Algorithm for Hypertension Therapy by Gene Expression Programming

Hideyasu HIRANO1), Kenichi MAKINO1,2), Kenta TOMONAGA2), Keiichi ARASHIDANI2), Naoki KUNUGITA2), and Takumi YOSHIMIZU1) 1) Internal Medicine, Showa Hospital, Akane Medical Corporation 2) Environmental Management, University of Occupational and Environmental Health

Abstract: Diabetes mellitus, hypertension, hyperlipidemia, and hyperuricemia are called lifestyle related disease. Gene Expression programming might be one of the best programming methods to reconstruct disease tissue histology. The arteriosclerosis represents the terminal state of vascular degeneration depending on long never-ending diabetes, hypertension, and hyperlipidemia. Histological reconstruction might induce the more better disease situation. We created 5 basic commands to control vascular atherosclerosis. One:β-oxidation, 2:Activate PPP, and 3:Inhibition of collagen synthesis, those are introduced from Biochemical Expression Programming (BEP). Four: digest collagen is introduced from Gene expression Programming (GEP). Five: Suspend embolism is an example of medicine-expression programming (MEP). We succeeded to decrease the hypotensives by GEP programmed to clean up atherosclerotic blood vessels. Keywords: Keywords thiamine, pantothenic acid, Glutathione, Tocopherol, Alfacalcidol

Hideyasu HIRANO Showa Hospital, Akane Medical Corporation, 35-1 Shioiri Shimonoseki Yamaguchi 750-0059 Japan Tel. +81-832-31-3888, Fax. +81-832-31-7957 E-mail: [email protected]

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1. INTRODUCTION 2. Clean up atherosclerosis Hypertension, hyperlipidemia, hyperuricemia, Inside of the Arteriosclerotic blood vessel carries stroke, ischemic heart disease, and cancer were defied fats (neutral fat =fatty acids + glycerin、cholesterol)、 as adult ailments. While many researchers reported thrombosis (inactivated round erythrocytes were car- those for congenital diseases, highly controlled nutri- rier of oxygen), the supporting collagens and mem- tion reduces the occurrence of such adult ailments. So brane. Many scientists analysis of blood vessel might the hypertension, hyperlipidemia, and hyperuricemia be true, therefore those inside substances may easily called life-style related diseases. Hyperuricemia is an be vanished away by using biological and gene ex- excess of uric acid in the blood diseases. In 1996, pression reactions. Ideal way have to be 1) fatty acids public health council proposed that there are many degenerate CO2 and H2O in b-oxidation reaction us- causes of adult ailments in our daily life, so they de- ing pantothenic acids and vitamin B1, 2) components fined as those diseases for life style diseases. Defini- of atheroma are a covering collagen membrane and tion of Lifestyle disease is a disease associated with supporting collagen fibers. To remove these collagens the way a person or group of people lives. Lifestyle we decided to use GEP, that is, ECM (extra cellular diseases include atherosclerosis, heart disease, and matrix) metallo-proteinase expressed by Vitamin D3 stroke; obesity and type 2 diabetes; and diseases as- might digest collagens [3-5]. 3) The third is to inhibit sociated with smoking and alcohol and drug abuse. clotting of erythrocytes by activating pentose phos- Regular physical activity helps prevent the arterio- phate pathway. This procedure regenerates erythro- sclerosis that represents the terminal state of vascular cytes from stomacyte shape to normal discocyte shape degeneration depending on long passed diabetes, hy- (biconcave discoid shape). Regenerated discocytes pertension, and hyperlipidemia. Our research was to might re-circulate blood vessel. 4) Atorvastatin inhib- grouping the disease state, passing, therapy situation its HMG-CoA reductase, which is the key enzyme of those might be cured with GEP (Gene Expression cholesterol synthesis. Programming [1]) were collected and analyzed them. Ursodeoxycholic Acid increases cholesterol excre- Here we created a program and found our program tion into feces, however these two reactions may not reconstruct efficiently the arteriosclerosis in the hu- work effectively. man body and those indicated that living human gene could control by Fuzzy ON/OFF, Fuzzy Chaos theory. The atherosclerotic blood vessels cured well with the created expression program almost no bugs.

Table１.Hypertension regulatory commands and in- tra-human Machine Language. The commands b-oxidation and Activate PPP were created from biochemical reactions (BEP). Digest collagens was introduced from gene expression (GEP). Thrombolysis was chosen from medicines’ effects (MEP)

Figure 1. Concept of human as a computer [2] Obesity, heart disease, hypertension, diabetes, metas- tasis of cancer, and premature mortality are the tar- gets of histological reconstruction by GEP.

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thesis at wounded area after peeling off atheroma by Vitamin D3.

