In this review, I would like to introduce Chinese natural herb, Huaier, for successful cancer recovery and health maintenance.  Please send me your opinions and questions later by e-mail or Telephone call.  Later, I will reply with detailed information.

In addition, I would like to emphasizen the obserbed influences of the repeated mRNA vaccinations against SARS-Cov-2.

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First, what is Huaier?  There is a long history on Huaier, first appeared in the litrature described at B.C. 200.  A result from a long trip to find the natural herb in Xin dynasty.  Currently, Huaier can be cultivated, and enough quantity prepared for clinics.

It costs very expensive, although efficacy depends on quantity, and not yet covered by National Insurance in Japan.

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Let me show the typical anti-cancer effects of Huaier. The successful dissection by endoscope was performed after 2 weeks of Huaier treatment.  See massive necrosis of the cancer lesion at the time of dissection.

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Huaier effects on liver metastasis in the severe advanced case of colorectal cancer. The recovery can be seen by CT image, together with significant decrease of tumor marker CEA.  Within one year, the patient was recovered completely.

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Huaier effects on pancreatic cancer, surgical detection not applicable, multiple metastasis in the liver and both lungs.  60 grams per day Huaier treatment resulted in significant decrease of cancer cells, also judged by tumor marker titers.  The patient successfully dissected pancreatic lesion and metastatic lesion, and currently no problem after four years

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Here, I make special attention to the destructive effects of conventional chemotherapy compared with Huaier effects.  Left panel indicates cisplatin for a year completely destroyed ribosomal RNA structures.  In Right panel, Huaier compensates destruction after one month of both conventional chemotherapy and Huaier treatment.  The destruction of ribosomal structure means no satisfactory RNA synthesis in new borne cells, which resulted in no tissue regeneration after cancer cell death.

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Examples of ribosomal RNA structures compared with normal control, mRNA vaccination, with or without conventional chemotherapy.  This damage of vaccinated normal control was fully recovered by administrating 20 grams of Huaier 3 months.   Surprisingly, a gross quantity of hair growth was observed simultaneously. We will further discuss about this normal control data later as Panel A in the last section of this review, relating to the genomic influence of repeated anti-COVID mRNA vaccination.

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  Additional Huaier effects are shown.  Huaier effects are dose-dependent. And 3 gram per day is enough to cure dermatitis.

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Cancer research has been investigated what happens in the process of carcinogenesis.  However, there are scarce information to explain what kind of molecular basis required for cancer recovery.

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In 2017, we decided to investigate the molecular basis of Huaier effects.  Since Huaier has a variety of efficacy not only on cancer, but also on many disorders, we should make a hypothesis to begin with.  As shown in the slide, we set Hippo Signaling Pathway rescue function to begin with. 

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Hippo signaling pathway was first found in Drosophila flies, so we started our experiments with transgenic Hippo mutant flies treatment.  These mutants are hepatoma model, too. All the genomes were completely analysed.  We are very pleased to introduce a simple and complete success to prove our hypothesis.  

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Cancer progression is expressed as malformation and disruption in Drosophila eye discs, easy to find and count. Hatched Hippo mutant larvae was raised with Huaier-containing food, resulted in the cures cancer within one week.  In this experiment, we could also confirm that dose-dependent action of Huaier, with no toxicity nor significant side effects.  

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One more advantage of Drosophila model is that we can know the metbolome profile of drosophila specimens used in the ecperiments, the small molecule composition.  Usual growth makes the composition move to clock-wise rotation, whereas cancer mutants has already rotated to counter-clockwise position.  Huaier treatment made stronger shift to the counter clockwise rotation, shifted to the time zero of life, to the embryonic stage.  I should emphasize that, just noted as a specific character of Hippo signaling pathway, the rescued function of Hippo is most effective and functional in iPS/ES cells.  The rescue of Hippo pathway by Huaier rewinds biological time to the early embryonic stage judging from the nutrition compositions.

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The schematic figure of Huaier rescue points on disrupted Hippo signaling pathway control. Red arrows show the point of Huaier action.

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To start with Hippo signaling pathway rescue, multiple functions are designated to be related to cell proliferation, apoptosis, immunological response, and neural differentiation.  Just like tyrosine kinase DYRK1A reported before.

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Here is shown schematic figure of intra-cellular signaling cascades.  Please note the strong similarity with integrated circuit in your smartphone.  This means none of simple stimulus stands alone.  Every signal relates each other, and spreads to every direction.

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Materials and Methods:
rom here, the genome scope results explaining how and what required for cancer recovery.  We are watching amazing aspects of genomic capability, flexibility. and possibility in human life,  please have a sky-high view to see the genome scape.  Never trapped in a trifle name of each factor.

