De-ageing

Admin on Jan th, 2019

During aging, the collagen family, elastin and Hyaluronic Acid will constantly lose and lower the activity of fibroblast.
The loss and lower itself will cause wrinkle and strain.
Of course, we can't add those materials through ordinary ways, we can only use ingredient which can help increase the synthesis of collagen and elastin family to regenerate your skin.


Epidermis
Grown Factor

A.  Proliferative Factors – stimulate DNA synthesis – cell hyperplasia
     Differentiative Factors – inhibit DNA synthesis – Keratinocyte differentiation
B.  EGF (Epidermal Growth Factor) – a kind of chemokinase
        ↳ EGF + EGFR (receptor) → activate tyrosine kinase ⇒ cell hyperplasia
C.  KGF (Keratinocyte Growth Factor) – fibroblast family
        ↳ KGF + tyrosine kinase receptor → cell hyperplasia ⇒ wound recover
            ↳ can also stimulate keratinocyte increasing.
D.  TGF (Polypeptide Transforming Growth Factor) – Ca2+, phorbol ester can increase synthesis
        ↳ TGF-α ⇒ help hyperplasia
        ↳ TGF-β ⇒ help differentiation
          ⇒ stimulate serine, threonine kinase receptor
          ⇒ keratinocyte contain TGF-β1, TGF-β2
          ⇒ lower the inflammation reaction and preventing scar
 
The epidermis is the first barrier in keeping skin healthy.
 ↳ AMPs (Antimicrobial Peptides)
   ↳ A.  Help against microorganism
      B.  The Cation – type peptides which can attract anion-type bacteria that increasing bacteria
                                membrane permeability in killing it easier.       
      C.  Cathelicidin – exist in inflammation keratinocyte
           Defensin – β-defensin-1 help keratinocyte differentiation.
    NMF (Natural Moisturizing Factor)


      A.  NMF is a highly hydrophilic molecule which can keep keratinocyte hydration. However, since
            the hydration of NMF is rich in the SC layer, it can help enzyme functionality. 
      B.   Lipids also help to keep NMF stay in cells.
            Lack of NMF may cause ichthyosis vulgaris.


Dermis
There are two types of dermis, oxytalan fibers, and elannin fibers. Oxytalan fibers are much more unmatured.
A.    Fibroblast
         ↳ Main types of cells, which help manufacture collagen, elastin, collagenase…etc.
B.     All the Immune cells stay in the dermis, ex. Mast cell, polymorphonuclear leukocytes,
         Lymphocytes, macrophage…etc.
C.     Papillary Dermis compares to Reticular Dermis has thinner collagen, more density cells, and
         more blood vessel. 
 
Collagen
↳ A. ① gives skins more flexible.
       ② There are 18 types when matured then more into the dermis.
       ③ Triple helix structure
       ④ Retinoids can prevent collagen lost during sunlight.
 B. Fibroblast → Pro-collagen → Collagen
                   ↓
               Proline  →   Fe2+, Vic C             →Hydroxy-proline.
               Lysine   →   α-ketoglutarate   →Hydroxy-lysine.
 
C.

Type I ⇒ 85% ⇒ ① the main issue effect aging, providing skin tensile strength
                            ② Damaging by UV light
Type III ⇒ 10~15% ⇒ The thinnest diameter collagens, providing skin’s softness, also called fetal collagen.
Type V ⇒ 5%
※    Type V, VII ⇒ stay in hemidesmosome → the most important structure binding.
※    Type VII ⇒ Lacking will cause Dominant Dystrophic Epidermolysis
        ⇒ if attacked by the immune system, cause Epidermolysis Bullosaacquisita(EBA)
D.    Collagen Glycation = Maillard Reaction
                                                     ↳  Amino acid + Sugar
 
             N-substituted glycosylamine + H2O
                                   ↓ Amadori Rearrangement
                                   ↓
                           Ketoamine
                                   ↓ Oxidation
             Advanced Glycation End Products (AGEs)
                                   ↓
             Cause fibroblast activity decreasing
                                   ↓
                               Aging!!
   

Elastin
A.     Abandum in children, adult won’t produce
B.     A connection tissue which does not dissolve in water.
C.     Surrounding by fibroblast
D.     
 

       ※    Microfibrils → Tropoelastin producing cells + Micrfibril
                  – Associated Glycoprotein(MAGP-1, MAGP-2) 
                                                 ↓
                                                 ↓                                                 
                                             Elastin
E.     Hydrophobic side ⇒ contains proline, valine, glycine ⇒ provide flexibility.
         Hydrophilic side  ⇒ Lysine + Lysyloxidase (contain Cu)
                                                ↓
                                         Desmosine
                                                ↓
                                       Iso-desmosine
                                                ↓
                                 Stable Elastin network
 
