6. Epub 2004 Mar 1..  
PMID: 14993613
Vitamin C is a biolgical regulator of CFTR-mediated CL secretion in
epithelia, indicating its potential for the treatment of sticky airway
secretions in Cystic Fibrosis.
Full Citation: "Vitamin C (l-ascorbate) is present in the respiratory lining fluid of human
lungs, and local deficits occur during oxidative stress. Here we report a unique function
of vitamin C on the cystic fibrosis (CF) transmembrane conductance regulator (CFTR),
a cAMP-dependent Cl channel that regulates epithelial surface fluid secretion. Vitamin
C (100 microM) induced the openings of CFTR Cl channels by increasing its average
open probability from 0 to 0.21 +/- 0.08, without a detectable increase in intracellular
cAMP levels. Exposure of the apical airway surface to vitamin C stimulated the
transepithelial Cl secretion to 68% of forskolin-stimulated currents. The average
half-maximal stimulatory constant was 36.5 +/- 2.9 microM, which corresponds to
physiological concentrations. When vitamin C was instilled into the nasal epithelium of
human subjects, it effectively activated Cl transport in vivo. In CF epithelia, previous
treatment of the underlying trafficking defect with trimethylamine oxide or expression of
WT CFTR restored the activation of Cl transport by vitamin C. Sodium dependency and
phloretin sensitivity, as well as the expression of transcripts for sodium-dependent
vitamin C transporter (SVCT)-1 and SVCT2, support a model in which an apical vitamin
C transporter is central for relaying the effect of vitamin C to CFTR. We conclude that
cellular vitamin C is a biological regulator of CFTR-mediated Cl secretion in
epithelia. The pool of vitamin C in the respiratory tract represents a potential
nutraceutical and pharmaceutical target for the complementary treatment of
sticky airway secretions by enhancing epithelial fluid secretion."
A novel natural product compound enhances cAMP-regulated chloride
conductance of cells expressing CFTR[delta]F508.
1: Mol Med. 2002 Feb;8(2):75-87.Click here to read  PMID: 12080183
A natural product compound derived from Trichilia rubescens, corrects the
defective CFTR gene expression in a yeast model of Cystic Fibrosis.
Full Citation: "BACKGROUND: Cystic fibrosis (CF) results from mutations in the cystic fibrosis
transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel localized at
the plasma membrane of diverse epithelia. The most common mutation leading to CF, Delta F508,
occurs in the first nucleotide-binding domain (NBD1) of CFTR. The Delta F508 mutation disrupts
protein processing, leading to a decreased level of mutant channels at the plasma membrane and
reduced transepithelial chloride permeability. Partial correction of the Delta F508 molecular defect in
vitro is achieved by incubation of cells with several classes of chemical chaperones, indicating that
further investigation of novel small molecules is warranted as a means for producing new therapies for
CF. MATERIALS AND METHODS: The yeast two-hybrid assay was used to study the effect of
CF-causing mutations on the ability of NBD1 to self-associate and form dimers. A yeast strain
demonstrating defective growth as a result of impaired NBD1 dimerization due to Delta F508 was used
as a drug discovery bioassay for the identification of plant natural product compounds restoring
mutant NBD1 interaction. Active compounds were purified and the chemical structures determined.
The purified compounds were tested in epithelial cells expressing CFTR Delta F508 and the resulting
effect on transepithelial chloride permeability was assessed using short-circuit chloride current
measurements. RESULTS: Wild-type NBD1 of CFTR forms homodimers in a yeast two-hybrid assay.
CF-causing mutations within NBD1 that result in defective processing of CFTR (Delta F508, Delta
I507, and S549R) disrupted NBD1 interaction in yeast. In contrast, a CF-causing mutation that does
not impair CFTR processing (G551D) had no effect on NBD1 dimerization. Using the yeast-based
assay, we identified a novel limonoid compound (TS3) that corrected the Delta F508 NBD1
dimerization defect in yeast and also increased the chloride permeability of Fisher Rat Thyroid (FRT)
cells stably expressing CFTR Delta F508. CONCLUSION: The establishment of a phenotype for the
Delta F508 mutation in the yeast two-hybrid system yielded a simple assay for the identification of
small molecules that interact with the mutant NBD1 and restore dimerization. The natural product
compound identified using the system (TS3) was found to increase chloride conductance in
epithelial cells to an extent comparable to genistein, a known CFTR activator. The yeast system
will thus be useful for further identification of compounds with potential for CF drug therapy."







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