1. Bintrein^TM Sol’n 400 (5%)

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    Bintrein^TM is a palmitoyl tripeptide of the CD99 agonist class, an anti-inflammatory molecule that is expressed in all human cells.

　   It activates CD99 and p53, which inhibits clustering of various pro-inflammatory cytokine receptors, such as TNFR and IL 1R, thereby exhibiting anti-inflammatory effects and also triggers apoptosis of Sebocytes, Senescent cells, and Tumor cells, respectively (fig. 1).

 

 

 

 

 

 

Anti-tumor effect

 

(1) Anti-tumor effect via p53-mediated Apoptosis induced by Bintrein^TM

 

　 Apoptosis is the process of programmed cell death. It is used during early development to eliminate unwanted cells; for example, those between the fingers of a developing hand. In adults, apoptosis is used to rid the body of cells that have been damaged beyond repair.

   Apoptosis also plays a role in preventing cancer. If apoptosis is for some reason prevented, it can lead to uncontrolled cell division and the subsequent development of a tumor (Fig. 2).

  p53, also known as Tumor protein P53, cellular tumor antigen p53, or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins are crucial in vertebrates, where they prevent cancer formation. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene.

 

p53 plays a role in regulation or progression through the cell cycle, apoptosis, and genomic stability by means of several mechanisms (Fig. 3):

 

- It can activate DNA repair proteins when DNA has sustained damage. Thus, it may be an important factor in aging.

- It can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition. If it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.

- It can initiate apoptosis if DNA damage proves to be irreparable.

- It is essential for the senescence response to short telomeres.

 

   The TP53 gene is the most frequently mutated gene (>50%) in human cancer, indicating that the ­TP53 gene plays a crucial role in preventing cancer formation. ­‑ gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome.

    As a central player in carcinogenesis, p53 is to be found mutated in the majority of human cancers. However, melanoma (skin cancer) commonly harbours wild-type (wt) p53 (over 80–95% of melanoma cases).

   For melanoma, p53 remains highly inhibited by MDM2 and unable to counteract tumor progression (1,2).

   For cancers that maintain wtp53, the main approach for clinical trial has been to identify small molecules that liberate p53 from inhibition by its negative regulators, most notably MDM2 or E6, thereby unleashing full p53 activity (3) (Fig. 4).

 

 

 

 

 

 

 

 

 

   Bintrein^TM induces the degradation of MDM2, which activates p53 (Fig. 5). Additionally, it promotes the interaction of p53 and RNA polymerase II. p53 can inhibit the activity of RNA polymerase II, thereby blocking the transcription of specific genes. This helps to suppress the overexpression of certain genes in cancer cells, thereby inhibiting tumor growth (Fig. 6).

 

 

 

 

 

 

 

 

2) Suppression tumor growth and metastasis via inhibition of β1 integrin induced by Binterin

 

   β1 integrin is the most commonly expressed integrins in tumor cells and are key players in tumor metastasis (4).

 

- It promotes cancer cell movement, enhancing invasiveness and facilitating metastasis, contributing to the spread of cancer.

- It activates signaling pathways associated with abnormal cell proliferation and survival in cancer cells. This can promote uncontrolled tumor growth and enhance cancer cell survival.

- Tumors require a blood supply for nutrients and oxygen, and β 1 integrin regulates interactions with cells involved in angiogenesis. It promotes the formation of blood vessels that support tumor growth.

 

　Bintrein^TM inhibits fibronectin-mediated β1 integrin activation through the SHP2/ERK/PTPN12/FAK signaling pathway (5) (Fig. 7). It can be described that Binterin has potential as novel therapeutic reagents to suppress tumor progression via negative regulation of β1 integrin activity. It can also suppress tumor growth and reduce skin redness by inhibiting angiogenesis.

 

 

 

 

 

 

 

Senolytic effect

 

　 Senolytic is to target and eliminate senescent cells, which are cells that have entered a state of cellular senescence or aging. Cellular senescence is characterized by a loss of cell function and the secretion of pro-inflammatory factors and toxic molecules, which can contribute to tissue dysfunction and chronic inflammation.

 　 These senescent cells can turn into cancer cells, trigger inflammatory reactions, and accelerate aging. Bintrein^TM is to target and remove Senescent cells by apoptosis. As a result of Senolytic, it has anti-tumor, anti-inflammatory and anti-aging effects (Fig. 8).

 

 

 

 

 

 

 

 

 

Anti-Inflammatory effect

 

　When damaged by UV or stress present in the epidermis and dermis of the skin, NF-kB (inflammatory factor) is activated, and as a result, the expression and action of inflammatory cytokines (TNF-a, IL 11 or so) are induced.

　CD99 is a protein that effectively inhibits the action of these inflammatory cytokines, and Binterin^TM activates CD99 to regulate the inflammatory response (Fig. 9).

 

 

 

 

 

 

 

 

Regulation of sebum secretion

 

    Binterin^TM activates CD99 and p53 to regulate sebum secretion. Acne is a condition characterized by the abnormal thickening of retained keratin, which blocks the pores and prevents the proper expulsion of sebum. This accumulation of sebum leads to inflammation around the hair follicle due to infection by acne-causing bacteria.

