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Cancer, Rheumatoid Arthritis, Heart Disease & Fibromyalgia Are Worsened by Acidity

Cancer, Rheumatoid Arthritis, Heart Disease & Fibromyalgia Are Worsened in an Acidic Body

This is an article that reveals the dangers of eating and drinking food and fluids that will make your body more acidic.  Your body can not remove all the acidic things you consume fast enough to prevent damage to your body on multiple levels.  I have very briefly summarized and translated this article at the top, in to more lay terms for the ease of understanding the technical aspects of this article.

A link to the complete article is in this page for those who would like to read the original.

Thanks for stopping by and be sure to read down a little further – I provide a solution to this problem of over acidity.  It is a simple, easy fix and enjoyable to engage.

Yours in Health,
Dr. Noreen Picken, BA, BS, DC

Gene Expressions for Signal Transduction under Acidic Conditions

Toshihiko Fukamachi,1 Syunsuke Ikeda,1 Xin Wang,1 Hiromi Saito,1 Masatoshi Tagawa,2 and Hiroshi Kobayashi1,*PMCID: PMC3899954
This is a summary of a peer viewed, published paper regarding the effect of acidosis on cells.  As you will see in the very first paragraph – it is “well known that some diseased areas, such as cancer nests, inflammation loci (localized inflammation) and infarction areas (heart or other organs that have had the blood supply cut off) are acidified”.

The conclusions this paper and these authors come to after extensive lab studies, is that diseased or unhealthy or cancerous or inflamed tissues like rheumatoid tissues are acidic tissues.  will rapidly change – 2 fold – within less than 1 hour.  In 24 hours, more genes will changes – This is a problem with the genes are within cancerous tissues causing them to increase in their speed of reproduction and function.

Rheumatoid arthritis pH abnormality –

The pH value of articular fluid in the rheumatoid human knee joint was around 6.6, compared to around 7.3 in normal knee joints [5]. Other studies also showed the acidification of synovial fluid in arthritis [6,7,8].

Some diseased areas, such as cancer nests, inflammatory loci, and infarction areas, are acidified, but the acidification is less than 1 pH unit in many cases.

Our present data clearly showed that acidification affects gene expression even if the pH change is small.

Approximately 24,000 genes, about two-thirds of the mammalian genes, were analyzed using mesothelioma cells. The expressions of 693 genes were up-regulated more than twofold at acidic pH, and genes encoding proteins for signal pathways numbered 165 among the 693 genes. The expressions of 856 genes were down-regulated more than twofold at acidic pH, and 194 among the 856 genes encoded proteins for signal pathways.

Final Conclusion

Tissues in the body – are negatively impacted when they are in an acidic environment – even just a minor acidic change in the pH of the surrounding extracellular fluids around these tissues, causes the genes to dramatically swing in their behavior.

How Can You Insure Better Health and Avoid Becoming Acidic?

Love Your Health - Invest In Healthy Water

Love Your Health – Invest In Healthy Water

Drink Anti-oxidant, Restructured, Oxygen Rich –  water from a our processors.  For all the details about owning your own water processor; how simple, easy and inexpensive it is to have one in your own home – go to contact me by email at DrNoreenPicken@gmail.com

The following is a condensed version of:

Gene Expressions for Signal Transduction under Acidic Conditions  by:

Toshihiko Fukamachi,1 Syunsuke Ikeda,1 Xin Wang,1 Hiromi Saito,1 Masatoshi Tagawa,2 and Hiroshi Kobayashi1,*PMCID: PMC3899954

 Abstract

Although it is now well known that some diseased areas, such as cancer nests, inflammation loci, and infarction areas, are acidified, little is known about cellular signal transduction, gene expression, and cellular functions under acidic conditions.

Our group showed that different signal proteins were activated under acidic conditions compared with those observed in a typical medium of around pH 7.4 that has been used until now.

Investigations of gene expression under acidic conditions may be crucial to our understanding of signal transduction in acidic diseased areas.

In this study, we investigated gene expression in mesothelioma cells cultured at an acidic pH using a DNA microarray technique.

