PHYSIOLOGICAL REGULATING MEDIC INE 1/2007

THERAPY OF THEEXTRACELLULAR MATRIXINTOXICATION WITH PHYSIOLOGICAL REGULATINGMEDICINE

The extracellular matrix (ECM) repre-sents and “forms” the ground system ofall living beings, a locus where nourish-ment, control and management of allcells are concentrated and a mutual ex-change of information (molecules-energy) takes place.From the organoleptic point of view, ECMis a sol-gel gangue composed of glyco-saminoglycans (GAGs) = heteropolysac-charides patterned in repeated helicaldisaccharide unities. They are highlyhydrophilic, viscous, negatively charged,perpendicularly gathering around a pro-tein core. The combination of manyGAGs units with a protein forms a pro-teoglycan (PG), giving the macromole-cule a typical “brush-filter” shape.The role of the free and linked (PGs)GAGs ensure homeostasis: isoionicity,isosmoticity, isotonia. Moreover, theECM is composed of self-assembly col-lagen, elastin, reticular glycoproteins, fi-bronectin, laminin, vitronectin, throm-bospondin, tenascin, lectins - all of themimmunogen mediators.An electromagnetic signal picked up bythe glycocalyx and its endocellular ex-tension loses little energy. In the ECM,the electromagnetic wave closes uponitself, becoming a photon and regainingits undulatory character when it movesto the cytoplasm. As soon as the cata-bolic, environmental, food pathogen to-xic agents pollute the glycocalyx, theH2O molecules change their dielectricconstant: the electromagnetic-signalwaves do not become photons and, asnot being recognized by the calyx pro-teins, trigger counter-response-patho-logy mechanisms. Every human carriesone or more than one genetic changeconcerning the complex biosynthesis ofthe GAGs and PGs molecules but thesedo not become macroscopically phe-notypes. During one's lifetime, catabo-lites are stored up making energy ex-changes from and towards cells difficult.Thanks to Trincher's principle (biologicaltime x Delta T = constant), every cell li-ves a finite time.

- One of the most effective PRM medi-cal product to clean up and restore thecomplex role of the ECM is undoubtedlyGUNA®-MATRIX. In this paper, GUNA®-MATRIX is analyzed and discussed onthe basis of current scientific updates.

PROTEOGLY-CANS (PGS), ESOSAMINOGLYCANS(GAGS), PHYSIOLOGICAL REGULATINGMEDICINE, GUNA®-MATRIX

SUMMARY

KEY WORDS

INTRODUCTION

The matrix is a fundamental extracellu-lar (ECM), pericellular and intracellularsubstance for metabolic interaction, aubiquitous tissue characterized byphysiological SOL-GEL synchronicity.The current unitary view of the matrixoverlooks neither the morphologicaland biochemical aspects of its consti-tuents, nor the general biologicalaspects in which it operates in a phylo-and ontogenetic unity that sees currentliving beings as the last surviving wit-nesses which have filtered through themesh of evolution. In this publication,the amorphous extracellular structuresof the matrix (interstitial matrix) are pri-marily considered; the author conside-red the cellular aspects in a previous pu-blication [Milani, 2003 (c)].

- The most important stages in the evo-lution of organisms - when organizedinto tissues - were accomplished in thefinal detailing of the structural genes aswell as the biosynthesis control of thematrix constituents.

Hyaluronic acid is phylogenetically the

earliest glycosaminoglycan (GAG). Itdoes not involve any nucleic acids. It isa biological fossil, the first componentof the matrix that appears during the de-velopment of the mesenchyme from the2nd week of human embryonic deve-lopment. It is not only present in the firstphases of the constitution of life but al-so in the very first phases of the consti-tution of a new life: the spermatozoonenters the ovocyte thanks to hyaluroni-dase. The molecular structure of the pro-teoglycans (PGs) is very conservative: it maintains the same form in all pluri-cellular organisms. PGs and GAGs arepresent only in the animal kingdom.

The sugar structure is not DNA-encodedlike the amino acid sequences, forwhich the matrix enjoys great adaptabi-lity through autocatalysis.

