Bothrops lanceolatus Anhang 2

[Dr. Egidio Gallio]

The advantages of incorporating into homeopathy the “omics” sciences, which aim at the characterization and quantification of biological molecules that translate into the structure, function, and dynamics of an organism.

BACKGROUND

Hahnemann tells us:

“The physician’s duty is the knowledge of the full medicinal power of the remedies” Organon par.3.

Is it possible to improve this knowledge by using modern ‘omics’ sciences? The object of omics science is to characterise biological molecules in order to delineate structure, function and dynamics in an organism. Genomics, transcriptomics and proteomics respectively study the genetic information (DNA), messenger RNAs (mRNA) and proteins of the cell.

‘omics’ sciences Siehe https://link.springer.com/chapter/10.1007/978-3-319-43033-1_1

The ‘whole’ to which the suffix omics alludes, is not only the totality of the information that DNA, RNA and proteins contain, but also the totality of the functional interactions that underlie cellular metabolic processes and determine the difference between cell and cell or organism and organism.

We now know that it is not just DNA that determines this difference: it is gene expression, its regulation, post-transcriptional modifications and post-translational modifications that proteins undergo. These are networks of ‘non-linear’ interactions that are created between the three components DNA, RNA, proteins.

We must remember, for example, that not all RNAs code for proteins, but many of them perform a function without ever being translated, such as Trna transporters of amino acids or the so-called non-coding RNAs that regulate cellular processes, first and foremost gene expression.

The integration of omics sciences and technologies, in what is known as complex systems biology, thus makes it possible to improve understanding of the system, considered as a set of biological molecules that make it up. These brief hints make us understand the innovative depth of an “omics” approach and the possibility of moving towards an increasingly “individualised” study that respects the uniqueness of the person and gives meaning to his “peculiar ways of feeling, acting and suffering”, which Hahnemann also places as the basis of the search for a remedy that carries similar information in its biology.

The venom of the snake Bothrops lanceolatus or jararaca, from which an important homeopathic remedy is derived, has been studied using this method, revealing a vast therapeutic power, opening up a new avenue for the knowledge and study of homeopathic remedies on a scientific basis.

Materials And Methods

The homeopathic Bothrops lanceolatus constitutes the likely anatomo-pathological simillimum for Covid -19 as evidenced by a range of evidence. Unique among snake venoms, it contains molecules such as:

1) an angiotensin-converting enzyme (ACE) inhibitor, BPP5a, (Bradykinin-Potentiating Peptide), which binds, like the virus, to the ACE receptor 2, structurally very similar to ACE, and part of a regulatory complex linked to the Renin-Angiotensin-Aldosterone (SRAA) system, which regulates extracellular fluid volume, particularly blood volume. This nonapeptide was the precursor to the ACE inhibitors and sartans that revolutionised hypertension therapy. The ACE2 receptor, which is almost ubiquitous in the body, is also the same binding site for the spike protein used by Sars-Cov-2 to penetrate human cells, and the spike is also the elective target of the immune reaction triggered by anti-Covid vaccines.

2) A BjSP serine protease from the venom is analogous to the viral transmembrane serine protease type 2 (TMPRS2), which increases viral uptake at the cell wall almost 100-fold.

And again, shared with other snake venoms:

3) metalloendopeptidases that degrade the extracellular matrix and components of the coagulation cascade leading to haemorrhage, oedema, inflammation and necrosis up

to consumption coagulopathy (DIC). Diffuse endothelitis and thromboinflammation cause severe heparin-resistant thromboembolic complications, typical of Covid.

4) Phospholipase A2: contributes to oedema, myotoxicity and coagulation disorders.

Bradykinin-mediated alveolar angioedema, released by zinc-dependent metalloproteinases and by phospholipase A2 of the venom, is characterised by resistance to corticosteroids.

5) C-type lectin with anticoagulant, procoagulant, platelet activation agonist/antagonist action.

In COVID-19, ACE2 is reduced (downregulation) and cannot balance ACE and its vasoconstrictive, inflammatory, oxidative stress and mitochondrial depletion effects.

The transformation of angiotensin II into angiotensin 1-7, which has “opposite” effects (vasodilation, antiproliferative and anti-fibrotic effects), is also reduced. 

The almost ubiquitous presence of ACE2 in many cell types, and also in a soluble circulating form, accounts for the great variety of symptoms expressed, but also for the

broad spectrum of action, still partly unknown, of Bothrops.

The homeopathic Bothrops is therefore a candidate not only for the treatment of COVID -19 pictures with thromboembolic complications from multi-organ vasculitis, as demonstrated in another publication, but also for preventing adverse events related to vaccines, both mRna and GMO viral vector, as they induce the synthesis of the spike protein, which is intrinsically capable of activating endothelitis.

It could also be considered in persistent symptoms of the so-called Long – Covid.