F.      Collagen + Elastin + Hyaluronic acid ⇒ forming 3D structure
         ※  H4 family ⇒ Versican
                                     Aggresan
                                     Neurocan
G.    Can be decomposed by Elastolytic Enzyme (ex. Human Leukocyte Elastase, HLE) and sunlight.
          ※  Lysosome will cover up with elastin in protecting being destructed by Elastolytic enzyme
H.    If elastin running low,
       ↳ Wrinkle skin Syndrome, Cutis laxa, Pseudoxanthoma Elasticum (PXE),
          Elastosis Perforans Serpiginosa (Lutz-Mieschers Syndrome),
          Dermatofibrosis Lenticularis (Buschke-Ollendorf Syndrome).
I.     Zinc
       ↳ Stimulate Epidermal Growth Factor Receptor Signaling Pathway
       ↳ Inhibit Protein Tyrosine Phosphatase(PTpase)
                                        ↓
                 [Protein Tyrosine Phosphorylation]↑
                                        ↓
            Mitogen-Activated Protein Kinase activated
                                        ↓
                              Skin flexibility↑

Glycoprotein (GP)
A.    Cell adhesion, Cell moving, wound healing
         ex. Vitronectin, thrombospondin, epibolin … etc.
               Fibronectin and tenascin are the most important
 
              Rich in growing skins, only exist in adult's Papillary Dermis
                 ①   Control synthesis of collagen and platelet
                 ②   Can combine with heparin, fibrin
Glycosaminoglycans (GACs)
A.    Maintain body moisture and electrolyte, it will lower as age growth.
        ex. Heparin, Heparin Sulfate, ketatan sulfate, chondroitin-4
B.     Hyaluronic acid (HA) and Dermatan Sulfate are the most content in the dermis.
        HA is the only one that not having sulfation. 
※    Hyaluronic Acid ⇒ Hyalos means glass in Greeks.
                 ↳ Glucuronic Acid + N-acetyl glucosamine

                      ⇒ can be replaced for producing other kinds of HA.
 
①   Responsible for absorbing water in keeping moisturizing and providing support of dermis.
       (But injective HA is for wrinkle treatment) 
②   Richi in sparse cell
③   With CD44 pathway, it's important in differentiation of Keratinocyte and formation of Lamellar bodies.
④   The only GACs which is not synthesis by Golgi apparatus.

※    Decorin
 ↳ ① The Small Leucinerich Proteoglycans (SLRPs) which enrich Leucine that decorating
         on collagen at Extracellular Matrix Protein. 
    ② Main protein – Leucine, Dermatan Sulfate, Chondroitin Sulfate.
    ③ [Decorin]↑ ⇒ Collagen Binding Stronger ⇒ skin stronger.
    ④ Interaction with Fibrinogen help wound recovered.
    ⑥ Stop G1 phase of Cancer cells.
    ⑦ Decorin can decompose to Decorunt, which abundant in adults, not in fetal.
          ※  Due to the binding strength of Decorunt and collagen which cause
                  older people arrangement not that good.
GF Family
A.  Including EGF, Amphiregulin (AR), Epiregulin, Neuregulin1, 2, 3, Insulin-like Growth Factor.
B.  Secrete by Keratinocyte, combine with EGF receptor upon it, induce Autocrine of Keratinocyte.
C.  EGF/TGF-α
      ↳ ① Increasing the metabolize of Keratinocyte from inside to surface.
         ② EGF can stimulate the movement and hyperplasia of fibroblast.
         ③ EGF/TGF-α can enhance the movement of Keratinocyte in order to faster the wound recovering.
※    Fibroblast hyperplasia+Reepithelization
                                        ↓
                                        ↓
                            wound healing
  
