Retinopathy is any damage to the retina of the eyes, which may cause vision impairment. Retinopathy often refers to retinal vascular disease, or damage to the retina caused by abnormal blood flow. Age-related macular degeneration is technically included under the umbrella term retinopathy but is often discussed as a separate entity. Retinopathy, or retinal vascular disease, can be broadly categorized into proliferative and non-proliferative types. Frequently, retinopathy is an ocular manifestation of systemic disease as seen in diabetes or hypertension. Diabetes is the most common cause of retinopathy in the U.S. as of 2008. Diabetic retinopathy is the leading cause of blindness in working-aged people. It accounts for about 5% of blindness worldwide and is designated a priority eye disease by the World Health Organization.
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and splitting, but processes such as coalescent angiogenesis, vessel elongation and vessel cooption also play a role. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.
Pericytes are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood capillaries, where they communicate with endothelial cells by means of both direct physical contact and paracrine signaling. The morphology, distribution, density and molecular fingerprints of pericytes vary between organs and vascular beds. Pericytes help to maintain homeostatic and hemostatic functions in the brain, one of the organs with higher pericyte coverage, and also sustain the blood–brain barrier. These cells are also a key component of the neurovascular unit, which includes endothelial cells, astrocytes, and neurons. Pericytes have been postulated to regulate capillary blood flow and the clearance and phagocytosis of cellular debris in vitro. Pericytes stabilize and monitor the maturation of endothelial cells by means of direct communication between the cell membrane as well as through paracrine signaling. A deficiency of pericytes in the central nervous system can cause increased permeability of the blood–brain barrier.
Vascular endothelial growth factor, originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis.
Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They also respond to instances of pseudohypoxia, such as thiamine deficiency. Both hypoxia and pseudohypoxia leads to impairment of adenosine triphosphate (ATP) production by the mitochondria.
Scutellaria baicalensis, with the common name Baikal skullcap or Chinese skullcap, is a species of flowering plant in the family Lamiaceae.
Honokiol is a lignan isolated from the bark, seed cones, and leaves of trees belonging to the genus Magnolia. It has been identified as one of the chemical compounds in some traditional eastern herbal medicines along with magnolol, 4-O-methylhonokiol, and obovatol.
Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the HIF1A gene. The Nobel Prize in Physiology or Medicine 2019 was awarded for the discovery of HIF.
Endothelial PAS domain-containing protein 1 is a protein that is encoded by the EPAS1 gene in mammals. It is a type of hypoxia-inducible factor, a group of transcription factors involved in the physiological response to oxygen concentration. The gene is active under hypoxic conditions. It is also important in the development of the heart, and for maintaining the catecholamine balance required for protection of the heart. Mutation often leads to neuroendocrine tumors.
Atiprimod is a substance being studied in the treatment of certain multiple myelomas and other advanced cancers. It may block the growth of tumors and the growth of blood vessels from surrounding tissue to the tumor. This drug is also being researched as a potential treatment for various autoimmune diseases. It was first developed by GlaxoSmithKline as a potential treatment for rheumatoid arthritis. The substance is also known as azaspirane, although this more properly refers to the class of chemicals to which atiprimod belongs.
Succinate receptor 1 (SUCNR1), previously named G protein-coupled receptor 91 (GPR91), is a receptor that is activated by succinate, i.e., the anionic form of the dicarboxylic acid, succinic acid. Succinate and succinic acid readily convert into each other by gaining (succinate) or losing (succinic acid) protons, i.e., H+ (see Ions). Succinate is by far the predominate form of this interconversion in living organisms. Succinate is one of the intermediate metabolites in the citric acid cycle (also termed the TCA cycle or tricarboxylic acid cycle). This cycle is a metabolic pathway that operates in the mitochondria of virtually all eucaryotic cells. It consists of a series of biochemical reactions that serve the vital function of releasing the energy stored in nutrient carbohydrates, fats, and proteins. Recent studies have found that some of the metabolites in this cycle are able to regulate various physiological and pathological functions in a wide range of cell types. The succinyl CoA in this cycle may release its bound succinate; succinate is one of these mitochondrial-formed bioactive metabolites.
