What is Angiogenesis?

Angiogenesis is the formation of new blood vessels. It is the process by which the body forms new blood vessels from existing ones. This process occurs throughout the life of an individual, starting in the uterus and continuing to old age. Angiogenesis occurs both in healthy tissues as well as in diseased ones, such as in cancer cell growths.

Why Does Angiogenesis Occur in the Body?

Angiogenesis takes place when a particular body part or tissue requires the supply of nutrients and to it. In hypoxia tissues, the need for oxygen supply to the parenchymal cells is detected by the oxygen sensing mechanisms, which then demands the formation of new blood vessels to meet this need.

Types of Angiogenesis

There are two types of angiogenesis, they are:

  1. Sprouting angiogenesis
  2. Intrussusceptive angiogenesis

Both sprouting and intrussusceptive angiogenesis, occur in the uterus and in adults.

Sprouting Angiogenesis (SA)

Sprouting angiogenesis is the process of growing new blood capillary vessels from pre-existing ones. When this occurs, the new blood vessels shall provide oxygen to expanding tissues and organs.

Sprouting angiogenesis plays important roles in many diseases, such as diabetes, rheumatoid arthritis, cardiovascular ischemic complications and cancer. In cancer, SA is involved not only in primary tumor but also in metastasis formation and further outgrowth of metastasis.

Steps in Sprouting Angiogenesis

Sprouting angiogenesis involves several steps, which include:

  1. Initiation of growth factors responsible for angiogenesis by low oxygen tension, low pH and high lactate levels.
  2. Expression of a transcription factor, hypoxia-inducible factor (HIF), by endothelia cells, which regulates expression of vascular endothelia growth factor (VEGF) and stimulates angiogenesis.
  3. Binding of growth factors to their receptors on endothelia cells and activating them. This is followed by detachment of pericytes.
  4. Binding of VEGF to its receptors and inducing a signaling cascades which enables one endothelia cell to form a tip cell while adjacent cells form stalk cells.
  5. Tip cells express VEGFR, delta-like ligand-4 (DLL-4), and matrix metalloproteinases (MMPs). They form filopodia, which are slender protrusions of the plasma membrane containing parallel bundles of actin filaments.
  6. Rhoa, Racl and Cdc42, members of Rho small GTPases, regulate the formation of filopodia.
  7. Activation of VEGFR leads to the extension of filopodia and migration of the tip cells forward.
  8. Activated endothelia cells secrete proteases, which are essential for the degradation of basement membrane. They allow tip cells to escape from the parent vessels and allow formation of sprouts and guidance of sprouts through the extracellular matrix (ECM).

Intrussusceptive Angiogenesis (IA)

In intrussusceptive angiogenesis, also called splitting angiogenesis, the blood vessel wall extends into the lumen, thereby causing a single vessel to split into two. It is fast and efficient compared to SA. This is because IA only requires reorganization of the existing endothelia cells; it does not rely on endothelia proliferation and migration. Like SA, however, IA also occur throughout the life of an individual, but it plays prominent roles in vascular development in embryos, where growth is fast with limited resources.

Promoters of Angiogenesis

Angiogenesis is regulated by a balance between pro-angiogenic and anti-angiogenic factors. The promoters include, HIF-1, VEGF, FGF, PDGE, TGF-β and angiopoietin and proteases.

Hypoxia-induced Factor-1 (HIF-1)

This is the most potent inducer of the expression of genes such as those encoding for glycolytic enzymes, VEGF and erythropoietin. HIF-1 is upregulated in hypoxia tumor cells; it activates transcription of target genes by binding to Cis-actin enhancers, hypoxia response element (HRE) close to the promoters of those genes.

Vascular Endothelia Growth factor (VEGF)

VEGF functions in angiogenesis by inducing the expression of DLL-4 in tip cells. It promotes the migration of endothelia cells by inducing expression of intergrins. It also stimulates production of MMPs, plasminogen activator and proteolytic enzymes by endothelia cells, which in turn promote the degradation of ECM.