    Therefore, regulating sebum secretion can help soothe acne symptoms. p53 is a key protein involved in regulating sebum secretion by inducing apoptosis of sebocytes, the cells responsible for sebum production. Binterin^TM activates CD99 to promote the regulation of sebum secretion by p53 (Fig. 8-b).

 

 

 

 

 

 

 

 

 

2. Licochalcone A

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    A derivative of the phenol chalconoid, found in and extracted from the roots of Glycyrrhiza inflata, with potential anti-inflammatory, antibacterial, and anticancer activities⁶.

 

Anti-inflammation (Table 1.)

　

   LA demonstrates anti-inflammatory activity via interaction with MAPK, NF-κB, NLRP3, and Nrf2 signaling in the acute lung, kidney, and liver injury (acute inflammation) and Arthritis, asthma and atopic dermatitis (chronic inflammation)

 

Anticancer activities

    Associated with epithelial carcinoma and mesenchymal sarcoma cells.

    Cancers mediated by epithelial carcinoma cells include hepatocellular, glioma, breast, gastric, colon, lung, cervical, ovarian, bladder, and oral squamous cell.

Melanoma is primary cancer caused by mesenchymal sarcoma cells (Fig. 10).

   　LA has anti-cancer effects of LA on Inducing Apoptosis and Inhibiting Proliferation Cancer Cells.

　Apoptosis is a form of programmed cell death that occurs in multicellular organisms. LA induces apoptosis in different cancers via multiple pathways, including P13-Akt-mTOR, VEGFR2, c-Met, PLCγ1, MAPT, JNK/p38, and ERK1/2, along with a combination of regulatory targets. Absolutely, LA induces apoptosis in B16 melanoma cells on the skin⁷ (Fig. 11).

    Unlimited proliferation is a crucial feature of cancer cells. The pharmacological ability to inhibit proliferation is a crucial aspect of the anticancer effects of LA. For LA, inhibition of cancer cell proliferation reflects blocking the cell cycle at different transition phases via regulating specific mRNAs and protein levels, such as Wee1, P21, Cyclins, MDM2, Survivin, and CDK1⁸.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1. Box, N.F.; Vukmer, T.O.; Terzian, T. Targeting p53 inmelanoma. Pigment Cell Melanoma Res. 2014, 27, 8–10.

2. Kwon, S.-K.; Saindane, M.; Baek, K.-H. p53 stability isregulated by diverse deubiquitinating enzymes. Biochim. Biophys. Acta Rev. Cancer. 2017, 1868, 404–411.

3. Ori Hassin, Moshe Oren. Drugging p53 in cancer: one protein, many targets. Nature Reviews Drug Discovery. 2023, 22, 127-14.

4. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer, 2010. 10:9–22.

5. Lee KJ, Kim Y, et al. CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of β1 Integrin through the rotein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway. Mol Cell Biol. 2017, 29;37(14):e00675-16.

6. Jiang, J., et al. Licochalcone A Inhibiting Proliferation of Bladder Cancer T24 Cells by Inducing Reactive Oxygen Species Production. Biomed. Mater Eng. 2014. 24 (1), 1019–1025.

7. Chen, R. et al. Licochalcone A Inhibits Melanoma Cell Growth and Migration via Arresting Cell Cycle and Suppressing Akt Phosphorylation. Front. Pharmacol. 2022. 13-2002 / doi.org/10.3389/fphar.2022.878776

8. Wang, J.et al. Licochalcone A from Licorice Root, an Inhibitor of Human Hepatoma Cell Growth via Induction of Cell Apoptosis and Cell Cycle Arrest. Food Chem. Toxicol. 2018. 120, 407–417.

9. Johannes Wohlrab and Daniela Kreft. Niacinamide –Mechanisms of Action and Its Topical Use in Dermatology. Skin Pharmacol Physiol. 2014;27:311–315.

10. O. Tanno, et al. Nicotinamide increases biosynthesis of ceramides as well as other stratum corneum lipids to improve the epidermal permeability barrier. British Journal of Dermatology. 2000;143:524-531.

11.Arnold Markovics, et al. Nicotinic acid suppresses sebaceous lipogenesis of human sebocytes via activating hydroxycarboxylic acid receptor 2 (HCA2). J Cellular Molecular Medi. 2019. 23(9):6203-6214.

12.Peter Elsner and Howard I. Maibach. Cosmeceuticals and active cosmetics. Drug versus Cosmetics. 2nd Edition. 2005. p.422-439

     After washing with Ciracle Red Spot Teatree Wash, apply this soothing Serum to the area of inflammation, and wait for it to absorb (to absorb the actives). Alternatively, it is also recommended for use throughout the inflammatory face.

 

     The method of using the entire face evenly absorbs a sufficient amount throughout the face during the serum stage after washing your face.  If you apply the product thickly, the barrier layer may get pushed, and this is the characteristic of this unique formula.