The Virchow paradigm (1862), whichregards the cell as an "elementary orga-nism", was made obsolete by Pischinger(1979), who not only suggested a chan-ge of polarity of current thinking but al-so pointed out the sense and the pur-pose of the single parts interacting withthe whole working system: terms such

L. Milani

LEC

TU

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PHYSIOLOGICAL REGULATING MEDIC INE 1/2007

as “synchronicity”, “synergy”, “biologi-cal unity”, revive and detail the reduc-tive principle of feed-back, thus alteringit; the purely mechanistic concept offeed-back must be replaced by the mo-re elastic concept of intra-relationshipand inter-relationship between parts un-derstood not as “bricks in a single wall”but rather as a “wall in toto”. The task of science is to focus on the de-tails of reality, anatomizing and descri-bing them meticulously, but without for-getting to reassemble them as far as pos-sible; from this operation, the substan-tial facts of the integrated vision of thePhysiological Regulating Medicineemerge and stand out: the total is morethan the sum of its parts.This gives the deeper and more subtlemeaning to the art of healing.

ECM

The ECM “represents” and “forms” thebasic system of living organisms. It is thelocus in which:1. Nourishment 2. Control 3. Managementof all cells find their own integrationand the moment of mutual informationexchange (molecule-energy).The matrix is a chronopatho-dependentextra- (ECM) and pericellular sol-gelgangue consisting of:

1) Glucosaminoglycan (GAGs)

Heteropolysaccharide built accordingto repetition of disaccharide units (up to25,000).

Each disaccharide unit consists of:a) N-acetylglucosamine or

N-acetylgalactosamineb) Residue of

glucuronic acid oriduronic acid } uronic acids

GAGs are characterized by the presenceof sulphuric esters which, with the car-boxyl groups of the uronic acids, conferon the molecules a considerable densityof negative charges and viscosity.Recently, various techniques as X raycrystallography, Circular dichroism, Ro-tatory optical dispersion, NMR, have re-vealed that GAGs have a characteristichelicoid-hyperboloid conformation.

Due to their:- Viscosity: they are the ideal molecu-

les for lubrication (e.g. synovial li-quid);

- Rigidity: they are the guarantors ofthe cellular structural integrity provi-ding the "passages" among cells, thusallowing cellular migration.

Liu and Coll. (2003) have shown howmolecular engineering can be used toform different types of ECM to create"permissive niches" in which the CNSprogenitor cells can be directed in therequired direction. They have developed 3 different pro-teins of artificial ECM in which a signalsystem instructs the neuronal progenitorto “choose” the or a glial destination.In actual fact, the GAGs relax the chro-matin structure and make it easy for thepolymerases to “read” DNA.

2) Proteoglycans (PGs)

The GAGs are perpendicularly bound toa protein (protein core) through a tri-saccharide link and an O=CH bond(FIG. 1).The point of attack consists of a -S resi-due. The form of a proteoglycan is thatof a brush-filter (FIG. 2).Thanks to the polyanionic GAGs of aPG, they can bind H2O, exchange ions,bind cytokines, growth factors, metalions, catabolites and toxins.Only hyaluronic acid and heparin(GAGs) are not bound to a protein ske-leton, free in the ground substance.The role of the free and linked (PGs)GAGs ensures homeostasis:

- Isoionicity- Isosmoticity- Isotonia.

During human lifetime, the PGs and theelastin start to decrease from the age of20-25 years, while the collagen increa-ses with a maximum peak at 50 years.These out-of-phase curves are responsi-ble for the structural deterioration of thematrix with important repercussions onthe biological vitality of the body.

Their structure varies according to thetype and number of the polysaccharidechains of GAGs and according to theamino acid sequences which form theprotein support chain (protein core). Some of these molecules can unite insupramolecular aggregates of very highmolecular weight.

The PGs are highly polymeric macro-molecules. In the aggrecan of cartilage,1 g of dry weight can absorb up to 50ml of H2O.

The H2O in the matrix, thanks to the factthat the fulcrums of the + and - chargesdo not coincide, thereby giving it a pe-culiar polar character, is principallybound to the sugars.

WATER ANOMALIES

The H2O is a real liquid, lacking in ano-malies upwards of 60°.

GAG Gal Gal

trisaccharide link

O CH Serine

NH

C

OH

Xyl

core

protein

FIG. 1

Orthogonal fixation

of a GAG to a

protein core

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PHYSIOLOGICAL REGULATING MEDIC INE 1/2007

Between 0° and 60° it is like a fluid icewith almost crystalline componentscombined with really liquid compo-nents.These 2 phases are in equilibrium at37.5° (Franks, 1972; Trincher, 1981).Through autocatalysis, continuousspontaneous reorganization is obtainedin the matrix with:1) promotion; 2) transfer; 3) informationcancellation.