Fibroblast Growth Factor (FGF)

FGF promotes proteases production and upregulates VEGF expression by endothelia cells. It also stimulates endothelia cells proliferation and migration.

Inhibition of Angiogenesis by Thymoquinone

Thymoquinone exerts its inhibitory effects on VEGF, FGF, PIGF, PDGF, which are pro-angiogenic factors, by suppressing the Akt/ERK signaling pathway.

 

REFERENCES

Carmeliet, P., & Jain, R. K. (2000). Angiogenesis in cancer and other diseases. Nature, 407, 249–257.

Martin, A., Komada, M. R., & Sane, D. C. (2003). Abnormal angiogenesis in diabetes mellitus. Medicinal Research Reviews, 23, 117–145.

Koch, A. E. (2003). Angiogenesis as a target in rheumatoid arthritis. Annals of the Rheumatic Diseases, 62 Suppl 2, ii60–67.

Cao, Y., Hong, A., Schulten, H., & Post, M. J. (2005). Update on therapeutic neovascularization. Cardiovascular Research, 65, 639–648.

Carmeliet, P. (2005). Angiogenesis in life, disease and medicine. Nature, 438, 932–936.

Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100, 57–70.

Kerbel, R. S. (2000). Tumor angiogenesis: Past, present and the near future. Carcinogenesis, 21, 505–515.

Yi T, Cho SG, Yi Z, Pang X, Rodriguez M, Wang Y, Sethi G, Aggarwal BB, Liu M. Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol Cancer Ther. 2008 Jul;7(7):1789-96.

Effect of Black Seed Thymoquinone on Rheumatoid Arthritis

Thymoquinone (2-isoprpyl-5-methyl-1,4-benzoquinone) is the most active component of Black cumin (Nigella sativa) seed oil. It is widely used in traditional medicine to treat a wide range of illnesses.

According to various research findings, thymoquinone exert important health-beneficial effects including antioxidant, anti-inflammatory and anti-cancer effects. As an antioxidant agent, thymoquinone normalizes glutathione levels and increases the activity of antioxidant enzymes such as glutathione peroxidase, catalase, and superoxide dismutase.

 

Black Cumin Tea Contains Thymoquinone

Black cumin seed is made into a tea and served as an antioxidant agent. Since it contains thymoquinone and other biologically active phytochemicals, black cumin seed tea should be recommended for patients who suffer rheumatoid arthritis. It can also be served to cancer patients who are undergoing chemotherapy.

How To Prepare Black Cumin Seed Tea

  • To prepare black cumin seed tea, assemble 2 cups of water, 2 tea spoonful of raw black cumin seeds and honey. Then follow the steps as follows:
  • Add the 2 cups of water and black cumin seeds in a pot and heat till it boils.
  • Remove from heat once it boiled.
  • Cover the pot and allow it to steep for about 10 minutes.
  • Strain the water into a cup using a mesh. You may add the seed to enjoy the whole benefits if you so wish.
  • Add two spoonful of honey and stir
  • Serve and enjoy your tea

 

Benefits of Thymoquinone and Black Cumin Seed Tea in Treatment of Rheumatoid Arthritis

The uncontrolled inflammation associated with rheumatoid arthritis arises as a result of the uncontrolled production and activity of various inflammatory cytokines, TNFα, IL-1, IL-17, IL-6 and the resulting inflammation is responsible for the pain, tenderness, swelling, redness and stiffness of joints.

Black cumin seeds and especially thymoquinone has been shown to be beneficial against rheumatoid arthritis and autoimmune diseases.

 

Thymoquinone Inhibits NF-kB Signaling In Rheumatoid Arthritis

NF-kB regulates the expression of many genes, enzymes, cytokines, cell cycle regulatory molecules as well as angiogenic factors. It induces inflammation by influencing the expression several pro-inflammatory cytokines, chemokines , acute phase proteins and growth factors.

