br Angiogenesis as a critical event in

Angiogenesis as a critical event in diabetic retinopathy Angiogenesis refers to the abnormal proliferation of blood vessels during various pathological conditions. It acquires the stature of being one of the most detrimental events responsible for the progression of diabetic retinopathy. Angiogenesis is particularly induced in retina due to an imbalance between the stimulators and inhibitors of angiogenesis. The various stimulators of angiogenesis include various growth factors or cytokines such as vascular endothelial growth factor (VEGF), insulin-like growth factor I (IGF-1), hepatocyte growth factor (HGF), basic CAL101 synthesis growth factor (b-FGF), platelet derived growth factor (PDGF), pro-inflammatory cytokines and angiopoietins, whereas the various inhibitors of angiogenesis include endostatin, thrombospondin, interferon α and β, prolactin, platelet factor 4 and angiostatin [10,11]. The inhibitors of angiogenesis generally rule over the amount of stimulators of angiogenesis present in the body in normal conditions. Hence, the angiogenic inhibitors keep a check on the process of angiogenesis, allowing it to occur only during required physiological conditions such as embryonic development, in the process of wound healing, tissue repair and organ regeneration. However, hyperglycemic conditions are known to cause disruption in the equilibrium of stimulators and inhibitors of angiogenesis [12]. A shift in this equilibrium towards the stimulator side is observed due to several biochemical and degenerative mechanical stimuli. These deleterious stimuli are a result various pathological conditions induced by hyperglycemia such as increased flux of polyol pathway, accumulation of advanced glycation end-products (AGEs) and overactivation of protein kinase C (PKC), all of which result in increased oxidative stress. The various reactive oxygen species (ROS) produced during hyperglycemia-induced oxidative stress have been demonstrated to be liable for inducing the angiogenic stimulators, however the mechanism for the same is not completely known [13,14]. The above discussed hyperglycemia-induced disruption in the homeostasis of stimulatory and inhibitory angiogenic factors results in the upregulation of angiogenic stimulators and the net result is activation of the process of angiogenesis.
Thalidomide and its antiangiogenic properties Thalidomide was launched in 1950s in the European countries for the therapy of insomnia. Later, the drug was also found to be useful in treating morning sickness in pregnant women. For the later property of thalidomide, it became a quite famous over-the-counter drug and its use became widespread in the subsequent years. However, following its utility amongst the pregnant women, numerous adverse effects were recorded. These ranged from increased miscarriages in pregnant women to severe physical abnormalities in the infants born to the thalidomide-treated women. Besides, an increase in the infant mortality rate was also observed following thalidomide treatment. The physical abnormalities presented in the infants included disfigured or improperly formed limbs (termed as phocomelia) or complete absence of limbs (termed as amelia). Many infants born to the thalidomide-treated pregnant women fell prey to the above mentioned adverse effects of thalidomide. Over 10,000 cases of limb abnormalities in infants were recorded during its utility period. Moreover, an increase of 40% in the infant mortality rate was recorded. These adverse consequences led to the imposition of ban on the use of thalidomide in the European countries in 1961. However, the use of thalidomide has been continued in several non-European countries for other purposes such as treating leprosy and various malignant tumors. It is now used mainly for its immunomodulatory, anti-inflammatory and anti-angiogenic properties. Also, the antiangiogenic properties of thalidomide have been regarded as one of the molecular basis of the limb deformities observed in the infants after its treatment in the pregnant women. Several other hypotheses have also been proposed to explain the possible reason behind the thalidomide-induced limb deformities. These include alterations in DNA sequence, alterations in the gene expression, increase in cellular death, elevated oxidative stress and distalization of limb bud. However, any of these proposed hypotheses has not been able to explain the specificity of thalidomide for the tissues of limbs [21,22].