After 24 h culture at pH 6.7, expressions of 379 genes were increased more than twofold compared with those in cells cultured at pH 7.5. Genes encoding receptors, signal proteins including transcription factors, and cytokines including growth factors numbered 35, 32, and 17 among the 379 genes, respectively.

Since the functions of 78 genes are unknown, it can be argued that cells may have other genes for signaling under acidic conditions.

The expressions of 37 of the 379 genes were observed to increase after as little as 2 hours.

After 24 h culture at pH 6.7, expressions of 412 genes were repressed more than twofold compared with those in cells cultured at pH 7.5, and the 412 genes contained 35, 76, and 7 genes encoding receptors, signal proteins including transcription factors, and cytokines including growth factors, respectively.

These results suggest that the signal pathways in acidic diseased areas are different, at least in part, from those examined with cells cultured at a pH of around 7.4.

1. Introduction

In mammals, the pH values of blood and tissues are usually maintained in a narrow range around 7.4 [1]. In contrast, diseased areas, such as cancer nests, inflammatory loci, and infarction areas, have been found to be acidic. The extracellular pH in the central regions of tumors decreases below 6.7 in several tumors as a consequence of lactate accumulation derived from a lack of sufficient vascularization or an increase in tumor-specific glycolysis under aerobic conditions combined with impaired mitochondrial oxidative phosphorylation [1,2,3]. Extracellular pH may also drop to a value below 6 due to leaking of intracellular contents and the destruction of blood vessels resulting in hypoxic metabolism and related lactic acid production during inflammation against the infection of pathogens [4]. Similar acidic environments were also associated with other inflammation.

The pH value of articular fluid in the rheumatoid human knee joint was around 6.6, compared to around 7.3 in normal knee joints [5]. Other studies also showed the acidification of synovial fluid in arthritis [6,7,8].

Although cell functions mediated by a large number of enzymes with pH-dependent catalytic activity are strongly affected by the disruption of pH homeostasis, there have been only a few studies of signal transduction, gene expression, and cellular functions under acidic conditions.

Our group previously found that different signal transduction pathways function under acidic environments [11,12], and that CTIB, an IκB-β variant, acted as a critical factor at pH 6.3 but not at pH 7.4 [13,14]. Our group also showed the elevated activation of p38 and ERK in human T cells cultured at acidic pH [12,15]. In addition to these reports by our group, activation of the MAPK pathways and increased COX-2 protein expression were reported in acid exposed cells in Barrett’s metaplasia [16]. Matrix metalloproteinase-9 (MMP-9) expression was induced at acidic extracellular pH in mouse metastatic melanoma cells through phospholipase D-mitogen-activated protein kinase signaling [17]. Carbonic anhydrase 9 (CA9) expression was increased by acidosis via a hypoxia-independent mechanism that operates through modulation of the basic CA9 transcriptional machinery [18]. The gene expression of VEGF was stimulated at low extracellular pH [19,20]. Glioma stem cells grown in low pH conditions displayed an increase in expressions of Olig2, Oct4, Nanog, interleukin-8 (IL-8), TIMP1, TIMP2, VEGF, Glut1, SerpinB9, and HIF2α, whereas expressions of Sox2, GFAP, and HIF1α were repressed in the cells [21]. The expression of HIF1α induced by hypoxia was decreased by acidosis and the expression of ATF4 was increased by the combination of acidosis with hypoxia [22].

These previous findings led us to assume that different signal pathways operate under acidic conditions in mammalian cells. In addition to the molecules reported in previous studies described above, numerous molecules may work preferentially under low pH conditions. To exhaustively identify genes working for cell proliferation under acidic conditions, we used cancer cells that were able to proliferate rapidly and investigated the gene expression in mesothelioma cells cultured at acidic pH using a DNA microarray technique in the present study. After 24 h culture at pH 6.7, expressions of 379 genes were increased more than twofold compared with those in cells cultured at pH 7.5. The 379 genes contained 84 genes encoding receptors, signal proteins, transcription factors, cytokines, and growth factors, suggesting that the signal pathways in acidic diseased areas are different, at least in part, from those examined with cells cultured at pH around 7.4. The identified genes may be potential candidates for cancer chemotherapeutics. After 24 h culture at pH 6.7, expressions of 412 genes were repressed more than twofold compared with those in cells cultured at pH 7.5, and genes encoding receptors, signal proteins, transcription factors, cytokines, and growth factors numbered 118 among the 412 genes.