Thymoquinone inhibits NF-kB induced inflammatory response in rheumatoid arthritis patients by inhibiting its translocation into the nucleus. Thymoquinone also inhibits NF-kB activities by suppressing TNF-induced-NF-kB activation. This is done by inhibiting TNF-induced IKBα phosphorylation and degradation as well as p65 phosphorylation and nuclear translocation.

 

Thymoquinone Inhibits Prostaglandins and COX-2 in Rheumatoid Arthritis

Prostaglandins (PGs) are arachidonic acid metabolites. They are found at elevated levels in synovial fluid and also in synovial membrane, where they function in the development of vasodilation, fluid extravasation and pain in synovial tissues. Aside these functions, Prostaglandin E2 (PGE2) and COX are upregulated in synovial tissues in rheumatoid arthritis patients, where PGE2 synergizes with IL-23 to stimulate Th17 cell proliferation.

Th17 in turn stimulates the release of pro-inflammatory cytokines and promotes bone resorption. PGE2 also mediates complex interactions that lead to the development of articular cartilage erosions and juxta-articular bone.

Cyclooxygenase enzymes (COX), especially COX-2 are involved in inflammatory responses. COX-2 is induced by pro-inflammatory cytokines, mainly IL-1.

Thymoquinone suppresses the expression of COX-2 protein by inhibiting NF-kB signaling pathway activation and induces the expression of cytoprotective enzymes.

Effect of Thymoquinone on PI3k/Akt Signaling Pathway

Phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway is an intracellular regulatory signal transduction pathway that is activated by toxic substances or cellular stimuli that regulate many cellular processes including cell growth, survival and apoptosis.

When abnormally activated, PI3K/Akt signaling pathway is involved in the pathogenesis of many diseases including diabetes mellitus, cancer, and rheumatoid arthritis. In RA, PI3K/Akt signaling pathway play important role through the expression of different types of pro-inflammatory mediators that degrade IKβ and activate NF-kB signaling pathway.

Thymoquinone induces apoptosis by blocking PI3K/Akt signaling pathway in DU-145 cell line. It also deactivate PI3K/Akt and NF-kB signaling pathway and regulate various gene products such as p65 and COX-2.

 

REFERENCES

J.K. Kundu, L. Liu, J.-W. Shin, Y.-J. Surh., Thymoquinone inhibits phorbol ester-induced activation of NF-κB and expression of COX-2, and induces expression of cytoprotective enzymes in mouse skin in vivo Biochem. Biophys. Res. Commun., 438 (4) (2013), pp. 721-727

 

Umar, J. Zargan, K. Umar, S. Ahmad, C.K. Katiyar, H.A. Khan Modulation of the oxidative stress and inflammatory cytokine response by thymoquinone in the collagen induced arthritis in Wistar rats Chem. Biol. Interact., 197 (1) (2012), pp. 40-46

 

Vaillancourt, P. Silva, Q. Shi, H. Fahmi, J.C. Fernandes, M. Benderdour

Elucidation of molecular mechanisms underlying the protective effects of thymoquinone against rheumatoid arthritis J. Cell. Biochem., 112 (1) (2011), pp. 107-117

 

Thymoquinone inhibits IL-1β-induced inflammation in human osteoarthritis chondrocytes by suppressing NF-κB and MAPKs signaling pathway Inflammation, 38 (6) (2015), pp. 2235-2241

 

Khan, A. Sureda, T. Belwal, S. Çetinkaya, İ. Süntar, S. Tejada, H.P. Devkota, H. Ullah, M. Aschner. Polyphenols in the treatment of autoimmune diseases. Autoimmun. Rev., 18 (7) (2019), pp. 647-657

 

Stańczyk J, Kowalski ML. Rola cyklooksygenaz oraz prostaglandyn w patogenezie reumatoidalnego zapalenia stawów [The role of cyclooxygenase and prostaglandins in the pathogenesis of rheumatoid arthritis]. Pol Merkur Lekarski. 2001 Nov;11(65):438-43.