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We have performed systematic transcriptome analysis by total mRNA and small non-coding RNA sequencing before and after the Huaier 

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Project summary.  Patients may undergo the surgical dissection during research period.  Basically, no other treatment during this clinical research, only one exception of pancreatic cancer shown before. 

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Results and Discussion: I introduce the striking results according to the process of translation and transcription.  First, RNA editing events.  We happened to identify enormous amount of SNP variant types from 92 sample analyses, and 92,427 SNP per sample, whereas 22,688 in total among normal healthy individuals.  Please note the extremely high numbers of mutated sites among all the expressed genes, most commonly found alteration is the skipping exons, different from the predicted pattern of alternative splicing. Huaier caused over thousands and thousands of mutations.

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The slide shows a comparison of up- and down-regulated transcribed genes transcriptomes before and after Huaier administration. Not only by quality, quantity of expressed genes was drastically changed.  In hepatoma patient, up to 85% of the total was upregulated within 30 days.  Then observed down-regulation and gene-silencing, until the end of research period.   The typical time-course of changes were detected in brain tumor and Hepatoma patients.

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The slide shows the real numbers of alterations in transcribed genes.  Let’s have a closer look into the numbers of the functional alterations induced by Huaier treatment. Please note the massive quantity changes found in each patient as noted by the previous slide.  

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The slide shows the summary of major changes of all the signaling cascades.  As expected, Hippo signaling pathway rescue is detected.

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There is signaling cascade summary by KEGG panels. You can put the sequence data, and can obtain these results easily for individual cancer. The quality change of each factor is demonstrated by cancer types.   Red letter means genetic mutation, red box indicates major mutated gene names. 

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For the rescue of dysfunction in each signaling cascade, chiefly by ageing, the transcriptional factors, written in red letters, contributed most.  As shown in the slide, the alteration of transcriptional factors changed at most for the rescue of every biological function.

Here we provide the typical answer to the question using he data obtained why and how Huaier is so effective.  Huaier causes surprising enhancement of gene function in almost all known transcriptional factors, responsible for the correction of transcriptional misregulation.  Thus, Huaier can modify and rescue the function of integrated intra- inter- signaling pathways.  These alterations in transcriptional factors can be detected in every cancer listed here.

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Schematic figure of transcription factor (TF)-differentially expressed genes (DEG) network  indicated unbelievable level of gene explosion, we call this “super-nova”.  The original gene functions of this patients were strongly inhibited and down-regulated by the long course of chemotherapy with molecular targeting drugs.  These changes will be silenced after the cure of cancer by Huaier treatment.  The drastic changes of altered transcribed genes were united by many transcription factors.  In this slide, the total changes of transcriptional factor and differentially expressed genes network showed galaxy structure like volcano eruption.  I have to note that these data can not be obtained by experiments using in vitro cultured cells, artificially.  Many researchers tried, and all the cells dead.  

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The slide shows the examples observed in prostate cancer patients.

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For easy understanding of the major factors for human life, here introduced nuclear factor kappa B to decide a fate of cancer recovery or more progression in prostate cancer.

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Decrease of this factor expression level inhibits cell proliferation, and increase promotes iPS/ES production.  Nuclear factor kappa B was first found in 1986 by Dr. Baltimore, and one of the most intensively investigated key molecule to health control.  It is important to keep the normal function of NF kappa-B function, not only for immunoregulation, but also for every situation in chronic intrinsic diseases, including cancer, collagen diseases, and other allergic disorders. 

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No compounds or anti-cancer drugs have been reported to evoke the similar drastic changes before, never the less within a short period of time (90 days at most), especially with no toxicity and side effects. I emphasize that the rescue effects ended up with gene silencing, massive suppression of gene expression such as NFkappaB. The patient has been long treated with strong anti-cancer drug (= significant shut down of gene function).  The explosive increase of quantitative and qualitative transcriptomes was occurred within 3 months’ Huaier treatment by 20g to 60g per day, seemed to be resulted in natural selection of iPS cells in vivo, with abundant c-myc and Oct3/4 gene expression,  and with normal level Sox2 and Kit4, together with severe opportunistic HTLV-1 infection. 

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Let’s have a closer look into another influencers of the transcription control.  Small nuclear RNAs.  Beyond our expectations, many novel factors are found and deposited to GeneBank.  So, most of their functionals are still unknown. This slide show the discovered novel factor level of each patient.

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For example, the quantitative changes of each factor are shown.  The quantity was changed according to the duration of Huaier treatment.  After surgical dissection, quantity regulation was completely reversed in some factors.

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In addition, I have to note that Huaier influences to neural transmission, too.  Here showed KEGG panel of Huntington's Disease signaling cascade, but there are more panels on Alzheimer's, Amyotrophic lateral sclerosis, and psychological disorders as Depression.