The homeopathic pathogenesis of B. is typically derived from:

— The homeopathic proving of Bothrops shows a certain number of physical and mental functional symptoms, but apart from having been carried out on relatively few subjects compared with similar remedies, such as Lachesis m. or Crotalus h., it can never be pushed to the point of harming the prover, nor can it be protracted for too long, with loss of information.

Moreover, it does not allow us to have data on the chronic action of the remedy, although it can highlight a certain sensitive type, through repeated provings. The quality

of the proving itself in general is very much conditioned by the experience and competence of the proving staff and it is difficult to replicate it on large numbers.

— The toxicology of the venom, which faithfully reproduces the typical clinical effects of Covid-19 in all stages of severity according to individual susceptibility, is fundamentally based on snakebite poisonings and provides insight into the related acute organ-lesional damage.

–Finally, the clinic, the third source of homeopathic pathogenesis, tells us of symptoms repeatedly cured over time by the prescription of the remedy, but with relative reliability.

A new possibility of study for deeper knowledge:

—Omic sciences (Die Untersuchung der molekularen Grundlagen von Krankheiten kann auf unterschiedlichen Ebenen und mit unterschiedlicher Komplexität erfolgen. Holistische Analysen werden häufig unter dem Begriff "omics"-Technologien zusammengefasst.) can provide access to a new source of pathogenetic information of homeopathic remedies, particularly those of biological origin, using information from analysis of the characteristic transcriptome and proteinome, far beyond simple traditional analysis.

From these data, it is possible to gain an insight into the complexity and peculiarities of the biological ‘totum’ of the substance of origin, as used in homeopathic medicine for the search of the simillimum, but starting from objective, measurable, reproducible data.

In classical pharmacological research, on the other hand, these analyses are mainly carried out to obtain active ingredients from which new therapeutic agents on specific functions can be obtained.

In the case of Bothrops jararaca, the great interest aroused by the richness and variety of biopeptides it contains led to a study (1) of deep sequencing of its mRNA library, allowing the identification through transcriptome analysis of as many as 76,765 de novo assembled isoforms, 96,044 transcribed genes and 41,196 unique proteins, 78 distinct functional classes of proteins, including toxins, inhibitors and tumour suppressors.

Another study applied a large-scale proteomic approach to gain extensive knowledge of the composition of the venom. Using functional genomics coupled with the connectivity map approach (C-map) in the above work, a direct search for the biological activities of venom incubated with the human mammary adenocarcinoma cell line (MCF7) was performed followed by RNA extraction and gene expression analysis.

The aim was to submit the list of up and down-regulated genes for C-map analysis in order to screen an expanded panel of biosimilar drug activities related to B. jararaca venom. In a list of 90 differentially expressed genes that was proposed for the discovery of 100 positively correlated drugs with the highest score, only the antihypertensive, antimicrobial (both antibiotics and antiparasitic) and anticancer classes had been previously reported for B. jararaca venom .

In a second study (2), a proteomic approach was devised in which Bothrops j. venom was fractionated by OFFGEL followed by chromatography, generating peptide and protein fractions. The latter was subjected to trypsin digestion. Both fractions were analysed separately by reversed-phase nanochromatography coupled to high-resolution mass spectrometry.

This strategy allowed deeper and joint characterisations of the peptidome and proteome (proteopeptidome) of this venom. Our results lead to the identification of 46 protein classes, comprising eight high-abundance venom components and 38 additional classes in lower abundance.

RESULTS

Summary information on the already known components of Bothrops jararaca venom:

Jararhagin, Metalloendopeptidase: Degrades components of the extracellular matrix and coagulation cascade leading to haemorrhage, oedema, inflammation and necrosis, apoptosis through production of ROS.

Serine endopeptidase: Affects platelet aggregation, blood coagulation, fibrinolysis, the complement system, blood pressure and the nervous system, has a high affinity for

the TMPRS2 protein which promotes penetration of SARS-CoV-2 into cells.

C-type lectin / similar to C-type lectin:  Anticoagulant, procoagulant, platelet activation agonist/antagonist

Cysteine-rich secretory protein: Induces an inflammatory response and affects the complement system (generation of anaphylatoxins), CNS action

Phospholipase A 2: Myotoxicity, neurotoxicity, anticoagulant effects, antiviral and antibiotic activity towards gram-positives and negatives

L-amino acid oxidase:  Agonist and antagonist of platelet aggregation; induces apoptosis

Vascular endothelial growth factor: Increases vascular permeability

Bothrojaracin (BJC): Potent antithrombotic action by selective thrombin inhibition

C-type natriuretic peptides and bradykinin potentiation:  Vasodilation by inhibition of angiotensin-converting enzyme through binding to ACE and ACE2 receptor

Phosphodiesterase:  Release of pyrimidines and purines, which may contribute to increased vascular permeability

Hyaluronidase:  Degrades hyaluronic acid present in the extracellular matrix, facilitating the spread of toxins

Ecto-5′-nucleotidase: Release of pyrimidine and purine, which may contribute to increased vascular permeability

Inhibitor of metalloendopeptidase: Inhibits enzymatic and haemorrhagic activity of snake venom metalloendopeptidases; found in abundance in snake plasma (protective mechanism)

Disintegrin: Inhibits platelet aggregation, anti-tumour action

Cobra venom factor b: Activates complement cascade

Three-finger toxin b , Sarafatoxin: Neurotoxicity and cardiotoxicity effects targeting nicotinic and muscarinic acetylcholinesterase receptors, beta1 and beta2-adrenergic receptors and L-type calcium channels.