From the moment in the course of lifewhen the GAGs and PGs decrease, aprogressive loss of fluid-crystalline H2Ois apparent with loss of the functions 1),2) and 3).

The proteoglycans (TAB. 1):1) They participate to a determining

measure in the formation of theECM;

2) They are present on the cell surface;3) Small PGs are present in the cyto-

plasm;4) They are a "bridge" (glycocalyx) bet-

ween cells and ECM; they cross thecell membrane that can come intocontact with the cytoskeleton (mi-crotubules).

The network resulting from these inte-ractions, besides having a supportingrole, can regulate the flow of diffusiblemolecules by acting as a filter, influen-cing the mechanisms that are found atthe level of every single cell.The large amount of H2O retained bythe PGs gives the tissue elasticity and re-sistance.During the aging processes, the PGs gotowards a diminution in chondroitinsulphate and an increase in keratan sul-phate (highly represented in the ECM)with lesser ability to retain H2O.These events explain the following:1 Biological senescence2) Cutaneous wrinkling3) Shrinkage in stature4) Implosion of the organs, especially

the parenchymatous organs.The PGs concentrate around them thecounter-ions causing + osmotic pressu-re on the tissue.The PGs have high affinity for calcium

and they intervene in the processes ofcalcification.Other recognized properties:- Wound repair

- Concentration of the urine in thekidneys

- Accumulation and release of bioge-nic amine

a

b

~20nm

1200 nm

300-400 nm

40 nm

20-50nm

a The structure of a

proteoglycan (PG) is

comparable to that of a

brush: the trisaccharide

Galactose-Galactose-

Xylose link (Fig. 1)

turns like a cardan

joint on the group

O=CH allowing the

glycosaminoglycan

(GAG) a certain degree

of rotation on itself:

from this perspective,

a PG runs like a

rotating brush;

b Curious

morphological and

functional analogies

among the PGs

meshwork of the ECM

and the baleens of the

cetaceans: as the

latter act as a water

filter to trap plankton,

the former filter the

macromolecules to be

selectively carried in

the cytoplasm.

FIG. 2

TAB. 1

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PHYSIOLOGICAL REGULATING MEDIC INE 1/2007

- Regulation of the activity of the lyso-somal enzymes

- Lubrication of the joints- Inhibition of thrombus formation.

The PGs on the cell surface are directlyor indirectly implicated in basic me-chanisms such as:- Cell division- Cell differentiation- Cell-cell adhesion- Ligand-receptor recognition- Neoplastic transformation and evo-

lution.

E Each individual carries one or moregenetic defects with an alteration of cer-tain enzyme groups, not necessarily withsignificant phenotypic pathologies[Chromosomic or genetic alterations ofmatrix small proteoglycans (e.g. Proge-ria, Marfan syndrome); genetic altera-tions of splitting GAGs enzymes (e.g.Hurler syndrome, Morquio syndrome)].These genetic defects also involve theoptimal neobiosynthesis of GAGs andPGs.During life (psycho-immune environ-mental stress) catabolites accumulatethat progressively poison the matrix ma-king energy exchanges difficult from andby the cells.

∆T = T cell – T matrix > 0

– The whole aging process is nothingmore than the diminution of ∆T.

E Trincher's principle = biological timex ∆T = constantThis means that energy transformationin every cell must necessarily have a fi-nite time.

OTHER ECM CONSTITUENTS

Glycoproteins

1) Collagens: 15 different types, sepa-rated into 3 groups– Fibrillar– Fibril-associated– Nonfibrillar.

In fibrillar collagens, the fibers arearranged in parallel, but “out of pha-se” longitudinally by 1/4 of theirlength.All the basal membranes consist oftype IV collagen.

2) Elastin: elastin is wound into micro-fibrils. Fibroblasts, macrophages,and smooth muscle cells have re-ceptors for elastin.

3) Reticular glycoproteins (RG):Fibronectin (FIG. 3), laminin, vitro-nectin, tenascin (hexabrachion), lec-tins.The RGs bind to the integrins of thecell adhesion receptors and they in-fluence the structure of the cytoske-leton. They participate in the consti-tution of the basal membranes. The reticular glycoproteins are ex-tremely sensitive to proteolysis.