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Huaier rescues the disrupted Hippo pathway, which decides cell fate, to initiate the normal specification of the damaged tissue cells, to recover the homeostasis of renewed tissues.  Huaier itself has a function to kill cancer cells, but surgical dissection is recommended if applicable.  Huaier-uptake initiated cell fate shift to embryogenesis, which was typically indicated by the metabolome profile.

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Ribosomal structures by HPLC analysis (left column), with TF-DEG network (middle column).  The time of sampling, and Pfizer-BioNTech vaccinations (panel A. normal control 1; panel B. normal control 2; panel c for patient data) are indicated on the left side of each panel. The red and green dots in the TF-DEG network represent the up-regulated and down-regulated DEGs, respectively. The purple ball represents a transcription factor, and the greater the node is, the more DEGs the transcription factor regulates. In the right column of each panel, a comparison of the numbers of differentially expressed genes (DEGs) was placed according to the time course of Pfizer-BioNTech vaccination; red bars represent up-regulated molecules, and blue bars represent down-regulated molecules. 

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Panel B. normal control 2, this 55 years’ old surgeon is having 3 grams of uaier daily for 4 years, Panel C for COVID-19 patient data indicated on the side. Chest CT image analysis before (March 15) and after 3 months of 20 grams daily Huaier treatment on the patient (June 28).

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Ribosomal structures by HPLC analysis (left column), with TF-DEG network (middle column), of this patient. 

In the next page, we demonstrated virions and virion particles in the vaccinated patient blood specimens after vaccination ( Panels A and B) as well as infected specimen (Panel C).
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KEGG pathway analysis on COVID-19 panel hsp05171 (Panel A) and transcriptional misregulation and the P13K/AKT signaling pathway Panel B). Huaier administration was applied in the patient and normal control No.2. (5 g/day). Red bars represent up-regulated molecules, and blue bars down-regulated molecules. The figure was chosen at the time of the highest transcription factor-DEG network flexibility in each patient among serial analyses over a long time course of treatment.

Here shows the representative signaling pathways function rescued by Huaier treatment.  The patient treated only by 20 grams of Huaier every day for two years.  You can see the wide variety of cellular function was rescued, and that by the time course of Huaier treatment.

Conclusion:  

Carcinogenesis is a long process caused by step-by-step accumulation of genetic mutations and environmental stresses.  But as shown in this presentation, the process of the cancer recovery required drastic alteration on transcribed genes within 4 weeks at first.  Please note that what kind of compounds can do this much changes in vivo?  
Molecular basis of Huaier effects exists in the expansion of genome power itself, and the rescue of transcriptional dysregulation not only in Hippo signaling pathway, but also all the integrated signal transduction systems, especially relating to tyrosine kinase pathways.  No other medicine has not yet been reported to evoke the equivalent changes.  These changes occurred spontaneously in the patient, with no toxicity nor side effect.  In addition, significant NF-kB increase and its signaling pathway seemed to be responsible for the natural selection and production of iPS/ES cells, with subsequent differentiation to normal cells.

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Acknowledgements:

The author wish to thank cancer patient volunteers and many healthy volunteers kindly collaborated with the present study. The author also wish to express special thanks to; all the co-workers in BGI-Shenzhen, BGI-Japan,  QiDong Gaitianli Medicines Co. Ltd., Jiangsu Province, China, Japan Kampo New Medicine, Co. Ltd., Tokyo, Japan, and Mr. Nobuhiko Shiroto and Medical Alumni Association attached to Tokyo Medical and Dental University (TMDU) Medical School.

Funding:

The present study was grant-in-aid from QiDong Gaitianli Medicines Co., Ltd. and Japan Kampo NewMedicine, Co., Ltd.

Author contributions:

M. T., F.T., H. L., designed the study from the clinical observation of the cancer patients with Huaier treatment (as a complementally therapy), and managed the sampling and clinical assessment of the patient volunteers, statistically analyzed the data, and drafted the manuscript. F. T., X. Z., H. L. Z. L., managed total RNA and small nuclear RNA sequencing and conducted systematic analysis of the data. S. S., T. S., and Y. M., contributed clinical diagnosis and treatment of the patients, together with the assessment of QOL and the effects of Huaier administration, Z. L., D. W., contributed to the provision of Huaier granules and clinical evaluation of the data, especially focused on Immunological evaluation.

Competing interests:

The authors declare no competing interests.

Data availability:

The complete sequencing data of the cases have been deposited to NCBI database, and the clinical outcomes of these cases are not publicly available for data privacy but are available from Dr. Manami Tanaka (e-mail: tubu0125@gmail.com, manami-tanaka@bradeion.com) upon request for research collaboration. The timeframe for response to data access requests is 30 days. There are no restrictions on the reuse of data. In addition, the raw data of the longitudinal cohort and healthy individuals analyzed in this study were available at GEO with identifiers of NCBI GEO (GSE157086).