2. Materials and Methods

See complete published paper at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899954/

3. Results

3.1. Highly Expressed Genes under Acidic Conditions in Mesothelioma Cells

Approximately 24,000 genes were examined by microarray in mesothelioma cells (supplementary table), and the expressions of 379 genes were elevated more than twofold in cells cultured at pH 6.7 for 24 h compared with the cells cultured at pH 7.5 (Table 2). The accuracy of microarray analysis is mainly dependent on the RNA preparation. When the copy number of mRNA was low, the standard deviations of real-time quantitative PCR were close to 50% (Figure 1). We therefore assumed that more than twofold changes were significant in the present study. The 379 genes contained 35, 32, and 17 genes encoding receptors, signal proteins including transcription factors, and cytokines including growth factors, respectively (Table 2). The functions of 78 genes among the 379 genes are unknown.

3.2. Gene Expression after Culture for a Short Period at pH 6.7

The gene expressions were also examined after 2 and 5 hours at pH 6.7, and genes whose expression was increased were classified into seven groups as shown in Table 3. The expressions of 260 genes increased more than twofold in cells cultured at pH 6.7 for 2 hours compared with pH 7.5. The 260 genes contained 29, 25, and 5 genes encoding receptors, signal proteins including transcription factors, and cytokines including growth factors, respectively (Table 2). The expressions of 15 among the 260 genes maintained high levels more than twofold for 24 h (Table 3, group A), while the expressions of 223 among the 260 genes decreased again after 24 h (Table 3, groups E and G). The 191 genes were expressed at a high level only at 2 hours after the pH shift to 6.7 (Table 3, group G). After 5 hours culture at pH 6.7, 175 genes were expressed more than twofold higher than the expression levels at pH 7.5 (Table 2), and the 91 genes were expressed at a high level only at 5 hours after acidic stress (Table 3, group F). Genes encoding proteins for signal pathways among the genes whose expression was increased at acidic pH are listed in Table 4.

4. Discussion

Some diseased areas are acidified, but the acidification is less than 1 pH unit in many cases. Such a small change in pH has been thought to have little effect on mammalian cell functions until now. Our present data, however, clearly showed that acidification affects gene expression even if the pH change is small. Approximately 24,000 genes, about two-thirds of the mammalian genes, were analyzed in the present study, and 693 genes were up-regulated and 856 genes were down-regulated more than twofold at acidic pH in mesothelioma cells (Table 3, Table 6).

The expressions of 260 genes increased more than twofold in cells cultured at pH 6.7 for 2 hours compared with pH 7.5. The expressions of 223 among the 260 genes decreased again after 24 hours (Table 3). The physiological significance of the expression for a short time remains unclear. It is probably not due to the fluctuation of internal pH because the internal pH was decreased within 1 hour after the acidic shift and then maintained at a constant level (data not shown). It has been generally accepted that the activation of the signal proteins increases rapidly after the stimulation and then decreases. It could be suggested that the expression levels of some genes for signal proteins decrease after the initial stimulation, although no direct evidence has yet been reported.

Our group found that the decrease in external pH below 7 changes the signal pathways, at least in part [11,12,15], and we identified a gene product that was essential for proliferation at acidic pH [13]. The present data showed that 84 genes for signaling were expressed more strongly after 24 hours culture at acidic pH. The functions of the 78 genes whose expressions were up-regulated at acidic pH are unknown. It might be possible that some of these unidentified genes encode proteins for cellular signaling.

Since translational activities are different in different genes, the mRNA level is not proportional to the enzyme level. Therefore, all protein levels encoded by genes whose expression is affected by pH may be required for clarifying the signal pathways working at acidic pH. Furthermore, there are some genes whose expression is constitutive, but function is preferential at acidic pH. Lao et al. found CTIB to be essential for growth at acidic pH, but its expression was not affected by pH in the range from 6 to 8 [13,14,27]. p38 and ERK were activated strongly at acidic pH [12,15], but our present results showed no significant stimulation of their expression by acidosis. Identification of such proteins will be essential for improving our understanding of signal pathways operating under acidic diseased loci, and our present data could be useful for these studies as a database at the transcriptional level.

