Impact of chronic khat chewing on liver function tests and fasting blood glucose levels among adult male khat chewers.

Diabetic retinopathy (DR) is a common complication of diabetes mellitus and a leading cause of visual loss in working-age adults. The global prevalence of diabetes is estimated to reach 700 million patients by 2045, and over 20% of them will suffer from DR. Early stages of DR are typically asymptomatic, but once vision declines, retinal damage may be irreversible. Thus, identifying upstream molecular events that precede the structural hallmarks of DR is critical for developing early interventions. Recent quantitative optical coherence tomography (OCT) studies revealed rod photoreceptor abnormalities in diabetic patients without DR and in those with only mild non-proliferative DR (non-PDR), suggesting that rod neurodegeneration is among the earliest retinal events triggered by diabetes. These observations suggest the presence of a central molecular pathway in the early process of neurodegeneration, preceding the onset of visible retinal pathology. One such pathway may involve the protease-activated receptor 1 (PAR1), a seven-transmembrane G protein-coupled receptor (GPCR) activated by serine proteases. Thrombin is the most potent activator of PAR1, although other proteases, such as FXa, granzyme A, metalloprotease-1 (MMP-1), and activated protein C (aPC), also cleave the receptor. Following cleavage, the tethered ligand activates PAR1-dependent intracellular signaling. Beyond its classical role in coagulation, PAR1 is expressed in neurons, astrocytes, microglia, and other cell types, where it mediates both neurodegenerative and neuroprotective functions. The balance between these outcomes depends on the nature of the activating agonist and the subsequent downstream signaling cascades. In diabetes, thrombin activity is intrinsically elevated in peripheral nerves, contributing to conduction block and structural damage at the node of Ranvier (NOR). Inhibition of thrombin prevents these deficits, indicating that the thrombin/PAR1 pathway represents a pivotal pathological process in diabetes-induced neurodegeneration. The need for a specific thrombin-PAR1 modulator that lacks significant anticoagulant properties and does not block PAR1 directly, thereby enabling alternative protective activation, has prompted us to develop a class of inhibitory compounds targeting the thrombin binding site on PAR1. PARIN5 is one of these inhibitory compounds. It includes a five amino-acids backbone, blocked by a Tosyl group on the N-terminus, which protects against degradation by amino peptidases. Another similar compound, composed of six rather than five amino acids (SIXAC), was previously found to inhibit thrombin-induced PAR1 activation, as demonstrated in vitro by preventing thrombin-induced molecular and cellular downstream effects such as ERK phosphorylation. These small inhibitory peptides, designed to interfere with thrombin’s binding to and activating PAR1, protect against diabetes-induced peripheral nerve dysfunction in experimental models without exerting anticoagulant effects. Such compounds illustrate that selective modulation of this pathway can redirect the course of disease progression.