        ④ Aging cause wound recovering slower than younger.
             ↳ Age↑
               ↳ EGF receptor activity↓ (due to the number decrease)
                  ↳ Amphiregulin (AR) in the dermis↓
                     ↳ Fibroblast moving and hyperplasia↓
                        ↳ Dermis itself growth↓
 D. TGF-β
    ↳ ① During wound recovering, or healing, TGF-β will attract Monocytes, Neutrophils
            and Fibroblast to damage place for recovering it. 
          ※    Activate Monocytes ⇒ releasing GF
                 Stimulate Fibroblast ⇒ increasing basic matrix (ECM), producing pro-collagen.                            
       ② Activate Keratinocyte, too
       ③ Photoaging will lower the performance of TGF-β (TGF-βII)
※    After 8 hrs of UV light ⇒ TGF-β pathway will be block
                                        ↓
                                  TGF-βII vanished
                                        ↓
                                  Type I Procollagen↓, smad 7↑
                                  (smad7, TGF negative regulator)
MMPs (Matrix Metal-loproteinases)
A. MMP-1 (Interstitial Collagenases)
    ↳ ① First discovered.
       ② Secrete by Fibroblast, which breaks down collagen I, II, III and collagen VII
            from anchoring fibrils
B. MMP-8 (Human Neutrophil Collagenases)
     ↳ ① Decompose collagen I, III
C. MMP-13 (Collagenases XIII)
     ↳ ① Stimulate fibroblast growth in order to cover scars.
D. Gelatinase
     ↳  MMP-2 (Gelatinase A)
         MMP-9 (Gelatinase B) ⇒Destroy gelatin and collagen IV
E. Stromelysin
     ↳ Break down Laminin, collagen IV
F. Matrilysin
     ↳ In cancer cells
   ※    MMPs will be regulated by Endogenous Tissue Inhibitor of
Metalloproteinase (TIMPs)
     ↳ ① Providing correct tissue remodeling
        ② TIMPs regulate by cytokinase, ex. IL-1, GF, Retinoids
                             Stimulate fibroblast synthesis MMP in 2-3 times
        ③ If [MMP]↑, [TIMPs]↓ ⇒ Cancer may translocation.
G. MMPs regulated by TLRs (Toll-like Receptor)
        ① Associate with inflammation and the immune system.
        ② Activated TLRs will stimulate cytokinase causing congenital immunity.
        ③ ILRs is one of the Pattern Recognization Receptor (PPRs)
                ↳ Recognize proteins like molds, virus' RNA… etc, and change them into
                  Pathogen-associated Molecule Pattern. 
        ④    TLRs have different domains, but with the same pathway.
                 ↳ Using MyD 88 pathway
                     ↳ NF-kB (Transcription Factor kB)
                        ↳ Nuclear starts translocation
                            ↳ Immune Regulation Gene translation.
        ⑤ Exist in Keratinocyte, Monocytes, Macrophage, and Fibroblast.
                                               ↓
                    TLR 1, 2, 3, 4, 5, 6, 9, 10, At granular layer is TLR9.
        ⑥ The TLR 2/1, 2/6, 3, 4, 5, 9 on Monocyte associate with aging.
                ↳ TLRs↓ ⇒ IL-6, TNF-α↓ ⇒ EGF↓, Fibroblast↓
        ※    TLR2 ⇒ associate with Acne
                            and Lepromatous Leprosy
                            Tuberculoid Leprosy
H. Classification ⇒ ① collagenase ② Stromelysins ③ Gelatinase ④ Metal-basal proteinase.
     ※   Collagenase breaks down collagen triple helix, through gelatinase and stromelysins.
            ↳ MMP↑ ⇒ Aging!
I. MMPs express by fibroblast, while Macrophage and Keratinocytes express by cytokinase.
     ※   Fibroblast + IL-1, IL-2, TNF-α, TNF-β → producing MMP-1
     ※   IL-4 will inhibit MMPs expression.
J. MMPs regulated by Tissue Inhibitors of Metalloproteinase (TIMPs)
     ※   TIMPs is a low molecule weight carbonprotein, synthesis by Fibroblast and Macrophage
              ↳ Through formate 1;1 molecule, TIMPs will inhibit MMP
                   ↳ cytokinase, GF also regulate TIMPs, ex. IL-6, EGF…etc.
     ※   If [TIMPs]↓, [MMPs]↑ ⇒ skin matrix destroyed.
K. UVA, UVB induces AP-1
     ※ AP-1 is the transcription faction of MMP1, 3, 9
                        ↓
                   causing photoaging
                        ↓
                  Fibrils arrangement not neat
L. Microbial Agents → Through TLR pathway → induce MMP
     ↳ ① Lyme Disease
              ↳ Borrelia burgdorferi (gram-), + TLR-2 → induce MMP 9
        ② Mycobacterial cell wall
              ↳ through TLR-2 → induce MMP 9
        ③ Oligodeoxynucleotide which include CpG is one of the TLR-9 ligand
              ↳ through TLR-9/NF-Kb depending signaling pathway
                                                  ↓
                             Macrophage induce MMP-9
M. Imiquimod is the ligand of TLR7, 9 → increasing TIMP → [MMP-9]↓
      ※ Imiquimod can reduce wrinkle, dyspigmentation and hyper-keratotic pores
          and cure atypia and atrophy. 
  
Retinoids
A. Combine with retinoic acid receptor
   ↳ anti-inflammation, inhibit skin disease and anti-photoaging
B. Lower the TLR-2  → inhibit MMP
                        Ap-1   → inhibit MMP   Anti-inflammaiton.
  Increase the TIMPs → inhibit MMP
 
※   Vitamin A   – Retinoids
       Vitamin B1 – Thiamine
       Vitamin B2 – Ribolavin
       Vitamin B3 – Niacin / Niacinamine
       Vitamin B5 – Pantothenic Acid / Pyridoxine
       Vitamin B7 – Biotin
       Vitamin B9 – Folic acid / Folinic acid
       Vitamin B12 – Cyanocobalamin / hyfroxycobalamin
       Vitamin C – Ascorbic acid
       Vitamin D – Cholecalciferol (D3) / Ergocalciferol (D2)
       Vitamin E – Tocopherols / Tocotrienols
       Vitamin K – Phylloquinone / Menaquinones
 
Summary
     TLR activing↑ ⇒ MMP↑ ⇒ Aging
                      TIMP↓ ⇒ MMP↑ ⇒ Matrix breaks down
          Retinoids↑ ⇒ TLR activity↓
                                          AP-1↓   ⇒ MMP↓ ⇒ anti-inflammation
                                          TIMP↑
      For good skin health
         ↳ TLR, AP-1, MMP↓
            TIMP, Retinoids↑