We found that different cytokines are expressed under different pH conditions (Table 4, Table 7). Especially IL-32 was found to express at a higher level at acidic pH in various cells. IL-32 was first identified in natural killer (NK) cells and IL-2 activated T cells [28], and was designated NK4. Since recombinant NK4 induced TNF-α production in human macrophages, it was assumed to have interleukin-like activity and hence was designated IL-32 [29].

Subsequent studies suggested that IL-32 is linked with pathological inflammation which often causes an acidic environment. Elevated IL-32 concentrations in synovial fluids and synovial tissues were demonstrated in rheumatoid arthritis but not in osteoarthritis patients [30,31].

Up-regulated IL-32 expression was also observed in the pancreatic ducts of chronic pancreatitis patients [32]. Taken together with our present data, IL-32 may be a factor that works under acidic conditions, but is not a cytokine specific to immune functions. IL-8, IL-15, and IL-16 were also up-regulated at acidic pH, and these interleukins may work in acidic diseased areas.

Our present data suggest that different signal pathways operate under different pH conditions. Why do mammalian cells have this multiplicity of signaling systems? The underlying mechanism is still unclear. Cytosolic pH changed with the change in extracellular pH, and the change in internal pH may affect protein activity because all proteins have pH-dependent activity. One possible explanation is that an enzyme having maximum activity at acidic pH works under acidic pH instead of the enzyme having maximum activity at alkaline pH.

Glycolysis was reported to increase in several tumors [1,2,3]. Only phosphoglycerate mutase 2 (muscle) was increased 2.03-fold at acidic pH (supplementary table), suggesting that other enzymes still work under acidic conditions without the elevation of transcription. Phosphoglycerate mutase 2 was reported to be a muscle-specific enzyme [33]. Since the muscles are often acidified, it can be argued that this enzyme works at acidic pH and the other isozyme does at alkaline pH.

The expressions of many receptor genes were affected by the pH change (Table 4, Table 7). Since receptors in the cytoplasmic membranes generally have a domain located outside the cells, the activity may be more sensitive to external acidosis compared with the cytosolic enzymes, and the gene expression of many receptors having an optimum activity at acidic pH may be stimulated by acidosis to compensate for the functional decline of receptors having an optimum activity at alkaline pH.

We used mesothelioma cells in the present study. Since the gene expression patterns were shown to be different in different cells, our present data may be applicable only to responses of mesothelioma cells. Analysis of the gene expressions in various cells, including non-tumor cells and normal tissues under acidic conditions will be essential for clarifying cell functions in acidic diseased areas.

The expressions of many receptor genes were affected by the pH change (Table 4, Table 7). Since receptors in the cytoplasmic membranes generally have a domain located outside the cells, the activity may be more sensitive to external acidosis compared with the cytosolic enzymes, and the gene expression of many receptors having an optimum activity at acidic pH may be stimulated by acidosis to compensate for the functional decline of receptors having an optimum activity at alkaline pH.

5. Conclusions

Some diseased areas, such as cancer nests, inflammatory loci, and infarction areas, are acidified, but the acidification is less than 1 pH unit in many cases. Our present data clearly showed that acidification affects gene expression even if the pH change is small. Approximately 24,000 genes, about two-thirds of the mammalian genes, were analyzed using mesothelioma cells. The expressions of 693 genes were up-regulated more than twofold at acidic pH, and genes encoding proteins for signal pathways numbered 165 among the 693 genes. The expressions of 856 genes were down-regulated more than twofold at acidic pH, and 194 among the 856 genes encoded proteins for signal pathways.

Thank you for taking your time to read through this timely and valuable study.  Please feel free to contact me if you would like additional information in regards to reducing your acidity levels and decreasing your chances of personally experiencing the negative results of having an acidic body.

Yours in Health,

Dr. Noreen Picken, BA, BS, DC
Nutritional Researcher & Longevity Specialist

Email – DrNoreenPicken@gmail.com
Or office phone –
1-931-761-6725  or 1-888-853-9391

 

 

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