‘Clean up arteriosclerosis [CLEANUPAS.BAS] *Start ‘Cleanup blood vessels with arteriosclerosis For repeat=1 to 3 For week_a=1 to 2 For day=1 to 7 b-oxidation Digest collagens Activate PPP Figure 2. The pathway for catabolism of fatty acids is Suspend embolism referred to as the b-Oxidation Pathway, because oxi- Next day dation occurs at the b-position of carbon (C3). Next week_a ‘Hold the internal vessel clean and cover with vascular end membrane For week_b=1 to 2 For day=1 to 7 GEP b-oxidation Suspend embolism Inhibit collagen synthesis Digest Collagens Next day Next week_b Next repeat *End

Figure 3. Binding after the vitamin D3 receptor on plasma membrane, this receptor and vitamin D3 4. Measuring age of the blood vessel by complexes internalized into cellular plasma, this FORM Pulse wave velocity (PWV) is an index of arterial formed spherical particle and move on to the surface stiffness, and a simple device for measuring bra- of the nuclear membrane, and fused into inside out chial-ankle PWV (baPWV) by measuring 4 inflatable forming to release vitamin D3 complex, which moved (Riva-Rocci) cuff with round metal panel placed again to bind vitamin D3 binding element at the pro- around the both upper arms and lower extremities on 2 moter of ECM metalloprotease gene, that switch on to cm upper ankles. The pulse wave velocity indicates transcribe mRNA. the age of arterial blood vessel. We defined 6 danger-

ous statuses as for

5: Very dangerous is for more than 115 years,

3. Making a program to run in human 4: Dangerous is for more than 85, The program to run must clean up atherosclerosis, 3: Relatively dangerous is for 20 years over the ac- then it will take for one week to digest collagens and tual age, b-oxidize fatty acids, next step of waiting endothe- 2: Need to control nutrition, and lium membrane formation inside blood vessel might 1: the rest of them are safety. need 2 weeks. It is possible to change this waiting 6: Out of normal ABI index (<0.9, 1.3<) indicates the existence of arteriosclerosis obliterans, in this program to use vitamin E that inhibit collagen syn- status no reliable baPWVs obtain, need immedi-

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ate div (drip infusion in vein) therapy. limited before GEP, while clear pulsation observed The case 6, 5, 4, and 3 need GEP therapy we de- after GEP. Inside and outside of the membrane fat scribing here. disappeared. Figure 4 shows FORM data of 86 years, the blood vessel age was over 115 years old while after the GEP therapy the age showed 95 years, 20 yeas had pull backed 5. GEP therapy effective to decrease hypotensives Patients with hypertension have to take hypotensives all their lives, our GEP therapy, however, succeeded to decrease their tablets taken. The name of the used tablets were Valsartan (40)(angiotensin II receptor blocker), amlodipine (2.5)(calcium channel an- tagonist), nifedipineL(10) (L-type calcium channel blockade), Imidapril (5) (Angiotensin-converting enzyme inhibitor), doxazosin(1) (α1-blocker), pra- zosin(0.5) (α-1 adrenergic blocker), DiltiazemR(100) (L-type Ca2+ channel blocker Diltiazem) and Aspi- rin(100) (long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets). All 4 patients decreased their hypotensives within 330 days. A rapid case spent 90 days, and a slow case needed 330 days. Main reason of this difference was the body weight controll. The best case was hospital- ized and controlled nutritionally. The longest case no

visit our clinic from 49th day to 153 days. Long days Figure 4.b up: before GEP, down: after GEP. FORM difference of this might be induced from Niacin, data indicated that her blood vessel age was changed which is the key vitamin to synthesize fatty acids. from115 yeas old to 95 years, this meant more than 20 years off her pre GEP therapy of blood vessel age.

6. Conclusions 1. BEP: β-oxidation, Activate PPP 2. GEP: Digest collagen 3. MEP: Suspend embolism We have defined 4 main GEP (BEP, GEP and MEP) commands to control arteriovenous histology. We used these command on the program mode against human body that induced artheriosclerotic restoration Figure 5. Echograms of before and after GEP therapy of vessels, and decreased their hypotensives. of carotid artery arteriosclerosis. Fatty generated inside and outside of carotid artery had almost cleared and recovered pulsation.

Figure 5 showed before and after the GEP therapy of carotid artery of echograms. The pulsation was very

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Figure 6. Four line graphs shows individual patients. All 4 members decreased their hypotensives tablets by GEP therapy.

Reference [1] Hirano-H, Makino-K, Tomonaga-K, Arashidani- K, Kunugita-K. Yoshimizu-T. Gene Expression Programming to Envelop Metastasized Cancer Cells by Commanding Adjacent Fibroblasts. J. Showa Hsp, Vol. 3 (2006) No. 1 pp.89-99 [2] http://en.wikipedia.org/wiki/Von_Neumann_arch itecture [3] Thomson BM, Atkinson SJ, Reynolds JJ, Meikle MC. Degradation of type I collagen films by mouse osteoblasts is stimulated by 1,25 dihydroxyvitamin D3 and inhibited by human recom- binant TIMP (tissue inhibitor of metallopro- teinases). Biochem Biophys Res Commun. 1987 Oct 29;148(2):596-602. [4] Uchida M, Shima M, Chikazu D, Fujieda A, Obara K, Suzuki H, Nagai Y, Yamato H, Kawa- guchi H. Transcriptional induction of matrix metalloproteinase-13 (collagenase-3) by 1alpha,25-dihydroxyvitamin D3 in mouse os- teoblastic MC3T3-E1 cells. J Bone Miner Res. 2001 Feb;16(2):221-30. [5] Grumbles RM, Shao L, Jeffrey JJ, Howell DS. Regulation of rat interstitial collagenase gene expression in growth cartilage and chondrocytes by vitamin D3, interleukin-1 beta, and okadaic acid. J Cell Biochem. 1996 Dec 15;63(4):395-409.

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Table 1

Figure 2.

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GEP

Digest Collagens

Figure 3.

Figure 5.