Pigment epithelium-derived factor (PEDF) also known as serpin F1 (SERPINF1), is a multifunctional secreted protein that has anti-angiogenic, anti-tumorigenic, and neurotrophic functions. Found in vertebrates, this 50 kDa protein is being researched as a therapeutic candidate for treatment of such conditions as choroidal neovascularization, heart disease, and cancer. In humans, pigment epithelium-derived factor is encoded by the SERPINF1 gene.
Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene.
As baicalin is a flavone glycoside, it is a flavonoid. It is the glucuronide of baicalein.
Aflibercept, sold under the brand names Eylea among others, is a medication used to treat wet macular degeneration and metastatic colorectal cancer. It was developed by Regeneron Pharmaceuticals and is approved in the United States and the European Union.
Baicalein (5,6,7-trihydroxyflavone) is a flavone, a type of flavonoid, originally isolated from the roots of Scutellaria baicalensis and Scutellaria lateriflora. It is also reported in Oroxylum indicum and Thyme. It is the aglycone of baicalin. Baicalein is one of the active ingredients of Sho-Saiko-To, which is a Chinese classic herbal formula, and listed in Japan as Kampo medicine.
Dauricine is a plant metabolite, chemically classified as a phenol, an aromatic ether, and an isoquinoline alkaloid. It has been isolated from the Asian vine Menispermum dauricum, commonly known as Asian moonseed, and the North American vine Menispermum canadense, commonly known as Canadian moonseed. Scientists Tetsuji Kametani and Keiichiro Fukumoto of Japan are credited with being the first to synthesize dauricine in 1964, using both the Arndt-Eistert reaction and Bischler-Napieralski reaction to do so. Dauricine has been studied in vitro for its potential to inhibit cancer cell growth and to block cardiac transmembrane Na+, K+, and Ca2+ ion currents.
Tumstatin is a protein fragment cleaved from collagen that serves as both an antiangiogenic and proapoptotic agent. It has similar function to canstatin, endostatin, restin, and arresten, which also affect angiogenesis. Angiogenesis is the growth of new blood vessels from pre-existing blood vessels, and is important in tumor growth and metastasis. Angiogenesis is stimulated by many growth factors, the most prevalent of which is vascular endothelial growth factor (VEGF).
Vasculogenic mimicry (VM) is a strategy used by tumors to ensure sufficient blood supply is brought to its cells through establishing new tumor vascularization. This process is similar to tumor angiogenesis; on the other hand vascular mimicry is unique in that this process occurs independent of endothelial cells. Vasculature is instead developed de novo by cancer cells, which under stress conditions such as hypoxia, express similar properties to stem cells, capable of differentiating to mimic the function of endothelial cells and form vasculature-like structures. The ability of tumors to develop and harness nearby vasculature is considered one of the hallmarks of cancer disease development and is thought to be closely linked to tumor invasion and metastasis. Vascular mimicry has been observed predominantly in aggressive and metastatic cancers and has been associated with negative tumor characteristics such as increased metastasis, increased tissue invasion, and overall poor outcomes for patient survival. Vascular mimicry poses a serious problem for current therapeutic strategies due to its ability to function in the presence of Anti-angiogenic therapeutic agents. In fact, such therapeutics have been found to actually drive VM formation in tumors, causing more aggressive and difficult to treat tumors to develop.
VEGFR-2 inhibitor, also known as kinase insert domain receptor(KDR) inhibitor, are tyrosine kinase receptor inhibitors that reduce angiogenesis or lymphangiogenesis, leading to anticancer activity. Generally they are small, synthesised molecules that bind competitively to the ATP-site of the tyrosine kinase domain. VEGFR-2 selective inhibitor can interrupt multiple signaling pathways involved in tumor, including proliferation, metastasis and angiogenesis.