4) Hyaluronic acid: is the first glyco-protein to appear in the phyleticscale (Poriphera = sponges), and itis the first one to appear in theembryo.

5) Heparin.

6) Silicic acid [Si(OH)]n.

IMPORTANCE OF SILICIC ACID IN ECM

The regulation of the ECM, partly trig-gered by genetic factors, is clearly ne-cessary for the continuous and varyingexposure to physical-chemical environ-mental factors (TAB. 2).

An important role in matrix homeosta-sis is assumed by silicic acid. The importance of the role of silicic acid[Si(OH)]n in the matrix is due to the fact

The structure and position of the fibronectin, with its classical “seesaw”

behavior, modulates and synchronizes the entrance of some macromolecules

into the cytoplasm from the ECM.

FIG. 3

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PHYSIOLOGICAL REGULATING MEDIC INE 1/2007

that this inorganic acid can polymerizewith great facility, as the organic mole-cules do.Thanks to the weak bonds, it can co-polymerize with GAGs and PGs for-ming and strengthening the tunnel mes-hes necessary for the transport of mate-rials in the ECM.

IMPORTANCE OF METALLOPROTEINASES IN ECM

Matrix metalloproteinases (MMPs) ormatrixins are high molecular weightproteins having enzymatic activity thatact exclusively in the ECM. Matrixinsmonitor intracellular transcription andextracellular activation of cytokines. For example: IL-1 beta has an extremelyimportant role in cartilage turn over bymeans of matrixin 13 increase.They are:- the makers of ECM turn over- the ECM modellers- they act actively in Gel-Sol phases.

A SANDWICH FOR LIFE

Let us consider a cell with the doublephospholipid membrane (potential dif-ference of 70 mV). The glycocalyxes arenegatively charged because of the pre-sence of sialic acid. They are connectedto the cell nucleus through the micro-tubules, actin filaments and trabecularmeshwork (FIG. 4).The microtubules consist of 13 poly-

L HIGHLY CONSERVATIVEMECHANISM

Since the system passes from higherenergy to lower and the electromagne-tic wave frequency cannot change, thewavelength has to be reduced.

In the ECM, the electromagnetic waveis packaged to become a photon, whi-le, passing into the cell cytoplasm, itreacquires its own undulatory structure.

- When a toxic stressor is deposited onthe glycocalyx, the H2O moleculeschange their dielectric constant: theelectromagnetic waves are not transfor-med into photons and are not recogni-zed by the glycocalix R pathologicalevent because of code non-recognition.

ROLE OF THE ECM IN PHYSIOLOGICAL REGULATINGMEDICINE (PRM)

ECM is the real “basic regulatingsystem”: every alteration in the externaland internal environment influencescell mechanisms by means of the ECM.The communication between cells andexternal environment takes placethrough the ECM: the huge quantity ofinformation the ECM can store are trans-mitted to cells as instructions for their

TAB. 2

peptide chains of tubulin, made up ofonly 2 types (monomers) of proteins: α and ß tubulin.

Every monomer has a directed chargeand the whole microtubule "forms" a dipole. For this reason, the H2O molecules areattracted by the microtubule and assu-me a more orderly spatial configurationrelative to the cytoplasm and the ECM.

The H2O next to the microtubule ispractically immobile and disperses litt-le energy, through which an electroma-gnetic signal captured by the glycocalyxand its prolongation (cytoskeleton) losesvery little energy by amplifying the de-gree of penetration.

FIG. 4

The microfilaments,

the intermediate

filaments and the

microtubules do not

only represent the

endocellular support

structures, but also

the “paths” through

which the exo-

endocellular

information passes.

own physiological functioning. In the ECM neurovegetative endingsbranch off; in the ECM psyco-neuro-en-docrine-immunological information tra-vels by means of neural and endocrinesubstances and cytokines. The informa-tion coordinates and monitors the ECMfunctioning through the binding withmembrane receptors.A stressors deposit at this level is thepossible trigger for the onset and the de-velopment of a pathology.- Through PRM the static notion of ECMis overcome. The connective tissue ismeant as a morpho-functional unit (ca-pillary, matrix, membrane receptor).

