Receptors

Injury to tissue induces the normal wound healing process to repair damage. This is a normal and critical response developed by the body to maintain short-term organ function, and therefore, survival. Should this process become aberrant, then fibrosis can develop. Fibrosis is the excess accumulation of extracellular matrix proteins. Unlike normal wound healing that is designed to maintain organ/tissue function, fibrosis interferes with the normal architecture of the organ and has long-term functional implications. Fibroblasts are the cells responsible for producing extracellular matrix in both wound healing and fibrosis. Substance P is the cognate ligand for the neurokinin-1 receptor, and both substance P and the neurokinin-1 receptor have been demonstrated to be involved in organ remodeling; this includes regulation of fibroblast function. In this review we will focus on substance P/neurokinin-1 receptor regulation of fibroblast function in the setting of both wound healing and fibrosis. This review describes actions of substance P and the neurokinin-1 receptor on fibroblasts from multiple organs, thus identifying central actions common to all fibroblasts studied. This review also identifies gaps in the literature and future directions needed to improve understanding of substance P and the neurokinin-1 receptor regulation of fibroblast phenotype.

Cannabinoids, compounds that interact with the endocannabinoid system, have shown promising neuroprotective effects in various neurodegenerative diseases, including those affecting the retina. This review evaluates evidence for the presence and action of cannabinoids in the retina, their function in protecting against oxidative stress and modulating neuroinflammation, and the outcomes observed in animal models of retinal diseases such as glaucoma and age-related macular degeneration (AMD), the most common causes of vision loss. Cannabinoids have proven effective in reducing the neurodegeneration seen in these eye diseases, acting via the CB1 and CB2 cannabinoid receptors. The cannabinoid neuroprotective effect is often of a similar magnitude to the other proven therapy of medical dosage of vitamins, though it confers a greater risk due to neurotoxicity with high THC:CBD ratios, making the vitamin therapy of greater efficacy when time is available. Given the increased ratio of THC:CBD in commercial cannabis strains, rising from 10:1 at the beginning of this century to 100:1 now, the risk of neurotoxicity has increased, reducing the neuroprotective benefit. The proven safety and efficacy of vitamin therapy may be a more viable neuroprotective method than cannabinoid use for chronic conditions, with cannabinoids proving their utility in more acute conditions. This review evaluates both the method of action of cannabinoids and the receptor pathway utilized and compares the suggested therapeutic applicability of cannabinoids with proven vitamin therapy.

Both primary and secondary hemostasis consist of finely regulated pathways, forming a blood clot to stop bleeding. These orchestrated mechanisms involve multiple plasma- and platelet/endothelial-derived receptors, factors, enzymes, and proteins, such as the von Willebrand factor (vWF), fibrinogen, and thrombin. Over-activation or improper resolution of the coagulation cascade leads to severe pathological disorders, arterial and venous. Despite the fact that the genetic etiology of thrombophilia has gained the main research interest, there is growing evidence that the disturbed redox network of key hemostatic pathways signals thrombus formation. Oxidized LDL in dyslipidemias and many endogenous and exogenous compounds act as pro-oxidant stimuli that lead to post-translational modifications of proteins, such as sulfenylation, nitrosation, disulfide formation, glutathionylation, etc. Oxidation of cysteine and methionine residues of vWF, fibrinogen, and thrombomodulin has been detected at thrombotic episodes. Increased homocysteine levels due to, but not restricted to, methylenetetrahydrofolate reductase gene (MTHFR) mutations have been incriminated as a causative factor for oxidative stress, leading to a pro-thrombotic phenotype. Alterations in the vascular architecture, impaired vascular relaxation through decreased bioavailability of NO, accumulation of Nε-homocysteinylated proteins, ER stress, and endothelial cells’ apoptosis are among the pro-oxidant mechanisms of homocysteine. This review article focuses on describing key concepts on the oxidant-based molecular pathways that contribute to thrombotic episodes, with emphasis on the endogenous compound, homocysteine, aiming to promote further molecular, clinical, and pharmacological research in this field.