Batroxobine : Effective in all heparin-resistant coagulation defects.                           Also makes a hemostatic superglue for wounds.

In a list of 90 differentially expressed genes that was proposed for the discovery of 100 positively correlated drugs with the highest score, only the antihypertensive, antimicrobial (both antibiotics and anti-parasitic) and anticancer classes had been previously reported for B. jararaca venom.

 Most of the drug classes identified were related to:

1) antimicrobial anti-parasitic and antiviral activity;

2) treatment of neuropsychiatric diseases (Parkinson’s disease, Alzheimer’s, schizophrenia, depression and epilepsy);

3) treatment of cardiovascular diseases, hypertension, heart failure, decompensation, arrhythmias;

4) anti-inflammatory and/or analgesic action, b-endorphin stimulation;

5) gastroesophageal diseases and diabetes;

6) oncological diseases, induction of oxidative stress and apoptosis in tumour cells.

The C-map results also indicated that the venom may have components that target G-protein-coupled receptors (muscarinic, serotonergic, histaminergic, dopaminergic, GABA and adrenergic) and ion channels.

In addition, this work has indicated the existence of additional active components of venom that could potentially be used in the treatment of other novel disorders.

The omics technologies, as demonstrated by the example of the Bothrops proteopeptidome, with their sequencing accuracy may open up new and interesting possibilities for study and research even in homeopathic medicine, which instead uses the energetic and biochemical ‘totum’ according to the Law of Similes, revealing misunderstood aspects such as to consider it a polychrest.

Derived considerations:

1) Demonstration of the wide spectrum of therapeutic action of a unique homeopathic remedy used in its totality thanks to its biological complexity, overcoming the limits of the single symptomatic active principle but on condition of a deep and global individualisation allowed only by the homeopathic methodology at present.

2) Scientifically founded justification of the symptomatology treated and curable by a certain remedy.

3) Enlargement in the knowledge of foreseeable effects resulting from homeopathic experimentation, from toxicology and from the clinic of a remedy, even if already known, both in acute and chronic conditions, thanks to the highlighting of the biological action tropisms in an enlarged systemic vision.

4) Potential contribution to the differential diagnosis between remedies and to a better selection of the individual simillimum.

5) Proposal of new remedies to be tested with a rich transcriptome and proteinome suggestive of high clinical interest.

6) Establishing scientific criteria of plausibility of the Law of Similitude and homeopathic therapy through pharmacological and biochemical correlations and interaction with the PNEI system.

7) Discovery of new fields of application, which currently escape the traditional methods of studying the therapeutic potential of substances.

8) Prediction of possible secondary or dissimilar effects of the incorrectly indicated remedy on the symptomatic whole.

9) Study of the in vitro action of different remedies, dilutions, dynamization, pharmacopraxis methods to demonstrate their efficacy and optimise their clinical use.

10) A revision of the homeopathic Materia Medica based on omics sciences would be of great interest to widen the pathogenesis and to justify it scientifically.

CONCLUSION

The study of the transcriptome and proteinome of Bothrops lanceolatus can be a precursor to an improved methodological approach for the study of homeopathic pharmacopoeia and its extension, improving the possibility of accurate prescription and differential diagnosis between similar remedies, to achieve more and more precision medicine.

The analysis of genomic patterns integrated by the expression of DNA, RNA, metabolites and proteins, to identify their biological roles in the response to diseases and drugs, is of great interest for a finally holistic approach to the biological complexity underlying the problems of health, disease and target therapy.

As has often been the case in the past, homeopathic medicine, with its original empirical-experimental-vitalist system, has anticipated the correct direction to take in order to orientate towards a radical and not merely symptomatic and ephemeral solution.

The omics sciences, which are in the vanguard of biomedicine, allow new possibilities of knowledge and research of new therapeutic molecules; however, if we do not overcome the reductionist and materialistic vision currently dominant, progress will be equally ephemeral.

Homeopathy, which has always been based on systemic concepts and on the personalisation of therapy, can take advantage of these new discoveries and technologies to perfect its knowledge and methodology, but also to build a bridge of ever closer scientific sharing with academic medicine which will allow a therapeutic continuum to be established between classical pharmacology, low-dose pharmacology and ultramolecular doses, enhancing with equal dignity both the therapeutic law of contraries and the law of similes, in order to achieve together the ideal of a single medicine that can provide the best possible solutions to diseases not only of man but also of all beings in the biosphere.

Vorwort/Suchen Zeichen/Abkürzungen Impressum