GUNA®-MATRIX

Each PRM complex medicine is an op-timal composition of remedies (MRP =Master Remedies Pattern), a therapeuticunit having a different and higher globaleffect compared to the summation ofthe therapeutic effects of the single in-gredients; as a consequence, the formeris more effective (synergy-balance-com-pleteness principle).In the homeo-pharmacological structu-re of GUNA®-MATRIX is inscribed itscorrect therapeutic use rationale.In GUNA®-MATRIX composition, thereare 5 different and interactive cores:

E 1st core: Matrix drainage

DHEA 6X ; Prolactine 2X ; IL-6 4C ; Con-junctiva tissue, Porcine 6X ; Pyrogenium12X ; Tyrosine 2X ; Phenilalanine 2X ; Hi-stidine 2X.- The therapeutic effect of the ingredientsof the 1st core is:1) increase of the ECM cynetics (protein

hydrolisis, hyper-ionicity, histamineactivity) and ECM turnover;

2) Symphatheticotonic stimulation;3) Vagotonic slowdown.

E 2nd core: Lymphatic drainage

Lymphatic vessel, Porcine 6X.- The therapeutic effect of the ingredientof the 2nd core is the canalization ofinactivated toxins towards the lympha-

tic circle for their drainage.

E 3rd core: Toxins neutralization

Fucus vesiculosus 3X; Tyrosine 2X.- The therapeutic effect of the ingredientsof the 3rd core is the synergic action withFucus of the thyroid hormones activatingthe sympatheticotonic nervous system.

E 4th core: Action against toxin impre-gnation

Thuja occidentalis 6/8/12/30/200X; Na-trium sulphuricum 6/8/12/30/200X; Hya-luronidase 6X; DHEA 6X; Prolactin 6X.- The therapeutic effect of the ingredientsof the 4th core is toxins centrifugation to-gether with the potential carrying of to-xins by lymphatic capillaries (see 2nd co-re), matrix solubilisation and general ac-tion against the dysmetabolic mesenchi-mopathies (in Homeopathy: sicosis).

E 5th core: Metabolic support

D-L malicum ac. 6X; Lacticum ac. 3X;Ascorbic ac. 2X; Natrium oxal. 6X; Natriumpyruv. 6X; Nadidium 6X; Trichynol 6X.- The therapeutic effect of the ingredientsof the 5th core is stimulation of the ener-getic mitochondrial activity and ECMacidification promoting the connectivereactivity.

It is possible to notice - from the analy-sis of the 5 therapeutic cores of GUNA®-MATRIX - that the medicine contains 20homeopathically diluted unitary reme-dies:- P.N.E.I. unitaries (DHEA 6X; Prolactin

6X; Tyrosine 2X; Interleukin-6 4C);- Enzymes (e.g. Hyaluronidase 6X);- Porcine derivatives (e.g. Conjunctiva

tissue, Porcine 6X ; Lymphatic vessel,Porcine 6X);

- Nosodes (e.g. Pyrogenium 12X);- Krebs cycle intermediates (e.g. DL ma-

lic acid 6X, Natrum pyruvicum 6X);- Amino acids (e.g. Phenylalanine 2X;

Histidine 2X);- Unitaries from plant origin (e.g. Fucus

vesiculosus 3X; Thuja occ. 6/8/12/30/200X).

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PHYSIOLOGICAL REGULATING MEDIC INE 1/2007

Therefore, GUNA®-MATRIX is a com-plete therapeutic unit in which remedies“saturate” every phase of the etiophato-genetic cascade for the optimal deep de-toxification of the ECM.

GUNA®-MATRIX is, as a consequence,indicated in the detoxification and op-timal drainage of the ECM, after an acu-te inflammation, during and after an al-lopathic therapy (e.g. antibiotics, cor-tisone, cytostatic drugs), during and af-ter a prolonged psychophysical stress,during the convalescence, for everychronic pathology. GUNA®-MATRIX isalso a geriatric aspecific remedy parti-cularly effective. L

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PHYSIOLOGICAL REGULATING MEDIC INE 1/2007

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Author's address

Prof. Leonello Milani, MD, PhD- Vice President of A.I.O. T.- Scientific director of

“La Medicina Biologica” and “Physiological RegulatingMedicine”

- Professor h.c. of the HigherInstitute of Health Studies,Rome; a collaborative Centre for the WHO

- Lecturer and tutor in the Schoolof Homeopathy, Homotoxicologyand Integrated Disciplines -Academy of BiologicalMedicine.

Via Vanvitelli 6I - 20129 Milano